UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

_______________



Form 10-K

_______________





 

(Mark One)

ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934

For the Fiscal Year Ended December 31, 20172020

or



 

TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934

For the transition period from _____ to _____

Commission File Number: 000-29959



Pain Therapeutics, CassavaSciences,Inc.

(Exact name of registrant as specified in its charter)



 

Delaware

91-1911336

(State or other jurisdiction of

(I.R.S. Employer

incorporation or organization)

Identification Number)



7801 N. Capital of Texas Highway,  Suite 260,  Austin,  TX 78731

 (512)  501-2444

(Address, including zip code, of registrant's principal executive offices and

telephone number, including area code)

Securities registered pursuant to Section 12(b) of the Act:

0

Title of each class

Trading

Symbol(s)

Name of each exchange on which registered

Common Stock, $0.001 par value

SAVA

NASDAQ Capital Market

Securities registered pursuant to Section 12(g) of the Act:  None

Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes   No 

Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ☐  No ☑

Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days.  Yes ☑  No ☐

Indicate by check mark whether the registrant has submitted electronically and posted on its corporate Web site, if any, every Interactive Data File required to be submitted and posted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit and post such files).  Yes ☑  No ☐.

Indicate by check mark if disclosure of delinquent filers pursuant to Item 405 of Regulation S-K is not contained herein, and will not be contained, to the best of registrant's knowledge, in definitive proxy or information statements incorporated by reference in Part III of this Form 10-K or any amendment to this Form 10-K.  ☐

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act..Act.  (Check one):



 

Large accelerated filer  ☐

Accelerated filer  ☐

Non-accelerated filer    

Smaller reporting company  ☑

(Do not check if a smaller reporting company)

Emerging growth company  ☐



If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 USC. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. 

Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act).  Yes ☐  No ☑

The aggregate market value of the voting and non-voting common equity held by non-affiliates was $22,840,436$71,146,906 computed by reference to the last sales price of $4.15$3.08 as reported on the Nasdaq Global SelectCapital Market, as of the last business day of the Registrant's most recently completed second fiscal quarter, June 30, 2017.2020. The number of shares outstanding of the Registrant's common stock on January 19, 2018March 18, 2021 was 6,595,509, as adjusted to reflect  a ratio of 7-for-1 reverse stock split effective May 10, 2017.39,898,325.

DOCUMENTS INCORPORATED BY REFERENCE

Portions of the Registrant's Proxy Statement for its 20182021 Annual Meeting of Stockholders (the "Proxy Statement")Proxy Statement), to be filed with the U.S. Securities and Exchange Commission, are incorporated by reference to Part III of this Form 10-K Report.



 

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PAIN THERAPEUTICS,CASSAVA SCIENCES, INC.



FORM 10-K

INDEX





 

 



 

Page

PART I

Item 1.

Business

4

Item 1A.

Risk Factors

2231

Item 1B.

Unresolved Staff Comments

4464

Item 2.

Properties

4564

Item 3.

Legal Proceedings

4564

Item 4.

Mine Safety Disclosures

4564



 

 

PART II

Item 5.

Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities

4565

Item 6.

Selected Financial Data

4565

Item 7.

Management’s Discussion and Analysis of Financial Condition and Results of Operations

4666

Item 7A.

Quantitative and Qualitative Disclosures About Market Risk

5073

Item 8.

Financial Statements and Supplementary Data

5074

Item 9.

Changes in and Disagreements with Accountants on Accounting and Financial Disclosure

6692

Item 9A.

Controls and Procedures 

6692

Item 9B.

Other Information 

6693



 

 

PART III

Item 10.

Directors and Executive Officers and Corporate Governance

6793

Item 11.

Executive Compensation

6793

Item 12.

Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters

6793

Item 13.

Certain Relationships and Related Transactions and Director Independence

6894

Item 14.

Principal Accountant Fees and Services

6894



 

 

PART IV

Item 15.

Exhibits and Financial Statement Schedules

6995

Item 16.

Form 10-K Summary

7096



 

 

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PART I



FORWARD-LOOKING STATEMENTS

This annual reportAnnual Report on Form 10-K contains certain statements that are considered forward-looking statements within the meaning of the Private Securities Reform Act of 1995. All statements other than statements of historical facts contained in this Annual Report are forward-looking statements. We intend that such statements be protected by the safe harbor created thereby. Forward-looking statements relate to expectations, beliefs, projections, future plans and strategies, anticipated events or trends and similar expressions concerning matters that are not historical facts. In some cases, you can identify forward-looking statements by terms such as “anticipate,” “believe,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “should,” “will” and “would” or the negatives of these terms or other comparable terminology.



The forward-looking statements are based on our beliefs, assumptions and expectations of our future performance, taking into account all information currently available to us. Forward-looking statements involve risks and uncertainties and our actual results and the timing of events may differ significantly from the results discussed in the forward-looking statements. Such forward-looking statements and our business are subject to numerous risks and uncertainties that you should consider before investing in our Company. These risks are described more fully in the section titled “Risk Factors.” Accordingly, you should not rely upon forward-looking statements as predictions of future events. Examples of such forward-looking statements include, but are not limited to statements about:

·

The timingour intention to initiate a pivotal Phase 3 clinical program with simufilam in Alzheimer’s disease, the anticipated scope of Phase 3 studies and topicsour estimated timeline for doing so;

·

our reliance on third-party contractors to make drug supply on a large-scale for our Phase 3 clinical program, or their ability to do so on-time or on-budget;

·

our intention to initiate a cognition maintenance study with simufilam in Alzheimer’s disease;

·

limitations around the interpretation of discussions with the U.S. Food and Drug Administration, or FDA, regarding the New Drug Application, or NDA, for REMOXY® ER (oxycodone capsules CII), or REMOXY;cognitive results from a long-term open-label study design, as compared to efficacy results from a fully completed, randomized controlled study design;

·

the timingexpected rate of the planned resubmission of the NDA for REMOXY; 

·

development activities to potentially support obtaining approval of REMOXY by the FDA;cognitive decline over time in untreated Alzheimer’s patients;

·

the ability of REMOXYthe Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), Neuropsychiatric Inventory (NPI), CANTAB or other clinical scales to capture a shareassess cognition or health in our trials of Alzheimer’s disease;

·

announcements or plans regarding any future interim analyses of our open-label study of simufilam and our estimated timeline for doing so;

·

any significant changes we have made, or anticipate making, to the market for extended release opioid drugs;design of an on-going open-label study of simufilam;

·

announcements regarding an End-of-Phase 2 meeting held January 2021 with the U.S. Food and Drug Administration (FDA);

·

our ability to initiate, conduct or analyze additional clinical and non-clinical studies with our product candidates targeted at Alzheimer’s disease and other neurodegenerative diseases;

·

the statusinterpretation of products and potential products which are competitive with REMOXY and the implicationsresults from our Phase 2 clinical studies;

·

our estimated timeline for publishing in a peer-reviewed technical journal clinical results of the FDA requirements for approvalour Phase 2b study of such competitive products;simufilam;

·

our plans to rely on third parties, including Durect Corporation, or Durect,initiate a validation study of SavaDx, our investigational blood-based diagnostic, and Noramco, Inc., or Noramco, to supply us with excipients and active pharmaceutical ingredients and to manufacture REMOXY;

·

discussions with potential strategic partnersour estimated timeline for the development and commercialization of REMOXY;doing so;

·

the outcome of research and development activities, including, without limitation, development activities for FENROCK™ andsafety, efficacy, or potential formulation of additional dosage forms of our drug candidates;

·

the potentialtherapeutic benefits of our product candidates such as REMOXY, FENROCK, PTI-125 or PTI-125DX including the potential ability of PTI-125 to prevent or reverse amyloid-related Alzheimer’s damage or PTI-125DX to diagnose Alzheimer’s disease;candidates;

·

the utility of protection, or the sufficiency, of our intellectual property;

·

our potential competitors or competitive products;

·

expected future sources of revenue and capital and increasing cash needs;

·

potential competitors or competitive products;

·

market acceptanceour use of Clinical Research Organizations (CROs) to conduct clinical studies of our drug candidates and potential drugproduct candidates;

·

expectations regarding trade secrets, technological innovations, licensing agreements and outsourcing of certain business functions;

·

our expenses increasing interest income decreasing or fluctuations in our financial or operating results;

·

our operating losses and anticipated operating and capital expenditures;

·

expected uses of capital resources;

·

expectations regarding the issuance of shares of common stock to employees pursuant to equity compensation awards, net of employment taxes;

3


·

anticipated hiringthe development and developmentmaintenance of our internal information systems and infrastructure;

·

our need to hire additional personnel and our ability to attract and retain such personnel;

·

existing regulations and regulatory developments in the United States and other jurisdictions;

·

our need to expand the size and scope of our physical facilities;

·

the sufficiency of our current resources to continue to fund our operations over operations;

·

the next twelve months;accuracy of our estimates regarding expenses, capital requirements, and needs for additional financing;

·

assumptions and estimates used for our disclosures regarding stock-based compensation.

3


Such forward-looking statements involve riskscompensation; and uncertainties, including, but not limited to, those risks and uncertainties relating to:

·

difficulties or delays in the preparation and filing of the NDA for REMOXY and in potentially obtaining regulatory approval of the NDA for REMOXY, including the potential for requests by the FDA for additional data which may require an extended period of time to obtain and submit;

·

unexpected adverse side effects or inadequate therapeutic efficacy or manufacturing or stability issue of our drug candidates that could slow or prevent product approval (including the risk that current and past results of clinical trials are not indicative of future results of clinical trials) or potential post-approval market acceptance;

·

having or obtaining sufficient resources for the successful development, manufacture and commercialization of REMOXY;

·

the quantity, quality or sufficiencylong-term impact of the data, materialsCOVID-19, a novel coronavirus first detected in 2019, on our operations and information transferred to us by Pfizer, Inc., or Pfizer regarding the REMOXY development program;

·

discussions with potential strategic partners for the development and commercialization of REMOXY;

·

the successful development of other drug candidates, independently as well as pursuant to our other collaboration agreements, and the continuation of such agreements;

·

difficulties or delays in development, testing, clinical trials (including patient enrollment), regulatory authorization or approval, production and commercialization of our drug candidates;

·

the uncertainty of protection of our intellectual property rights or trade secrets;

·

potential infringement of the intellectual property rights of third parties;

·

pursuing in-license and acquisition opportunities;

·

maintenance or third party funding of our collaboration and license agreements;

·

legislation or regulatory actions affecting product pricing, reimbursement or access;

·

significant breakdown or interruption of our information technology and infrastructure;

·

significant issues that may arise related to outsourcing certain preclinical studies, clinical trials and formation and manufacturing activities;

·

hiring and retaining personnel; and

·

our financial position and our ability to obtain additional financing if necessary.condition.



In addition, such statements are subject toWe cannot assure you that we will realize the risks and uncertainties discussedresults or developments we expect or anticipate or, even if substantially realized, that they will result in the "Risk Factors" section and elsewhereconsequences or affect us or our operations in this document.

All informationthe way we expect. The forward-looking statements included in this Annual Report on Form 10-K has been retroactively adjustedare made only as of the date hereof. We undertake no obligation to reflect the ratiopublicly update or revise any forward-looking statement as a result of a  7-for-1 reverse stock split that took effect on May 10, 2017,new information, future events or otherwise, except as otherwise described or as required by law. See “Part II-Item 1 Management’s Discussion

In addition, statements that “we believe” and Analysissimilar statements reflect our beliefs and opinions on the relevant subject. These statements are based upon information available to us as of Financial Conditionthe date of this report, and Resultswhile we believe such information forms a reasonable basis for such statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have conducted an exhaustive inquiry into, or review of, Operations-Recent developmentsall potentially available relevant information. These statements are inherently uncertain and you are cautioned not to unduly rely upon these statements.

Our research programs in neurodegeneration benefit from longstanding scientific and financial support from the National Institutes of Health (NIH). The contents of this Annual Report are solely our responsibility and do not necessarily represent any official views of NIH.



Item 1.Business



Overview



Pain Therapeutics,Cassava Sciences, Inc. develops proprietary drugs that offer significant improvements to patients and healthcare professionals. We generally focus our drug development efforts on disorders of the nervous system. 

Our expertise consists of developing new drug candidates and guiding these through various regulatory and development pathways in preparation for their eventual commercialization. By necessity, the conduct of drug development is complex, lengthy, expensive and risky. The FDA has not yet established the safety or efficacy of our drug candidates.

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Reverse Stock Split

On May 4, 2017, following stockholder approval, our board of directors approved a reverse stock split at a ratio of 7-for-1. On May 4, 2017, we filed with the Secretary of State of the State of Delaware a Certificate of Amendment to the Company’s Amended and Restated Certificate of Incorporation to effect the 7-for-1 reverse stock split of our outstanding shares of common stock. The number of outstanding shares of common stock on the date of the reverse split was reduced from 46.1 million to 6.6 million shares. Our common stock began trading on the Nasdaq Global Market on a split-adjusted basis when the market opened for trading on May 10, 2017. As a result, all common stock share amounts included in this Annual Report on Form 10-K have been retroactively reduced by a factor of seven, and all common stock per share amounts have been increased by a factor of seven, with the exception of our common stock par value.

The following is a summary of our pipeline of drug assets:

REMOXY ER (extended-release oxycodone capsules CII)clinical-stage biotechnology company. Our mission is to detect and treat neurodegenerative diseases, such as Alzheimer’s disease. Our novel science is based on stabilizingREMOXY, our lead drug candidate, isbut not removing – a proprietary abuse-deterrent, twice-daily, oral oxycodone to treat severe chronic pain.  We plan to resubmitcritical protein in the REMOXY NDA to the FDA, with Priority Review in Q1 2018.  We own exclusive rights to develop and commercialize REMOXY worldwide, with a sales royalty obligation to one of our technology partners.brain.



FENROCK™ (transdermal fentanyl patch CII) – FENROCK is a proprietary, abuse-deterrent fentanyl skin patchOver the past 10 years, we have combined state-of-the-art technology with new insights in neurobiology to treat severe pain. This is an early-stage program that is substantially funded by a competitive research grant award from the National Institute on Drug Abuse (NIDA), the primary agency of the U.S. governmentdevelop novel solutions for research on drug abuse. We own exclusive, worldwide rights to FENROCK, with no royalty obligations to any third party.

PTI-125 –  PTI-125 is a proprietary small molecule drug for the treatment of Alzheimer’s disease (AD).  In 2017, we completedand other neurodegenerative diseases. Our strategy is to leverage our unique scientific/clinical platform to develop a first-in-human Phase I study with PTI-125.  Thisfirst-in-class program is substantially funded by competitive research grant awards from the National Institutes of Health (NIH), the primary agency of the U.S. government for biomedical research.  We own exclusive, worldwide rights to PTI-125, with no royalty obligations to any third party.

PTI-125DX –  PTI-125 is a proprietary, blood-based diagnostic/biomarker to detect Alzheimer’s disease (AD).  This clinical-stage program is substantially funded by competitive research grant awards from the NIH. We own exclusive, worldwide rights to PTI-125DX, with no royalty obligations to any third party.

REMOXY ER -  a drug candidate for severe chronic pain

Our lead drug candidate is called REMOXY ER (extended-release).  REMOXY is a proprietary, abuse-deterrent, twice-daily, capsule formulation of oral oxycodone, a strong opioid drug.  REMOXY is intended to meet the needs of healthcare professionals who appropriately prescribe extended-release oxycodone and who seek to minimize the risks of drug diversion, abuse or accidental patient misuse.  In particular, REMOXY’s thick, sticky, high viscosity formulation may deter unapproved routes of drug administration,treating neurodegenerative diseases, such as injection, snorting or smoking.  The proposed indication for REMOXY is for "the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate."Alzheimer’s.  



We own exclusive, worldwide rights to REMOXY.currently have two clinical-stage biopharmaceutical assets under development:



Opioid drugs, such as oxycodone, are an important treatment option for patients with severe chronic pain. However, misuse, abuse and diversion of these prescription drugs remains a serious, persistent problem.  For over a decade, we have pioneered technology, tools and techniques that enable the development of Abuse-Deterrent Formulations (ADFs). ADFs are intended to make opioid drugs difficult to abuse yet provide steady pain relief when used appropriately by patients. ADFs are intended to help in the fight against prescription drug abuse.

In March 2016, we resubmitted to the FDA a New Drug Application (NDA) for REMOXY.  In September 2016, we received a Complete Response Letter, or CRL, from the FDA for the REMOXY NDA. The CRL informed us that REMOXY could not be approved in its present form and specified additional actions and data needed for drug approval. The CRL substantially focused on the need to conduct a clinical abuse-deterrent study via the nasal route of administration, and additional in vitro (non-clinical) studies to further characterize the abuse-deterrent properties of REMOXY.  The 2016 CRL

5


made no mention of clinical safety, drug efficacy, manufacturing, stability, bioequivalence or any other issues from a prior CRL.

In February 2017, we met with the FDA regarding REMOXY.  During this meeting, we reached written agreement with the FDA on a roadmap to resubmit the NDA for REMOXY.  Final minutes of our FDA meeting confirmed two key requirements needed for the resubmission of the REMOXY NDA:

·

To supportour lead therapeutic product candidate is called simufilam, and it is a potential drug label claim against abuse by injection: Repeat an injectability/syringeability study using thin films of drug, smaller volumes of solvents, additional mixed solventsnovel treatment for Alzheimer’s disease; and alternative extraction methods and syringe filter.

·

To supportour lead investigational diagnostic product candidate is called SavaDx, and it is a potential drug label claim against abuse by snorting: Conduct an intranasal abuse potential study in human volunteers.novel way to detect the presence of Alzheimer’s disease from a small sample of blood, possibly years before the overt appearance of clinical symptoms.



During 2017, we conducted these mandated studies with REMOXY.Our scientific approach for the treatment of Alzheimer’s disease seeks to simultaneously improve both neurodegeneration and neuroinflammation. We believe positiveour ability to improve multiple vital functions in the brain represents a new, different and crucial approach to address Alzheimer’s disease.

Our lead therapeutic product candidate, simufilam, is a proprietary small molecule (oral) drug. Simufilam targets an altered form of a protein called filamin A (FLNA) in the Alzheimer’s brain. Published studies have demonstrated that the altered form of FLNA causes neuronal dysfunction, neuronal degeneration and neuroinflammation. 

We believe simufilam improves brain health by reverting altered FLNA back to its native, healthy conformation, thus countering the downstream toxic effects of altered FLNA. We have generated and published experimental and clinical

4


evidence of improved brain health with simufilam. Importantly, simufilam is not dependent on clearing amyloid from the brain. Since simufilam has a unique mechanism of action, we believe its potential therapeutic effects may be additive or synergistic with that of other therapeutic candidates aiming to treat neurodegeneration.

Simufilam has demonstrated a multitude of beneficial effects in animal models of disease, including normalizing neurotransmission, decreasing neuroinflammation, suppressing neurodegeneration, and restoring memory and cognition. 

In 2019, we completed a small, first-in-patient, clinical-proof-of-concept, open-label Phase 2a study of simufilam in the U.S., with substantial support from the National Institute on Aging (NIA), a division of the NIH. Treatment with simufilam for 28 days significantly improved key biomarkers of Alzheimer’s pathology, neurodegeneration and neuroinflammation (p<0.001).  Biomarkers effects were seen in all patients in both cerebrospinal fluid (CSF) and plasma.

In September 2020, we announced final results of a Phase 2b study with simufilam in Alzheimer’s disease. In this clinical study funded by the NIH, Alzheimer’s patientstreated with 50 mg or 100 mg of simufilam twice-daily for 28 days showed statistically significant (p<0.05) improvements in CSF biomarkers of disease pathology, neurodegeneration and neuroinflammation, versusAlzheimer’s patients who took placebo. In addition, Alzheimer’s patientstreated with simufilam showed improvements in validated tests of episodic memory and spatial working memory,versus patients on placebo  (Effect Size 17-46%). Cognitive improvements correlated most strongly (R2=0.5) with decreases in levels of P-tau181.

In March 2020, we initiated a long-term open-label extension study to evaluate simufilam in patients with Alzheimer’s disease. This open-label, multi-center, extension study is intended to monitor the long-term safety and tolerability of simufilam 100 mg twice-daily for 12 or more months. The study’s initial target enrollment was approximately 100 patients with mild-to-moderate Alzheimer’s disease and, in February 2021, was increased to approximately 150 patients. This study uses the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog-11) to assess cognitive symptoms of dementia and the Neuropsychiatric Inventory (NPI) to assess the presence and severity of dementia-related behavior. Both scales are widely used clinical tools in trials of Alzheimer’s disease.

On February 2, 2021, we announced results of the first of two preplanned interim analysis of our open-label study of simufilam. The first interim analysis summarizes clinical data at the midway point of enrollment, i.e., the first 50 patients who have completed at least 6 months of drug treatment. Patients’ cognition and behavior scores both improved following six months of simufilam treatment, with no safety issues. Six months of simufilamtreatment improved cognition scores by 1.6 points on ADAS-Cog11, a 10% mean improvement from baseline to month 6. In these studies supportsame patients, simufilam also improved dementia-related behavior, such as anxiety, delusions and agitation, by 1.3 points on the Neuropsychiatric Inventory, a 29% mean improvement from baseline to month 6. 

Based on the interim results and inbound demand from Alzheimer’s patients and their caregivers, we announced significant changes to the open-label program, including an increase in the enrollment target by up to 50 additional patients, for a total target of approximately 150 patients. This study had enrolled approximately80 patients as of February 2021.

We expect to announce results of a second planned interim analysis on safety and cognition for our open-label study approximately mid-2021. The second interim analysis is intended to summarize clinical data on the first 50 patients who complete at least 12 months of open label claims against abuse by injection and abuse by snorting.  In November 2017,drug treatment.

On February 22, 2021, we concluded a pre-NDAannounced the successful completion of an End-of-Phase 2 (EOP2) meeting with the FDA.  The purpose of this pre-NDAFDA for simufilam. Official EOP2 meeting was tominutes indicate we and the FDA agree on submission requirementskey elements of a pivotal Phase 3 clinical program in support of a New Drug Application (NDA) filing for simufilam in Alzheimer’s disease. We believe agreements reached during the EOP2 meeting show a clear path forward for advancing simufilam into Phase 3 studies. We expect to initiate a pivotal Phase 3 program with simufilam in Alzheimer’s disease in the second half of 2021.

Our diagnostic effort, called SavaDx, is an early-stage program focused on detecting the presence of Alzheimer’s disease from a small sample of blood, possibly years before the overt appearance of clinical symptoms. We are developing SavaDx as a fast, accurate and quantitative blood-based investigational biomarker/diagnostic to detect and monitor Alzheimer's disease. The goal is to make the detection of Alzheimer’s disease as simple as getting a blood test. We expect to initiate a validation/disease specificity study of SavaDx in 2021.

5


About Alzheimer’s Disease

Alzheimer’s disease is a progressive neurodegenerative disorder that affects cognition, function and behavior. There are no disease-modifying drug therapies to treat the disease. As such, cognition will always continue to decline over time in patients with Alzheimer’s.

As of 2020, there were approximately 50 million people worldwide living with dementia, a figure expected to increase to 150 million by 2050 and the annual global cost of dementia is now above $1 trillion, according to Alzheimer’s Disease International, a charitable organization. 

Our Scientific Approach is Different

Over the last ten years, we have developed a new and promising scientific approach for the REMOXY NDA under Section 505(b)(2)treatment and diagnosis of neurodegenerative diseases, such as Alzheimer’s disease. Importantly, we do not seek to clear amyloid out of the Federal Food, Drug,brain. Rather, we seek to stabilize a critical protein in the brain that has many downstream effects.

Our scientific approach is to treat neurodegeneration by targeting an altered form of a scaffold protein called FLNA. Through years of basic research, we and Cosmetic Act.   Duringour academic collaborators identified FLNA as a structurally altered protein in the pre-NDA meeting,Alzheimer’s brain. We have shown that the altered form of FLNA is pervasive in the Alzheimer’s brain and undetectable in healthy control brains.

Using scientific insight and advanced techniques in molecular biochemistry, bioinformatics and imaging, we received commentshave elucidated this protein dysfunction. Through this work, we have produced experimental evidence that altered FLNA plays a critical role in Alzheimer’s disease. We engineered a family of high-affinity, small molecules to target this structurally altered protein and clarification fromrestore its normal shape and function. This family of small molecules, including our lead therapeutic candidate, simufilam, was designed in-house and characterized by our academic collaborators.

Our lead therapeutic product candidate, simufilam, is a small molecule (oral) drug with a novel mechanism of action. The target of simufilam is altered FLNA, the FDAbrain protein we seek to stabilize (simufilam does not bind to healthy, normal FLNA). Importantly, since simufilam has a unique mechanism of action, we believe its potential therapeutic effects may be additive or synergistic with that of other therapeutic candidates aiming to treat neurodegeneration.

Given the biopharmaceutical industry’s challenging track record in Alzheimer’s research, we believe there is an urgent need to consider more recent and innovative approaches to combat this disease. We believe our scientific approach may broaden the range of possible treatment approaches for this complex disease.

Our science is based on stabilizing a critical protein in the acceptabilitybrain

Proteins are essential for cell function because they participate in virtually every biological process. If protein function is impaired, the health consequences can be devastating. Technological advances in medicine and improvements in lifestyle are making our lives longer. But with age, genetic mutations and other factors conspire against healthy cells, resulting in altered proteins. Sometimes a cell can rid itself of altered proteins. However, when disease changes the shape and function of critical proteins, multiple downstream processes are impaired. There are many clinical conditions in which proteins become structurally altered and impair the normal function of cells, tissues and organs, leading to disease.  Conversely, restoring altered proteins back to health –called proteostasis – is a well-accepted therapeutic strategy in clinical medicine.

For over 100 years, scientists have ascribed various neurodegenerative diseases to proteins that misfold and are rendered pathological. In Alzheimer’s disease, certain proteins, such as amyloid and tau, lose their normal shape and function. Such misfolded proteins can breakdown or aggregate in clumps and form plaque in the brain. Destruction of neuronal synapses, accelerated nerve cell death, and dysfunction of the databrain support cells, are all widely believed to be includeddirect consequences of misfolded proteins.

FLNA is a scaffolding protein widely found throughout the body. A healthy scaffolding protein brings multiple proteins together, initiating their interaction. However, an altered form of FLNA protein is found in the REMOXY NDA resubmission, including a recent intranasal study.  All questions were addressedAlzheimer’s brain. Our experimental evidence shows that altered FLNA protein contribute to Alzheimer’s disease by disrupting the normal function of neurons, leading to neurodegeneration and summarized in official minutes ofbrain inflammation. Our product candidate, simufilam, aims to counter the meeting issued by the FDA.  There are no discrepancies or requests for clarifications following receipt of final meeting minutes. 

As a result, we intend to resubmit the REMOXY NDA in Q1 2018 with Priority (six-month) Review.

Background on Uses and Abuse of Opioid Drugs

Opioid drugs are primarily used to relieve pain. They are among the world’s oldest known drugs. The term ‘opioid’ refers to an entire class of analgesic substances that are derived from the opium poppy plant. Drugs that fall within this class include oxycodone, hydrocodone, fentanyl, heroin, morphine and many other related substances.

In recent decades, oxycodone, a semi-synthetic opium derivative, has become a standard of care to treat severe chronic pain. Oxycodone is in Schedule II of the federal Controlled Substances Act of 1970, which means it has accepted medical use with severe restrictions, a high potential for abuse and regulations around its manufacture, possession, storage, use and distribution.

Oxycodone can provide significant therapeutic benefits for patients in pain when used as prescribed. In recent years, patients with severe chronic pain have benefited from oxycodone in long-acting formulations. Long-acting formulations contain a very high dose of oxycodone that is intended to release evenly over 12 hours. Long-acting oxycodone offers the convenience of less-frequent dosing intervals and improved compliance, a potential win-win for prescribers and for patients with severe chronic pain.

However, the emergence of long-acting oxycodone has also corresponded with a dramatic increase in opioid drug abuse. Drug abuse is the use of opioid drugs for reasons other than what the drug was prescribed for, and often via unapproved routes of administration, such as injection, snorting or smoking. Opioids such as oxycodone are primarily abused due to their ability to produce a strong, if fleeting, euphoric high.

Drug abusers have learned effective ways to tamper with, and defeat, long-acting oxycodone formulations. Defeating the long-acting properties of an oxycodone formulation can be as easy as crushing or grinding tablets, then swallowing, injecting, snorting or smoking the crushed substance. This release high levels of oxycodone faster than intended (called “dose-dumping”), resulting in an immediate and powerful euphoric high, as compared to swallowing an intact tablet as prescribed.

Misuse of oxycodone is not always intentional.  According to a medical publication, about two-thirds of surveyed patients with chronic pain did not think that cutting, crushing, or grinding their medication would change the way it worked (Pergolizzi et al., 2014).

 

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In addition,altered and toxic form of FLNA in the pain-relieving effectsbrain, thus restoring the normal function of OxyContin® (oxycodone HCI),this critical protein. Our novel science is based on stabilizing – but not removing – a widely used abuse-deterrent extended-release formulation of oxycodone, often wears off early, according to a lengthy investigation published bycritical protein in the Los Angeles Times in 2016.  The Los Angeles Times investigation reports that a single dose of twice-daily oxycodone often does not last for the intended 12 hours and performs more like “an 8-hour drug.”  This makes some patients take extra doses or stronger ones, raising the risk of abuse and addiction.  An additional problem for physicians and patients alike can arise when insurance plans will not reimburse, and pharmacists will not dispense, more than two doses of OxyContin per day.brain.



Opioid abuse is extremely dangerous. Opioid abuse can lead to drug-seeking behavior, tolerance and physical or psychological dependence. Even a single episode of opioid abuse can also lead to overdose, respiratory depression or death.

The Role of Abuse-deterrent Formulations

Policy makers have developed a multi-pronged approach aimed at combating opioid misuse, abuse and addiction. One targeted effort has been to encourage the pharmaceutical industry to develop ADFs.  In April 2015, the FDA issued a final guidance to assist the pharmaceutical industry in developing ADF opioid drug, products.

ADFs attempt to raise the bar on opioid abuse by making it more difficult, longer or aversive to tamper with a long-acting formulation, while recognizing that no drug or drug formulation can be made abuse-proof. In particular, an ADF drug can still be misused and result in overdose simply by ingesting the drug in higher than recommended doses. ADFs are not designed to prevent opioid-induced euphoria. ADF technology aims to decrease the likelihood that a long-acting opioid formulation will dose-dump under conditions of abuse or accidental misuse. By mitigating dose-dumping, the likelihood of overdose and death associated may decrease.multiple effects



The intentionOur lead therapeutic candidate, simufilam, binds to altered FLNA with very high (femtomolar) affinity. This drug effect restores the normal shape of ADFs is to displace non-abuse-deterrent drug products.   First-generation ADFs were introduced into the marketplace in 2010. However, we believe the relative weakness of first generation ADFs means opioid abuse continues to be a serious public health issue.In 2016, over 64,000 people died in the United States from opioid overdose, increasing from over 33,000 in 2015, according to the Centers for Disease Control Prevention. According to the FDA, “for each death [due to narcotic pain relievers], there are an additional ten treatment admissions, 32 emergency department visits and 825 nonmedical users of these drugs.” (Source: FDA’s Efforts to Address the Misuse and Abuse of Opioids, 2/6/2013).

As a pioneer in the design and development of ADFs, we believe a robust design for a novel ADF for twice-daily oxycodone revolves around four basic objectives: (i) safety and clinical efficacy over the entire 12-hours when used as prescribed; ii) abuse-deterrent when abused; (iii) ease of large scale manufacturing; and (iv) novel, non-infringing intellectual property. Many ADF programs may achieve three of these four objectives but the practical reality is that few ADFs achieve all four. We believe this is reflected in the industry’s relatively high failure rate with regards to ADFs developments for long-acting opioid formulations.

Market Opportunity for REMOXY ER

REMOXY targets the market for opioid therapy.  The global opioid market has been estimated by third-parties to be valued at nearly $35 billion in 2015.  North America dominates the global market, with about 60-65% market share, or about $20 billion.  We estimate extended‑release opioid drugs are an approximately $4 billion market in the United States.

We believe REMOXY can capture a share of the approximately $4 billion market in the United States for extended‑release opioid drugs, including a portion of the existing multi-billion OxyContin (Purdue Pharma L.P.) franchise. OxyContin remains the largest selling extended‑release opioid in the United States by dollars.  Despite OxyContin’s commercial success, we believe the drug carries a stigma due to widespread, well-documented cases of abuse and overdose; the persistence of negative media reports around this drug; the magnitude of the opioid epidemicFLNA and the sheer numbernormal function of deaths associated with this problem;key brain receptors, including: the alpha-7 nicotinic acetylcholine receptor; the N-methyl-D-aspartate (NMDA) receptor; and on-going legal actions against Purdue by government agenciesthe insulin receptor. These receptors have pivotal roles in brain cell survival, cognition and private parties.memory. 



In animal models, treatment with simufilam resulted in dramatic improvements in brain health, such as reduced amyloid and tau deposits, improved receptor signaling and improved learning and memory. In addition, simufilam has another beneficial treatment effect of significantly reducing inflammatory cytokines in the brain. In animal models of disease, treatment with simufilam greatly reduced levels of IL-6 and suppressed TNF-alpha and IL-1beta levels by 86% and 80%, respectively, illustrating a powerful anti-neuroinflammatory effect. 

By restoring function to multiple receptors and exerting powerful anti-inflammatory effects, we believe our approach has potential to slow the progression of neurodegeneration in patients. Thus, we have designed simufilam to slow or, potentially, even reverse the deterioration of brain cells.

In 2019, a small, first-in-patient, clinical proof-of-concept Phase 2a study funded by NIH, showed that open-label treatment with simufilam for 28 days significantly improved key biomarkers of Alzheimer’s pathology, neuroinflammation and neurodegeneration (p<0.001).  On July 15, 2020, we presented additional Phase 2a clinical results at the Biomarkers for Alzheimer’s Disease Summit, a virtual scientific conference. In addition to targetingshowing that SavaDx could distinguish and stratify patients with Alzheimer’s disease, this presentation provided direct evidence for target engagement and for the oxycodone market, REMOXY targetstreatment effects of simufilam. Target engagement is a crucial step in drug research because it shows that our small molecule drug candidate binds to its intended site of action in cells and confirms that treatment effects are caused by the approximately 10-15 million additional prescriptionsdrug hitting its target.

In March 2020, we completed a randomized, placebo-controlled, double-blind Phase 2b study of simufilam in 64 patients with mild-to-moderate Alzheimer’s disease, 50-85 years of age, with MMSE scores 16 to 26. Study participants received simufilam 100 mg, 50 mg or matching placebo, twice-daily, for non‑abuse‑deterrent extended‑release opioids annually28 continuous days. This study was substantially funded by a research grant award from NIH.

In September 2020, we reported positive final study results for our Phase 2b study. Drug was safe and well-tolerated. Simufilam significantly (P<0.05) improved an entire panel of validated biomarkers of disease in patients with Alzheimer’s disease compared to a placebo group. In addition, Alzheimer’s patients treated with simufilam showed directional improvements in validated tests of episodic memory and spatial working memory, versus patients on placebo(Effect Sizes 46-17%). Cognitive improvements correlated most strongly (R2=0.5) with decreases in levels of CSF P-tau181. The study achieved a 98% response rate, defined as the United States. Manyproportion of study participants taking simufilam who showed improvements in biomarkers. Importantly, we believe these opioids include active pharmaceutical ingredients,data are consistent with prior clinical and preclinical results, the drug’s mechanism of action and over 10 years of basic research.

To our knowledge, no competing drug candidate has demonstrated the ability to reduce an entire panel of biomarkers of disease in patients with Alzheimer’s disease. For this reason, CSF biomarker data generated in our Phase 2a and Phase 2b studies may not be directly comparable to clinical results generated by our competitors.

On February 2, 2021, we announced results of a preplanned interim analysis of our open-label study of simufilam. This first interim analysis summarizes clinical data at the midway point of enrollment, i.e., the first 50 patients who have completed at least 6 months of drug treatment. Patients’ cognition and behavior scores both improved following six months of simufilam treatment, with no safety issues. Six months of simufilamtreatment improved cognition scores by 1.6 points on ADAS-Cog11, a 10% mean improvement from baseline to month 6. In these same patients, simufilam also improved dementia-related behavior, such as morphine, that may be perceived as having greater side effects than oxycodone‑based formulations.anxiety, delusions and agitation, by 1.3 points on the Neuropsychiatric Inventory, a 29% mean improvement from baseline to month 6. 

 

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Opioid prescriptions in the United States peaked in 2010We expect to announce results of a second planned interim analysis on safety and have decreased each year through 2017.  The reasonscognition for this erosion are complex, but center aroundstudy in mid-2021.

Based on positive clinical results and inbound demand from clinical sites, patients, and their caregivers, we expanded the fact that opioid abuse remainssize of the ongoing open-label study of simufilam. In February 2020, we increased the target enrollment by up to 50 additional patients with mild-to-moderate Alzheimer’s disease, for a serious, pervasive and persistent problem for physicians and patients alike.  In particular, prescriptions for non-abuse deterrent opioids are likelytotal target enrollment of up to continue to drop significantly in the years ahead.150 patients.



We also plan to initiate a 6-month, double-blind, randomized, placebo-controlled study in patients with Alzheimer’s disease who complete at least one year of open-label treatment with simufilam. This is a Cognition Maintenance Study (CMS), in which patients who complete one year of open-label treatment will subsequently be randomized (1:1) to simufilam or placebo for six months. The CMS is designed to compare simufilam’s effects on cognition and behavior in patients who continue with drug treatment versus those who discontinue drug treatment. For ethical and other reasons, patients who successfully complete the six-month CMS will have the option to receive open-label simufilam.

Our science is published in multiple peer-reviewed journals. In addition, government actions serveour research has been supported by NIH under multiple research grant awards. Each grant was awarded following an in-depth, peer-reviewed evaluation of our approach for scientific and technical merit by a panel of outside experts in the field. Strong, long-term support from NIH has allowed us to materially limitadvance our two product candidates for neurodegeneration, simufilam and SavaDx, into clinical development.

Overview of Alzheimer’s disease

Alzheimer’s disease is a progressive neurodegenerative disorder that affects cognition, function and behavior. There are no disease-modifying drug therapies to treat the marketdisease. As of 2020, there were approximately 50 million people worldwide living with dementia, a figure expected to increase to 150 million by 2050 and the annual global cost of dementia is now above $1 trillion, according to Alzheimer’s Disease International, a charitable organization. According to the non-profit Alzheimer's Association, Alzheimer’s disease is expected to nearly triple in the U.S. between now and 2050. If this occurs, there is potential for opioid therapyAlzheimer's disease to only thosecause a major financial drain on the national economy.

Currently marketed drug therapies for Alzheimer’s disease have limited therapeutic effect

There are no disease-modifying drug therapies to treat Alzheimer’s disease. The FDA has not approved any new drugs for Alzheimer’s disease since 2003. Biogen, Inc., a large biopharmaceutical company, is currently seeking FDA approval for an investigational drug, aducanumab, for the treatment of Alzheimer’s disease.

Currently marketed drug therapies focus solely on treating symptoms, mostly in patients who havewith mild-to-moderate Alzheimer's disease. At the time of diagnosis, patients are initiated on a class of drugs called cholinesterase inhibitors. The Alzheimer’s brain has low levels of a neurotransmitter called acetylcholine. Cholinesterase inhibitors prevent an appropriate need for such drugs.  For example,enzyme in response to an epidemic of opioid overdoses, in 2017 the Center for Disease Control (CDC) released important new clinical guidelines for physicians treating adult patients for chronic pain.  The CDC guidelines provide specific recommendations to clinicians about the appropriate prescribing of opioids to improve pain managementbrain, called acetylcholinesterase, from breaking down acetylcholine. Currently marketed cholinesterase inhibitors include donepezil (marketed by Eisai Co., Ltd. and patient safety, including:  Pfizer, Inc. as Aricept“When opioids are started, the lowest possible effective dosage should be prescribed to reduce risks of opioid use disorder®), rivastigmine (marketed by Novartis AG as Exelon®) and overdose.” galantamine (marketed by Janssen Pharmaceuticals, Inc. as Razadyne(Source: CDC Guideline for Prescribing Opioids for Chronic Pain®). We believe theseCholinesterase inhibitors may benefit some patients for several months, after which the targeted brain receptors are desensitized, and other actions will continuedrug efficacy is lost. To our knowledge, no drug for Alzheimer’s has shown an ability to restrictstabilize cognition in patients, much less restore loss cognition, beyond a few months.

Simufilam is our Proprietary Drug for the approvability, use, promotion and distributionTreatment of opioid drugs in the United States, and may serve to eliminate the market for non‑abuse‑deterrent opioids.Alzheimer’s Disease.



We own exclusive, worldwide rightshave generated and published experimental evidence of improved brain health by restoring altered FLNA with simufilam, our lead therapeutic product candidate. Simufilam is a proprietary small molecule drug that represents an entirely new scientific approach to REMOXY. If approvedtreat neurodegeneration. Published studies have demonstrated that simufilam targets an altered form of a protein called FLNA that is pervasive in the Alzheimer’s brain. Altered FLNA causes neuronal dysfunction, neuronal degeneration and granted appropriate label claims, we believe REMOXY may have potential to distinguish itself from competitors with:

ü

best-in-class abuse-deterrent properties;

ü

true twice-daily dosing;

ü

lowest initial starting dose;

ü

minimal food effect;

ü

lack of generic drug substitution; and

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over 15 years of intellectual property protection.

neuroinflammation. We believe direct competitors to REMOXY will include the two ADFs of twice-daily oxycodone that are commercially available in the United States:

·

OxyContin ER (oxycodone HCI) from Purdue Pharma L.P. - A reformulated version of the original OxyContin OC, this drug received FDA approval in April 2010.  According to its package insert, "OxyContin is formulated with inactive ingredients intended to make the tablet more difficult to manipulate for misuse and abuse."  Some patients have complained that the new formulation is not as effective or causes gastrointestinal problems, according to Pain News Network (2016).

·

Xtampza® ER (oxycodone) from Collegium Pharmaceuticals, Inc. - Xtampza ERreceived FDA approved in April 2016 and is available in capsules containing microspheres formulated with oxycodone base and inactive ingredients that make the formulation more difficult to manipulate for the purpose of abuse.  Each capsule contains 9, 13.5, 18, 27, or 36 mg of oxycodone (equivalent to 10, 15, 20, 30 or 40 mg of oxycodone HCl, respectively).

The FDA has approved two other extended-release, ADFs of oxycodone.  However, neither of these two drugs were ever launched into the marketplace in the United States: a) in 2016, the FDA approved Troxyca® ER (Pfizer, Inc), a capsule combination of oxycodone HCL and naltrexone, an opioid antagonist; and b) in 2014, the FDA approved Targiniq® ER (Purdue Pharma LP), a tablet combination of oxycodone HCL and naloxone, an opioid antagonist. 

REMOXY will compete against all extended‑release opioids, including generic drug products.  In November 2017, the FDA issued final guidance on the regulatory pathway for generic abuse‑deterrent opioid products.  Among other requirements, the new FDA guidance emphasizes that sponsors of generic abuse-deterrent oxycodone must ensure that a generic opioid drug is no less abuse deterrent than the original opioid and must also evaluate all potential routes of abuse, even those routes of abuse for which a generic sponsor does not seek a label-claim. We believe these new FDA requirements represents a high bar for generic drug developers in terms of added development time, expenses, technical expertise and regulatory risks. 

Currently we have no capability to launch or to commercialize REMOXY. We continue to review potential launch and commercialization strategies for REMOXY.  Options include a potential strategic transaction around all of our drug candidates;candidate, simufilam, improves brain health by reverting altered FLNA back to its native, healthy conformation, thus countering downstream toxic effects of altered FLNA. Importantly, simufilam is not dependent on clearing amyloid from the brain. The following is a commercial collaboration for REMOXY; or establishing commercial capabilities in-house to launch REMOXY on our own.

summary profile of simufilam’s drug development program. 



 

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Chronology of REMOXY ERIND submission to FDA



We initiatedOver the developmentpast ten years, we successfully conducted basic research, in vitro studies and preclinical studies in support of REMOXY over a decade ago, before any formal guidance was in place with regards to regulatory pathways for ADFs. As a result of our pioneering efforts with REMOXY, we have developed a foundation of practical and scientific experience with regard to regulatory and development pathways for ADFs.

The following is a top-line reverse chronology of the development of REMOXY:

·

As a result of our pre-NDA meeting, we intend to resubmit the REMOXY NDA to the FDA in Q1 2018 with Priority (six-month) Review.

·

In November 2017, we concluded a pre-NDA meeting with the FDA. 

·

In February 2017, we met with the FDA regarding REMOXY.

·

In September 2016, we received a CRL from the FDA regarding the NDA for REMOXY. 

·

In March 2016, we resubmitted the NDA for REMOXY with the FDA.

·

In 2015, we generated additional abuse-deterrent data, continued an on-going stability study and made other preparations necessary to resubmit the NDA for REMOXY with the FDA.

·

In 2015, we and Pfizer concluded the transfer of the REMOXY program. We believe Pfizer has transferred to us its data, materials, capital equipment and other assets related to REMOXY.

·

In 2014, Pfizer provided us with written notice of termination of its development of REMOXY. We and Pfizer agreed on an orderly transfer of all rights, data, IP, etc.

·

From 2011-2014, Pfizer conducted fundamental investigations of the REMOXY formulation and its manufacture. As a result, Pfizer modified the REMOXY formulation and conducted successful studies to establish bioequivalence of the current formulation to the original formulation of REMOXY, to generate additional abuse-deterrent data and to provide manufacturing stability. 

·

In 2011, Pfizer received a CRL on the REMOXY NDA filed by King. Once again, FDA cited manufacturing issues (specifically, in vitro drug stability). Once again, the CRL did not question REMOXY’s safety, clinical efficacy, abuse-deterrent properties or use of the reference listed drug.

·

In 2010, King resubmitted the REMOXY NDA with the FDA. In early 2011, Pfizer acquired King. References to Pfizer include references to Pfizer’s subsidiary King.

·

In 2009, King assumed sole control and responsibility for REMOXY.

·

In 2008, we filed an NDA for REMOXY with the FDA. Later that year, we received a CRL over manufacturing issues (specifically, in vitro drug stability). However, the CRL did not question REMOXY’s safety, clinical efficacy, abuse-deterrent properties or use of the reference listed drug.

·

In 2005, we and King Pharmaceuticals, Inc., or King, entered into an exclusive agreement to develop and commercialize REMOXY.

·

In 2003, we filed an Investigational New Drug application, or IND, for REMOXY with the FDA.

FENROCK™ -a drug candidate for severe pain

FENROCK is a proprietary transdermal patch that contains the prescription drug fentanyl to manage pain and incorporates novel abuse-deterrent technology.  This is an early-stage, pre-IND program that is substantially funded by a competitive research grant award from the NIH’s NIDA.

Fentanyl is an opioid drug that is up to 100 times more potent than morphine. When used properly by patients under the care of a qualified physician, a fentanyl patch releases the drug slowly over 72 hours. This helps to manage pain that is severe enough to require daily around-the-clock, long-term treatment. However, fentanyl is also abused by non-patients for its euphoric effects. Abusers can chew on a fentanyl patch, or simply extract the fentanyl from a patch, then inject or ingest the contents. This practice is illicit and highly dangerous. It can quickly introduce into the body a massive amount of fentanyl, which can lead to addiction, overdose and death.

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In November 2017, we announced a research and development grant from NIDA following a competitive, in-depth evaluation of FENROCK technology for scientific and technical merit.  The grant of approximately $2.2 million provides us with funding to develop FENROCK.

We developed in-house the technology for FENROCK and own all development and commercial rights, without royalty or milestone obligations to any third-parties.

Fentanyl is a schedule II substance under the U.S. Controlled Substance Act.

PTI-125 -a drug candidate to treat Alzheimer’s Disease

PTI-125 is a proprietary, experimental drug for the treatment of Alzheimer’s disease (AD).  AD is a progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks.  Damage to the brain starts a decade or more before problems appear.  During this early stage of disease, people seem to be symptom-free, but toxic changes are taking place in the brain.  Eventually, brain damage becomes widespread and affected people are often unable to care for themselves.  Currently, AD cannot be detected until symptoms appear.  Over five million Americans live with AD, a number that is expected to increase significantly in the coming years.

PTI-125 is a small molecule drug candidate that was designed by us and characterized by outside collaborators.  PTI-125 has been shown to significantly improve AD neuropathologies in mouse models of the disease and in post-mortem brain tissue from AD patients, including receptor dysfunctions, neuroinflammation, tau hyperphosphorylation, insulin resistance and plaques and tangles that are hallmarks of AD.

PTI-125 works by binding to filamin A (FLNA), a protein critical to beta amyloid’s toxicity.  Beta amyloid exerts multiple toxic effects, eventually causing the plaques and tangles found in the brains of people with AD.  By binding to FLNA, PTI-125 may prevents and even reverse amyloid-related AD damage.

To date, the underlying science for PTI-125 has been published in Journal of Neuroscience,  Neurobiology of Aging,  Journal of Biological Chemistry,  PLOS-One and other peer-reviewed scientific journals.

In June 2017, we announced that the NIH's National Institute on Aging awarded us a $1.7 million research grant following a competitive, in-depth evaluation of PTI-125 for scientific and technical merit.  This NIH research grant enabled us to begin testing PTI-125 in human subjects.  Subsequently, an Investigational New Drug (IND) applicationsubmission to FDA for PTI-125 was submittedsimufilam, including requisite studies around safety pharmacology, toxicology, genotoxicity and accepted by the FDA.bioanalytical methods. In 2017 we filed an IND with FDA for simufilam.



In OctoberClinical safety of simufilam in a Phase 1 study

Following FDA acceptance of our IND in 2017, we announced the successful completion of a Phase I clinical study for PTI-125.  This study investigated for the first time the safety, dosing and pharmacokinetic profile of PTI-125simufilam in healthy human volunteers. The design of our first-in-human Phase 1 study was based on regulatory feedback, clinical and scientific rationale and observations from previously conducted preclinical and in vitro studies.



In this first-in-humana Phase 1 study, PTI-125simufilam was evaluated in 24 healthy human volunteers in a single-sitesingle site in the United StatesU.S. for safety, tolerability and pharmacokinetics. Study subjects were administered a single oral dose of 50, 100 or 200 mg of PTI-125.  The drugsimufilam. Drug was well-tolerated in all subjects. Importantly, PTI-125simufilam showed no treatment-related adverse effects and no dose-limiting safety findings. Pharmacokinetic measurements showed PTI-125,demonstrated that simufilam, a small molecule, was rapidly absorbed. Dose-proportionality outcomes werewas observed over the entirefull dose range of 50 to 200 mg. There were two key findings forResults of this Phase I Study:1 study were presented at the 10th Annual International Conference on Clinical Studies on Alzheimer's Disease in 2017.

·

PTI-125 was safe and well-tolerated at all doses studied; and    

·

PTI-125 demonstrated favorable pharmacokinetics for further drug development.



Mean PTI-125 Plasma Concentration Concentration (ng/mL) 0 500 100 1500 0 4 8 12 16 g 200 mg Time (

Given the absence of any observable dose-limiting effects in healthy adults an excellent non-clinical safety database,in a Phase 1 study, a strong scientific rationale, and multiple peer-reviewed publications and research grant awards, we believe there is significant meritthis program demonstrated favorable proof-of-principle for the development of simufilam in Alzheimer’s disease.

Phase 2 clinical development program for simufilam

In 2018, we mapped out, in collaboration with outside science advisors and medical experts, a strategic clinical plan to moveadvance simufilam into a comprehensive Phase 2 clinical development program. The general objective of our Phase 2 program with simufilam was to gain an initial estimate of the safety, tolerability and biological activity of this drug candidate in patients with Alzheimer’s disease. We believe meaningful Phase 2 data now enable us to design and conduct a large-scale Phase 3 efficacy program for simufilam and may also enable us to the next level of development.seek one or more strategic collaborations with pharmaceutical or biotechnology companies.



We own exclusive, worldwide rightsPhase 2a Clinical Study

In 2019, we completed a first-in-patient, clinical proof-of-concept study of simufilam in the U.S. Our Phase 2a was an open-label, multi-center, safety and pharmacokinetic study of simufilam. Thirteen (13) patients with mild-to-moderate Alzheimer’s disease, age 50-85, received 100 mg oral simufilam twice daily for 28 days. A diagnosis of Alzheimer’s disease was confirmed with Mini-Mental State Examination (MMSE) ≥ 16 and ≤ 24 and a cerebrospinal fluid (CSF) T-tau/Aβ42 ratio ≥ 0.30. Safety was assessed by ECGs, clinical labs, adverse event monitoring and physical examinations. CSF was drawn from patients before dosing started and again after 28 continuous days of dosing with simufilam. CSF samples were then analyzed for biomarkers of Alzheimer’s pathology (T-tau, P-tau, Aβ42); neurodegeneration (NfL, neurogranin); and neuroinflammation (YKL-40, IL-6, IL-1β and TNFα). A consulting biostatistician conducted an independent analysis of the data set.

A key objective of our Phase 2a study was to PTI-125,measure levels of CSF biomarkers in the brain. Key results of this study include (Figure 1):

·

Total tau (T-tau) decreased 20% (p<0.001)

·

Phosphorylated tau (P-tau) decreased 34% (p<0.0001)

·

Neurofilament light chain (NfL), a marker for neurodegeneration, decreased 22% (p<0.0001)

·

Neurogranin, a marker for cognitive decline, decreased 32% (p<0.0001)

·

Neuroinflammatory marker YKL-40, an indicator of microglial activation, decreased 9% (p<0.0001)

·

Proinflammatory Interleukin 6 (IL-6) decreased 14% (p<0.0001)

·

Proinflammatory Interleukin 1 beta (IL-1β) decreased 11% (p<0.0001)

·

Proinflammatory Tumor Necrosis Factor alpha (TNFα) decreased 5% (p<0.001)  

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·

The ratio of CSF P-tau to Aβ42, a widely accepted biochemical value of Alzheimer’s disease, improved in all patients (p<0.001)

Figure 1: Simufilam treatment reduces levels of CSF biomarkers in patients with no royalty obligationsAlzheimer’s in a Phase 2a study.

Neurogranin*

NfL*

T-tau+

P-tau181*

YKL40*

IL-6*

IL-1β*

TNFα+

Picture 5

Neurogranin* NfL* T-tau+ P-tau181* YKL40* IL-6* IL-1β* TNFα+ -32% -22% -20% -34% -9% -14% -11% -5%

Figure 1. Percent change from baseline in CSF biomarkers measured by ELISA. Eight CSF biomarkers of disease in Alzheimer’s patients were significantly reduced with simufilam treatment.  *p < 0.0001, +p < 0.001 in paired t test comparing Day 28 to any third party.

pre-dose baseline.

 

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In addition, visual line plots, which are also known as spaghetti plots, of each individual patient and each individual biomarker measurement show that all patients had a biomarker response to treatment with simufilam in our Phase 2a study (Figure 2).

Figure 2. Individual patient response to treatment with simufilam in a Phase 2a study. CSF data are plotted as pg/mL.



PTI-125DX -Picture 7

0 200 400 600 800 1000 1200 Neurogranin 0 100 200 300 400 500 600 700 800 Neurofilament Light Chain 0 2 4 6 8 10 12 Phospho-tau (T181)

a blood-based diagnosticPicture 8

0 100 200 300 400 500 Total tau Screening Day 28 0 50 100 150 200 250 300 350 400 450 A42 Screening Day 28 0 10 20 30 40 50 60 70 80 90 YKL40 Screening Day 28 0 5 10 15 20 25 IL-6 Screning Day 28 0 10 20 30 40 50 60 IL-1 Screening Day 28 0 5 10 15 20 25 30 35 40 45 TNF Screening Day 28

Figure 2. Each spaghetti plot shows change from baseline to detectDay 28 for each patient and each biomarker.

Consistent with over 10 years of basic research and pre-clinical data, we believe our Phase 2a study showed clinical evidence of simufilam’s mechanism of action and drug-target engagement, including:

·

Improvements in biomarkers of Alzheimer’s disease in CSF, plasma and lymphocytes;

·

Consistency across biomarker improvements in CSF, plasma, and lymphocytes;

·

Significant reductions (p<0.01) in both nitrated and phosphorylated forms of tau protein;

·

Evidence that each individual patient showed biomarker responses to simufilam;

·

Evidence that simufilam reversed the shape of altered filamin A in lymphocytes;

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·

Evidence that simufilam reduced levels of amyloid bound to alpha 7 nicotinic receptors in lymphocytes;

·

Early clinical validation of the drug target – altered filamin A – as a facilitator protein between amyloid beta and both neuroinflammation and tau pathology.

In December 2019, we presented data from our Phase 2a study at the 12th International Conference on Clinical Trials on Alzheimer’s Disease(CTAD 2019), a conference for the medical and scientific community held in San Diego, CA. Our Phase 2a presentation was selected as a Late Breaking Oral Communication by CTAD 2019. 

In February 2020, our Phase 2a study was published in The Journal of Prevention of Alzheimer’s Disease (JPAD), a technical journal for the research community. This peer-reviewed publication highlighted that biomarkers of Alzheimer’s disease pathology (P-tau, total tau and Aβ42), neurodegeneration (NfL and neurogranin) and neuroinflammation (YKL-40, IL-6, IL-1β and TNFα) improved significantly after 28 days of treatment with simufilam.

On July 15, 2020, we presented additional Phase 2a clinical results at the Biomarkers for Alzheimer’s Disease Summit, a virtual scientific conference. In addition to showing that SavaDx, our investigational diagnostic product candidate, could distinguish and stratify patients with Alzheimer’s disease, this presentation provided direct evidence for target engagement and for the treatment effects of simufilam.  Presenting evidence of target engagement is a crucial step in drug research because it shows that a drug candidate binds to its intended site of action in cells and confirms that treatment effects are caused by the drug hitting its target.

Cognition and function were not assessed in this small Phase 2a study. However, independent research has shown that high levels of CSF biomarkers of P-tau and total tau/Aβ42 ratio correlate with worse performance on a wide range of memory and attention tests. Conversely, we believe lowering a panel of CSF biomarkers of disease may benefit patients.

Phase 2b Clinical Study

In March 2020, we announced the completion of a double-blind, randomized, placebo-controlled, multi-center clinical study of simufilam. Sixty-four patients with mild-to-moderate Alzheimer’s disease, age 50-85, were randomized (1:1:1) to 100mg or 50 mg oral simufilam or matching placebo. Treatment was administered twice daily for 28 days. Nine U.S. study sites enrolled patients. A clinical diagnosis was confirmed with the MMSE ≥16 and ≤26 and a CSF T-tau/Aβ42 ratio ≥0.28. Safety was assessed by ECGs, clinical labs, adverse event monitoring and physical examinations.This study was substantially funded by a research grant award from NIH.

In May 2020, we announced that an outside lab with whom we had no prior work experience had generated an initial bioanalysis of CSF samples from our Phase 2b study. The data set from the initial bioanalysis showed unnaturally high variability and other problems, such as no correlation among changes in levels of biomarkers over 28 days, even in the placebo group, and different biomarkers of disease moving in opposite directions in the same patient. Importantly, we later observed no statistical correlation between levels of simufilam in plasma and CSF, further indicating an invalid analysis. Overall, we believe data from the initial bioanalysis can be interpreted as anomalous and highly improbable. With its validity in question, the initial bioanalysis serves no useful purpose. Backup CSF samples were subsequently sent to a second outside lab for bioanalysis. All bioanalyses were conducted under blinded conditions to eliminate any possibility of bias.

On September 14, 2020, we reported final positive Phase 2b clinical study results. Drug was safe and well-tolerated in this study. Simufilam significantly (P<0.05) improved an entire panel of validated biomarkers of disease in patients with Alzheimer’s disease compared to a placebo group. In addition, Alzheimer’s patients treated with simufilam showed directional improvements in validated tests of episodic memory and spatial working memory, versus patients on placebo(Effect Sizes 46-17%). Cognitive improvements correlated most strongly (R2=0.5) with decreases in levels of P-tau181 in CSF. The study achieved a 98% response rate, defined as the proportion of study participants taking simufilam who showed improvements in biomarkers. We later observed a direct correlation between levels of simufilam in plasma and CSF, which provides strong evidence of a valid analysis.Importantly, we believe these data are consistent with prior clinical and preclinical results, the drug’s mechanism of action and over 10 years of basic research.

Phase 2b results with simufilam were selected for a late-breaking oral presentation by the 13thInternational Conference onClinical Trials on Alzheimer’s Disease (CTAD 2020), whichtook place virtually November 4-7th, 2020. Members of CTAD 2020’s scientific committee select research abstracts for late-breaking, oral presentation based on medical and scientific significance, quality of data and methodology.

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The ability to improve multiple biomarkers from distinct biological pathways with one drug has never been shown before in patients with Alzheimer’s disease. Phase 2b study results are expected to be published in a peer-reviewed publication at a future date.

The Phase 2b clinical study was designed to evaluate safety, tolerability and drug effects of simufilam on biomarkers of Alzheimer’s disease. The primary endpoint was improvement in biomarkers of Alzheimer’s disease from baseline to Day 28. CSF was drawn from patients before dosing started and again after 28 continuous days of dosing with simufilam. CSF samples were then analyzed for biomarkers of Alzheimer’s pathology (T-tau, P-tau, Aβ42); neurodegeneration (NfL, neurogranin); and neuroinflammation (YKL-40, IL-6, sTREM2, HMGB1) and BBB integrity (IgG, albumin). A consultingbiostatistician conducted an independentanalysis of the data set.

A further objective of this study was to measure drug effects on cognition.Patients were tested at baseline and again on Day 28. Changes in episodic memory and spatial working memory were assessed on CANTAB, a validated, computer-based battery of tests. CANTAB is designed to measure cognitive skills regardless of the subject’s language skills, speed, gender or education.

Key biomarker results include the following (all p-values versus placebo) (Figure 3):

·

Core markers of Alzheimer’s pathology are total tau (T-tau), phosphorylated tau (P-tau181), and amyloid beta42 (Aβ42). In Alzheimer’s, tau and P-tau levels are elevated and Aβ42 is low.

o

T-tau decreased 15% (p<0.01) for patients in the 50 mg drug group.

o

T-tau decreased 18% (p<0.01) for patients in the 100 mg drug group.

o

P-tau decreased 8% (p<0.01) for patients in the 50 mg drug group.

o

P-tau decreased 11% (p<0.01) for patients in the 100 mg drug group.

o

42 increased 17% (p<0.01) for patients in the 50 mg drug group.

o

42 increased 14% (p<0.01) for patients in the 100 mg drug group.

·

Elevated CSF levels of two proteins, Neurogranin (Ng) and Neurofilament Light Chain (NfL) indicate neurodegeneration.

o

Ng decreased 36% (p<0.01) for patients in the 50 mg drug group.

o

Ng decreased 43% (p<0.01) for patients in the 100 mg drug group.

o

NfL decreased 28% (p<0.05) for patients in the 50 mg drug group.

o

NfL decreased 34% (p<0.01) for patients in the 100 mg drug group.

·

Proinflammatory IL-6 (Interleukin 6) is produced in response to tissue stress and injury.

o

IL-6 decreased 10% (p<0.01) for patients in the 50 mg drug group.

o

IL-6 decreased 11% (p<0.01) for patients in the 100 mg drug group.

·

Elevated levels of neuroinflammatory marker YKL-40 indicate microglial activation.

o

YKL-40 decreased 10% (p<0.01) for patients in the 50 mg drug group.

o

YKL-40 decreased 12% (p<0.01) for patients in the 100 mg drug group.

·

sTREM2 is a neuroinflammation biomarker that has commanded substantial recent attention from researchersfor its role in Alzheimer’s disease and frontotemporal dementia.

o

sTREM2 decreased 43% (p<0.01)for patients in the 50 mg drug group.

o

sTREM2decreased 46% (P<0.01) forpatients in the 100 mg drug group.

·

Simufilam Significantly Reduced Levels of HMGB1 in Cerebrospinal Fluid (CSF).

o

HMGB1 decreased 33% (p<0.001) in patients treated with 50 mg simufilam

o

HMGB1 decreased 32% (p<0.001) in patients treated with 100 mg simufilam    

·

Simufilam Significantly Improved the Integrity of the Blood-brain Barrier (BBB).

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o

CSF IgG decreased 30% (p<0.05) in patients treated with 50 mg simufilam

o

CSF IgG decreased 30% (p<0.05) in patients treated with 100 mg simufilam

o

CSF albumin decreased 15% (p<0.05) in patients treated with 50 mg simufilam

o

CSF albumin decreased 28% (p<0.05) in patients treated with 100 mg simufilam

·

Simufilam Improved the Albumin Ratio, a Test of Blood-brain Barrier (BBB) Permeability:

o

BBB permeability can be clinically evaluated by comparing levels of albumin in CSF and plasma. The albumin ratio is a test for BBB permeability because albumin protein is not synthesized in CSF. Hence, albumin in CSF necessarily comes from plasma through the BBB. The albumin ratio is frequently elevated in patients with dementia and various other disorders.

o

In the Phase 2b study, the albumin ratio was unchanged for Alzheimer’s patients on placebo. The albumin ratio improved by approximately 5 and 7 points for patients treated with simufilam, 50 mg and 100 mg, respectively, over 28 days.

Changes in the Albumin Ratio by Treatment Group



 

 

 



 

 

 

Treatment

Day 0

Day 28

Change-Day 0 to 28

Placebo

24

24

No change

50 mg simufilam

25

20

-  20%

100 mg simufilam

25

18

-  28%

Figure 3.Simufilam improved levels of CSF biomarkers in patients with Alzheimer’s in a Phase 2b study.

Picture 1

% Change  Baseline to Day 28 -55% -45% -35% -25% -15% -5% 5% 15% 25% A42 T-tau P-tau181 Nurogranin NfL YKL-40 IL-6 sTREM2 HMGB1 Albumin IgG Placebo 50 mg 100 mg +p < 0.05 p < 0.01, # p < 0.001, p < 0.0001 vs. placebo

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Figure 4.  Study response rate, defined as the proportion of study participants taking simufilam who showed improvements in biomarkers.

Picture 2

% of Patients Who Responded to Simufilam on CSF Biomarkets Tau/p- Tau Biomarkers 98% Biomarkers of Neuroinflammation 98% Biomarkers of Neurodegeneration 98% Biomarkers of BBB Integrity 95% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Key cognition results. Only directional trends are observed, due to limitations around study size (N=64). (Figure 5):

·

Alzheimer’s patients in both drug groups showed directional improvements on tests of episodic memory and spatial memory after 28 days of treatment, versus patients on placebo. Effect Sizes were 46-17% versus placebo.

·

Episodic memory improved by -5.7 (lower score is better) for Alzheimer’s patients in the 50 mg drug group, versus -1.5 for patients on placebo.

·

Episodic memory improved by -4.3 (lower score is better) for Alzheimer’s patients in the 100 mg drug group, versus -1.5 for patients on placebo.

·

Spatial memory improved by -1.6 (lower score is better) for Alzheimer’s patients in the 50 mg drug group, versus -0.4 for patients on placebo.

·

Spatial memory improved by -3.3 (lower score is better) for Alzheimer’s patients in the 100 mg drug group, versus -0.4 for patients on placebo.

·

Improvements in cognition correlated most strongly (statistical R2=0.5) with decreases in CSF P-tau181, a biomarker that, when elevated, leads to tangles in the brain. Simufilam decreased brain levels of Ptau-181 by 8-11%, versus placebo.

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Figure 5.  Episodic Memory and Spatial Working Memory Improvements

Picture 11

Change in Errors Baseline to Day 28 -6.0 -5.0 -4.0 -3.0 -2.0 -1.0 0.0 Placebo -1.5 50 mg -5.7 100 mg -4.5 37% Effect Size 2% Effect Size  -3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0.0 Placebo -0.41 50 mg -1.65 100 mg -3.33

Figure 6. Improvements in cognition correlated most strongly (statistical R2=0.5) with decreases in CSF P-tau181.

Picture 9

Cognition/Biomarker Correlations (R2) 1 YKL NfL T-tau Albumin II-6 P-tau181 0.30 0.36 0.37 0.37 0.41 0.48

Open-label Extension Clinical Study

In  March 2020, we announced the initiation of an open-label extension study to evaluate simufilam in patients with Alzheimer’s disease. This open-label, multi-center, extension study is designed to monitor the long-term safety and tolerability of simufilam at 100 mg twice-daily for 12 months. The study’s target enrollment is approximately 150 patients with mild-to-moderate Alzheimer’s disease, including patients from a prior study of simufilam.  

ADAS-Cog-11 is being used to assess cognitive symptoms of dementia in patients enrolled in the open-label study. The NPI is being used to assess the presence and severity of Alzheimer’s related behavior.

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On February 2, 2021, we announced results of the first of two preplanned interim analysis from our open-label study of simufilam. The first interim analysis summarized clinical data at the midway point of enrollment, i.e., the first 50 patients who have completed at least 6 months of drug treatment. Patients’ cognition and behavior scores both improved following six months of simufilam treatment, with no safety issues. In the study, six months of simufilam treatment improved cognition scores by 1.6 points on ADAS-Cog11, a 10% mean improvement from baseline to month 6. In these same patients, simufilam also improved dementia-related behavior, such as anxiety, delusions and agitation, by 1.3 points on the Neuropsychiatric Inventory, a 29% mean improvement from baseline to month 6. The safety profile of simufilam in the interim analysis was consistent with prior human studies. There were no drug-related serious adverse events. Adverse events were mild and transient. Based on these results and other factors, we announced significant changes to the design of our open-label study, including a 50% increase in the enrollment target and other potential enhancements to the study design. This study has approximately 80 patients enrolled as of February 2021.

On February 8, 2021, we announced additional changes to our open-label program with simufilam in Alzheimer’s disease. We plan to initiate a 6-month, double-blind, randomized, placebo-controlled study in patients with Alzheimer’s disease who complete at least one year of open-label treatment with simufilam. This is a cognition maintenance study (CMS), in which patients who complete one year of open-label treatment will subsequently be randomized (1:1) to simufilam or placebo for six months. The CMS is designed to compare simufilam’s effects on cognition and behavior in patients who continue with drug treatment versus those who discontinue drug treatment.

Figure 7.  Cognition Maintenance Study Design

Picture 10

SCREEN Ongoing Open-label Study simufilam 100 mg BID (n=up to 150) Month 12 Cognition study completers Radomization 1:1 COGNITION MAINTENANCE STUDY Double-blind, randomized, placebo-controlled study simufilam 100 mg BID placebo Month 6 cognition study completers Open-labe Treatment simufilam 100 mg BID Month 0 Month 12 Month 0 Month 6

We expect to announce results of a second interim analysis on safety and cognition for this study in the mid-2021, after approximately 50 patients have completed at least 12 months of drug treatment.  To our knowledge, no drug for Alzheimer’s has shown an ability to stabilize cognition in patients, much less restore loss cognition, beyond a few months.

Phase 3 Clinical Strategy



We held an end-of-phase 2 (EOP2) meeting with FDA in January 2021. An EOP2 meeting is a critical regulatory milestone to ensure that meaningful data will be generated during a Phase 3 clinical program. Our objectives for the EOP2 meeting were to gain agreement around proposed Phase 3 clinical plans and protocols, and to identify outstanding requirements around safety, product development or manufacturing, or any other information needed to support the statutory requirements for a 505(b)(1) NDA submission and marketing approval of simufilam for the treatment of mild-to-moderate Alzheimer’s disease.

Official EOP2 meeting minutes were issued by the FDA in February 2021. We believe these indicate FDA and Company agreement on key elements of a pivotal Phase 3 clinical program in support of a New Drug Application (NDA) filing for simufilam in Alzheimer’s disease. Agreements reached during the EOP2 meeting show a clear path forward for advancing simufilam into a pivotal Phase 3 program, which we plan to initiate in the second half of 2021.

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Official EOP2 meeting minutes also indicate agreement that the use of separate clinical scales to assess cognition (ADAS-cog1) and function (ADCS-ADL2) are developing innovative technologyappropriate co-primary endpoints of efficacy. A clinical scale that combines cognition and function, such as iADRS3, is a secondary efficacy endpoint. 

Our pivotal Phase 3 clinical program consists of two double-blind, randomized, placebo-controlled studies, each described below.

Our first Phase 3 study is designed to diagnose ADevaluate disease-modifying effects of simufilam in Alzheimer’s disease. The goal is to demonstrate a slower rate of decline in cognition and health function in subjects treated with simufilam compared to placebo.

Details of the first Phase 3 study include:

Ø

Approximately 1,000 subjects with mild-to-moderate Alzheimer’s disease to be enrolled.

Ø

Subjects to be randomized (1:1:1) to simufilam 100 mg, 50 mg, or placebo BID.

Ø

Subjects to be treated for 18 months.

Ø

The co-primary efficacy endpoints are ADAS-Cog, a cognitive scale, and ADCS-ADL, a functional scale; both are widely used clinical tools in trials of Alzheimer’s disease.

Ø

A secondary efficacy endpoint is iADRS, a widely used clinical tool in trials of Alzheimer’s disease that combines cognitive and functional scores from ADAS-Cog & ADCS-ADL.

Ø

Other secondary endpoints include biomarkers of disease and NPI4, a clinical tool that assesses the presence and severity of dementia-related behavior.

Ø

We plan to initiate the first pivotal Phase 3 study approximately Q3 2021.

Our second Phase 3 study is designed to evaluate symptomatic improvement in Alzheimer’s disease. The goal is to demonstrate improved cognition and health function in subjects treated with simufilam compared to placebo.

Details of the second Phase 3 study include:

Ø

Approximately 600 subjects with mild-to-moderate Alzheimer’s disease to be enrolled.

Ø

Subjects to be randomized (1:1) to simufilam 100 mg or placebo BID.

Ø

Subjects to be treated for 9 to 12 months.

Ø

The co-primary efficacy endpoints are ADAS-Cog, a cognitive scale, and ADCS-ADL, a functional scale; both are widely used clinical tools in trials of Alzheimer’s disease.

Ø

A secondary efficacy endpoint is iADRS, a widely used clinical tool in trials of Alzheimer’s disease that combines cognitive and functional scores from ADAS-Cog & ADCS-ADL.

Ø

Other secondary endpoints include biomarkers of disease and NPI, a clinical tool that assesses the presence and severity of dementia-related behavior.

Ø

We plan to initiate the second pivotal Phase 3 study approximately Q4 2021.

_____________________________

1 ADAS-Cog = The Alzheimer’s Disease Assessment Scale – Cognitive Subscale, a measure of cognition

2 ADCS-ADL = Alzheimer’s Disease Cooperative Study – Activities of Daily Living, a measure of health function

3 iADRS = integrated Alzheimer’s Disease Rating Scale, a composite measure of cognition and health function

4 Neuropsychiatric Inventory (NPI)

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Figure 8.  Phase 3 Program Design

Picture 4

FDA has provided further flexibility to us by agreeing to review the final version of each protocol for the two Phase 3 studies, and to conduct a Special Protocol Assessment (SPA) for each Phase 3 study. An SPA is a formal regulatory procedure that confirms certain critical details of a Phase 3 study protocol, such as the statistical analyses, meet FDA’s standards of approvability.

SavaDx

Our diagnostic effort, called SavaDx, is an early-stage program focused on detecting Alzheimer’s disease from a small sample of blood, possibly years before the overt appearance of clinical symptoms. The goal of SavaDx, an early-stage product candidate, is to make the detection of Alzheimer’s disease as simple as getting a blood test. We believe finding a way to diagnose AD at an early-stage is vitally important.  A blood test may help detect AD before symptoms occur, or rule out other possible causes of memory problems, or might be usedare developing SavaDx as a biomarkerfast, accurate and quantitative blood-based biomarker/diagnostic to measure the efficacy of drug candidates during clinical trials, or to define new potential therapies for AD.

Our diagnostic technology is related to PTI-125, our clinical-stage drug candidate for AD, whose underlying science has been published in Journal of Neuroscience,  Neurobiology of Aging,  Journal of Biological Chemistry,  PLOS-Onedetect and other peer-reviewed scientific journals.  PTI-125DX is not a genetic based assay, nor does it rely on neuroimaging markers.  PTI-125DX highlights critical changes that occur in the brain by detecting biochemical markers that are found in blood during the course of themonitor Alzheimer's disease.

The PTI-125DX assay is relatively quick, easy, non-hazardous and inexpensive, and can be repeated as necessary without contraindications. If successful, we believe the data generated by PTI-125DX can be used by clinicians or algorithmsSavaDx has potential to classify patients at different stages of AD and/or to distinguish AD from other related diseases with better specificity or reliability than current methodologies.make obsolete more invasive approaches for diagnosing Alzheimer’s disease.



PTI-125DXOver the past ten years, we discovered that altered FLNA is an early-stage program.a hallmark feature of brain pathology in patients with Alzheimer’s disease. We have generated data from hundredsbelieve SavaDx, which is a complex and unique detection system for altered filamin A (FLNA), can reveal early traces of blood samples using PTI-125DX.  Results have not been published to date in order to better protect the intellectual property around this technology.disease, potentially even before the overt appearance of disease symptoms, such as memory loss. 



In September 2017, we announced a $1.8 million research grant award from the NIH for PTI-125DX.  SavaDx. The NIH's National Institute on AgingNIH awarded us this research grant following a confidential, competitive and in-depth evaluation of PTI-125DXSavaDx technology for scientific and technical merit. The researchThis technical milestone-based grant is a technical-milestone based award that will enableenables us to work collaboratively with leaders in the field to develop and test oncollect clinical samples aneeded to develop our blood-based diagnostic for AD. Alzheimer’s disease.   

A diagnostic test usually measures one or more biomarkers, which are biological indicators of disease. A deep understanding of the biology of disease is required to identify and develop a diagnostic. A valid diagnostic has certain baseline characteristics to be functional and useful for clinical practice. It must detect disease in patients and, conversely, not detect disease in healthy subjects; and it is preferably quantitative, giving some indication of severity or stage of disease. Collectively, the ability to selectively detect disease indicators can be useful to provide diagnostic information (i.e., detect the disease) or prognostic information (i.e., predict the disease or its future course).



PTI-125DX was designed by usCurrently, the most definitive method to diagnose Alzheimer’s disease is through autopsy after death, which is not particularly helpful. Methods to detect Alzheimer’s disease during its course can be expensive, invasive, subjective, risky or uncomfortable. Importantly, because of the expense and characterized by outside collaborators.  We own worldwide commercial rights to PTI-125DX and related technology, without royalty or milestone obligations to any third parties.

Strategy

Our corporate strategy has changed little over the years: to spend carefully but to keep innovation at the topinvasiveness of our agenda.  Elements of our corporate strategy include:current tests, most people are not tested until they show obvious cognitive decline.



Focus on Clinical Development Stage Products.Current approaches for diagnosing Alzheimer’s disease include measurement of amyloid-β (specifically, Aβ42), total tau (T-tau) or phosphorylated tau (P-tau) levels in CSF; structural neuroimaging techniques, including magnetic resonance imaging (MRI) or computerized tomography (CT); positron-emission tomography (PET) imaging of brain amyloid (AmyVid   We believe this focus will enable us®); and batteries of cognitive tests. Usually, a combination of more than one test is necessary to generate product revenues earlier than if we were focused on early-stage researchprovide a working diagnosis. When such tests and discovery activities.

Retain Significant Rights to Our Drugs.   We currently retain worldwide commercialization rights to alltechniques are used together, the totality of our technologydata can be sensitive and drug candidates in all markets and indications, including REMOXY. In general, we intend to independently develop our drug candidates through late-stage clinical trials.

Outsource Key Functions.   We intend to continue to outsource preclinical studies, clinical trials and formulation and manufacturing activities. We believe outsourcing permits significant time savings and allows for more efficient deployment of our resources.

We also conduct basic research and development in collaboration with academic and other partners. Our research and development expenses were $7.6 million and $9.2 millionspecific for the year ended December 31, 2017detection of Alzheimer’s disease. In practice, however, such tests and 2016, respectively. Seetechniques are only used after overt symptoms of impaired memory. “Item 7 Management’s Discussion and Analysis of Financial Condition and Results of Operations” for additional details regarding our research and development activities.



 

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Our Intellectual PropertyWe believe there is a profound need for a blood-based diagnostic test for Alzheimer’s disease. A quick, simple, inexpensive test may benefit the medical community in many ways. Advantages may include confirming the presence of Alzheimer’s disease earlier, when lifestyle changes and potential therapeutics may have the most impact, or conversely, to rule out Alzheimer’s disease at such early stages. Other potential benefits include discriminating Alzheimer’s disease from other causes of dementias; helping to identify stage of Alzheimer’s disease; selection and enrollment of appropriate patients into clinical studies of experimental product candidates; and better alignment of a patient’s specific diagnosis with a targeted therapeutic. 



It is widely accepted that in Alzheimer’s disease, pathological changes in the brain occur at least 10-15 years before clinical symptoms appear. These “pre-symptomatic” changes include deposits of certain misfolded or impaired proteins in the brain. Our long-term goal with SavaDx is to identify people with Alzheimer’s disease, potentially long before clinical symptoms occur. Early detection may be critical for any intervention to cease - or at least slow down - brain damage before it is too late. Importantly, a non-invasive screen for latent Alzheimer’s disease prior to overt symptoms could be conducted as a general health screen, not just in patients at risk by family history or in patients already showing cognitive impairment. Once a disease-modifying treatment is found, early detection is likely to be critically important. Early detection and treatment may also be critical in identifying such a disease-modifying treatment, as many believe one reason for clinical study failures in Alzheimer’s disease is that treatment has routinely started too late in the course of disease to make any impact.

Moreover, with repeat measurements over time, SavaDx may provide a probability of cognitive decline or disease progression. Even if SavaDx does not provide a precise numerical cutoff value for Alzheimer’s disease, we believe it may be important to incorporate data from SavaDx into the overall diagnostic framework for neurodegeneration, and Alzheimer’s disease in particular. As with any diagnosis of disease, some people may embrace a way to detect Alzheimer’s disease long before clinical symptoms appear, while others may prefer not to know – at least until a treatment is found.

Diagnostic development program for SavaDx.

Diagnostic development differs from drug development in many important ways. As a result, diagnostic development requires substantial differences in planning, study design and study execution.

Some of the ways that diagnostic development differs from drug development include the following:

·

We may need to choose among a wider range of regulatory pathways for approval of SavaDx, depending on factors such as intended use and user, test type and complexity and role in patient-care decisions;

·

Drug studies usually deal primarily with one office within FDA, but the regulatory pathway for SavaDx may require us to consider the policies of multiple federal or state regulatory agencies and offices;

·

Unlike drug programs, statistical analysis with SavaDx does not focus on efficacy and safety endpoints. Rather, study endpoints for SavaDx will focus on sensitivity (true positives), specificity (true negatives), positive predictive value (percentage of correct positive diagnoses of known positive cases) and negative predictive value (percentage of correct negative diagnoses of known negative cases);

SavaDx is an investigational diagnostic product candidate that has not yet been reviewed by FDA. Clinical testing consists of collecting blood samples on a limited scale to validate SavaDx. Our ability to test such samples depends on multiple factors, many of which are beyond our control. For example, optimal sample collection depends on risk of sample degradation, storage requirements to preserve samples, cost of sample storage and actual vs. predicted time of assay validation.

Over the past four years, we have conducted four such rounds of early validation tests, with funding from NIH. In three blinded studies of test samples, SavaDx detected more than a 10-fold separation between Alzheimer’s patients and normal healthy control subjects (N=232 test samples). In these three proof-of-concept studies, SavaDx demonstrated nearly 100% accuracy and specificity. The three studies deployed a research grade antibody manufactured by an outside vendor. 

A fourth blinded study of SavaDx failed to generate meaningful diagnostic data. We believe the fourth study deployed a faulty research antibody sourced from an outside vendor. Commercially available research antibodies can present certain technical flaws, such as improper validation, significant batch-to-batch variations or inconsistent storage, any of which can jeopardize results of studies and experiments. For these reasons, and in order to increase consistency of quality, reliability and availability, we are now developing and validating a proprietary, fit-for-purpose, antibody system for use with SavaDx. NIH is funding the development expenses for this project. Such technical activities are on-going.

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SavaDx was selected as a keynote presentation at the Biomarkers for Alzheimer’s Disease Summit, a virtual conference, on July 15, 2020.  The Biomarkers for Alzheimer’s Disease Summit is a scientific forum dedicated to solving the challenges of developing clinically validated biomarkers to detect Alzheimer’s disease.

We are prioritizing the development of simufilam for the treatment of Alzheimer’s disease over the development of SavaDx for the detection of Alzheimer’s disease in light of our assessment of each product candidate’s ability to address unmet clinical needs, severity of disease burden, market potential, growth potential, and other factors. We expect to initiate a validation/disease specificity study of SavaDx in 2021.

The legal system for intellectual property around diagnostic methods is highly complex and uncertain. In the U.S., patent courts have struggled to define a clear means of patent eligibility for modern age diagnostics. Generally, a simple process involving correlations between blood test results and patient health is not eligible for patent claims because such processes incorporate “laws of nature”. However, different outcomes from different courts, including Federal Circuit, district court and Patent Trial and Appeal Board decisions, have continued to create a sometimes vague or conflicting legal framework for determining the eligibility of patent claims for diagnostic methods. As a result, we cannot be certain how SavaDx fits into the current U.S. legal framework for obtaining effective patent claims. Furthermore, claims for diagnostic methods can be complicated to enforce. We currently have no patents or patent applications with respect to SavaDx, and is protected in the United States by trade secrets, know-how and other proprietary rights technology.

Expansion of our science to other indications.

It is well-known that protein misfolds occur in a wide variety of biological processes and diseases. We may leverage our scientific insights in neurodegeneration and advanced tools in biochemistry, bioinformatics and imaging to expand our science to other diseases. New indications and new drug development approaches may complement our initial focus on Alzheimer’s disease. 

Pre-clinical programs are always visionary, sometimes innovative and often of high biomedical potential. However, by definition such programs are exploratory and risky. Moreover, most pre-clinical programs fail for scientific or other reasons, regardless of the amount of effort or resources that are brought to bear upon such programs. For these reasons, in general we do not intend to disclose our pre-clinical programs until such time as they become material to our pipeline of product candidates.

We own worldwide rights to our neurodegeneration program.

We own intellectual property, including patents, patent applications, technology, trade secrets and know-how in the U.S. and other countries. The protection of patents, designs, trademarks and other proprietary rights that we own or license is critical to our success and competitive position. We own or license a number of U.S. and foreign patents, patent applications and rights to patents covering our products and technology. We consider the overall protection of our patents and other intellectual property rights to be of material value and act to protect these rights from infringement.



We seek to protect our technology by, among other methods, filing and prosecuting U.S. and foreign patents and patent applications with respect to our technology and products and their uses. The focus of our patent strategy is to secure and maintain intellectual property rights to technology for our program in neurodegeneration.

Simufilam and SavaDx were both discovered and designed in-house and were characterized by our academic collaborators during research activities that were conducted from approximately 2008 to date. We own exclusive, worldwide rights to these drug assets and related technologies, without royalty obligations to any third party. Our patent protection with respect to simufilam and use of simufilam for Alzheimer’s disease and other neurodegenerative disease currently runs through 2033 and includes six issued patents and related patent filings and applications. In addition, we have patent protection with respect to simufilam for use in treating certain cancers that runs through 2034. We currently have no patents or patent applications with respect to SavaDx, and is protected in the following categoriesUnited States by trade secrets, know-how and other proprietary rights technology.

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Our Development Team

Our product development team is led by seasoned professionals with a proven track record of innovation in drug discovery and development, as well as substantial business expertise.

Our Founder and Chief Executive Officer, Remi Barbier, has over 25 years of biopharmaceutical industry experience and has led teams responsible for pioneering several pharmaceutical innovations, including abuse-deterrent drugs; the clinical development of multiple pain drugs; an innovative antibody program in cancer; and other programs in neuroscience and other therapeutics areas. Before founding Cassava Sciences (formerly known as Pain Therapeutics, Inc.), he held leadership roles and was founder or co-founder of four life science companies, three of which are now publicly traded.

Our Chief Medical Officer, Nadav Friedmann PhD, MD, has eight prior FDA drug approvals and previously served as CEO of Daiichi Pharmaceuticals USA and Head of Johnson & Johnson’s Biotechnology Research Center.

James Kupiec, MD, has two prior FDA drug approvals and previously served as VP, Global Clinical Leader for Parkinson’s Disease and Clinical Head of the Neuroscience Research Unit for Pfizer, Inc. and also held leadership roles at Sanofi and Ciba-Geigy Pharmaceuticals.

Lindsay Burns, PhD, SVP, Neuroscience, worked on the development of several product candidates in neuroscience and other therapeutics areas while at Neurex (acquired by Elan Pharmaceuticals) and Abgenix (acquired by Amgen).

Michael Zamloot, SVP of Technology Operations, has four prior FDA drug approvals and has worked in drug operations and supply chain management at Boehringer Mannheim (acquired by Roche Diagnostics), Athena Neuroscience (acquired by Elan Pharmaceuticals) and Ciba-Geigy (acquired by Novartis).

George (Ben) Thornton, PhD, SVP of Technology, has led research and development teams at Johnson & Johnson as well as translated basic science to the clinical setting at biotechnology start-ups such as GeneMedicine and Apovia.

Our management team is further supported by scientific advisors that share our business:commitment to advancing new treatments for Alzheimer’s disease. Leading experts in the field who advise us include:

·

the technology that forms the basisJeff Cummings, MD, Director of REMOXYCleveland Clinic Lou Ruvo Center for Brain Health and FENROCK, our other abuse-deterrent drug candidates;Professor of Neurotherapeutics and Drug Development, Cleveland Clinic. 

·

Hoau-Yan Wang, PhD, Tenured Medical Professor at CUNY Medical School; co-lead scientist on discovery & development of simufilam and SavaDx.

·

Steven E. Arnold, MD, Translational Neurology Head of the technologies relatedInterdisciplinary Brain Center, Massachusetts General Hospital, Harvard Medical School.  

·

Barbara Sahakian, FBA, FMedSci, Professor of Clinical Neuropsychology at the Department of Psychiatry and Medical Research Council /Wellcome Trust Behavioral and Clinical Neuroscience Institute, University of Cambridge.

·

Trevor W. Robbins, CBE FRS FMedSci, Professor of Cognitive Neuroscience at the University of Cambridge and Past President of the British Neuroscience Association.

Our Strategy

Our goal is to develop product candidates to diagnose and treat neurodegeneration, such as Alzheimer’s disease. Key elements of our business strategy to achieve this mission include:

·

building a lean company that is narrowly focused on developing innovative product candidates for Alzheimer’s disease and other areas of neurodegeneration;

·

validating our unique scientific approach with competitive research grants and publishing our scientific data in peer-reviewed journals;

·

applying our development capabilities to PTI-125advance our product candidates through clinical proof-of-concept studies and PTI-125DXbeyond;

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·

using our expertise and experience to continue to focus on discovering new indications and product candidates;candidates, validated by experimental evidence and leading experts in the field; and

·

the manufacturecontinuing to outsource preclinical studies, clinical studies and useformulation development activities in order to allow more efficient deployment of our product candidates.resources



However, we may rely on certain proprietary technologiesWe also conduct basic research and know-how thatdevelopment in collaboration with academic and other partners. Our research and development expenses were $3.1 million and $1.6 million for the year ended December 31, 2020 and 2019, respectively. These amounts are not patentable. We protectnet of significant reimbursement received from NIH. See “Item 7 Management’s Discussion and Analysis of Financial Condition and Results of Operations” for additional details regarding our proprietary information, in part, by the use of confidentiality agreements with our employees, consultants,research and certain of our contractors.development activities.



We plan to prosecute and defend our patent applications, allowed patents, issued patents and proprietary information. Our competitive position and potential future revenues will depend in large part upon our ability to protect our intellectual property from challenges and to enforce our patent rights against potential infringements.Competition



Patents expire,The drug discovery and development industry is characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products. We face potential competition from many different sources, including pharmaceutical and biotechnology companies, academic institutions and governmental agencies and public and private research institutions. Any product candidates that we successfully develop and commercialize, such as simufilam or SavaDx, may compete with existing therapies and new therapies that may become available in the future.

Historically, the drug industry has attempted to treat Alzheimer’s disease by developing drugs that block the synthesis of, or remove or dis-aggregate, beta amyloid and, more recently another protein in the brain called tau. Essentially, the prevailing doctrine says amyloid must be cleared out of the brain. This scientific approach – known as the amyloid hypothesis - has been repeatedly tested by our competitors in late stage clinical studies using a country by country basis, atvariety of antibody backbones, epitopes, target conformations, biomarkers and in various times dependingstages of disease. While this approach may yet work, to date the amyloid hypothesis has failed to generate unambiguous therapeutic benefit in patients with Alzheimer’s disease. More recent competitors in Alzheimer’s research are focused on various factors, includingmodulating proteins in the filingbrain that have anti-inflammatory or other properties, an approach known as immunotherapy.

In contrast, our scientific approach seeks to simultaneously improve neurodegeneration and neuroinflammation. We believe improving multiple vital functions in the brain represents a new, different and crucial approach to address Alzheimer’s disease.

Regardless of scientific approach, improvements in cognition and function remains a key criterion for FDA approval of a new drug in Alzheimer’s disease, a hurdle which, to date, of corresponding patent applications. Our patentsno drug candidate has met with clear and the patents we license from third parties include the following issued U.S. Patents:  8,168,217; 8,153,152; 8,147,870;  8,133,507;  8,354,124; 8,415,401; 8,420,120; 8,974,821; 8,945,614; 8,951,556; 9,233,160; 9,517,271; 9,555,113; 9,592,204; 9,855,333; and 9,572,885.compelling clinical data.



Our issued U.S. patent for REMOXY with the longest patent term extends to March 2034. Outside the United States, our granted patent with the longest patent term for REMOXY extends to 2028. Patentscompetitors may have their term extendedsignificantly greater financial resources, an established presence in the market, expertise in research and development, manufacturing, preclinical and clinical testing, obtaining regulatory approvals and reimbursement and marketing-approved products. These competitors also compete with us in recruiting and retaining qualified scientific and technical personnel, establishing clinical study sites and patient registration for various reasons including the grant of patent term adjustments, patent term extensions,clinical studies, as well as in acquiring or supplemental protection certificates,developing technologies complementary to, or necessary for, our programs. Smaller or early-stage companies may have their term shortened for various reasons including by terminal disclaimers. Certain United States patent applicationsalso prove to be significant competitors, particularly through collaborative arrangements with large and patent applications outside the United states are pending.established companies.



In addition,The key competitive factors affecting the success of simufilam, and any other product candidates that we use a uniquedevelop to address neurodegenerative disorders, if approved, are likely to be their efficacy, safety, convenience, price, the level of generic competition, patient and complex process to manufacture REMOXY. We also protect as trade secretsphysician acceptance and the significant pharmaceutical know-howavailability of reimbursement from government and detailed knowledge of a complex supply chain to manufacture REMOXY.other third-party payors. Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are more effective, have fewer or less severe side effects, are more convenient or are less expensive than any products that we may develop.



REMOXY, REMOXY EROur competitors also may obtain FDA approval for their products more rapidly than we may obtain approval for ours. For example, Biogen, Inc., a large biopharmaceutical company, is currently seeking regulatory approval in the U.S. for aducanumab. Aducanumab is a proprietary investigational drug candidate (human monoclonal antibody) that has been intensely studied for the treatment of Alzheimer’s disease. The safety and FENROCKefficacy data with aducanumab are trademarks of Pain Therapeutics, Inc.

Formulation Agreementcomplex and subject to debate. However, aducanumab may become the first therapy since 2003 to receive FDA approval in patients with Durect Corporation

We have an exclusive, worldwide Development and License Agreement, or the Durect Agreement, with Durect to use a patented controlled-release technology that forms the basis for REMOXY.

Under the terms of the Durect Agreement, we are solely responsible for clinical development, Durect is responsible for furnishing suitable laboratory facilities, equipment and personnel during pre-clinical phases of development and we and Durect are jointly responsible for certain pre-clinical activities.  We reimburse Durect’s expenses and have made milestone payments based on the achievement of certain clinical or regulatory milestones. We paid Durect approximately $40.4 million from the inception of the Durect Agreement to December 31, 2017. We could pay another $1.5 million milestone payment to Durect under the Durect Agreement.

We are obligated to pay Durect royalties on commercial sales of REMOXY. These royalties range from 6.0% to 11.5% of net sales, depending on the volume of sales of REMOXY in a given calendar year.  There are no minimum payments, and the royalty rate resets back to 6.0% at the beginning of each calendar year.Alzheimer’s disease.



 

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In recent years, we have observed ramped-up worldwide efforts aimed at developing blood-based techniques to detect and monitor Alzheimer’s disease. The Durect Agreement terminateskey competitive factors affecting the success of SavaDx, and any other product candidates that we develop to diagnose neurodegeneration, if approved, are likely to be their measure of accuracy, such as specificity and sensitivity, as well as their convenience, patient acceptance, price and the availability of reimbursement from government and other third-party payors. Our competitors in the diagnostic area are pharmaceutical and biotechnology companies, academic institutions and governmental agencies and public and private research institutions. Despite increased research effort, the field has generally been hampered by lack of reproducibility and an unclear path on a country-by-country basis upon the later of the expiration of the lasthow to expire of the patents licensed under such agreement or a certain number of years following first commercial sale in such country. Currently, the last to expire patent covered by such agreement expires in 2034. However, such date may be extended by the issuance of any additional patents pursuant to pending patent applications. We can terminate the Durect Agreement with notice to Durect, and we and Durect can terminate such agreement under certain circumstances, including material breach and insolvency.move academic discoveries into clinical utilization.



Prior Agreements with Pfizer

Between 2005In addition to blood-based techniques to detect Alzheimer’s disease, competitors are examining the use of novel tracing agents and 2014, Pfizer paid usimaging techniques to map the course of neurodegeneration. In 2012, FDA approved Amyvid® (Eli Lilly Pharmaceuticals), which is a totalradioactive diagnostic agent for brain imaging of $290 million, including $155 millionamyloid plaque. Amyvid can rule out Alzheimer’s disease but does not confirm its presence. That is, a negative scan means little or no plaque is present; however, a positive scan does not necessarily indicate Alzheimer’s disease. In addition, Amyvid cannot be used to stage Alzheimer’s disease because some people take years to show cognitive decline after amyloid plaque develops, while other others rapidly develop advanced Alzheimer’s disease within months. Since its approval in upfront fees, $30 million in milestone payments2012, Amyvid has had modest clinical utilization due to its high cost, lack of widespread reimbursement and $105 million to reimburse expenses we incurred under the agreements we had with Pfizer. Pfizer has no further obligations to us. We have no further obligations to Pfizer, except that we will owe Pfizer a one-time payment of $200,000, payable at the time REMOXY is approved by the FDA, related to certain commercial manufacturing equipment we purchased from Pfizer.

need for specialized training. 



Manufacturing



We do not own or lease any manufacturing facilities. We outsource formulation, manufacturing and related activities to third parties. For the foreseeable future, we will continue to rely on third parties to conduct certain quality control and assurance testing, shipping or storage of our product candidates.

We currently rely on contract development and manufacturing organizations (CDMOs) for the manufacture of all our materials for preclinical and clinical studies and expect to continue to do so, and for commercial supply of any product candidates that we may develop. We currently have established relationships with several CDMOs for the manufacturing of our product candidates.

We believe our manufacturing strategy is on-track to ensure sufficient drug supply for a Phase 3 program, including both drug substance (i.e., active ingredient) and drug product (i.e., oral tablets). On March 8, 2021, we entered into an agreement with Evonik Corporation to supply large-scale, clinical-grade quantities of drug substance for simufilam. The goal is to ensure the integrity of the drug supply chain on a worldwide basis, in compliance with FDA standards.

We believe raw materials for our drug product are readily available from reliable sources. We have experienced no supply chain disruption due to COVID-19.



Our suppliers must comply with current good manufacturing practices or GMP(cGMP), enforced by the FDA and other government agencies such as the U.S. Drug Enforcement Administration, or DEA.agencies. Our suppliers are subject to unannounced inspection by regulators, including pre-approval inspections by the FDA, and the DEA, to ensure they are in strict compliance with government regulations and standards. Our suppliers may be forced to stop producing, storing, shipping or testing our drug products if they fall out of compliance with government regulations and standards.



We have no control over our suppliers’ compliance, or lack thereof, with the multitude of regulations and standards that affect our drug products. We cannot control decisions by our suppliers that affect their ability or willingness to continue to supply us on acceptable terms, or at all. 



We may not be able to replace a commercial supplier on commercially reasonable terms, or at all. Replacing any of our commercial suppliers will be expensive and time consuming. Further, if REMOXY is approved, our commercial suppliers may encounter difficulties in achieving high volumes of production to satisfy commercial demands. Failure by any of our suppliers to perform as expected could delay or prevent commercialization of REMOXY or result in shortages, cost overruns, or other problems and would materially harm our business.

Commercial supply of certain excipientsStrategic Shift Away from DurectAnalgesic Drug Development



We will relyUntil approximately 2018, our efforts in neurology drug development had focused on Durect as the sole source of certain excipients in REMOXY. Durect has limited experience manufacturing pharmaceutical products and maintaining GMP-compliant operations. A Pre-Approval Inspection, or PAI, by the FDA officials is often integralanalgesic drugs. In late 2018, we announced a strategic shift away from analgesic drugs to the FDA approval process. A PAI is an unannounced evaluation of a manufacturing or test site for readiness for commercial scale manufacturing, conformance with commitments made in an NDA and data integrity. To our knowledge, the FDA has never conducted a PAI of any Durect facility.  We do not and cannot know whether Durect’s manufacturing or test facilities could pass a PAI inspection related to REMOXY, or whether Durect has invested in the necessary systems to pass a PAI inspection.

We relyfocus exclusively on Durect to supply to us certain excipients for the REMOXY formulation. Under the Durect Agreement, these excipients are supplied to us at Durect’s cost, plus thirty (30) percent. We currently do not have a long-term commercial supply agreement in place with Durect. We expect that we and Durect will negotiate a supply agreement for these excipients. neurodegeneration.We may not be able to establish a commercial supply agreement on acceptable terms. Until a commercial supply agreement is in place with Durect, we expect to obtain excipients from Durect via individual purchase orders.

If we receive marketing approval for REMOXY, Durect may need to materially expand its manufacturing capacity. Durect may not be able to increase its manufacturing capacity for REMOXY in a timely or economic manner, or at all. Moreover,

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significant scale up of manufacturing will require additional validation studies, which are subject to the FDA review and approval.

Commercial supply of oxycodone with Noramco

We expect to rely on Noramco as the sole source of the oxycodone base used in REMOXY. We currently do not have a long-term commercial supply agreement in place with Noramco. We expect to negotiate with Noramco a commercial supply agreement to supply us with oxycodone base. We may not be able to establish a commercial supply agreement on acceptable terms, or at all. Until we have a commercial supply agreement in place with Noramco, we expect to obtain oxycodone base from Noramco via individual purchase orders.

Commercial drug supply agreement with Mallinckrodt

Our sole supplier for commercial supplies of REMOXY is Mallinkcrodt Pharmaceuticals, or Mallinckrodt. In October 2007, we and Mallinckrodt entered into a long-term supply agreement, or the Mallinckrodt Agreement when Pfizer was responsible for commercialization of REMOXY. Pfizer assigned the Mallinckrodt Agreement to us upon the termination of the Pfizer Agreements. In March 2010, we and Mallinckrodt entered into an amended and restated long-term supply agreement.  In a letter dated February 21, 2017, Mallinckrodt alleged a breach of contract because REMOXY had not yet been approved by the FDA. However, since then we and Mallinkcrodt have continued to work towards the approvability of REMOXY and commercial readiness.  We continue to rely on our agreement with Mallinkcrodt to move forward with the REMOXY program.

We expect to continue to rely on Mallinckrodt as the sole-source drug product manufacturer of REMOXY pursuant to the Mallinckrodt Agreement. In addition to drug product manufacturing, Mallinckrodt is responsible for sourcing excipients in REMOXY other than those provided by the Durect Agreement.

Commercial manufacturing and supply agreements

We will rely on third parties to conduct certain quality control and assurance testing, shipping or storage of REMOXY.



Government Regulation



Regulation by governmentalGovernment authorities in the United StatesU.S. at the federal, state and local level and in other countries isregulate, among other things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of drug and

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diagnostic products. Generally, before a significant factor innew drug or diagnostic can be marketed, considerable data demonstrating its quality, safety and efficacy and/or specificity must be obtained, organized into a format specific for each regulatory authority, submitted for review and approved by the manufactureregulatory authority.

U.S. Drug Development

In the U.S., FDA regulates drugs under the Food, Drug, and marketing of pharmaceuticalsCosmetic Act (FDCA). Both drugs and in our ongoing research and development activities. All of our products will require regulatory approval by governmental agencies prior to commercialization. In particular, human therapeutic productsdiagnostics also are subject to rigorous preclinical testingother federal, state and clinical trialslocal statutes and other pre-marketing approval requirements byregulations. The process of obtaining regulatory approvals and the FDAsubsequent compliance with appropriate federal, state, local and regulatory authorities in other countries. In the United States, various federal, and in some cases state,foreign statutes and regulations also governrequires the expenditure of substantial time and financial resources. Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process or impact the manufacturing, safety, labeling, storage, record keepingpost-market may subject an applicant to administrative or judicial sanctions. These sanctions could include, among other actions, FDA’s refusal to approve pending applications, withdrawal of an approval, a clinical hold, untitled or warning letters, product recalls or market withdrawals, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement and marketing of our products. The lengthy process of seeking required approvals and the continuing need for compliance with applicable statutes and regulations require us to spend substantial resources. Regulatory approval, when and if obtained,civil or criminal penalties. Any agency or judicial enforcement action could have a material adverse effect on us.

Product candidates must be approved by FDA before they may be limited in scope which may significantly limit the indicated uses for which our products may be marketed. Further, approved drugs, as well as their manufacturers, are subject to ongoing review and discovery of previously unknown problems with such products that may result in restrictions on their manufacture, sale or use or in their withdrawal from the market.

Applicable FDA regulations require the filing of an NDA or a Biologic License Application, or BLA and approval by the FDA prior to commercialization of any of our drug candidatescommercialized in the United States.

U.S. The Drug Approval Process

We will be required to complete several activities before we can market any of our drug candidates for human use inapproval process generally involves the United States, including:following:

 

·

Completion of extensive preclinical studies;studies in accordance with applicable regulations, including studies conducted in accordance with good laboratory practice;

·

submissionSubmission to the FDA of an IND, which must become effective before human clinical trials commence;

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·

adequate and well-controlled human clinical trials to establish the safety and efficacy of the drug candidate;studies may begin;

·

submissionApproval by an independent institutional review board (IRB) or ethics committee before each study may be initiated;

·

Performance of adequate and well-controlled human clinical studies in accordance with applicable IND regulations, code of good clinical practice (cGCP), requirements and other clinical trial-related regulations to establish the safety and efficacy of the investigational product for each proposed indication;

·

Submission to FDA of an NDA;

·

A determination by FDA within 60 days of its receipt of an NDA to accept the filing for review;

·

Satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities where the drug will be produced to assess compliance with cGMP, requirements to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;

·

Potential FDA audit of the preclinical study and/or clinical study sites that generated the data in support of the NDA;

·

FDA review and approval of the NDA, including consideration of the views of any FDA advisory committee, prior to any commercial marketing or sale of the drug in the U.S.; and

·

FDA approval ofCompliance with any post-approval requirements, including the NDA priorpotential requirement to any commercial sale or shipment of the drug.conduct post-approval studies.



The data required to support an NDA are generated in two distinct developmental stages: preclinical and clinical. The preclinical and clinical testing and approval process requires substantial time, effort and financial resources, and we cannot be certain that any approvals for any future product candidates will be granted on a timely basis, or at all.

Preclinical testsStudies and IND

The preclinical developmental stage generally involves laboratory evaluations of drug chemistry, formulation and stability, as well as studies to evaluate toxicity in animals, which support subsequent clinical testing. As sponsor, we must submit the results of the preclinical studies, together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol, to FDA as part of the IND. An IND is a request for authorization from FDA to administer an investigational product to humans and must become effective before human clinical studies may begin.

Preclinical studies include laboratory evaluation of product chemistry and formulation, as well asin vitro and animal studies to assess the potential safetyfor adverse events and in some cases to establish a rationale for therapeutic use. The conduct of the product. Preclinical safety testspreclinical studies is subject to federal regulations and requirements, including cGCP regulations for safety/toxicology studies. An IND sponsor must be conducted by laboratories that comply with the FDA regulations regarding Good Laboratory Practice. We submittedsubmit the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans for clinical studies, among other things, to the FDA as part of our INDs prior to commencingan IND. Some long-term preclinical testing, such as long-term toxicity tests, animal tests of reproductive adverse events and carcinogenicity, may

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continue after the IND is submitted. An IND automatically becomes effective 30 days after receipt by FDA, unless before that time FDA raises concerns or questions about any aspect of the program. In such a case, the IND sponsor and FDA must resolve any outstanding concerns before the clinical trials. We may be required to conduct additional toxicology studies.study can begin.



Based on preclinical testing, an IND is filed withClinical Studies

The clinical stage of development involves the FDA to begin human testingadministration of the druginvestigational product to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the study sponsor’s control, in accordance with cGCP requirements, which include the United States. The IND becomes effective if not rejectedrequirement that all research subjects provide their informed consent for their participation in any clinical trial. Clinical studies are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters to be used to monitor subject safety and assess efficacy. Each protocol, and any subsequent amendments to the protocol, must be submitted to FDA as part of the IND. Furthermore, each clinical study must be reviewed and approved by an IRB for each institution at which the FDA within 30 days. The IND must indicate the results of previous experiments, how, where and by whom the new clinical trialsstudy will be conducted to ensure that the chemical structurerisks to individuals participating in the clinical studies are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the informed consent form that must be provided to each clinical study subject or his or her legal representative and must monitor the clinical study until completed. There also are requirements governing the reporting of ongoing clinical studies and completed clinical study results to public registries.

A  sponsor who wishes to conduct a clinical study outside of the compound,U.S. may, but need not, obtain FDA authorization to conduct the method by which itclinical study under an IND. If a foreign clinical study is believednot conducted under an IND, the sponsor may submit data from the clinical study to workFDA in support of an NDA. The FDA may accept a well-designed and well-conducted foreign clinical study not conducted under an IND if the human body, any toxic effects of the compound found in the animal studies and how the compound is manufactured. All clinical trials must bestudy was conducted in accordance with Good cGCP requirements and FDA is able to validate the data through an onsite inspection if deemed necessary. In 2020 we did not conduct any clinical studies outside of the U.S. We plan to launch clinical sites in Canada in 2021 and may perform additional clinical studies outside of the U.S. in the future.

Clinical Practice. In addition, an Institutional Review Board, or IRB,studies in the U.S. generally comprised of physicians at the hospital or clinic where the proposedare conducted in three sequential phases, known as Phase 1, Phase 2 and Phase 3, and may overlap.

·

Phase 1 clinical studies generally involve a small number of healthy volunteers or disease-affected patients who are initially exposed to a single dose and then multiple doses of the product candidate. The primary purpose of these clinical studies is to assess the metabolism, pharmacologic action, tolerability and safety of a drug candidate.

·

Phase 2 clinical studies involve studies in disease-affected patients to determine the proper dose required to produce the desired benefits. At the same time, safety and further pharmacokinetic and pharmacodynamic information is collected, possible adverse effects and safety risks are identified, and a preliminary evaluation of efficacy may be observed.

·

Phase 3 clinical studies generally involve many patients at multiple sites and are designed to provide the data necessary to demonstrate the effectiveness of the product for its intended use, its safety in use and to establish the overall benefit/risk relationship of the product and provide an adequate basis for product approval. These studies may include comparisons with placebo and/or other comparator treatments. The duration of treatment is often extended to mimic the actual use of a product during marketing.

Post-approval studies, sometimes referred to as Phase 4 clinical trials willstudies, may be conducted must review and approveafter initial marketing approval. These studies are used to gain additional experience from the IND. The IRB also continues to monitortreatment of patients in the intended therapeutic indication. In certain instances, FDA may mandate the performance of Phase 4 clinical trial. We must submit progressstudies as a condition of approval of an NDA.

Progress reports detailing the results of the clinical trialsstudies, among other information, must be submitted at least annually to FDA. Written safety reports and the investigators for serious and unexpected adverse events, or any other findings suggesting a significant risk to humans exposed to the drug must be submitted to FDA.

Phase 1, Phase 2, and Phase 3 clinical studies may not be completed successfully within any specified period, if at all. The FDA at least annually. In addition,or the FDAsponsor may suspend or terminate a clinical study at any time duringon various grounds, including a finding that the 30-day periodresearch subjects or at any time thereafter, impose a clinical hold on proposed or ongoing clinical trials. If the FDA imposes a clinical hold, clinical trials under the IND cannot commence or recommence without the FDA authorization and then only under terms authorized by the FDA. An FDA imposed clinical hold on an IND application can result in substantial delay and large, unforeseen expenses, and it may cancel the viability of developing a new drug candidate in the United States.

Clinical trials are typically conducted in three sequential phases that may overlap. Phase I clinical trials typically study a drug’s safety profile and may include the safe dosage range. Phase I clinical trials also determine how a drug is absorbed, distributed, metabolized and excreted by the body, and the duration of its action. In addition, we may, to the extent feasible, assess early indicators of a drug’s efficacy in our Phase I clinical trials. In Phase II clinical trials, controlled studies are conducted on volunteer patients with the targeted disease or condition. The primary purpose of these tests is to evaluate the effectiveness of the drug on the volunteer patients as well as to determine a drug’s side effect profile. These clinical trials may be conducted concurrently with Phase I clinical trials. In addition, Phase I/II clinical trials may be conducted to evaluate not only the efficacy of the drug on the patient population, but also its safety. During Phase III clinical trials, the drug is studied in an expanded patient population and in multiple sites. Physicians monitor the patients to determine efficacy and to observe and report adverse events that may result from use of the drug.

Our clinical trials are designed to produce clinical information about how our drugs perform compared to placebo or compared to existing drugs where appropriate. We have designed most Phase II and Phase III clinical trials to date as randomized, double-blind, placebo-controlled, dose-ranging studies. A randomized clinical trial is one in which patients are randomly assigned to the various study treatment arms. A double-blind clinical trial is one in which the patient, the physician and our trial monitor are unaware if the patient is receiving placebo or study drug in order to preserve the integrity of the clinical trial and reduce bias. A placebo-controlled clinical trial is one in which a subset of patients is purposefully given inactive medication.

We may not successfully complete Phase I, Phase II or Phase III clinical trials within any specified time period, or at all, with respect to any of our drug candidates. Furthermore, we or the FDA may suspend clinical trials at any time in response to concerns that participants arebeing exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical study at its institution if the clinical study is not being conducted in accordance with the IRB’s

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requirements or if the drug has been associated with unexpected serious harm to patients. Additionally, some clinical studies are overseen by an independent group of qualified experts organized by the clinical study sponsor, known as a data safety monitoring board or committee. This group provides authorization for whether a study may move forward at designated check-points based on access to certain data from the trial. Concurrent with clinical studies, companies usually complete additional animal studies and must develop additional information about the chemistry and physical characteristics of the drug as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the product and, among other things, companies must develop methods for testing the identity, strength, quality and purity of the final product. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that our product candidates do not undergo unacceptable deterioration over their shelf life.



After theNDA Review Process

Following completion of the clinical trials, if therestudies, data is substantial evidence thatanalyzed to assess whether the druginvestigational product is safe and effective for the proposed indicated use or uses. The results of preclinical studies and clinical studies are then submitted to FDA as part of an NDA, along with proposed labeling, chemistry and manufacturing information to ensure product quality and other relevant data. In short, the NDA is a request for approval to market a drug for one or more specified indication and must contain proof of safety and efficacy for a drug’s purity and potency. The application may include both negative and ambiguous results of preclinical studies and clinical studies, as well as positive findings. Data may come from company-sponsored clinical studies intended to test the safety and efficacy of a product’s use or from several alternative sources, including studies initiated by investigators. To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and efficacy of the investigational product to the satisfaction of FDA. FDA approval of an NDA must be obtained before a drug may be marketed in the U.S.

Under the Prescription Drug User Fee Act (PDUFA), as amended, each NDA must be accompanied by a user fee. FDA adjusts the PDUFA user fees on an annual basis. According to FDA’s fiscal year 2021 fee schedule, effective through September 30, 2021, the user fee for an application requiring clinical data, such as an NDA, is filed with the FDA. The NDA must contain allapproximately $2.9 million. Fee waivers or reductions are available in certain circumstances, including a waiver of the informationapplication fee for the first application filed by a small business. Additionally, no user fees are assessed on NDAs for products designated as orphan drugs, unless the drug gathered to that date, including data from the clinical trials. NDAs often exceed 100,000 pages in length.product also includes a non-orphan indication.



The FDA reviews all submitted NDAs before it accepts them for filing and may request additional information beforerather than accept the NDA for filing. The FDA must decide on accepting an NDA. In such an event, the NDA must be resubmitted with the additional information and, again, is subject to review before filing.for filing within 60 days of receipt. Once the submission is accepted for filing, the FDA begins an in-depth review of the NDA. Under the Federal Food, Druggoals and Cosmetic Act,policies agreed to by FDA under PDUFA, FDA has 10 months, from the FDA reviews thefiling date, in which to complete its initial review of a new molecular-entity NDA and respondsrespond to the applicant.applicant, and six months from the filing date of a new molecular-entity NDA designated for priority review. The FDA does not always meet its PDUFA goal dates for standard and priority NDAs, and the review process is typicallyoften extended for significant amounts of time by the FDA’sFDA requests for additional information or clarification regarding information already provided in the submission.

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clarification.



ItBefore approving an NDA, FDA may conduct a pre-approval inspection of the manufacturing facilities for the new product to determine whether they comply with cGMP requirements. The FDA will not approve the product unless it determines that the manufacturing processes and facilities fully comply with cGMP requirements and are adequate to assure consistent production of the product within required specifications. The FDA also may audit data from clinical studies to ensure compliance with cGCP requirements. Additionally, FDA may refer applications for novel product candidates which present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions, if any. The FDA is not bound by recommendations of an advisory committee, but it considers such recommendations when making decisions on approval. The FDA policy to convene an expert Advisory Committee meetinglikely will reanalyze the clinical study data, which could result in extensive discussions between FDA and the applicant during the review cycle for opioid drug products.  The purpose ofprocess. After FDA evaluates an Advisory Committee is to provide third-party input on key regulatory decisions, including approval and labeling of abuse-deterrent products, and whether the totality of the data submitted by a sponsor is sufficient to support marketing approval in the United States and labeling of the product with claims on abuse-deterrence.  Advisory Committee meetings are non-binding, that is, the FDA is not legally bound to follow any recommendation, vote or input of an Advisory Committee on any matter.

If the FDA’s evaluations of the NDA, and the manufacturing facilities are favorable, the FDA mayit will issue either a CRL indicating either an approval letter or may identify conditions that must be met in order to secure final approval of the NDA. When and if those conditions have been met to the FDA’s satisfaction, the FDA will issue ana Complete Response Letter (CRL). An approval letter authorizingauthorizes commercial marketing of the drug with specific prescribing information for certainspecific indications. If theA CRL indicates that FDA’s evaluationreview of the application is complete and the application cannot be approved in its present form. A CRL usually describes the specific deficiencies in the NDA submission identified by FDA. The CRL may require additional clinical data, additional pivotal Phase 3 clinical trial(s) and/or manufacturing facilitiesother significant and time-consuming requirements related to clinical studies, preclinical studies or manufacturing. If a CRL is not favorable,issued, the applicant may either resubmit the NDA, addressing all the deficiencies identified in the CRL, or withdraw the application. Even if such data and information are submitted, FDA may refuse to approvedecide that the NDA or issue adoes not approvable letter.satisfy the criteria for

 

If the FDA approves the NDA, the drug becomes available for physicians to prescribe. Periodic reports must be submitted to the FDA, including descriptions of any reported adverse reactions. The27


approval. Data obtained from clinical studies are not always conclusive and FDA may request additional post-marketing studies, or Phase IV clinical trials, to evaluate long-term effects ofinterpret data differently than we interpret the approved drug.

Risk Evaluation and Mitigation Strategy (REMS) 

The FDA requires a Risk Evaluation and Mitigation Strategy, or REMS, as a condition of the approval of an NDA or after approval to ensure that the benefits of a drug outweigh its risks. In determining whether a REMS is necessary, the FDA considers the size of the population likely to use the drug, the seriousness of the disease or condition to be treated, the expected benefit of the drug, the duration of treatment, the seriousness of known or potential adverse events, and whether the drug is a new molecular entity.  If the FDA determines a REMS is necessary for a new drug, the drug sponsor must submit a proposed REMS plan as part of its NDA prior to approval. A REMS for a newly approved drug can include medication guides, communication plans for healthcare professionals, and Elements To Assure Safe Use, or ETASU. ETASU can include, but are not limited to, special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring, and the use of patient registries. In addition, the REMS must include a timetable to periodically assess the strategy, at a minimum, at 18 months, three years, and seven years after the REMS approval. The requirement for a REMS can materially affect the potential market and profitability of a drug.

The FDA has initiated efforts to develop a standardized REMS for opioid medications to ensure their safe use.  In July 2012, the FDA approved a class‑wide REMS for extended‑release formulations of oxycodone. Manufacturers subject to this class‑wide REMS must work together to implement the REMS as part of a single shared system to reduce the burden of the REMS on the healthcare system. The central component of the extended release/long acting opioid REMS program is an education program for prescribers and patients.  REMS include a Medication Guide available for distribution to patients who are dispensed the drug, as well as ETASU. ETASU include training for healthcare professionals who prescribe the drug; information provided to prescribers that they can use to educate patients in the safe use, storage, and disposal of opioids; and information provided to prescribers of the existence of the REMS and the need to successfully complete the necessary training. Prescriber training required as part of the REMS is conducted by accredited, independent continuing education providers, without cost to healthcare professionals, under unrestricted grants funded by opioid analgesic manufacturers. Moreover, REMS assessments must be submitted on an annual basis to assess the extent to which ETASU are meeting the goals of the REMS and whether the goals or elements should be modified. 

same data.



Advertising and Promotion 



The FDA and other federal regulatory agencies closely regulate the marketing and promotion of drugs through, among other things, standards and regulations for direct‑to‑consumer advertising, communications regarding unapproved uses, industry‑sponsored scientific and educational activities, and promotional activities involving the Internet. Our lead drug candidate, REMOXY, cannotNone of our product candidates can be commercially promoted before receiving FDA approval. After approval, product promotion can include only those claims relating to safety and effectiveness that are consistent with the labeling approved by the FDA. Healthcare providers are permitted to prescribe drugs for “off‑label” uses — that is, uses not approved by the FDA and therefore not described in the drug’s labeling — because the FDA does not regulate the practice of medicine. However, FDA

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regulations impose stringent restrictions on manufacturers’ communications regarding off‑label uses. Failure to comply with applicable FDA requirements and restrictions in this area may subject us to adverse publicity and enforcement action by the FDA, the U.S. Department of Justice, or the Office of the Inspector General of the HHS,Health and Human Services, as well as state authorities. This could subject us to a range of penalties that could have a significant commercial impact, including civil and criminal fines and agreements that materially restrict the manner in which we promote or distribute REMOXY.our product candidates.



Post‑Approval Requirements



Once an NDAAfter a product candidate receives regulatory approval, it is approved, REMOXY will beoften subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to drug listing and registration, recordkeeping, periodic reporting, product sampling and distribution, adverse event reporting and advertising, marketing and promotion restrictions.



Adverse event reporting and submission of periodic reports is required following FDA approval of an NDA. The FDA also may require post‑market testing, known as Phase 4 testing, REMS, and surveillance to monitor the effects of an approved product, or the FDA may place conditions on an approval that could restrict the distribution or use of the product. In addition, quality control, drug manufacture, packaging, and labeling procedures must continue to conform to Current Good Manufacturing Practices (cGMPs)cGMP after approval. Drug manufacturers and certain of their subcontractors are required to register their establishments with the FDA and certain state agencies. Registration subjects entities tomay result in periodic announced or unannounced inspections by the FDA or these state agencies, during which the agency inspects manufacturing facilities to assess compliance with cGMPs.cGMP. Accordingly, manufacturers must continue to expend time, money, and effort in the areas of production and quality control to maintain compliance with cGMPs.cGMP. Regulatory authorities may withdraw product approvals or request product recalls if a company fails to comply with regulatory standards, if it encounters problems following initial marketing, or if previously unrecognized problems are subsequently discovered. In addition, other regulatory actions may be taken,aken, including, among other things, warning letters, the seizure of products, injunctions, consent decrees placing significant restrictions on or suspending manufacturing operations, refusal to approve pending applications or supplements to approved applications, civil penalties, and criminal prosecution.



The FDA may require post‑approval clinical studies and clinical trials ifto help assure continued safety or effectiveness of the FDA finds that scientific data, including information regarding related drugs, deem it appropriate. The purpose of such studies would be to assess a known serious risk or signals of serious risk related to the drug or to identify an unexpected serious risk when available data indicate the potential for a serious risk.approved drug. The FDA may also require a labeling change if it becomes aware of new safety information that it believes should be included in the labeling of a drug.



The Hatch‑Waxman Amendments 



Orange Book Listing 



In seeking approval for REMOXYour product candidates through an NDA, we will be required to list with the FDA each patent whose claims cover the drug product. Upon receiving regulatory approval, of REMOXY, each of the patents listed in the application for this drug is then published in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the “Orange Book”. Drugs listed in the Orange Book can, in turn, be cited by potential generic competitors in support of approval of an abbreviated NDA, or ANDA. An ANDA provides for marketing of a drug product that has the same active ingredient in the same strengths and dosage form as the listed drug and has been shown through bioequivalence testing to be therapeutically equivalent to the listed drug. Other than the requirement for bioequivalence testing, ANDA applicants are not required to conduct, or submit results of, preclinical or clinical tests to prove the safety or efficacy of their drug product. However, in November 2017, the FDA issued final guidance on the regulatory pathway for generic abuse‑deterrent opioid products.  Among other requirements, the new FDA guidance emphasizes that sponsors of generic abuse-deterrent oxycodone must ensure that a generic opioid drug is no less abuse deterrent than the original opioid and must also evaluate all potential routes of abuse, even those routes of abuse for which a generic sponsor does not seek a label-claim.  Drugs approved in this way are commonly referred to as “generic equivalents” to the listed drug, and can often be substituted by pharmacists under prescriptions written for the original listed drug.

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The ANDA applicant is required to make certain certifications to the FDA concerning any patents listed for the approved product in the FDA’s Orange Book. Specifically, the applicant must certify that: (i) the required patent information has not

17


been filed; (ii) the listed patent has expired; (iii) the listed patent has not expired but will expire on a particular date and approval is sought after patent expiration; or (iv) the listed patent is invalid or will not be infringed by the new product. The ANDA applicant may also elect to submit a section viii statement certifying that its proposed ANDA label does not contain (or carves out) any language regarding the patented method‑of‑use rather than make certifications concerning a listed method‑of‑use patent. If the applicant does not challenge the listed patents, the ANDA application will not be approved until all the listed patents claiming the referenced product have expired.



A certification that the new product will not infringe the already approved product’s listed patents, or that such patents are invalid, is called a Paragraph IV certification. If the ANDA applicant has provided a Paragraph IV certification to the FDA, the applicant must also send notice of the Paragraph IV certification to the NDA and patent holders once the ANDA has been accepted for filing by the FDA. The NDA and patent holders may then initiate a patent infringement lawsuit in response to the notice of the Paragraph IV certification. The filing of a patent infringement lawsuit within 45 days of the receipt of a Paragraph IV certification automatically prevents the FDA from approving the ANDA until the earlier of 30 months, expiration of the patent, settlement of the lawsuit, or a decision in the infringement case that is favorable to the ANDA applicant. The ANDA application also will not be approved until any applicable non‑patent exclusivity listed in the Orange Book for the referenced product has expired.



Exclusivity

Upon NDA approval of a new chemical entity, or NCE, which is a drug that contains no active moiety that has been approved by the FDA in any other NDA, that drug receives five years of marketing exclusivity during which the FDA cannot receive any ANDA seeking approval of a generic version of that drug or any Section 505(b)(2) NDA that relies on the FDA’s findings regarding that drug. A drug may obtain a three‑year period of exclusivity for a change to the drug, such as the addition of a new indication to the labeling or a new formulation, during which the FDA cannot approve an ANDA or any Section 505(b)(2) NDA, if the supplement includes reports of new clinical trials (other than bioavailability clinical trials) essential to the approval of the supplement.

An ANDA may be submitted one year before NCE exclusivity expires if a Paragraph IV certification is filed. If there is no listed patent in the Orange Book, there may not be a Paragraph IV certification, and, thus, no ANDA may be filed before the expiration of the exclusivity period.

Section 505(b)(2) NDAs

Generally, drug products obtain FDA marketing approval pursuant to an NDA or an ANDA. A third alternative is a Section 505(b)(2) NDA, which enables the applicant to rely, in part, on data not developed by the applicant, such as the FDA’s findings of safety and efficacy in the approval of a similar product or published literature in support of its application.

Section 505(b)(2) NDAs may provide an alternate path to FDA approval for new or improved formulations or new uses of previously approved products. Section 505(b)(2) permits the filing of an NDA where at least some of the information required for approval comes from clinical trials not conducted by, or for, the applicant and for which the applicant has not obtained a right of reference. If the Section 505(b)(2) applicant can establish that reliance on the FDA’s previous findings of safety and efficacy is scientifically appropriate, it may eliminate the need to conduct certain preclinical or clinical trials of the new product. The FDA may also require companies to perform additional clinical trials or provide additional materials to support the change from the approved product. The FDA may then approve the new product candidate for all, or some, of the label indications for which the referenced product has been approved, as well as for any new indication sought by the Section 505(b)(2) applicant.

To the extent that the Section 505(b)(2) applicant is relying on the FDA’s findings of safety and effectiveness for an already approved product, the applicant is required to certify to the FDA concerning any patents listed for the approved product in the Orange Book to the same extent that an ANDA applicant would. Therefore, approval of a Section 505(b)(2) NDA can be stalled until all the listed patents claiming the referenced product have expired; until any non‑patent exclusivity, such as exclusivity for obtaining approval of a new chemical entity, listed in the Orange Book for the referenced product has expired; and, in the case of a Paragraph IV certification and subsequent patent infringement suit, until the earlier of 30 months, settlement of the lawsuit or a decision in the infringement case that is favorable to the Section 505(b)(2) applicant. In the interim period, the FDA may grant tentative approval. Tentative approval indicates that the FDA has determined that the applicant meets the standards for approval as of the date that the tentative approval is granted. Final regulatory approval can

18


only be granted if the FDA is assured that there is no new information that would affect final regulatory approval. As with traditional NDAs, a Section 505(b)(2) NDA may be eligible for three‑year marketing exclusivity, assuming the NDA includes reports of new clinical trials (other than bioavailability clinical trials) essential to the approval of the NDA.

Disclosure of Clinical TrialStudy Information 



Sponsors of clinical trialsstudies of FDA‑regulated products, including drugs, are required to register and disclose certain clinical trialstudy information. Information related to the product, patient population, phase of investigation, clinical trialstudy sites and investigators, and other aspects of the clinical trialstudy is then made public as part of the registration. Sponsors are also obligated to post certain information regarding the results of their clinical trialsstudies after completion. Disclosure of the results of these trialsstudies can be delayed until the new product or new indication being studied has been approved. Competitors may use this publicly available information to gain knowledge regarding the progress of development programs.



DEAOther Regulatory Requirements



Our lead drug candidate, REMOXY, is regulated as a controlled substance under the Controlled Substances Act, or CSA.  CSA establishes registration, security, recordkeeping, reporting, storage, distribution, importation, exportation and other requirements administered by the DEA. The DEA regulates the handling of controlled substances through a closed chain of distribution. This control extends to the equipment and raw materials used in their manufacture and packaging of REMOXY, in order to prevent loss and diversion into illicit channels of commerce. 

REMOXY, an abuse‑deterrent oral formulation of oxycodone, is listed by the DEA as a Schedule II controlled substance under the CSA. Consequently, the manufacturing, shipping, storing, selling and use of the products is subject to a high degree of regulation. Schedule II drugs are subject to the strictest requirements for registration, security, recordkeeping and reporting. Also, distribution and dispensing of these drugs are highly regulated. For example, all Schedule II drug prescriptions must be signed by a physician, physically presented to a pharmacist andWe may not be refilled without a new prescription.

Annual registration is required for any facility that manufactures, distributes, dispenses, imports or exports any controlled substance. The registration is specific to the particular location, activity and controlled substance schedule. For example, separate registrations are needed for import and manufacturing, and each registration will specify which schedules of controlled substances are authorized.

The DEA typically inspects a facility to review its security measures prior to issuing a registration. Security requirements vary by controlled substance schedule, with the most stringent requirements applying to Schedule I and Schedule II substances. Required security measures include background checks on employees and physical control of inventory through measures such as cages, surveillance cameras and inventory reconciliations. Records must be maintained for the handling of all controlled substances, and periodic reports made to the DEA, for example distribution reports for Schedule I and II controlled substances, Schedule III substances that are narcotics, and other designated substances. Reports must also be made for thefts or losses of any controlled substance, and to obtain authorization to destroy any controlled substance. In addition, special permits and notification requirements apply to imports and exports of narcotic drugs.

In addition, a DEA quota system controls and limits the availability and production of controlled substances in Schedule I or II. Distributions of any Schedule I or II controlled substance must also be accompanied by special order forms, with copies provided to the DEA. Because REMOXY is regulated as a Schedule II controlled substance, it will be subject to federal, state and local environmental laws and regulations, including the DEA’s productionEnvironmental Protection Act and procurement quota scheme. The DEA establishes annuallythe Clean Air Act. Although we believe that our safety procedures for handling and disposing of controlled materials comply with the standards prescribed by state and federal regulations, accidental contamination or injury from these materials may occur. In the event of such an aggregate quotaoccurrence, we could be held liable for how much oxycodone may be produced in total in the United States based on the DEA’s estimate of the quantity needed to meet legitimate scientificany damages that result and medicinal needs. The limited aggregate amount of opioids that the DEA allows to be produced in the United States each year is allocated among individual companies, who must submit applications annually to the DEA for individual production and procurement quotas. We andany such liability could exceed our contract manufacturers must receive an annual quota from the DEA in order to produce or procure any Schedule I or Schedule II substance, including oxycodone base for use in manufacturing REMOXY. The DEA may adjust aggregate production quotas and individual production and procurement quotas from time to time during the year, although the DEA has substantial discretion in whether or not to make such adjustments.

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To enforce these requirements, the DEA conducts periodic inspections of registered establishments that handle controlled substances. Failure to maintain compliance with applicable requirements, particularly as manifested in loss or diversion, can result in administrative, civil or criminal enforcement action that could have a material adverse effect on our business, results of operations and financial condition. The DEA may seek civil penalties, refuse to renew necessary registrations or initiate administrative proceedings to revoke those registrations. In certain circumstances, violations could result in criminal proceedings. In addition, individual states also independently regulate controlled substances. We and our contract manufacturers will be subject to state regulation on distribution of these products.

Other Regulatory Requirementsresources.



We may also be subject to regulations under other federal, state, and local laws, including the Occupational Safety and Health Act, the Environmental Protection Act, the Clean Air Act, national restrictions on technology transfer, and import, export, and customs regulations. It is possible that any portion of the regulatory framework under which we operate may change and that such change could have a negative impact on our current and anticipated operations. Failure to comply with these requirements could result, among other things, in suspension of regulatory approval, recalls, injunctions or civil or criminal sanctions.



Third‑Party Payor Coverage and Reimbursement



The commercial success of REMOXY,our product candidates, if approved, will depend, in part, upon the availability of coverage and adequate reimbursement from third‑party payors at the federal, state and private levels. Third‑party payors include governmental programs such as Medicare or Medicaid, private insurance plans and managed care plans. These third‑party payors may deny coverage or reimbursement for REMOXYour product candidates in whole or in part if they determine that our drug product iscandidates are not medically appropriate or necessary. Also, third partythird-party payors attempt to control costs by limiting coverage through the use of formularies and other cost‑containment mechanisms and the amount of reimbursement for particular procedures or drug treatments.



Some third‑party payors also require pre‑approval of coverage for new or innovative devices or drug therapies before they will reimburse healthcare providers who use such therapies. While we cannot predict whether any proposed cost‑containment measures will be adopted or otherwise implemented in the future, these requirements or any announcement

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or adoption of such proposals could have a material adverse effect on our ability to obtain adequate prices for REMOXYour approved product candidates to operate profitably.



Competition

Our success will depend, in part, upon our ability to achieve market share at the expense of existing and established and future products in our target markets. Existing and future products, therapies, technological approaches or delivery systems will compete directly with REMOXY. Competing products may provide greater therapeutic benefits for a specific indication, or may offer comparable performance at a lower cost. Companies that currently sell generic or proprietary opioid formulations in the United States may include, but are not limited to, Purdue Pharma, Collegium, Inc., Roxane Laboratories, Mylan, Abbott Laboratories, Endo Pharmaceuticals, Teva Pharmaceuticals, Elkins-Sinn, Watson Laboratories, Hikma Pharmaceuticals, Pernix, Mallinckrodt, Eaglet Pharmaceuticals, Ortho-McNeil Pharmaceutical and Forest Pharmaceuticals, as well as several generic companies.

Alternative technologies are being developed to address the issue of abuse or misuse of opioid painkillers or increase opioid potency, as well as alternatives to opioid therapy for pain management, several of which are in clinical trials or are awaiting approval from the FDA.

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We compete with fully integrated pharmaceutical companies, smaller companies that are collaborating with larger pharmaceutical companies, academic institutions, government agencies and other public and private research organizations. Many of these competitors have opioid drugs already approved by the FDA or in development and operate larger research and development programs in these fields than we do. In addition, many of these competitors, either alone or together with their collaborative partners, have substantially greater financial resources than we do, as well as significantly greater experience in:

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developing drugs;

·

undertaking preclinical testing and human clinical trials;

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obtaining FDA and other regulatory approvals of drugs; 

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formulating and manufacturing drugs; and

·

launching, marketing, distributing and selling drugs.

Developments by competitors may render our drug candidates or technologies obsolete or non-competitive. We also compete with these companies for qualified personnel and opportunities for product acquisitions, joint ventures or other strategic alliances.

Incorporation

We were incorporated in Delaware in May 1998.

EmployeesHuman Capital



As of December 31, 2017,2020, we had 911 full-time employees. None of our employees are represented by a labor union or covered under a collective bargaining agreement. We also engage numerous consultants from time to time to perform services on retainer, a per diem or an hourly basis.



We focus on identifying, recruiting, developing and retaining a small team of highly talented and motivated employees. The principal purposes of our equity and cash incentive plans are to attract, retain and reward personnel through the granting of stock-based and cash-based compensation awards in order to increase stockholder value by motivating such individuals to perform to the best of their abilities and achieve our objectives. The success of our business is fundamentally connected to the health, safety and well-being of our employees. In an effort to protect the health and safety of our employees, we took proactive action from the earliest signs of the COVID-19 outbreak, which included implementing social distancing policies at our office, facilitating remote working arrangements and imposing employee travel restrictions.

Available

Corporate Information

We were incorporated as a Delaware corporation in May 1998 under the name Pain Therapeutics, Inc. In March 2019, we changed our company name to Cassava Sciences, Inc. Our principal offices are located at 7801 N. Capital of Texas Highway, Suite 260, Austin, TX, 78731. Our telephone number is 512-501-2444. Our website address is www.CassavaSciences.com.

We use Cassava Sciences, the Cassava Sciences logo, artwork and other marks as trademarks in the United States and other countries. Solely for convenience, trademarks and trade names referred to in this Annual Report, including logos, artwork, and other visual displays, may appear without the ® or TM symbols, but such references are not intended to indicate in any way that we will not assert, to the fullest extent under applicable law, our rights, or the rights of the applicable licensor to these trademarks and trade names. We do not intend our use or display of other entities’ trade names, trademarks, or service marks to imply a relationship with, or endorsement or sponsorship of us by, any other entity.



We file electronically with the Securities and Exchange Commission, or SEC, our annual reports on Form 10-K, quarterly reports on Form 10-Q and current reports on Form 8-K pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934. The public may read or copy any materials we file with the SEC at the SEC’s Public Reference Room at 450 Fifth Street, NW, Washington, DC 20549. The public may obtain information on the operation of the Public Reference Room by calling the SEC at 1-800-SEC-0330. The SEC maintains an Internet site that contains reports, proxy and information statements, and other information regarding issuers that file electronically with the SEC. The address of thatthe site is http://www.sec.gov.



You may obtain a free copy of our annual reports on Form 10-K, quarterly reports on Form 10-Q and current reports on Form 8-K and amendments to those reports on the day of filing with the SEC on our website at http://www.paintrials.com,www.cassavasciences.com, by contacting our corporate offices by calling 512-501-2444512-501-2450 or by sending an e-mail message to IR@paintrials.com.IR@cassavasciences.com.



 

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Item 1A.Risk Factors

RISK FACTORS



Investing in our common stock involves a high degree of risk.

You should carefully consider the risks described below, as well as all other information contained in this Annual Report on Form 10-K, including our financial statements and the related notes thereto and the section entitledtitled “Management’s Discussion and Analysis of Financial Condition and Results of Operations.Operations,Ifbefore deciding whether to invest in our common stock. The occurrence of any of the following risks occur,events or developments described below could harm our business, financial condition, operating results prospectsof operations, and ability to accomplish our strategic objectives could be materially harmed. As a result,growth prospects. In such an event, the tradingmarket price of our common stock could quickly decline, by a material amount, and you couldmay lose all or part of your investment.



Below is a summary of the principal factors that make an investment in our common stock speculative or risky. Additional risks and uncertainties not presently known to us or that we currently deem immaterial also may also impair our business operations and the market price of our common stock.

Clinical and Regulatory Risks

Our success depends in large part on receiving FDA approval for our lead product, REMOXY.

To date, we have invested substantial resources in the development of our lead product, REMOXY.  Despite these investments, the REMOXY NDA received CRL from the FDA in 2008, 2011 and 2016 indicating our drug was not yet ready for approval.  Collectively, these CRLs have resulted in long delays to product revenue; sudden, severe and prolonged drops in our stock price; loss of our initial competitive advantages in the market for abuse-deterrent opioid drugs; and dwindling cash balances.  Accordingly, we cannot assure you that we will be able to receive FDA approval for REMOXY, or successfully commercialize this drug candidate. If we cannot do so, or are significantly delayed in doing so, our business will be materially harmed, and we may not be able to survive as a business.

The FDA may not approve product labeling for REMOXY that would permit us to market and promote this drug in the United States by describing their abuse-deterrent features.

There can be no assurance that REMOXY will receive final FDA-approved product labeling that adequately describes its abuse deterrent features. We have invested substantial time and money conducting abuse deterrence studies to ensure that REMOXY complies with the FDA’s guidance regarding opioid abuse deterrence. If the FDA does not approve product labeling containing abuse deterrence claims for REMOXY, we will not be able to promote REMOXY based on its abuse deterrent features and may not be able to differentiate our drug from other opioid products containing the same active pharmaceutical ingredients.  This would make REMOXY less competitive, or even un-competitive, in the market. Furthermore, the FDA’s April 2015 final guidance on abuse deterrent opioids expects sponsors to compare their formulations against approved abuse deterrent versions of the same opioid based on the relevant categories of testing. If the FDA decides that REMOXY is less resistant to manipulation than an approved product, our lead drug candidate may not be approved or may lack product labeling containing abuse deterrence claims

Even if REMOXY is approved for marketing with certain abuse-deterrence claims, the April 2015 final FDA guidance on abuse-deterrent opioids is not binding law and may be superseded or modified at any time. Also, if the FDA determines that our post-marketing data do not demonstrate that REMOXY’s abuse-deterrent properties do in fact result in reduction of abuse, or demonstrate a shift to routes of abuse that present a greater risk, the FDA may find that product labeling revisions are needed, and potentially may require the removal of any abuse-deterrence claims.

If we fail to obtain the necessary regulatory approvals, or if such approvals are limited, we and our collaborators will not be allowed to commercialize our drug candidates, and we will not generate product revenues.



Satisfaction of all regulatory requirements for commercialization of a drug candidate typically takes many years, is dependent upon the type, complexity and novelty of the drug candidate, and requires the expenditure of substantial resources for research and development. In December 2008, we received from the FDA a CRL for the REMOXY NDA. In this CRL, the FDA indicated that additional non-clinical data was required to support the approval of REMOXY. However, the FDA did not request or recommend additional clinical efficacy studies prior to approval. In March 2009, King Pharmaceuticals, Inc., or King, assumed sole responsibility for the regulatory approval of REMOXY. In December 2010, King resubmitted the NDA for REMOXY. In June 2011, we and Pfizer announced that King received a CRL from the FDA in response to King’s

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resubmission of the REMOXY NDA. The FDA’s CRL raised concerns related to, among other matters, the Chemistry, Manufacturing, and Controls section of the NDA for REMOXY. Certain drug lots showed inconsistent release performance during in vitro testing. Pfizer completed work designed to address the June 2011 CRL.  On April 21, 2015, we announced that we resumed responsibility for REMOXY under the terms of a letter agreement with Pfizer. The letter agreement was entered into within the scope of the previously disclosed provisions of the Collaboration Agreement between us and Pfizer relatingRisks Related to the returnDiscovery, Development, and Commercialization of REMOXY.Our Product Candidates



We believe Pfizer has now transferred to us its data, materials, capital equipment and other assets related to REMOXY. Pfizer and the FDA had discussed and agreed to a regulatory plan to refile the NDA for REMOXY. The FDA had agreed that we may follow this plan for the NDA for REMOXY.

In March 2016, we resubmitted to the FDA the NDA for REMOXY. In April 2016, the FDA determined that the NDA for REMOXY was sufficiently complete to permit a substantive review. On May 19, 2016, we announced that the FDA planned to hold an Advisory Committee meeting to review the NDA for REMOXY. On July 1, 2016, we announced that the FDA had determined that an Advisory Committee meeting for REMOXY was unnecessary and would not be held.

In September 2016, we received a  CRL from the FDA on the resubmission of NDA for REMOXY. The CRL informed us that the NDA for REMOXY could not be approved in its present form and specifies additional actions and data that are needed for drug approval. The CRL focuses on the abuse-deterrent properties of REMOXY and proposed drug labeling.

On February 13, 2017, we met with the FDA regarding REMOXY. During this meeting, we reached agreement with the FDA on a roadmap to resubmit the NDA for REMOXY.  Final minutes of our FDA meeting confirmed two key requirements needed for the resubmission of the REMOXY NDA: a) to conduct a clinical abuse potential study via the intranasal route of abuse; and b) to conduct a non-clinical abuse potential study using household solvents.

During 2017, we conducted these mandated studies with REMOXY.  In November 2017, we concluded a regulatory meeting with the FDA.  The purpose of this pre-New Drug Application (NDA) meeting was to agree on submission requirements for the REMOXY NDA under 505(b)(2) of the Federal Food, Drug, and Cosmetic Act.   We received comments and clarification from the FDA on the acceptability of the data to be included in the REMOXY NDA resubmission, including a recent intranasal study.  All questions were addressed and summarized in official minutes of the meeting issued by the FDA.  There are no discrepancies or requests for clarifications following receipt of final meeting minutes.  As a result, we intend to resubmit the REMOXY NDA in Q1 2018 with Priority (six-month) Review.

There can be no assurance that the FDA will approve an NDA for REMOXY or that the FDA will not require submission of additional clinical or non-clinical data. Obtaining data from such studies (even if completed) that is insufficient to support approval of REMOXY, or any adverse decisions by the FDA (including any decision by the FDA to require additional clinical or non-clinical data) may significantly delay or prevent the potential approval of REMOXY.

Our research and clinical approaches may not lead to drugs that the FDA considers safe for humans and effective for indicated uses we are studying. The FDA may require additional studies, in which case we or our collaborators would have to expend additional time and resources and would likely delay the date of potentially receiving regulatory approval. The approval process may also be delayed by changes in government regulation, future legislation or administrative action or changes in FDA policy that occur prior to or during our regulatory review. Delays in obtaining regulatory approvals would:

·

delay commercializationSince 2017, we have concentrated a substantial portion of our research and development efforts on the treatment and detection of Alzheimer’s disease, an area of research that has seen significant failure rates. Further, our product revenues from, our drug candidates;candidates are based on new scientific approaches and novel technology, which makes it difficult to predict the time and cost of product candidate development and likelihood of success.

·

diminishWe are heavily dependent on the competitive advantagessuccess of simufilam and SavaDx, our product candidates which are still under clinical development. If these product candidates do not receive regulatory approval, we will be unable to generate product revenue and our business will be harmed.

·

We have a limited operating history in our business targeting Alzheimer’s disease and no history of product approvals for commercial sale, which may make it difficult to evaluate our current business and predict our future success and viability.

·

We cannot give any assurance that any of our product candidates will receive regulatory approval, which is necessary before they can be commercialized.

·

There can be no assurance that results of smaller Phase 1 and Phase 2 clinical trials with simufilam will be reproduced in the additional large, well-controlled studies that are required to demonstrate safety and efficacy in order to potentially receive regulatory approval.

·

We may encounter substantial delays in our clinical studies or may not be able to conduct or complete our clinical studies on the timelines we expect, if at all.

·

If physicians and patients do not accept and use our drugs, we will not achieve sufficient product revenues and our business will suffer.

Risks Related to Government Regulation and Other Legal Compliance Matters

·

If we are ultimately unable to obtain regulatory approval for our product candidates, we will be unable to generate product revenue and our business will be substantially harmed.

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Our ability to market and promote our product candidates will be determined and limited by FDA-approved labeling.

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Our employees, independent contractors, consultants, commercial partners, and vendors may have otherwise enjoyed, which would have an adverse effect onengage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements.

·

If we fail to comply with the complex federal, state, local and foreign laws and regulations that apply to our business, we could suffer severe consequences that could materially and adversely affect our operating results and financial condition.

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Government agencies may establish and promulgate usage guidelines that could limit the use of our product candidates.



EvenRisks Related to Our Intellectual Property

·

If we are unable to obtain and maintain sufficient patent protection for any product candidates we develop, our competitors could develop and commercialize products similar or identical to ours, and our ability to successfully commercialize any product candidates we may develop may be adversely affected.

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·

U.S. intellectual property rights around diagnostic methods is a complex, evolving area of law and effective patent claims may not be available to us for our investigational diagnostic product candidate, SavaDx, in the United States.

·

Issued patents covering our product candidates and other technologies could be found invalid or unenforceable if challenged in court or before administrative bodies in the U.S. or abroad.

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If we do not obtain patent term extension and data exclusivity for any product candidates we may develop, our business may be materially harmed.

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If we are unable to protect the confidentiality of our trade secrets, our business and competitive position would be harmed.

Risks Related to Our Business and Operations

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The worldwide outbreak of an infectious disease, called COVID-19, may materially and adversely affect our business operations and our ability to conduct clinical studies.

·

Our reliance on third parties for both the supply and manufacture of materials for our product candidates carries the risk that we will not have sufficient quality or quantities of such materials or product candidates, or that such supply will not be available to us at an acceptable cost, which could delay, prevent, or impair our development or commercialization efforts.

·

We expect to grow the size and capabilities of our organization, including accessing new physical facilities, and we may experience difficulties in effectively managing this growth.

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Our internal computer systems, or those used by third-parties on whom we rely, may fail or suffer other breakdowns, cyberattacks, or information security breaches that could compromise the confidentiality, integrity, and availability of such systems and data, result in material disruptions of our development programs and business operations, risk disclosure of confidential, financial, or proprietary information, and affect our reputation.

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Our business involves environmental risks that may result in liability for us.

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Business disruptions and lack of appropriate levels of commercial insurance could seriously harm our future revenue and financial condition and increase our costs and expenses.

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Social media platforms present risks and challenges.

Risks Related to Financial Condition and Capital Requirements

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We have incurred significant net losses in each period since our inception and anticipate that we will continue to incur net losses for the foreseeable future.

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We have broad discretion in the use of the net proceeds from any of our financing transactions and may not use them effectively.

Risks Related to the Ownership of Our Common Stock

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We do not know whether a sufficient market will continue to develop for our common stock or what the market price of our common stock will be, and, as a result, it may be difficult for investors to sell shares of our common stock.

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The market price of our common stock has historically been highly volatile and we expect it to continue to be volatile, which could result in substantial losses for investors who purchase our shares.

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If we are unable to maintain effective internal controls, our business, financial position, and results of operations could be adversely affected.

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Anti-takeover provisions in our charter documents and Delaware law may prevent or delay removal of incumbent management or a change of control.

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Changes in our ownership could limit our ability to utilize net operating loss carryforwards.

Risks Related to the Discovery, Development, and Commercialization of Our Product Candidates

Since 2017, we have concentrated a substantial portion of our research and development efforts on the treatment and detection of Alzheimer’s disease, an area of research that has seen significant failure rates. Further, our product candidates are based on new scientific approaches and novel technology, which makes it difficult to predict the time and cost of product candidate development and likelihood of success.

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Since 2017, we have concentrated a substantial portion of our research and development efforts on experimental methods for the treatment and detection of Alzheimer’s disease. Prior efforts by biopharmaceutical companies to develop new treatments for Alzheimer’s disease have seen very limited clinical success. No new treatments have been approved for Alzheimer’s disease since 2003, and since that time, while many large clinical studies have been completed, no drug candidate has shown clear evidence of clinical efficacy in large, Phase 3 clinical studies. FDA-approved drugs for Alzheimer’s disease only address symptoms, and there are no FDA-approved disease modifying therapeutics available for patients with Alzheimer’s disease. Notwithstanding these substantial challenges to date, we seek to improve brain health by addressing the neurodegeneration and neuroinflammation components of Alzheimer’s disease. Our lead drug candidate for Alzheimer’s disease is based on a new approach of stabilizing – but not removing – a critical protein in the brain. We cannot be certain that our novel technologies will lead to an approvable or marketable product. In addition, because FDA has limited comparators to evaluate our collaborators comply with all FDAlead drug candidate, we could experience a longer than expected regulatory requirements,review process and increased development costs.

We are heavily dependent on the success of simufilam and SavaDx, our drugproduct candidates which are still under clinical development. If these product candidates do not receive regulatory approval, we will be unable to generate product revenue and our business may be harmed.

Since inception, we have not succeeded in getting regulatory approval for our product candidates and we may never do so. In recent years we have invested a significant portion of our efforts and financial resources in the development of simufilam and SavaDx for the treatment and detection of Alzheimer’s disease, respectively. Our future success is substantially dependent on our ability to successfully complete clinical development and obtain regulatory approval.approval for our product candidates, which may never occur. We expect that a substantial portion of our efforts and expenditures over the next few years will be devoted to simufilam and SavaDx. This will require additional clinical development, management of clinical and manufacturing activities, regulatory approval in one or more national jurisdictions and obtaining commercial-scale manufacturing supply. Substantial investment and significant efforts will be required before we can generate any revenues from any commercial sales. We cannot be certain that we will be able to successfully complete any of these activities.

We have a limited operating history in our business targeting Alzheimer’s disease and no history of product approvals for commercial sale, which may make it difficult to evaluate our current business and predict our future success and viability.

We are an early clinical-stage biopharmaceutical company with a limited operating history in our business targeting Alzheimer’s disease. Since we commenced operations in 1998, we have had no product candidates approved for commercial sale and have not generated any revenue from product sales. Drug development is a highly uncertain undertaking and involves a substantial degree of risk. To date, we have not initiated or completed a pivotal clinical study involving Alzheimer’s disease, obtained marketing approval for any product candidates, or conducted sales and marketing activities necessary for successful product commercialization. Our long operating history as a company without product revenue makes any assessment of our future success and viability subject to significant uncertainty.

We will continue to encounter risks and difficulties frequently experienced by early-stage biopharmaceutical companies in rapidly evolving fields. We have not yet demonstrated an ability to successfully overcome such risks and difficulties. If we ordo not successfully address these risks and difficulties, our collaboratorsbusiness, results of operations and financial condition will suffer materially.

We cannot give any assurance that any of our product candidates will receive regulatory approval, which is necessary before they can be commercialized.

We are at the early stages of development of our product candidates. To date, we have invested substantial effort and financial resources to identify, procure intellectual property for, and develop our programs in neurodegeneration, including conducting preclinical studies and early-stage clinical studies for our product candidates, simufilam and SavaDx, and providing general and administrative support for these operations. Our future success is dependent on our ability to successfully develop, obtain regulatory approval for, and then successfully commercialize our product candidates, and we may fail to obtaindo so for many reasons, including the following:  

·

our product candidates may not successfully complete preclinical studies or clinical studies;

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·

a product candidate may, on further study, be shown to have harmful side effects or other characteristics that indicate it is unlikely to be effective or otherwise does not meet applicable regulatory criteria;

·

our competitors may develop products that render our product candidates obsolete or less attractive;

·

the product candidates that we develop may not be sufficiently covered by intellectual property;

·

the product candidates that we develop may be challenged by third parties’ patents or other intellectual property or exclusive rights;

·

the market for our product candidates may change so that the continued development of a product candidate is no longer reasonable or commercially attractive;

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our product candidate may not be capable of being produced in commercial quantities at an acceptable cost, or at all;

·

if a product candidate obtains regulatory approval, we may be unable to establish sales and marketing capabilities, or successfully market such approved product candidate, to gain market acceptance; and

·

 a product candidate may not be accepted as safe, effective or useful by patients, the medical community or third-party payors, if applicable.

If any of these events occur, we may be forced to abandon our development efforts for a program or programs, which would have a material adverse effect on our business and could potentially cause us to cease operations.

We may not be successful in our efforts to further develop our current product candidates. We are not permitted to market or promote any of our product candidates before we receive regulatory approval from FDA or comparable foreign regulatory authorities, and we may never receive such regulatory approval for any of our drugproduct candidates. Each of our product candidates is in the early stages of development and will require significant additional clinical development, management of preclinical, clinical, and manufacturing activities, regulatory approval, adequate manufacturing supply, a commercial organization, and significant marketing efforts before we generate any revenue from product sales, if at all.

We have never completed a product development program in neurodegeneration. None of our product candidates in neurodegeneration have advanced into late-stage development and we may not be able to initiate such program on anticipated timelines, if at all. Further, we cannot be certain that any of our product candidates will have fewerbe successful in clinical studies. We may in the future advance product candidates into clinical studies and terminate such studies prior to their completion.

If any of our product candidates successfully complete clinical studies, we may seek regulatory approval to market our product candidates in the U.S., the European Union, and in additional foreign countries where we believe there is a viable commercial products, if any, and corresponding lower product revenues, if any. Even if our drug candidatesopportunity. We may never receive regulatory approval to market any product candidates even if such product candidates successfully complete clinical studies, which would adversely affect our viability. To obtain regulatory approval may involve limitations on the indications and conditions of use or marketing claims for our products. Further, later discovery of previously unknown problems or adverse events could result in additional regulatory restrictions, including withdrawal of products. The FDA may also require us or our collaborators to commit to perform lengthy Phase IV post-approval clinical efficacy or safety studies. Our expending additional resources on such trials would have an adverse effect on our operating results and financial condition.

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In jurisdictionscountries outside the United States,U.S., we must receive marketing authorizations from the appropriatewould need to comply with numerous and varying regulatory authorities before commercializingrequirements of such other countries regarding safety, efficacy, manufacturing and controls, clinical studies, commercial sales, pricing, and distribution of our drugs. Regulatoryproduct candidates. Even if we are successful in obtaining approval processes outside the United States generally include all of the aforementioned requirements and risks associated with FDA approval.

in one jurisdiction, we cannot ensure that we will obtain approval in any other jurisdictions. If we are unable to design, conductobtain approval for our product candidates in multiple jurisdictions, our business, financial condition, results of operations, and complete preclinicalour growth prospects could be negatively affected.

Even if we receive regulatory approval to market any of our product candidates, whether for the treatment or diagnosis of neurodegenerative diseases or other diseases, we cannot provide assurance that any such product candidate will be successfully commercialized, widely accepted in the marketplace or more effective than other commercially available alternatives.

Investment in biopharmaceutical product development involves significant risk that any product candidate will fail to demonstrate adequate efficacy or an acceptable safety profile, gain regulatory approval, and become commercially viable. We

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cannot provide any assurance that we will be able to successfully advance any of our product candidates through the development process or, if approved, successfully commercialize any of our product candidates.

There can be no assurance that results of smaller Phase 1 and Phase 2 clinical trials successfully,with simufilam will be reproduced in the additional large, well-controlled studies that are required to demonstrate safety and efficacy in order to potentially receive regulatory approval.

Results of our drug candidatesPhase 1, Phase 2 and open-label safety studies with simufilam may not be predictive of the results of later-stage clinical trials. Simufilam may fail to show the desired safety and efficacy in later clinical trials despite having progressed through preclinical studies and initial clinical trials. Many companies in the biopharmaceutical industry have suffered significant setbacks in advanced clinical trials due to lack of efficacy or adverse safety profiles, notwithstanding promising results in earlier trials. In addition, conclusions based on data from analyses of Phase 1 and Phase 2 clinical studies and open-label results may not be reproduced when implemented in large, well-controlled, randomized clinical trials. Even if our clinical trials for simufilam are completed as planned, we cannot be certain that their results will support the safety and efficacy sufficient to obtain regulatory approval.

We may encounter substantial delays in our clinical studies or may not be able to receive regulatory approval.

In order to obtain FDA approval for any ofconduct or complete our drug candidates,clinical studies on the timelines we must submit to the FDA an NDA that demonstrates with substantive evidence that the drug candidate is both safe and effective in humans for its intended use. This demonstration requires significant research and animal tests, which are referred to as preclinical studies, as well as human tests, which are referred to as clinical trials.

Preclinical studies may not provide results we believe are sufficient to support the filing of an IND. Success in early preclinical studies does not ensure success in later preclinical or clinical studies. The FDA may disagree with the design of our preclinical studies or our interpretations of data from preclinical studies. The FDA may not accept an IND for our product candidate and may require additional preclinical studies to support the filing of an IND.

Success in preclinical studies and early clinical trials does not ensure that later clinical trials will be successful. Results from Phase I clinical programs may not support moving a drug candidate to Phase II or Phase III clinical trials. Phase III clinical trials may not demonstrate the safety or efficacy of our drug candidates. Results of later clinical trials may not replicate the results of prior clinical trials and preclinical studies. Evenexpect, if the results of Phase III clinical trials are positive, we or our collaborators may have to commit substantial time and additional resources to conducting further preclinical studies and clinical trials before obtaining FDA approval for any of our drug candidates.at all.



Clinical trials are verytesting is expensive, time consuming, and difficult to design and implement, in part because they are subject to rigorous requirements. Theuncertainty. We cannot guarantee that any clinical trial process also consumesstudies will be conducted as planned or completed on schedule, if at all. We cannot be sure that submission of an IND or a significant amount of time. Furthermore,clinical study application (CTA) will result in FDA or European Medicines Agency (EMA), as applicable, allowing clinical studies to begin in a timely manner, if patients in clinical trials suffer drug-related adverse reactions during the course ofat all. Moreover, even if these studies begin, safety or other issues may arise that could suspend or terminate such clinical trials,studies. A failure of one or if we, our collaborators or the FDA believe that participating patients are being exposed to unacceptable health risks, suchmore clinical trials will have to be suspended or terminated. Failurestudies can occur at any stage of the clinical trials, and we or our collaborators could encounter problems that cause abandonment or repetition of clinical trials.

Clinical trials with REMOXYtesting, and our potential future clinical trials for other drug candidates for treatment of pain measure clinical symptoms, such as pain and physical dependence, that are not biologically measurable. The success in these clinical trials depends on reaching statistically significant changes in patients’ symptoms based on clinician-rated scales. Due in part to a lack of consensus on standardized processes for assessing clinical outcomes, these scores may orstudies may not be reliable, usefulsuccessful. Events that may prevent successful or acceptable to regulatory agencies.

In addition,timely initiation or completion of clinical trials can be delayed by numerous factors, including:studies include:

·

inability to generate sufficient preclinical, toxicology, or other in vivo or in vitro data to support the initiation or continuation of clinical studies;

·

delays in confirming target engagement, patient selection, or other relevant biomarkers to be utilized in preclinical and clinical product candidate development;

·

delays in reaching a consensus with regulatory agencies on study design;

·

delays in reaching an agreement on acceptable terms with prospective contract research organizations (CROs) and clinical study sites, the terms of which can be subject to extensive negotiation and may vary significantly among different CROs and clinical study sites;

·

delays in identifying, recruiting, and agreeingtraining suitable clinical investigators;

·

delays in obtaining required IRB approval for each clinical study site;

·

 imposition of a temporary or permanent clinical hold by regulatory agencies for a number of reasons, including:

·

 after review of an IND or amendment, CTA or amendment, or equivalent application or amendment;

·

 as a result of a new safety finding that presents unreasonable risk to clinical study participants;

·

 a negative finding from an inspection of our clinical study operations or study sites; or

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the finding that the investigational protocol or plan is clearly deficient to meet its stated objectives;

·

delays in identifying, recruiting, and enrolling suitable patients to participate in our clinical studies, and delays caused by patients withdrawing from clinical studies, or failing to return for post-treatment follow-up;

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·

delays caused by disease epidemics or pandemics, such as COVID-19;

·

difficulty collaborating with patient groups and investigators;

·

failure by our CROs, other third parties, or us to adhere to clinical study requirements;

·

failure to perform in accordance with FDA’s or any other regulatory authority’s Code of Good Clinical Practice (GCPs) requirements, or applicable EMA or other regulatory guidelines in other countries;

·

occurrence of adverse events associated with the product candidate that are viewed to outweigh its potential benefits;

·

changes in regulatory requirements and guidance that require amending or submitting new clinical protocols;

·

changes in the standard of care on acceptable terms with prospectivewhich a clinical trial sites;development plan was based, which may require new or additional studies;

·

the cost of clinical studies of our product candidates being greater than we anticipate;

·

clinical studies of our product candidates producing negative or inconclusive results, which may result in our deciding, or regulators requiring us, to conduct additional clinical studies or abandon product development programs; and

·

delays in manufacturing, testing, releasing, validating, or importing/exporting sufficient stable quantities of our product candidates for use in clinical studies or the inability to do any of the foregoing.

Any inability to successfully initiate or complete clinical studies could result in additional costs to us or impair our ability to generate revenue. In addition, if we make manufacturing or formulation changes to our product candidates, we may be required to, or we may elect, to conduct additional studies to bridge our modified product candidates to earlier versions. Clinical study delays could also shorten any periods during which our products have patent protection and may allow our competitors to bring products to market before we do, which could impair our ability to successfully commercialize our product candidates and may harm our business and results of operations.

We may in the future advance product candidates into clinical studies and terminate such studies prior to their completion, which could adversely affect our business.

Delays in the completion of any clinical study of our product candidates will increase our costs, slow down our product candidate development and approval process and delay, or potentially jeopardize our ability to commence product sales and generate revenue. In addition, many of the factors that cause, or lead to, a delay in the commencement or completion of clinical studies may also ultimately lead to the denial of regulatory approval of our product candidates.

If physicians and patients do not accept and use our drugs, we will not achieve sufficient product revenues and our business will suffer.

Even if FDA approves our drugs, physicians and patients may not accept and use them. Acceptance and use of our drugs will depend on a number of factors including:

·

when the drug is launched into the market and related competition;

·

approved label claims;

·

perceptions by members of the healthcare community, including physicians, about the safety and effectiveness of our drugs;

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·

perceptions by physicians regarding the cost-benefit of our product candidates;

·

published studies demonstrating the cost effectiveness of our drugs relative to competing products;

·

availability of reimbursement for our products from government or healthcare payers;

·

effectiveness of marketing and distribution efforts by us and other licensees and distributors.

Because we expect to rely on sales generated by our current lead product candidates for substantially all of our revenues for the foreseeable future, the failure of any of these drugs to find market acceptance would harm our business and could require us to seek additional financing.

We may not be successful in developing our product candidates in neurodegeneration.

Our product candidates in neurodegeneration are still in the early stages of development and will take several more years to develop and must undergo extensive clinical and scientific validations.Even if we are successful in developing any of our product candidates through clinical and scientific validation, we may not be able to develop a drug or a diagnostic that:

·

meets applicable regulatory standards, in a timely manner or at all;

·

slower than expected rates of patient recruitmentsuccessfully competes with other technologies and enrollment;tests;

·

unanticipated patient dropout rates;avoids infringing the proprietary rights of others;

·

increases in time required to complete monitoring of patients during or after participation in a clinical trial; andare adequately reimbursed by third-party payors;

·

unexpected need for additional patient-related data.

Any of these delays could significantly impact the timing, approval and commercialization of our drug candidates and could significantly increase our overall costs of drug development.

Even if clinical trials are completed as planned, their results may not support expectations or intended marketing claims. The clinical trials process may fail to demonstrate that our drug candidates are safe and effective for indicated uses. Such failure would cause us to abandon a drug candidate and could delay development of other drug candidates.

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Clinical trial designs that were discussed with regulatory authorities prior to their commencement may subsequently be considered insufficient for approval at the time of application for regulatory approval.

We discuss with and obtain guidance from regulatory authorities on certain of our clinical development activities. With the exception of our Special Protocol Assessment (SPA), these discussions are not binding obligations on the part of regulatory authorities.

Regulatory authorities may revise previous guidance or decide to ignore previous guidance at any time during the course of our clinical activities or after the completion of our clinical trials. Even with successful clinical safety and efficacy data, including such data from a clinical trial conducted pursuant to a SPA, we or our collaborators may be required to conduct additional, expensive clinical trials to obtain regulatory approval.

Developments by competitors may establish standards of care that affect our ability to conduct our clinical trials as planned.

We have conducted clinical trials of our drug candidates comparing our drug candidates to both placebo and other approved drugs. Changes in standards related to clinical trial design could affect our ability to design and conduct clinical trials as planned. For example, regulatory authorities may not allow us to compare our drug candidates to placebo in a particular clinical indication where approved products are available. In that case, both the cost and the amount of time required to conduct a clinical trial could increase.

The U.S. Drug Enforcement Agency, or DEA, limits the availability of the active ingredients in certain of our current drug candidates and, as a result, quotas for these ingredients may not be sufficient to complete clinical trials, or to meet commercial demand, or may result in clinical delays.

The DEA regulates chemical compounds as Schedule I, II, III, IV or V substances, with Schedule I substances considered to present the highest risk of substance abuse and Schedule V substances the lowest risk. Certain active ingredients in our current drug candidates, such as oxycodone, are listed by the DEA as Schedule II under the Controlled Substances Act of 1970. Consequently, their manufacture, research, shipment, storage, sale and use are subject to a high degree of oversight and regulation. For example, all Schedule II drug prescriptions must be signed by a physician, physically presented to a pharmacist and may not be refilled without a new prescription. Furthermore, the amount of Schedule II substances that can be obtained for clinical trials and commercial distribution is limited by the DEA and quotas for these substances may not be sufficient to complete clinical trials or meet commercial demand. There is a risk that DEA regulations may interfere with the supply of the drugs used in clinical trials for our product candidates, and, in the future, the ability to produce and distribute our products in the volume needed to meet commercial demand.

Conducting clinical trials of our drug candidates or potential commercial sales of a drug candidate may expose us to expensive product liability claims, and we may not be able to maintain product liability insurance on reasonable terms or at all.

The risk of product liability is inherent in the testing of pharmaceutical products. If we cannot successfully defend ourselves against product liability claims, we may incur substantial liabilities or be required to limit or terminate testing of one or more of our drug candidates. Our inability to obtain sufficient product liability insurance at an acceptable cost to protect against potential product liability claims could prevent or inhibit the commercialization of our drug candidates. We currently carry clinical trial insurance but do not carry product liability insurance. If we successfully commercialize one or more of our drug candidates, we may face product liability claims, regardless of FDA approval for commercial manufacturing and sale. We may not be able to obtain such insurance at a reasonable cost, if at all. Even if our agreements with any current or future corporate collaborators entitle us to indemnification against product liability losses, such indemnification may not be available or adequate should any claim arise.

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If our drug candidates receive regulatory approval, we and our collaborators will be subject to ongoing FDA obligations and continued regulatory review, such as continued safety reporting requirements, and we and our collaborators may also be subject to additional FDA post-marketing obligations or new regulations, all of which may result in significant expense and limit our and our collaborators’ ability to commercialize our potential drugs.

Any regulatory approvals that our drug candidates receive may also be subject to limitations on the indicated uses for which the drug may be marketed or contain requirements for potentially costly post-marketing follow-up studies. In addition, if the FDA approves any of our drug candidates, the labeling, packaging, adverse event reporting, storage, advertising, promotion and record keeping for the drug will be subject to extensive regulatory requirements. The subsequent discovery of previously unknown problems with the drug, including but not limited to adverse events of unanticipated severity or frequency, or the discovery that adverse events previously observed in preclinical research or clinical trials that were believed to be minor actually constitute much more serious problems, may result in restrictions on the marketing of the drug, and could include withdrawal of the drug from the market.

The FDA’s policies may change and additional government regulations may be enacted that could prevent or delay regulatory approval of our drug candidates. We cannot predict the likelihood, nature or extent of adverse government regulation that may arise from future legislation or administrative action, either in the United States or abroad. If we are not able to maintain regulatory compliance, we may be subject to fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution. Any of these events could prevent us from marketing our drugs and our business could suffer.

We may not be able to successfully develop or commercialize FENROCK, a proprietary abuse-deterrent transdermal pain patch (fentanyl), designed to prevent common methods of abuse of fentanyl.

We have no history of developing transdermal patches. We do not know whether any of our planned development activities for FENROCK will result in approval of such drug candidate by the FDA, or, if FENROCK is approved, it will be a commercially viable product.

We may not be able to successfully develop or commercialize PTI-125, a proprietary drug candidate to treat Alzheimer’s disease. 

We have no history of developing treatment for AD.  The biopharmaceutical industry as a whole has a poor track record in developing drugs for AD.  Drug candidates aimed at AD have almost universally failed in every attempt to show late-stage efficacy in clinical studies.   We do not know whether any of our planned development activities for AD will result in approval of such drug candidate by the FDA, or, if PTI-125 is approved, it will be a commercially viable product.

We may not be able to successfully develop or commercialize PTI-125DX, a blood-based test to detect Alzheimer’s disease. 

We have no history of developing diagnostics.  The biopharmaceutical industry as a whole has a poor track record in developing blood-based diagnostics for AD.  Diagnostics aimed at detecting AD have almost universally failed in large studies despite evidence of success in early testing.   We do not know whether any of our planned development activities for AD will result in approval of a diagnostic by the FDA, or, if PTI-125DX is approved, it will be a commercially viable product.

Risks Relating to our Collaboration Agreements

If Pfizer did not transfer to us all data and documentation or the quality of the data and documentation transferred is insufficient, our ability to achieve approval of the NDA for REMOXY will be negatively impacted and our business will suffer.

In April 2015, we announced that we resumed responsibility for REMOXY under the terms of a letter agreement with Pfizer. The letter agreement was entered into within the scope of the previously disclosed provisions of the Collaboration Agreement between us and Pfizer relating to the return of REMOXY.

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We believe Pfizer has transferred to us data, materials, capital equipment and other assets related to REMOXY. In preparing to resubmit the NDA for REMOXY, we may find that there are additional data, materials or agreements that Pfizer should have transferred to us. If Pfizer did not meet its obligations to transfer all such materials or if the quality of the data and documentation transferred is insufficient, we would be significantly delayed in our ability to achieve FDA approval of the NDA for REMOXY, and may need to conduct further development activities or clinical trials to prepare any potential resubmission. As a result, any further development, regulatory approval and product introduction for REMOXY would be delayed or prevented and our business would suffer.

If outside collaborators fail to devote sufficient time and resources to drug development programs related to our product candidates, or to the manufacture of our products, or if their performance is substandard, regulatory submissions and introductions for our products may be delayed.

We rely on Durect as the sole-source provider of certain components of REMOXY. Durect’s failure for any reason to provide these components could result in delays or failures in product testing or delivery, cost overruns or other problems that could materially harm our business.

We depend on independent investigators and collaborators, such as universities and medical institutions, to conduct our clinical trials under agreements with us. These investigators and collaborators are not our employees, and we cannot control the amount or timing of resources that they devote to our programs. They may not assign as great a priority to our programs or pursue them as diligently as we would if we were undertaking such activities ourselves. If these investigators or collaborators fail to devote sufficient time and resources to our drug development programs, or if their performance is substandard, the approval of our regulatory submissions and our introductions of new drugs will be delayed or prevented.

Our collaborators may also have relationships with other commercial entities, some of which may compete with us. If outside collaborators assist our competitors to our detriment, the approval of our regulatory submissions will be delayed and the sales from our products, if any are commercialized, will be less than expected.

If we fail to enter into or maintain collaboration agreements and licenses for REMOXY and other drugs designed to reduce potential risks of unintended use, we may have to reduce or delay our drug candidate development.

Our plan for developing, manufacturing and commercializing REMOXY currently requires us to successfully maintain our license from Durect. If we are unable to meet the obligations necessary to maintain our license with Durect for one or more potential products we may lose the rights to utilize Durect’s technology for such potential products, our potential future revenues may suffer and we may have to reduce or delay development of our other drug candidates. In addition, we expect to seek a new corporate collaborator with respect to REMOXY. If we do not enter into a new collaboration with respect to the continued development and potential commercialization of REMOXY, we will be required to undertake and fund such activities ourselves and may need to seek additional capital (which may not be available on acceptable terms, if at all), personnel or other resources. If we are not successful in such efforts, development and commercialization of REMOXY and our other drug candidates would be delayed or prevented, and our business would suffer.

We may not succeed at in-licensing drug candidates or technologies to expand our product pipeline.

We may not successfully in-license drug candidates or technologies to expand our product pipeline. The number of such candidates and technologies is limited. Competition among large pharmaceutical companies and biopharmaceutical companies for promising drug candidates and technologies is intense because such companies generally desire to expand their product pipelines through in-licensing. If we fail to carry out such in-licensing and expand our product pipeline, our potential future revenues may suffer.

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Our collaborative agreements may not succeed or may give rise to disputes over intellectual property, disputes concerning the scope of collaboration activities or other issues.

Our collaborative agreements with third parties, such as our license agreement with Durect, are generally complex and contain provisions that could give rise to legal disputes, including potential disputes concerning ownership of intellectual property under collaborations or disputes concerning the scope of collaboration activities. Such disputes can delay or prevent the development of potential new drug products, or can lead to lengthy, expensive litigation or arbitration. Other factors relating to collaborative agreements may adversely affect our business, including:

·

the development of parallel products by our collaboratorscan be performed at commercial levels or by a competitor;

·

arrangements with collaborative partners that limit or preclude us from developing certain products or technologies;

·

premature termination of a collaborative or license agreement;at reasonable cost; or

·

failure by a collaborative partner to provide required funding, to devote sufficient resources to the development of or legal defense of our potential products or to provide data or other information to us as required by our collaborative agreements.can be successfully marketed.



Risks Relating to CommercializationTo the extent we are not successful in developing our new product candidates in neurodegeneration, our results of operations and business will be materially adversely affected. 



We currently have no in-house capabilities to manufacture or commercialize our product candidates and we rely on third-party commercial drug products.manufacturers for clinical drug supplies. If we are unable to develop our own manufacturing, sales, marketing and distribution capabilities, or if we are not successful in contracting with third parties for these services on favorable terms, or at all, our product revenues could be disappointing.adversely impacted.



We currently rely on Mallinckrodt as the sole manufacturer for REMOXYvarious third parties to manufacture, fill, label, store, test and commercialization of REMOXY is dependentship our product candidates. We plan to continue to outsource formulation, manufacturing and related activities. These suppliers must comply with cGMP regulations enforced by FDA and other government agencies, and are subject to ongoing periodic unannounced inspection, including preapproval inspections by FDA and corresponding state and foreign government agencies to ensure strict compliance with cGMP and other standards. These manufacturers may subsequently be stopped from producing, manufacturing, filling, labeling, storing, testing and shipping our product candidates due to their non-compliance with federal, state or local regulations. We do not have control over our suppliers’ compliance with these regulations and standards and we cannot control decisions by our suppliers that affect their ability or willingness to continue to supply us on continuation of such relationship. acceptable terms, or at all.

Disputes in the past have arisen with Mallinckrodtsome of these third parties with respect to us fulfilling our obligations under the Mallinckrodt Agreement.certain conditions and obligations. There can be no guarantee that such disputes will not arise again in the future, which may lead to Mallinckrodt terminating the Mallinckrodt Agreement.termination of an agreement. If the Mallinckrodt Agreementan agreement is terminated, we would not be able to commercialize REMOXYour product candidates until another manufacturer is identified and we have entered into a manufacturing agreement with such manufacturer. If we are requiredWe may not be able to replace Mallinckrodta commercial supplier on commercially reasonable terms, or at all. Replacing any of our commercial suppliers would be expensive and time consuming. Failure by any of our suppliers to perform as expected could delay or prevent the manufacturercommercialization or potential regulatory approval of REMOXY, it is likely to delay commercialization of REMOXYour product candidates for an extended period of time.time, result in shortages, cost overruns or other problems and would materially harm our business.



We currently have no sales, marketing or distribution capabilities. We have not established commercial strategies regarding any of our product candidates, including REMOXY.candidates. In order to commercialize our products, if any are approved by the FDA, we will either have to develop such capabilities internally or collaborate with third parties who can perform these services for us.



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If we decide to commercialize any of our drugs ourselves, we may not be able to

·

hire and retain the necessary experienced personnel;

·

build sales, marketing and distribution operations in a cost-effective manner which are capable of successfully launching new drugs;

·

obtain access to adequate numbers of physicians to prescribe our products; or

·

generate sufficient product revenues.



In addition, establishing such operations on our own will take time and involve significant expense. If our commercial operations lack complementary products, we may not be able to compete in a cost-effective manner with competitors with more products to sell. If we engage third-party collaborators to perform any commercial operations, our future revenues may depend significantly upon the performance of those collaborators.



If we decide to enter into new co-promotion or other licensing arrangements with third parties, we may be unable to locate acceptable collaborators because the number of potential collaborators is limited and because of competition from others for similar alliances with potential collaborators.alliances. Even if we are able to identify one or more acceptable new collaborators, we may not be able to enter into any collaborative arrangements on favorable terms, or at all.

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In addition, due to the nature of the market for our drugproduct candidates, it may be necessary for us to license all or substantially all of our drugproduct candidates to a single collaborator, thereby eliminating our opportunity to commercialize these other products independently. If we enter into any such new collaborative arrangements, our revenues are likely to be lower than if we marketed and sold our products ourselves.



In addition, any revenues we receive would depend upon our collaborators’ efforts which may not be adequate due to lack of attention or resource commitments, management turnover, change of strategic focus, business combinations or other factors outside of our control. Depending upon the terms of our collaboration, the remedies we have against an under-performing collaborator may be limited. If we were to terminate the relationship, it may be difficult or impossible to find a replacement collaborator on acceptable terms, or at all.



If physiciansAlzheimer’s disease has failed every attempt at drug approval.

Despite billions of dollars invested by the biopharmaceutical industry in research programs to develop novel therapeutics for Alzheimer’s disease, no FDA approved treatments have been developed in the past 15 years. In that span of time, many new types and patients doclasses of drugs have been developed and tested in Alzheimer’s disease, including monoclonal antibodies, g-secretase modulators and inhibitors, β-site amyloid precursor protein cleaving enzyme (BACE) inhibitors, receptor for advanced glycation end-products (RAGE) inhibitors, nicotinic agonists, serotonin subtype receptor (5HT6) antagonists, and others. Virtually all of these scientific programs have failed in clinical testing.

We may not acceptbe successful in our efforts to expand our technology or product candidates in other indications.

Our drug development strategy is to clinically test and useseek regulatory approval for our drugs,product candidates in Alzheimer’s disease, our primary indication. We may expand our research efforts outside of this primary indication and into other areas of clinical medicine based on genetic, biological or mechanistic overlap with the primary indication. Conducting clinical studies for additional indications for our product candidates will require substantial technical, financial and human resources and is prone to the inherent risks of failure in drug development. We cannot provide you any assurance that we will not achieve sufficientbe successful in our effort to expand our technology or our product revenues andcandidates in additional indications, even if we obtain approval for our business will suffer.product candidate in Alzheimer’s disease.



Even ifIf we fail to successfully identify and develop additional product candidates, our commercial opportunity will be limited to Alzheimer’s disease or other neurodegenerations. 

Identifying, developing, obtaining regulatory approval, and commercializing additional product candidates requires substantial expertise and funding and is prone to the FDA approvesrisks of failure inherent in drug development. We cannot provide any assurance that we will be able to successfully identify or acquire additional product candidates, advance any additional product candidates through the development process, or assemble sufficient resources to identify, acquire, or develop additional

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product candidates. If we are unable to successfully identify, acquire, develop, and commercialize additional product candidates, our drugs, physicians and patientscommercial opportunity may be limited.

Early indications of safety, tolerability or biomarker results from our small clinical studies with simufilam may not acceptpredict the results of later studies.

Results of a Phase 1 clinical study with simufilam demonstrated safety, tolerability and use them. Acceptancepharmacokinetics in 24 healthy subjects exposed to 50-200 mg in a single ascending dose study. However, this was a small, “first-in-human” Phase 1 study designed to assess the initial safety characteristics of simufilam in healthy subjects and usethis study was not designed to, and did not, evaluate safety, tolerability and efficacy of simufilam in patients. Additional large, well-controlled, multi-dose studies will be required to evaluate the safety, tolerability and efficacy of simufilam to treat patients with any indication, including Alzheimer’s disease. There can be no assurance that such future studies will demonstrate the safety, tolerability or efficacy of simufilam.

Results of Phase 2 clinical studies with simufilam demonstrated a reduction in biomarkers of disease. However, these were small, clinical-proof-of-concept Phase 2 studies designed to assess the initial safety characteristics of simufilam in patients. Our Phase 2 program was not designed to, and did not, evaluate large-scale or long-term safety, tolerability and efficacy of simufilam in patients. Additional large, well-controlled, multi-dose studies will be required to evaluate the safety, tolerability and efficacy of simufilam to treat patients with any indication, including Alzheimer’s disease. There can be no assurance that such future studies will demonstrate the safety, tolerability or efficacy of simufilam. The failure of simufilam to show safety, tolerability or efficacy in any future clinical studies would significantly harm our drugsbusiness.

We have never obtained FDA approval for a diagnostic test and we may not be able to secure such approval in a timely manner or at all.

We are developing a blood-based diagnostic test for Alzheimer’s disease, called SavaDx, which will depend onrequire FDA approval prior to commercialization. Our diagnostic product candidate, marketing, sales and development activities and manufacturing processes are subject to extensive and rigorous regulation by FDA pursuant to the FDCA, by comparable agencies in foreign countries, and by other regulatory agencies and governing bodies. Under the FDCA, a numberdiagnostic must receive FDA clearance or approval before it can be commercially marketed in the U.S. The process of factors including:obtaining marketing approval or clearance from FDA or by comparable agencies in foreign countries for new products could:

·

when the drug is launched into the market and related competition;take a significant period of time;

·

approved label claims;require the expenditure of substantial resources;

·

perceptions by membersinvolve rigorous pre-clinical testing, as well as increased post-market surveillance;

·

require changes to products; and

·

result in limitations on the indicated uses of products.

If we do not compete effectively with scientific and commercial competitors, we may not be able to successfully develop our diagnostic test for Alzheimer’s disease.

The field of clinical laboratory testing is highly competitive. Diagnostic tests that are developed are characterized by rapid technological change. Our competitors in the U.S. and abroad are numerous and include, among others, major diagnostic companies, reference laboratories, molecular diagnostic firms, universities and other research institutions. Most of our potential competitors have considerably greater financial, technical, marketing and other resources than we do, which may allow these competitors to discover important biological markers and determine their function before we do. We could be adversely affected if we do not discover proteins or biomarkers and characterize their function, develop diagnostic and pharmaceutical and clinical services based on these discoveries, obtain required regulatory and other approvals and launch these tests and their related services before our competitors. We also expect to encounter significant competition with respect to any diagnostic tests that we may develop or commercialize. Those companies that bring to market new diagnostic tests before we do may achieve a significant competitive advantage in marketing and commercializing their tests. We may not be able to develop additional diagnostic tests successfully and we may not obtain or enforce patents, if any, covering these tests that provide protection against our competitors. Moreover, our competitors may succeed in developing diagnostic tests that circumvent our technologies or tests. Furthermore, our competitors may succeed in developing technologies or tests that are more effective or less costly than those developed by us or that would render our technologies or tests less competitive or obsolete. We expect competition to intensify in the fields in which we are involved as technical advances in these fields occur

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and become more widely known and changes in intellectual property laws generate challenges to our intellectual property position.

We will need to develop our own proprietary antibodies to advance our SavaDx and our diagnostic program.

SavaDx currently relies on the use of commercially available antibodies, which are complex molecules that can recognize and bind to an intended protein. Commercially available antibodies present certain technical flaws, such as improper validation, significant batch-to-batch variations or inconsistent storage, any of which can jeopardize our studies and experiments. Because antibody underperformance can be a significant drain on time and resources, we are developing and validating our own, fit-for-purpose antibody for use with SavaDx and such technical activities are on-going. The complexity of developing our own antibody gives rise to many technical issues that are challenging to solve, and we cannot be certain that we will be able to successfully complete any of these activities, in which case our program may be harmed.

We have concentrated a substantial portion of our research and development efforts on the treatment and detection of Alzheimer’s disease, an area of research that has seen significant failure rates. Further, our product candidates are based on new scientific approaches and novel technology, which makes it difficult to predict the time and cost of product candidate development.

We focus substantially all of our research and development efforts on addressing neurodegenerations, such as Alzheimer’s disease. Collectively, efforts by biopharmaceutical companies in the field of neurodegenerative diseases have seen many failures and limited success in drug development. For example, there are no therapeutic options available to reverse Alzheimer’s disease, or even to halt its progress. Our future success is highly dependent on the successful development of our product candidates for treating Alzheimer’s disease. Developing and, if approved, commercializing our product candidates for treatment of Alzheimer’s disease subjects us to many challenges, including obtaining regulatory approval from FDA and other regulatory authorities who have only a limited set of precedents to rely on. We cannot be sure that our approach will yield satisfactory therapeutic products that are safe and effective, scalable, or profitable.

Our Phase 2 clinical studies with simufilam in patients with Alzheimer’s disease are not designed to show a statistically meaningful difference between those patients who receive placebo and those who receive drug.

Clinical research data is often analyzed with statistical probability (p-value) to address the question of whether a clinical observation is related to a treatment effect, a random effect or something else. This, in turn, requires a clinical study to incorporate a sufficiently large sample patient population to infer the appropriate statistical analysis. By design, our Phase 2 clinical program with simufilam does not include a sufficiently large patient population to generate statistical probability on clinical observations. This feature may make it difficult for investors to properly interpret whether clinical observations in our Phase 2 studies with simufilam are important or meaningful. Conversely, our clinical studies may generate statistically meaningful data (i.e., p<0.05) with regard to biomarkers, or other endpoints, that have unknown or no clinical importance. In general, the distinction between statistical significance and clinical significance is a complex area of research that continues to evolve and may be subject to differences of opinion among scientists, clinicians and other professionals.

We may encounter difficulties enrolling patients in our clinical studies, and our clinical development activities could thereby be delayed or otherwise adversely affected.

The timely completion of clinical studies in accordance with their protocols depends, among other things, on our ability to enroll enough patients who remain in the study until its conclusion. We may experience difficulties in patient enrollment in our clinical studies for a variety of reasons, including:

·

the size and severity of disease in the patient population;

·

the patient eligibility criteria defined in the protocol, including biomarker-driven identification and/or certain highly-specific criteria related to stage of disease progression, which may limit the patient populations eligible for our clinical studies to a greater extent than competing clinical studies for the same indication that do not have biomarker-driven patient eligibility criteria;

·

the size of the healthcare community, including physicians, aboutstudy population required for analysis of the safety and effectivenesstrial’s primary endpoints;

·

the design of our drugs,study protocol;

·

our ability to recruit clinical study investigators with the appropriate competencies and experience;

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·

competing clinical studies for similar therapies or targeting patient populations meeting our patient eligibility criteria;

·

clinicians’ and patients’ perceptions as to the potential advantages and side effects of the product candidate being studied in particular, relation to other available therapies and product candidates;

·

our ability to obtain and maintain patient consents;

·

physicians’ patient referral practices that are out of our control;

·

our ability to adequately monitor patients and their caregivers during and after treatment; and

·

the effectivenessrisk that patients enrolled in clinical studies will not complete such studies, for any reason.

Our clinical studies may fail to demonstrate substantial evidence of the safety and efficacy of our product candidates, which would prevent, delay, or limit the scope of regulatory approval and commercialization.

Before obtaining regulatory approvals for any of our product candidates, we must demonstrate through lengthy, complex, and expensive preclinical experiments and clinical studies that our product candidates are both safe and effective for use in an intended population. Each product candidate must demonstrate an adequate risk versus benefit profile in its intended patient population and for its intended use.

Clinical testing is expensive and can take many years to complete, and its outcome is inherently uncertain. Failure can occur at any time during the clinical study process. The results of preclinical studies of our product candidates may not be predictive of the results of early-stage or later-stage clinical studies, and results of early clinical studies of our product candidates may not be predictive of the results of later-stage clinical studies. The results of clinical studies in one set of patients or disease indications may not be predictive of those obtained in another. In some instances, there can be significant variability in safety or efficacy results between different clinical studies of the same product candidate due to numerous factors, including changes in study procedures set forth in protocols, differences in the size and type of the patient populations, changes in and adherence to the dosing regimen, and other clinical study protocols and the rate of dropout among clinical study participants. Open-label extension studies may also extend the timing and cost of a clinical study substantially. Product candidates in later stages of clinical studies may fail to show the desired safety and efficacy profile despite having progressed through preclinical studies and initial clinical studies. Many companies in the biopharmaceutical industry have suffered significant setbacks in advanced clinical studies due to lack of efficacy or unacceptable safety issues, notwithstanding promising results in earlier studies. This is particularly true in neurodegenerative diseases, where failure rates historically have been higher than in many other disease areas. Most product candidates that begin clinical studies are never approved by regulatory authorities for commercialization.

We have limited experience in designing clinical studies in neurodegeneration and may be unable to design and execute a clinical study to support marketing approval. We cannot be certain that our current clinical studies or any other future clinical studies will be successful. Additionally, any safety concerns observed in any one of our clinical studies in our targeted indications could limit the prospects for regulatory approval of our product candidates in those and other indications, which could have a material adverse effect on our business, financial condition, and results of operations.

In addition, even if such clinical studies are successfully completed, we cannot guarantee that FDA or foreign regulatory authorities will interpret the results as we do, and more studies could be required before we submit our product candidates for approval. To the extent that the results of the studies are not satisfactory to FDA or foreign regulatory authorities for support of a marketing application, we may be required to expend significant resources, which may not be available to us, to conduct additional studies in support of potential approval of our product candidates. Even if regulatory approval is secured for any of our product candidates, the terms of such approval may limit the scope and use of our product candidates, which may also limit its commercial potential.

If our drug candidate causes or contribute to a death or a serious injury before or after approval, we will be subject to medical reporting regulations, which can result in voluntary corrective actions or agency enforcement actions.

Our drug candidate in Alzheimer’s disease is aimed at a frail, elderly patient population that is in a state of perpetual cognitive decline. Under FDA medical reporting regulations, we are required to report to the FDA information that our drug candidate has or may have caused or contributed to a death or serious injury. Any such serious adverse event involving our drug could result in future FDA action, such as an inspection, enforcement action or warning, or in more serious cases, a complete shutdown of our clinical program. In the context of our ongoing clinical trial, we report adverse events to the FDA in accordance with applicable national and local regulations. Any corrective action, whether voluntary or involuntary, and

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either pre- or post-market, needed to address any serious adverse events will require the dedication of our time and capital, distract management from operating our business, and may harm our reputation and financial results.

The market opportunities for simufilam and SavaDx, if approved, may be smaller than we anticipate.

If our clinical development programs succeed, we expect to seek regulatory approval of simufilam and SavaDx for patients with Alzheimer’s disease. Our projections of the number of patients with Alzheimer’s disease is based on our beliefs and estimates. These estimates have been derived from a variety of sources, including scientific literature, patient foundations and market research, and may prove to be incorrect. The actual number of patients may turn out to be lower than expected. Additionally, the potential patient population for our current programs or future product candidates may be limited. Even if we obtain significant market share for any product candidate, if approved, if the potential target populations are smaller than anticipated, we may never achieve profitability without obtaining marketing approval for additional indications.

We face significant competition in an environment of rapid technological and scientific change, and there is a possibility that our competitors may achieve regulatory approval before us or develop therapies that are safer, more advanced, or more effective than ours, any of which may harm our business operations.

The development and commercialization of new product candidates is highly competitive. Moreover, the neurodegenerative field is characterized by intense and increasing competition, and a strong emphasis on intellectual property. We may face competition with respect to any of our product candidates that we seek to develop or commercialize in the future from major pharmaceutical companies, specialty pharmaceutical companies, and biotechnology companies worldwide. Potential competitors also include academic institutions, government agencies, and other public and private research organizations that conduct research, seek patent protection, and establish collaborative arrangements for research, development, manufacturing, and commercialization.

Several large pharmaceutical and biotechnology companies are currently pursuing the development of products for the treatment of neurodegenerative diseases, including Alzheimer’s disease. Many of these current or potential competitors, either alone or with their strategic partners, have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical studies, obtaining regulatory approvals, and marketing approved products than we do.

Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient, or are less expensive than any products that we may develop. Furthermore, currently approved products could be discovered to have application for treatment of neurodegenerative disease indications, which could give such products significant advantages over any of our product candidates. Our competitors also may obtain FDA, EMA, or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market. Additionally, products or technologies developed by our competitors may render our potential product candidates uneconomical or obsolete, and we may not be successful in marketing any product candidates we may develop against competitors.

In addition, we could face litigation or other proceedings with respect to the scope, ownership, validity, and/or enforceability of our patents relating to our competitors’ products and our competitors may allege that our products infringe, misappropriate, or otherwise violate their intellectual property. The availability of our competitors’ products could limit the demand, and the price we are able to charge, for any products that we may develop and commercialize.

Risks Related to Government Regulation and Other Legal Compliance Matters

If we are ultimately unable to obtain regulatory approval for our product candidates, we will be unable to generate product revenue and our business will be substantially harmed.

The time required to obtain approval by FDA, EMA, and comparable foreign regulatory authorities is unpredictable, typically takes many years following the commencement of clinical studies, and depends upon numerous factors, including the type, complexity, and novelty of the product candidates involved. In addition, approval policies, regulations, or the type and amount of clinical data necessary to gain approval may change during the course of a product candidate’s clinical development and may vary among jurisdictions, which may cause delays in the approval or the decision not to approve an

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application. Regulatory authorities have substantial discretion in the approval process and may refuse to accept any application or may decide that our data are insufficient for approval and require additional preclinical, clinical, or other studies. The FDA has not approved a new drug for Alzheimer’s disease since 2003. We have not obtained regulatory approval for any product candidate, including our product candidates aimed at Alzheimer’s disease, and it is possible that none of our existing product candidates or any product candidates we may seek to develop in the future will ever obtain regulatory approval.

Applications for our product candidates could fail to receive regulatory approval in an initial or subsequent indication for many reasons, including but not limited to the following:

·

FDA, EMA, or comparable foreign regulatory authorities may disagree with the design, implementation, or results of REMOXY in reducing potential risks ofour clinical studies;

·

FDA, EMA, or comparable foreign regulatory authorities may determine that our product candidates are not safe and effective, only moderately effective or have undesirable or unintended side effects, toxicities, or other characteristics that preclude our obtaining marketing approval or prevent or limit commercial use;

·

perceptions by physicians regarding the cost benefit of REMOXYpopulation studied in reducing potential risks of unintended use;the clinical program may not be sufficiently broad or representative to assure efficacy and safety in the full population for which we seek approval;

·

published studies demonstratingwe may be unable to demonstrate to FDA, EMA or comparable foreign regulatory authorities that a product candidate’s risk-benefit ratio when compared to the cost-effectivenessstandard of our drugs relative to competing products;care is acceptable;

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availabilityFDA, EMA, or comparable foreign regulatory authorities may disagree with our interpretation of reimbursement for our productsdata from governmentpreclinical studies or healthcare payers;clinical studies;

·

the data collected from clinical studies of our product candidates may not be sufficient to support the submission of a new drug application (NDA), or our collaborators’ abilityother submission or to implement a risk management plan priorobtain regulatory approval in the United States or elsewhere;

·

FDA, EMA, or comparable foreign regulatory authorities may fail to approve the distributionmanufacturing processes, test procedures, and specifications, or facilities of any Schedule II drug;third-party manufacturers with which we contract for clinical and commercial supplies; and

·

effectivenessthe approval policies or regulations of marketing and distribution efforts by us and other licensees and distributors.FDA, EMA, or comparable foreign regulatory authorities may significantly change in a manner rendering our clinical data insufficient for approval.



Because we expectThis lengthy approval process, as well as the unpredictability of the results of clinical studies, may result in our failing to rely on sales generated by our current lead drug candidates for substantially allobtain regulatory approval to market any of our revenues for the foreseeable future, the failure of any of these drugs to find market acceptanceproduct candidates, which would significantly harm our business, results of operations, and could require us to seek additional financing.

The science of abuse-deterrence is relatively new.

The analytical, clinical, and statistical methods for evaluating abuse-deterrent technologies and study results are new and rapidly evolving. Although we believe the FDA will take a flexible, adaptive approach to the evaluation and labeling of potentially abuse-deterrent products, such as REMOXY, we cannot be certain that our interpretation of abuse-deterrent data for REMOXY is consistent with the views of the FDA. In our opinion, the FDA has limited data correlating the potentially abuse-deterrent properties of certain opioid drug products, such as REMOXY, with actual reduction in abuse or adverse events associated with abuse. In addition, the FDA has stated it is not able to provide specific guidance on the magnitude of effect that would be sufficient to support any particular type of label claim for abuse-deterrence.growth prospects.



Our ability to market and promote REMOXY and its abuse-deterrent featuresour product candidates will be determined and limited by FDA-approved labeling.



The commercial success of REMOXY and certain of our other product candidates will depend upon our ability to obtain FDA-approved labeling describing their abuse-deterrent features. Our failure to achieve FDA approval of product labeling containing such information will prevent us from advertising and promoting the abuse-deterrentkey features of our product candidates in order to differentiate them from other similar products. This would make our products less competitive in the market.



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Abuse-deterrent label claims for REMOXYOur employees, independent contractors, consultants, commercial partners, and vendors may not be broad enough to demonstrate a substantial benefit to health care providers and patients.

FDA approval is requiredengage in order to make claims that a product has an abuse-deterrent effect. In April 2015, the FDA published final guidance with regard to the evaluation and labeling of abuse-deterrent opioids. The guidance provides direction as to the studies and data required for obtaining abuse-deterrent claims in a product label. FDA guidance describes three categories of pre-market studies that may lead to an abuse-deterrent claim:

Category 1 – laboratory manipulation and extraction studies;

Category 2 – pharmacokinetic studies; and

Category 3 – human abuse potential studies.

According to the FDA guidance, label claims for abuse-deterrence should describe the product’s specific abuse-deterrent properties as well as the specific routes of abuse that the product has been developed to deter. When data predict or show that a product’s potentially abuse-deterrent properties can be expected to, or actually do, result in a significant reduction in that product’s abuse potential, these data, together with an accurate characterization of what the data mean, may be included in product labeling.

If a product is approved by the FDA to include such claims in its label, the applicant may use the approved labeling information about the abuse-deterrent features of the product in its marketing efforts to physicians.

Although we intend to provide data to the FDA to support approval of abuse-deterrence label claims for REMOXY, there can be no assurance that REMOXY or any of our other product candidates will receive FDA-approved labeling that describes the abuse-deterrent features of such products. The FDA may find that our studies and data do not support abuse-deterrent labeling or that our product candidates do not provide substantial abuse-deterrence because, for example, their deterrence mechanisms do not address the way they are most likely to be abused. Further, the FDA is not required to follow its guidance and could change this guidance, which could require us to conduct additional studies or generate additional data. If the FDA does not approve abuse-deterrent labeling, we will not be able to promote such products based on their abuse-deterrent features and our business may suffer.

Even if we do receive FDA approval for abuse-deterrent claims, the claims may not be broad enough to demonstrate a substantial benefit to health care providers and patients. For instance, the claims may not encompass the more common forms of abuse for products like our product candidates. Moreover, continued investigation in Phase IV studies following product approval, if required, is expensive and may not support the continued use of abuse-deterrent claims.

If we cannot compete successfully for market share against other drug companies, we may not achieve sufficient product revenues and our business will suffer.

The market for our drug candidates is characterized by intense competition and rapid technological advances. If our drug candidates receive FDA approval, they will compete with a number of existing and future drugs and therapies developed, manufactured and marketed by others. Existing or future competing products may provide greater therapeutic convenience or clinicalmisconduct or other benefits for a specific indication than our products, or may offer comparable performance at a lower cost. If our products are unable to captureimproper activities, including noncompliance with regulatory standards and maintain market share, we may not achieve sufficient product revenues and our business will suffer.requirements.



We and our collaborators will compete for market share against fully integrated pharmaceutical companiesare exposed to the risk of fraud, misconduct, or other companiesillegal activity by our employees, independent contractors, consultants, commercial partners, and vendors. Misconduct by these parties could include intentional, reckless, and negligent conduct that are collaborating with larger pharmaceutical companies, academic institutions, government agencies and other public and private research organizations. Many of these competitors have drugs already approved or drug candidates in development that will or may compete against our approved drug candidates. In addition, many of these competitors, either alone or together with their collaborative partners, operate larger research and development programs and have substantially greater financial resources than we do, as well as significantly greater experience in:fails to:

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developing drugs;comply with the laws of FDA, EMA, and other comparable foreign regulatory authorities;

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conducting preclinical testingprovide true, complete, and human clinical trials;accurate information to FDA, EMA, and other comparable foreign regulatory authorities;

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obtaining FDA and other regulatory approvals of drugs;comply with manufacturing standards we have established;

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comply with healthcare fraud and abuse laws in the U.S. and similar foreign fraudulent misconduct laws; or

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report financial information or data accurately or to disclose unauthorized activities to us.

Activities subject to laws also involve the improper use of information obtained in the course of patient recruitment for clinical studies, which could result in regulatory sanctions and cause serious harm to our reputation. Further, it is not always possible to identify and deter misconduct by employees and third parties, and the precautions we take to detect and prevent

 

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this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of significant fines or other sanctions.

If we fail to comply with the complex federal, state, local and foreign laws and regulations that apply to our business, we could suffer severe consequences that could materially and adversely affect our operating results and financial condition.

Our operations are subject to extensive federal, state, local and foreign laws and regulations, all of which are subject to change. These laws and regulations currently include, among other things:



·

formulatingThe Clinical Laboratory Improvement Amendments (CLIA) of 1988, which are United States federal regulatory standards that apply to all clinical laboratory testing performed on humans in the United States, requires that laboratories obtain certification from the federal government, and manufacturing drugs;state licensure laws;

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FDA laws and regulations;

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The Health Insurance Portability and Accountability Act (HIPAA), which imposes comprehensive federal standards with respect to the privacy and security of protected health information and requirements for the use of certain standardized electronic transactions, including penalties for violators, enforcement authority to state attorneys general and requirements for breach notification;

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state laws regulating testing and protecting the privacy of test results, as well as state laws protecting the privacy and security of health information and personal data and mandating reporting of breaches to affected individuals and state regulators;

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the federal anti-kickback law, or the Anti-Kickback Statute, which prohibits knowingly and willfully offering, paying, soliciting, receiving, or providing remuneration, directly or indirectly, in exchange for or to induce either the referral of an individual, or the furnishing, arranging for, or recommending of an item or service that is reimbursable, in whole or in part, by a federal health care program;

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the federal False Claims Act (FCA), which imposes liability on any person or entity that, among other things, knowingly presents, or causes to be presented, a false or fraudulent claim for payment to the federal government;

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the federal Civil Monetary Penalties Law, which prohibits, among other things, the offering or transfer of remuneration to a Medicare or state health care program beneficiary if the person knows or should know it is likely to influence the beneficiary’s selection of a particular provider, practitioner, or supplier of services reimbursable by Medicare or a state health care program, unless an exception applies;

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other federal and state fraud and abuse laws, such as anti-kickback laws, prohibitions on self-referral, and false claims acts, which may extend to services reimbursable by any third-party payor, including private insurers;

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the federal Physician Payments Sunshine Act, which requires manufacturers to track and report to the federal government certain payments and other transfers of value made to physicians and teaching hospitals and ownership or investment interests held by physicians and their immediate family members;

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Section 216 of the federal Protecting Access to Medicare Act of 2014 (PAMA), which requires applicable laboratories to report private payer data in a timely and accurate manner every three years (and in some cases annually);

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state laws that impose reporting and other compliance-related requirements; and

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launching, marketing, distributingsimilar foreign laws and selling drugs.regulations that will apply to us in foreign countries in which we may choose to operate in the future. 



If we failGovernment agencies may establish and promulgate usage guidelines that could limit the use of our product candidates.

Government agencies, professional and medical societies, and other groups may establish usage guidelines that apply to obtain acceptable pricesour product candidates. These guidelines could address such matters as usage and dose, among other factors. Application of such guidelines could limit the clinical use or an adequate levelcommercial appeal of reimbursement for our products from healthcare payers, our ability to generate product revenues will be diminished.candidates.

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Our product candidates may cause undesirable side effects or have other properties that could halt their clinical development, prevent their regulatory approval, limit their commercial potential, or result in significant negative consequences.

We have not yet completed long-term safety studies with simufilam to determine if this product candidate is safe for humans. Adverse events or other undesirable side effects caused by simufilam could cause us or regulatory authorities to interrupt, delay, or halt clinical studies and could result in a more restrictive label or the delay or denial of regulatory approval by FDA, EMA, or other comparable foreign regulatory authorities.

Drug-related side effects could affect patient recruitment, the ability of enrolled patients to complete the study, and/or result in potential product liability claims. We are required to maintain product liability insurance pursuant to certain of our development and commercialization agreements. We may not be able to maintain insurance coverage at a reasonable cost or in sufficient amounts to protect us against losses due to liability. A successful product liability claim or series of claims brought against us could adversely affect our results of operations, business, and reputation. In addition, regardless of merit or eventual outcome, product liability claims may result in impairment of our business reputation, withdrawal of clinical study participants, costs due to related litigation, distraction of management’s attention from our primary business, initiation of investigations by regulators, substantial monetary awards to patients or other claimants, the inability to commercialize our product candidates, and decreased demand for our product candidates, if approved for commercial sale.

If our product candidates receive regulatory approval, we and our collaborators will be subject to ongoing FDA obligations and continued regulatory review, such as continued safety reporting requirements, and we and our collaborators may also be subject to additional FDA post-marketing obligations or new regulations, all of which may result in significant expense and limit our and our collaborators’ ability to commercialize drugs we (alone or with other collaborators)our potential drugs.

Any regulatory approvals that our product candidates receive may develop will depend in partalso be subject to limitations on the extent toindicated uses for which reimbursement canthe drug may be obtainedmarketed or contain requirements for such drugs from:

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government and health administration authorities;

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private health maintenance organizations and health insurers; and

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other healthcare payers.

Significant uncertainty exists as to the reimbursement status of newly approved healthcare products. Healthcare payers, including Medicare, health maintenance organizations and managed care organizations, are challenging the prices charged for medical products and services and/or are seeking pharmacoeconomic data to justify formulary acceptance and reimbursement practices. We currently have not generated pharmacoeconomic data onpotentially costly post-marketing follow-up studies. In addition, if FDA approves any of our product candidates, the labeling, packaging, adverse event reporting, storage, advertising, promotion and record keeping for the drug will be subject to extensive regulatory requirements. The subsequent discovery of previously unknown problems with the drug, including but not limited to adverse events of unanticipated severity or frequency, or the discovery that adverse events previously observed in preclinical research or clinical studies that were believed to be minor actually constitute much more serious problems, may result in restrictions on the marketing of the drug, and could include withdrawal of the drug from the market.

The FDA’s policies may change, and additional government regulations may be enacted that could prevent or delay regulatory approval of our product candidates. GovernmentWe cannot predict the likelihood, nature or extent of adverse government regulation that may arise from future legislation or administrative action, either in the U.S. or abroad. If we are not able to maintain regulatory compliance, we may be subject to fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and other healthcare payers increasingly are attempting to contain healthcare costs by limiting both coverage and the levelcriminal prosecution. Any of reimbursement for drugs, and by refusing, in some cases, to provide coverage for uses of approved products for disease indications for which the FDA has or has not granted labeling approval. Adequate third-party insurance coverage may not be available to patients for any products we discover and develop, alone or with collaborators. If government and other healthcare payers do not provide adequate coverage and reimbursement levels forthese events could prevent us from marketing our products market acceptance ofand our drug candidatesbusiness could be limited.suffer.



Enacted and future legislation may increase the difficulty and cost for us to commercialize our product candidates and may reduce the prices we are able to obtain for our product candidates.



Legislative and regulatory changes and future changes regarding the healthcare system could prevent or delay marketing approval of our product candidates, restrict or regulate post-approval activities or affect our ability to profitably sell any product candidates for which we obtain marketing approval.



In the United States,U.S., the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 or the(the Medicare Modernization Act,Act) established the Medicare Part D program and provided authority for limiting the number of drugs that will be covered in any therapeutic class thereunder. The Medicare Modernization Act, including its cost reduction initiatives, could limit the coverage and reimbursement rate that we receive for any of our approved products. Private payors may follow Medicare coverage policies and payment limitations in setting their own reimbursement rates resulting in similar limits in payments from private payors.



The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or collectively, the Affordable Care Act, among other things, imposes a significant annual fee on companies that manufacture or

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import branded prescription drug products.product candidates. It also contains substantial provisions intended to, among other things, broaden access to health insurance, reduce or constrain the growth of health care spending, enhance remedies against healthcare fraud and abuse, add new transparency requirements for the healthcare and health insurance industries, and impose additional health policy reforms, any of which could have a material adverse effect on our business. A significant number of provisions are not yet, or have only recently become, effective, but the Affordable Care Act may result in downward pressure on pharmaceutical pricing, especially under the Medicare program, and may also increase our regulatory burdens and operating costs.



The Affordable Care Act, as well as other healthcare reform measures that have been and may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we receive for any approved product, and could seriously harm our future revenues. Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from private payors. The implementation of cost containment measures or other healthcare reforms may compromise our ability to generate revenue, attain profitability or commercialize our products.



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The Affordable Care Act is a highly complex piece of legislation that continues to evolve. We do not and cannot understand or anticipate the full impact and potential implications of the Affordable Care Act on our business or on our drugs.

Even if we are able to commercialize any of our product candidates, our products may become subject to unfavorable pricing regulations or third-party coverage and reimbursement policies, which could have a material adverse effect on our business.

Our ability to commercialize any products successfully will depend in part on the extent to which coverage and adequate reimbursement for these products and related treatments will be available from government health administration authorities, private health insurers and other organizations. Government authorities and third-party payors, such as private health insurers and health maintenance organizations, determine which medications they will cover and establish reimbursement levels. A primary trend in the U.S. healthcare industry and elsewhere is cost containment. Government authorities and other third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications. Increasingly, third-party payors are requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged for medical products. We cannot be sure that coverage and reimbursement will be available for any product that we commercialize and, if reimbursement is available, what the level of reimbursement will be and whether it will be satisfactory. Coverage and reimbursement may impact the demand for, or the price of, any product candidate for which we obtain marketing approval. If coverage and reimbursement are not available or reimbursement is available only to limited levels, we may not be able to successfully commercialize any product candidate for which we obtain marketing approval.

There may be significant delays in obtaining coverage and reimbursement for newly approved drugs, and coverage may be more limited than the purposes for which the drug is approved by the FDA or foreign regulatory authorities. Moreover, eligibility for coverage and reimbursement does not imply that any drug will be paid for in all cases or at a rate that covers our costs, including research, development, manufacture, sale and distribution. Interim reimbursement levels for new drugs, if applicable, may also be insufficient to cover our costs and may only be temporary. Reimbursement rates may vary according to the use of the drug and the clinical setting in which it is used, may be based on reimbursement levels already set for lower cost drugs and may be incorporated into existing payments for other services. Net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the United States. Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement policies. Our inability to promptly obtain coverage and profitable reimbursement rates from both government-funded and private payors for any approved products that we develop could have a material adverse effect on our operating results, our ability to raise capital needed to commercialize products and our overall financial condition.

Public concern over the abuse of opioids, including law enforcement concerns over diversion of opioid and regulatory efforts to combat abuse, could decrease the potential market for our product candidates.

Media stories regarding prescription drug abuse and the diversion of opioids and other controlled substances are commonplace. Law enforcement and regulatory agencies may apply policies that seek to limit the availability of opioids. Such efforts may inhibit our ability to commercialize our product candidates. Aggressive enforcement and unfavorable publicity regarding, for example, the use or misuse of oxycodone or other opioid drugs; the limitations of ADFs; the ability of drug abusers to discover previously unknown ways to abuse our products; public inquiries and investigations into prescription drug abuse; litigation; or regulatory activity regarding sales, marketing, distribution or storage of opioid drugs could have a material adverse effect on our reputation. Such negative publicity could reduce the potential size of the market for our product candidates and decrease the revenues we are able to generate from their sale. To the extent opioid abuse becomes less prevalent or less urgent of a public health issue, regulators and third party payers may not be willing to pay a premium for ADFs of opioids.

Efforts by the FDA and other regulatory bodies to combat abuse of opioids may negatively impact the market for our product candidates. For example, on September 10, 2013, the FDA announced its intention to effect labeling changes to all approved long-acting opioid formulations. In particular, the FDA announced its intention to update the indication for long-acting opioid formulations so that long-acting opioid formulations will be indicated only for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. On April 16, 2014, the FDA updated these indications. It is possible that such changes could reduce the number of prescriptions for opioids written by physicians and negatively impact the potential market for our product candidates.

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If the FDA or other applicable regulatory authorities approve generic products with abuse-deterrent claims that compete with any of our product candidates, it could reduce our sales of those product candidates.

Once an NDA, including a Section 505(b)(2) application, is approved, the product covered thereby becomes a "listed drug" which can, in turn, be cited by potential competitors in support of approval of an abbreviated NDA, or ANDA. Potential competitors may create modified, non-infringing versions of a drug to facilitate the approval of an ANDA or other application for generic substitutes. These competitors might only be required to conduct a relatively inexpensive study to show that their product has the same active ingredients, dosage form, strength, route of administration, and conditions of use, or labeling, as our products and that the generic product is absorbed in the body at the same rate and to the same extent as, or is bioequivalent to, our products. These generic equivalents would be significantly less costly than ours to bring to market and companies that produce generic equivalents are generally able to offer their products at lower prices. Thus, after the introduction of a generic competitor, a significant percentage of the sales of any branded product are typically lost to the generic product. Accordingly, competition from generic equivalents to our products would substantially limit our ability to generate revenues and therefore to obtain a return on the investments we have made in our product candidates.



Our relationships with customers and payors will be subject to applicable anti-kickback, fraud and abuse, transparency, and other healthcare laws and regulations, which could expose us to criminal sanctions, civil penalties, exclusion from government healthcare programs, contractual damages, reputational harm, administrative burdens, and diminished profits and future earnings.



Healthcare providers, physicians and payors play a primary role in the recommendation and prescription of any product candidates for which we may obtain marketing approval. Our future arrangements with payors and customers may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we market, sell and distribute any product candidates for which we may obtain marketing approval. Even though we do not and will not control referrals of healthcare services or bill directly to Medicare, Medicaid or other third-party payors, federal and state healthcare laws and regulations pertaining to fraud and abuse and patients' rights are and will be applicable to our business. Restrictions under applicable federal, state and foreign healthcare laws and regulations may affect our ability to operate and expose us to areas of risk, including:

·

the federal Anti-Kickback Statute, which prohibits, among other things, knowingly and willfully soliciting, offering, receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward either the referral of an individual for, or the purchase, order or recommendation of, any good or service, for which payment may be made under federal and state healthcare programs such as Medicare and Medicaid. A person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation;

·

the federal False Claims Act,FCA, which imposes criminal and civil penalties, including through civil whistleblower or qui tam actions, against individuals or entities for knowingly presenting, or causing to be presented, to the federal government, claims for payment that are false or fraudulent or making a false statement to avoid, decrease or conceal an obligation to pay money to the federal government. In addition, the government may assert that a claim including items and services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the False Claims Act;FCA;

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the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which imposes criminal and civil liability for executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters. Similar to the federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute to defraud any healthcare benefit program or specific intent to violate it in order to have committed a violation;

·

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009 or HITECH, and its implementing regulations, which also imposes obligations on certain covered entity healthcare providers, health plans, and healthcare clearinghouses as well as their business associates that perform certain services involving the use or disclosure of individually identifiable health information, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually identifiable health information;

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·

federal laws requiring drug manufacturers to report information related to payments and other transfers of value made to physicians and other healthcare providers, as well as ownership or investment interests held by physicians and their immediate family members, including under the federal Open Payments program, commonly known as the Sunshine Act, as well as other state and foreign laws regulating marketing activities; and

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·

state and foreign equivalents of each of the above laws, including state anti-kickback and false claims laws, which may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental payors, including private insurers; state laws which require pharmaceutical companies to comply with the pharmaceutical industry's voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government or otherwise restricting payments that may be made to healthcare providers; and state and foreign laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.



Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare laws and regulations will involve substantial costs. Nonetheless, it is possible that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations. If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, imprisonment, exclusion from participation in government funded healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of our operations.



Government agencies may establish and promulgate usage guidelines thatAny future litigation against us could limit the use of our drug candidates.

Government agencies, professional and medical societies, and other groups may establish usage guidelines that apply to our drug candidates. These guidelines could address such matters as usage and dose, among other factors. Application of such guidelines could limit the clinical use or commercial appeal of our drug candidates.

Risks Relating to our Intellectual Property

Our ability to commercialize our drug candidates will depend on our ability to sell such products without infringing the patent or proprietary rights of third parties. If we are sued for infringing the intellectual property rights of third parties, such litigation will be costly and time-consuming to defend.

Innovative drug development is highly litigious, and we may become subject, from time consumingto time, to legal proceedings, claims and an unfavorable outcome wouldallegations that arise in the ordinary course of business or pursuant to governmental or regulatory enforcement activity. Regardless of merit, any lawsuits against us, individually or in the aggregate, may have a significantmaterial adverse effect on our business, financial condition, results of operations or cash flows. In addition, any litigation to which we subsequently become a party might result in substantial costs and divert management's attention, time and resources, which might seriously harm our business, financial condition, results of operations and cash flows. Our insurance policies might not cover such claims, might not provide sufficient payments to cover all of the costs to resolve one or more such claims, and might not continue to be available on terms acceptable to us. In particular, any claim could result in potential liability for us if the claim is outside the scope of the indemnification agreement we have with our third-party partners, or our third-party partners do not abide by the indemnification agreement as required, or the liability exceeds the amount of any applicable indemnification limits or available insurance coverage. A claim brought against us that is uninsured or underinsured could result in unanticipated costs and could have a material adverse effect on our financial condition, results of operations, cash flows or reputation.

A recent federal court ruling may mandate significant new disclosure requirements for clinical data dating back over a decade which may lead to costly or burdensome disclosures.

A recent federal court ruling may require all clinical study sponsors to report a decade’s worth of previously exempted clinical study data to the federal government for publication on ClinicalTrials.gov. In February 2020, the U.S. District Court for the Southern District of New York invalidated a prior interpretation of NIH regulations that had exempted many clinical studies conducted between 2007 and 2017 from reporting requirements mandated by the Food and Drug Administration Amendments Act. If this court ruling takes effect without appeal, or if it is upheld on appeal, it could require us to submit an onerous amount of old clinical data to the federal government. In many cases, we were the responsible party for generating such clinical data, but such prior data may be difficult or not feasible for us to access as a result of our strategic shift away from analgesic drug development in 2019.  We may no longer have control over, or access to, prior clinical data that we may legally be required to report to NIH in the future.  Furthermore, it is unclear whether such new disclosure requirements apply to inactive, failed or abandoned drug development programs. As a result of these uncertainties, the government’s recent ruling may leave us in a conflicted position or out of compliance with new disclosure requirements.  We currently do not and cannot understand or anticipate the full impact and potential implications of this court ruling on our business.



Risks Related to Our Intellectual Property

If we are unable to obtain and maintain sufficient patent protection for any product candidates we develop, our competitors could develop and commercialize products similar or identical to ours, and our ability to successfully commercialize our drugany product candidates will dependwe may develop may be adversely affected.

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Our success depends in large part on our ability to sell such products without infringing the patents or other proprietary rights of third parties. Intellectual property rightsobtain and maintain patent protection in the areasU.S. and other countries with respect to our proprietary product candidates and other technologies we may develop. We seek to protect our proprietary position by filing patent applications in the U.S. and abroad relating to our core programs and product candidates, as well as other technologies that are important to our business. Given that the development of controlled-releaseour product candidates is at an early stage, our intellectual property portfolio with respect to certain aspects of our product candidates is also at an early stage. For example, we have filed or intend to file patent applications on aspects of our technology and pharmaceutical ingredients are complicated and are continuously evolving. Holders of patent rights in these areas may allege that the commercialization of REMOXY or our other drug candidates infringes such patent rights. While we believe that we would have valid defenses to any claim of infringement,core product candidates; however, there can be no assurance that any such patent applications will issue as granted patents. Furthermore, in some cases, we have only filed provisional patent applications on certain aspects of our technology and product candidates and each of these provisional patent applications is not eligible to become an issued patent until, among other things, we file a non-provisional patent application within 12 months of the filing date of the applicable provisional patent application. Any failure to file a non-provisional patent application within this timeline could cause us to lose the ability to obtain patent protection for the inventions disclosed in the associated provisional patent applications.

Furthermore, in some cases, we may not be able to obtain issued claims covering compositions relating to our core programs and product candidates, as well as other technologies that are important to our business, and instead may need to rely on filing patent applications with claims covering a method of use and/or method of manufacture for protection of such core programs, product candidates, and other technologies. There can be no assurance that any such patent applications will issue as granted patents, and even if they do issue, such patent claims may be insufficient to prevent third parties, such as our competitors, from utilizing our technology. Any failure to obtain or maintain patent protection with respect to our core programs and product candidates could have a material adverse effect on our business, financial condition, results of operations, and growth prospects.

U.S. intellectual property rights around diagnostic methods is a complex, evolving area of law and effective patent claims may not be available to us for our investigational diagnostic product candidate, SavaDx, in the United States.

The legal system for intellectual property around diagnostic methods is highly complex, remains uncertain and continues to evolve. In the U.S., patent courts have struggled to define a clear means of patent eligibility for modern age diagnostics. Case law interpretations from the U.S. Supreme Court has left certain important scientific advances in the area of diagnostics without effective patent claims. In 2012, the Supreme Court held that a simple process involving correlations between blood test results and patient health is not eligible for patent claims because such processes incorporate “laws of nature”. Since then, different outcomes from different courts, including Federal Circuit, district court and Patent Trial and Appeal Board decisions, have continued to create a sometimes vague or conflicting legal framework for determining the eligibility of patent claims for diagnostic methods. As a result, we cannot be certain how SavaDx fits into the current U.S. legal framework for obtaining effective patent claims. We currently have no U.S. patents or patent applications with respect to SavaDx, and it is only protected in the United States by trade secrets, know-how and other proprietary rights technology. Furthermore, claims for diagnostic methods can be complicated to enforce. For patent infringement to occur with a protected diagnostic, the patented method must generally either be performed by one person in its entirety or performed by multiple parties all under the control or direction of a single party. Accordingly, even if effective patent claims are issued for SavaDx, it may be impractical, impossible or even undesirable to enforce potential infringement claims.

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Issued patents covering our product candidates and other technologies could be found invalid or unenforceable if challenged in court or before administrative bodies in the U.S. or abroad.

If we initiated legal proceedings against a third party to enforce a patent covering our product candidates or other third-partytechnologies, the defendant could counterclaim that such patent is invalid or unenforceable. In patent litigation in the U.S., defendant counterclaims alleging invalidity or unenforceability are commonplace. Grounds for a validity challenge could be an alleged failure to meet any of several statutory requirements, including lack of novelty, obviousness, or non-enablement. Grounds for an unenforceability assertion could be an allegation that someone connected with prosecution of the patent withheld relevant information from the USPTO, or made a misleading statement, during prosecution. Third parties may raise claims challenging the validity or enforceability of our patents before administrative bodies in the U.S. or abroad, even outside the context of litigation. Such mechanisms include re-examination, post-grant review, inter partesreview, interference proceedings, derivation proceedings, and equivalent proceedings in foreign jurisdictions (e.g., opposition proceedings). Such proceedings could result in the revocation of, cancellation of, or amendment to our patents in such a way that they no longer cover our product candidates or other technologies. The outcome following legal assertions of invalidity and unenforceability is unpredictable. With respect to the validity question, for example, we cannot be certain that there is no invalidating prior art, of which we or our licensing partners and the patent examiner were unaware during prosecution. If a third party were to prevail on a legal assertion of invalidity or unenforceability, we would lose at least part, and perhaps all, of the patent protection on our product candidates or other technologies. Such a loss of patent protection would have a material adverse impact on our business, financial condition, results of operations, and growth prospects.

If we do not obtain patent term extension and data exclusivity for any product candidates we may develop, our business may be materially harmed.

Depending upon the timing, duration, and specifics of any FDA marketing approval of any product candidates we may develop, one or more of our U.S. patents may be eligible for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Act). The Hatch-Waxman Act permits a patent term extension of up to five years as compensation for patent term lost during FDA regulatory review process. A patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval, only one patent may be extended and only those claims covering the approved drug, a method for using it, or a method for manufacturing it may be extended. Similar extensions as compensation for patent term lost during regulatory review processes are also available in certain foreign countries and territories, such as in Europe under a Supplementary Patent Certificate. However, we may not be granted an extension in the U.S. and/or foreign countries and territories because of, for example, failing to exercise due diligence during the testing phase or regulatory review process, failing to apply within applicable deadlines, failing to apply prior to expiration of relevant patents, or otherwise failing to satisfy applicable requirements. Moreover, the applicable time period or the scope of patent protection afforded could be less than we request. If we are unable to obtain a patent term extension or the term of any such extension is shorter than what we request, our competitors may obtain approval of competing products following our patent expiration, and our business, financial condition, results of operations, and growth prospects could be materially harmed.

If we are unable to protect the confidentiality of our trade secrets, our business and competitive position would be harmed.

In addition to seeking patents for our product candidates and other technologies, we also rely on trade secrets and confidentiality agreements to protect our unpatented know-how, technology, and other proprietary information and to maintain our competitive position. We consider trade secrets and know-how to be one of our primary sources of intellectual property. Trade secrets and know-how can be difficult to protect. We expect our trade secrets and know-how to over time be disseminated within the industry through independent development, the publication of journal articles describing the methodology, and the movement of personnel from academic to industry scientific positions.

We seek to protect these trade secrets and other proprietary technology, in part, by entering into non-disclosure and confidentiality agreements with parties who have access to them, such as our employees, corporate collaborators, outside scientific collaborators, CROs, CDMOs, consultants, advisors, and other third parties. We also enter into confidentiality and invention or patent assignment agreements with our employees and consultants as well as train our employees not to bring or use proprietary information or technology from former employers to us or in their work, and remind former employees when they leave their employment of their confidentiality obligations. We cannot guarantee that we have entered into such agreements with each party that may have or have had access to our trade secrets or proprietary technology and processes. Despite our efforts, any of these parties may breach the agreements and disclose our proprietary information, including our

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trade secrets, and we may not be able to obtain adequate remedies for such breaches. Enforcing a claim that a party illegally disclosed or misappropriated a trade secret is difficult, expensive, and time-consuming, and the outcome is unpredictable. In addition, some courts inside and outside the U.S. are less willing or unwilling to protect trade secrets. If any of our trade secrets were to be lawfully obtained or independently developed by a competitor or other third party, we would have no right to prevent them from using that technology or information to compete with us. If any of our trade secrets were to be disclosed to or independently developed by a competitor or other third party, our competitive position would be materially and adversely harmed.

If any of our patent applications do not issue as patents in any jurisdiction, we may not be able to compete effectively.

Changes in either the patent laws or their interpretation in the U.S. and other countries may diminish our ability to protect our inventions, obtain, maintain, and enforce our intellectual property rights and, more generally, could affect the value of our intellectual property or narrow the scope of our patents with respect to our product candidates. With respect to our intellectual property related to our product candidates, we cannot predict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or whether the claims of any issued patents will provide sufficient protection from competitors or other third parties.

The patent prosecution process is expensive, time-consuming, and complex, and we may not be able to file, prosecute, maintain, or enforce all necessary or desirable patent applications at a reasonable cost or in a timely manner. It is also possible that we will fail to identify patentable aspects of our research and development output in time to obtain patent protection. Although we enter into nondisclosure and confidentiality agreements with parties who have access to confidential or patentable aspects of our research and development output, such as our employees, outside scientific collaborators, CROs, CDMOs, consultants, advisors, and other third parties, any of these parties may breach the agreements and disclose such output before a patent application is filed, thereby jeopardizing our ability to seek patent protection. In addition, our ability to obtain and maintain valid and enforceable patents depends on whether the differences between our inventions and the prior art allow our inventions to be patentable. Furthermore, publications of discoveries in the scientific literature often lag behind the actual discoveries, and patent applications in the U.S. and other jurisdictions are typically not published until 18 months after filing, or in some cases not at all. Therefore, we cannot be certain that we were the first to make the inventions claimed in any of our patents or pending patent applications, or that we were the first to file for patent protection of such inventions.

If the scope of any patent protection we obtain is not sufficiently broad, or if we lose any of our patent protection, our ability to prevent our competitors from commercializing similar or identical technology and product candidates would be adversely affected.

The patent position of biotechnology and pharmaceutical companies generally is highly uncertain, involves complex legal and factual questions, and has been the subject of much litigation in recent years. As a result, the issuance, scope, validity, enforceability, and commercial value of our patent rights are highly uncertain. Our pending and future patent applications may not result in patents being issued which protect our product candidates or other technologies or which effectively prevent others from commercializing competitive technologies and product candidates.

Moreover, the coverage claimed in a patent application can be significantly reduced before the patent is issued, and its scope can be reinterpreted after issuance. Even if patent applications we own currently or in the future issue as patents, they may not issue in a form that will provide us with any meaningful protection, prevent competitors or other third parties from competing with us, or otherwise provide us with any competitive advantage. Any patents to which we have rights may be challenged, narrowed, circumvented, or invalidated by third parties. Consequently, we do not know whether product candidates or other technologies will be protectable or remain protected by valid and enforceable patents. Our competitors or other third parties may be able to circumvent our patents by developing similar or alternative technologies or products in a non-infringing manner which could materially adversely affect our business, financial condition, results of operations and growth prospects.

The issuance of a patent is not conclusive as to its inventorship, scope, validity, or enforceability, and our patents may be challenged in the courts or patent offices in the U.S. and abroad. We may be subject to a third-party pre-issuance submission of prior art to the United States Patent and Trademark Office (USPTO) or become involved in opposition, derivation, revocation, reexamination, post-grant and inter partes review, or interference proceedings or other similar proceedings challenging our patent rights. An adverse determination in any such submission, proceeding, or litigation could reduce the scope of, or invalidate or render unenforceable, such patent rights, allow third parties to commercialize our product candidates

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or other technologies and compete directly with us, without payment to us, or result in our inability to manufacture or commercialize products without infringing third-party patent rights. Moreover, we may have to participate in interference proceedings declared by the USPTO to determine priority of invention or in post-grant challenge proceedings, such as oppositions in a foreign patent office, that challenge our priority of invention or other features of patentability with respect to our patents and patent applications. Such challenges may result in loss of patent rights, loss of exclusivity, or in patent claims being narrowed, invalidated, or held unenforceable, which could limit our ability to commercialize REMOXYstop others from using or commercializing similar or identical technology and products, or limit the duration of the patent protection of our product candidates and other drug candidates.technologies. Such proceedings also may result in substantial cost and require significant time from our scientists and management, even if the eventual outcome is favorable to us. If we are unsuccessful in any such proceeding or other priority or inventorship dispute, we may be required to obtain and maintain licenses from third parties, including parties involved in any such interference proceedings or other priority or inventorship disputes. Such licenses may not be available on commercially reasonable terms or at all or may be non-exclusive. If we are unable to obtain and maintain such licenses, we may need to cease the development, manufacture, and commercialization of one or more of the product candidates we may develop. The loss of exclusivity or the narrowing of our owned and licensed patent claims could limit our ability to stop others from using or commercializing similar or identical technology and products.



In addition, given the amount of time required for the development, testing, and regulatory review of new product candidates, patents protecting such product candidates might expire before or shortly after such product candidates are commercialized. As a result, our intellectual property may not provide us with sufficient rights to exclude others from commercializing products similar or identical to ours.

We may not be able to protect our intellectual property and proprietary rights throughout the world.

Filing, prosecuting, and defending patents on our product candidates and other technologies in all countries throughout the world would be prohibitively expensive, and the laws of foreign countries may not protect our rights to the same extent as the laws of the U.S.

Consequently, we may not be able to prevent third parties from practicing our inventions in all countries outside the U.S., or from selling or importing products made using our inventions in and into the U.S. or other jurisdictions. Competitors may use our technologies in jurisdictions where we have not obtained patent protection to develop their own products, and, further, may export otherwise infringing products to territories where we have patent protection, but enforcement is not as strong as that in the U.S. These products may compete with our products, and our patents or other intellectual property rights may not be effective or sufficient to prevent them from competing.

Many companies have encountered significant problems in protecting and defending intellectual property rights in foreign jurisdictions. The legal systems of certain countries, particularly certain developing countries, do not favor the enforcement of patents, trade secrets, and other intellectual property protection, particularly those relating to biotechnology products, which could make it difficult for us to stop the infringement of our patents or marketing of competing products in violation of our intellectual property and proprietary rights generally. Proceedings to enforce our intellectual property and proprietary rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly, could put our patent applications at risk of not issuing, and could provoke third parties to assert claims against us. We may not prevail in any lawsuits that we initiate, and the damages or other remedies awarded, if any, may not be commercially meaningful. Accordingly, our efforts to enforce our intellectual property and proprietary rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop or license.

Obtaining and maintaining our patent protection depends on compliance with various procedural, document submission, fee payment, and other requirements imposed by government patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these requirements.

Periodic maintenance fees, renewal fees, annuity fees, and various other government fees on patents and applications will be due to be paid to the USPTO and various government patent agencies outside of the U.S. over the lifetime of our owned or licensed patents and applications. The USPTO and various non-U.S. government agencies require compliance with several procedural, documentary, fee payment, and other similar provisions during the patent application process. In some cases, an inadvertent lapse can be cured by payment of a late fee or by other means in accordance with the applicable rules. There are situations, however, in which non-compliance can result in abandonment or lapse of the patent or patent application, resulting

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in a partial or complete loss of patent rights in the relevant jurisdiction. In such an event, potential competitors might be able to enter the market with similar or identical products or technology, which could have a material adverse effect on our business, financial condition, results of operations, and growth prospects.

Changes in U.S. patent law could diminish the value of patents in general, thereby impairing our ability to protect our products.

Changes in either the patent laws or interpretation of the patent laws in the U.S. could increase the uncertainties and costs surrounding the prosecution of patent applications and the enforcement or defense of issued patents. Assuming that other requirements for patentability are met, prior to March 2013, in the U.S., the first to invent the claimed invention was entitled to the patent, while outside the U.S., the first to file a patent application was entitled to the patent. After March 2013, under the Leahy-Smith America Invents Act (the America Invents Act) enacted in September 2011, the U.S. transitioned to a first inventor to file system in which, assuming that other requirements for patentability are met, the first inventor to file a patent application will be entitled to the patent on an invention regardless of whether a third party was the first to invent the claimed invention. A third party that files a patent application in the USPTO after March 2013, but before us could therefore be awarded a patent covering an invention of ours even if we had made the invention before it was made by such third party. This will require us to be cognizant going forward of the time from invention to filing of a patent application. Since patent applications in the U.S. and most other countries are confidential for a period of time after filing or until issuance, we cannot be certain that we were the first to either (i) file any patent application related to our product candidates or other technologies or (ii) invent any of the inventions claimed in our patents or patent applications.

The America Invents Act also includes a number of significant changes that affect the way patent applications will be prosecuted and also may affect patent litigation. These include allowing third party submission of prior art to the USPTO during patent prosecution and additional procedures to attack the validity of a patent by USPTO administered post-grant proceedings, including post-grant review, inter partesreview, and derivation proceedings. Because of a lower evidentiary standard in USPTO proceedings as compared to the evidentiary standard in U.S. federal courts necessary to invalidate a patent claim, a third party could potentially provide evidence in a USPTO proceeding sufficient for the USPTO to hold a claim invalid even though the same evidence would be insufficient to invalidate the claim if first presented in a district court action. Accordingly, a third party may attempt to use the USPTO procedures to invalidate our patent claims that would not have been invalidated if first challenged by the third party as a defendant in a district court action. Therefore, the America Invents Act and its implementation could increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents, all of which could have a material adverse effect on our business, financial condition, results of operations, and growth prospects.

In addition, the patent positions of companies in the development and commercialization of pharmaceuticals are particularly uncertain. Recent U.S. Supreme Court rulings have narrowed the scope of patent protection available in certain circumstances and weakened the rights of patent owners in certain situations. This combination of events has created uncertainty with respect to the validity and enforceability of patents, once obtained. Depending on future actions by the U.S. Congress, the federal courts, and the USPTO, the laws and regulations governing patents could change in unpredictable ways that could have a material adverse effect on our existing patent portfolio and our ability to protect and enforce our intellectual property in the future.

We may be subject to claims challenging the inventorship of our patents and other intellectual property.

We may be subject to claims that former employees, scientific collaborators or other third parties have an interest in our patents, trade secrets, or other intellectual property as an inventor or co-inventor. For example, we may have inventorship disputes arise from conflicting obligations of employees, consultants, or others who are involved in developing our product candidates or other technologies. Litigation may be necessary to defend against these and other claims challenging inventorship or ownership of our patents, trade secrets, or other intellectual property. If the defense of any such claims fails, in addition to paying monetary damages, we may lose valuable intellectual property rights, such as exclusive ownership of, or right to use, intellectual property that is important to our product candidates and other technologies. Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management and other employees. Any of the foregoing could have a material adverse effect on our business, financial condition, results of operations, and growth prospects.

We may not be successful in obtaining necessary rights to our product candidates or other technologies.

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Many pharmaceutical companies, biotechnology companies, and academic institutions that compete with us in the field of neurodegeneration therapy may have patents filed and are likely filing patent applications potentially relevant to our business. In order to avoid infringing these third-party patents, we may find it necessary or prudent to obtain licenses to such patents from such third-party intellectual property holders. We may also require licenses from third parties for certain technologies for use with future product candidates. In addition, with respect to any patents we co-own with third parties, we may wish to obtain licenses to such co-owner’s interest to such patents. However, we may be unable to secure such licenses or otherwise acquire any compositions, methods of use, processes, or other intellectual property rights from third parties that we identify as necessary for our future product candidates. The licensing or acquisition of third-party intellectual property rights is a competitive area, and several more established companies may pursue strategies to license or acquire third-party intellectual property rights that we may consider attractive or necessary. These established companies may have a competitive advantage over us due to their size, capital resources, and greater clinical development and commercialization capabilities. In addition, companies that perceive us to be a competitor may be unwilling to assign or license rights to us. We also may be unable to license or acquire third-party intellectual property rights on terms that would allow us to make an appropriate return on our investment or at all. If we are unable to successfully obtain rights to required third party intellectual property rights or maintain the existing intellectual property rights we have, we may have to abandon development of the relevant program or product candidate, which could have a material adverse effect on our business, financial condition, results of operations, and growth prospects.

We may be subject to claims that our employees, consultants, or advisors have wrongfully used or disclosed alleged trade secrets of their current or former employers or claims asserting ownership of what we regard as our own intellectual property which may prevent or delay the development of our product candidates.  

The field of developing innovations for neurodegenerative diseases is highly competitive and dynamic. Due to the focused research and development that is taking place by several companies, including us and our competitors, the intellectual property landscape in this field is in flux, and it may remain uncertain in the future. Additionally, no products utilizing our underlying science and technology have yet reached the market. As such, there may be significant intellectual property related litigation and proceedings relating to our, and other third party, intellectual property and proprietary rights in the future.

Many of our employees, consultants, and advisors are currently or were previously employed at universities or other biotechnology or pharmaceutical companies, including our competitors and potential competitors. Although we try to ensure that our employees, consultants, and advisors do not use the proprietary information or know-how of others in their work for us, we may be subject to claims that we or these individuals have used or disclosed intellectual property, including trade secrets or other proprietary information, of any such individual’s current or former employer. Litigation may be necessary to defend against these claims. If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel. Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management.

In addition, while it is our policy to require our employees and contractors who may be involved in the conception or development of intellectual property to execute agreements assigning such intellectual property to us, we may be unsuccessful in executing such an agreement with each party who, in fact, conceives or develops intellectual property that we regard as our own. The assignment of intellectual property rights may not be self-executing, or the assignment agreements may be breached, and we may be forced to bring claims against third parties, or defend claims that they may bring against us, to determine the ownership of what we regard as our intellectual property. Such claims could have a material adverse effect on our business, financial condition, results of operations, and growth prospects.

Our commercial success depends in part on our ability to develop, manufacture, market, and sell any product candidates that we develop and to use our proprietary technologies without infringing, misappropriating, and otherwise violating the patents and other intellectual property rights of third parties. There is a substantial amount of complex litigation involving patents and other intellectual property rights in the biotechnology and pharmaceutical industries, as well as administrative proceedings for challenging patents, including interference, derivation, and reexamination proceedings before the USPTO or oppositions and other comparable proceedings in foreign jurisdictions. We may become party to, or threatened with, such actions in the future, regardless of their merit. As discussed above, recently, due to changes in U.S. law referred to as patent reform, new procedures including inter partes review and post-grant review have been implemented. As stated above, this reform adds uncertainty to the possibility of challenge to our patents in the future.

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Numerous U.S. and foreign issued patents and pending patent applications owned by third parties exist in the fields in which we are developing our product candidates. As the biotechnology and pharmaceutical industries expand and more patents are issued, the risk increases that our product candidates and other technologies may give rise to claims of infringement of the patent rights of others. Although we believe that we do not infringe on any third parties’ patents or other intellectual property, we cannot assure you that our product candidates and other technologies that we have developed, are developing or may develop in the future will not infringe existing or future patents owned by third parties. We may not be aware of patents that have already been issued to a third party, such as a competitor in the fields in which we are developing product candidates, who might assert infringement of patents it may hold by our current or future product candidates or other technologies, including claims to compositions, formulations, methods of manufacture or methods of use or treatment that cover our product candidates or other technologies. It is also possible that patents owned by third parties of which we are aware, but which we do not believe are relevant to our product candidates or other technologies, could be found to be infringed by our product candidates or other technologies. In addition, because patent applications are published sometime after filing, and because applications can take severalmany years to issue, there may be currently pending third party patent applications that are unknown to us, which may later result in issued patents. If apatents that our product candidates or other technologies may infringe.

Engaging in litigation to defend against third party claimsparties alleging that we infringe on itshave infringed, misappropriated, or otherwise violated their patents or other proprietaryintellectual property rights is very expensive, particularly for a company of our size, and time-consuming. Some of our competitors may be able to sustain the costs of litigation or administrative proceedings more effectively than we can because of greater financial resources. Patent litigation and other proceedings may also absorb significant management time. Uncertainties resulting from the initiation and continuation of patent litigation or other proceedings against us could faceimpair our ability to compete in the marketplace. The occurrence of any of the foregoing could have a numbermaterial adverse effect on our business, financial condition, results of issuesoperations, and growth prospects.

We may become involved in lawsuits to protect or enforce our patents and other intellectual property rights, which could be expensive, time consuming, and unsuccessful.

Competitors may infringe on our patents or the patents of our licensing partners, or we may be required to defend against claims of infringement. In addition, our patents or the patents of our licensing partners also may become involved in inventorship, priority, or validity disputes. To counter or defend against such claims can be expensive and time consuming. In an infringement proceeding, a court may decide that a patent in which we have an interest is invalid or unenforceable, the other party’s use of our patented technology falls under the safe harbor to patent infringement, or may refuse to stop the other party from using the technology at issue on the grounds that our patents do not cover the technology in question. An adverse result in any litigation proceeding could seriously harmput one or more of our patents at risk of being invalidated or interpreted narrowly. Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information could be compromised by disclosure during this type of litigation.

Even if resolved in our favor, litigation or other legal proceedings relating to intellectual property claims may cause us to incur significant expenses and could distract our personnel from their normal responsibilities. In addition, there could be public announcements of the results of hearings, motions, or other interim proceedings or developments, and if securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our common stock. Such litigation or proceedings could substantially increase our operating losses and reduce the resources available for development activities or any future sales, marketing, or distribution activities. We may not have sufficient financial or other resources to conduct such litigation or proceedings adequately. Some of our competitors may be able to sustain the costs of such litigation or proceedings more effectively than we can because of their greater financial resources and more mature and developed intellectual property portfolios. Uncertainties resulting from the initiation and continuation of patent litigation or other proceedings could have a material adverse effect on our ability to compete in the marketplace.

Intellectual property rights do not necessarily address all potential threats.

The degree of future protection afforded by our intellectual property rights is uncertain because intellectual property rights have limitations and may not adequately protect our business or permit us to maintain our competitive position, including:advantage. For example:

·

infringementothers may be able to make products that are similar to our product candidates or utilize similar technology but that are not covered by the claims of the patents that with or without merit, can be costly and time consuming to litigate, can delay the regulatory approval process and can divert management’s attention from our core business strategy;we may own;

·

substantial damages for past infringement which we maymight not have been the first to pay if a court determines that our products or technologies infringe upon a competitor’smake the inventions covered by the issued patent or other proprietarypending patent application that we own now or in the future;

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·

we might not have been the first to file patent applications covering certain of our inventions;

·

others may independently develop similar or alternative technologies or duplicate any of our technologies without infringing our owned intellectual property rights;

·

a court order prohibiting us from commercializingit is possible that our productscurrent or technologies unless the holder licenses thefuture pending patent or other proprietary rightsapplications will not lead to us, which such holder is not required to do;issued patents;

·

ifissued patents that we hold rights to may be held invalid or unenforceable, including as a license is available from a holder, we may have to pay substantial royalties or grant cross licenses toresult of legal challenges by our patents or other proprietary rights; and

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·

redesigning our process so that it does not infringe third party intellectual property rights, which may not be possible, or which may require substantial time and expense including delays in bringing our own products to market. Such actions could harm our competitive position and our ability to generate revenue and could result in increased costs.

If we are unable to protect our intellectual property, our competitors could develop and market products with similar features that may reduce demand for our drug candidates.

Our success, competitive position and potential future revenues will depend in part on our ability to protect our intellectual property. If we or our collaborators fail to file, prosecute, obtain or maintain certain patents, our competitors could market products that contain features and clinical benefits similar to those of our products, and demand for our products could decline as a result.

We and our collaborators have filed patent applications in the United States and select international jurisdictions to protect our intellectual property. The coverage sought in a patent application can be denied or significantly reduced before or after the patent is issued. Consequently, we do not know whether any of our pending applications will result in the issuance of patents, or if any existing or future patents will provide significant protection or commercial advantage or will be circumvented by others. There can be no assurance that patents will issue from our pending or future patent applications or, if issued, that such patents will be of commercial benefit to us, afford us adequate protection from competing products, or not be challenged or declared invalid. Thus, if these patent applications do not result in issued patents or result in a patent that is challenged by others, the duration or scope of our patent rights may be limited and our future revenues could be lower as a result.

We may be involved in challenges to our intellectual property. If our competitors are able to successfully challenge the validity or scope of our patent rights, based on the existence of prior art or otherwise, they might be able to market products that contain features and clinical benefits similar to those of our drug candidates, and demand for our drug candidates could decline as a result. An adverse outcome of a challenge to our intellectual property could result in loss of claims of patents or other intellectual property rights that pertain to certain drugs we currently have under development and could have a material adverse impact on our future revenues.

We intend to file additional patent applications relating to our technology, products and processes. We may direct our collaborators to file additional patent applications relating to the licensed technology or we may do so ourselves. However, our competitors may challenge, invalidate or circumvent any of our current or future patents. These patents may also fail to provide us with meaningful competitive advantages.

We may become involved in expensive litigation or other legal proceedings related to our existing intellectual property rights, including patents.

We expect that we will rely upon patents, trade secrets, know-how, continuing technological innovations and licensing opportunities to develop and maintain our competitive position. While we use confidentiality agreements with our employees, consultants and certain of our contractors, if trade secrets or other confidential information is made public, our business may be harmed and our legal remedies may be limited or insufficient. Others may independently develop substantially equivalent proprietary information or be issued patents that may prevent the sale of our products or know-how or require us to license such information and pay significant fees or royalties in order to produce our products.

Our technology could infringe upon claims of patents owned by others. If we were found to be infringing on a patent held by another, we might have to seek a license to use the patented technology. In that case, we might not be able to obtain such a license on terms acceptable to us, or at all. If a legal action were to be brought against us or our licensors, we could incur substantial defense costs, and any such action might not be resolved in our favor. If such a dispute were to be resolved against us, we could have to pay the other party large sums of money and our use of our technology and the testing, manufacture, marketing or sale of one or more of our proposed products could be restricted or prohibited.

If we are unable to protect the confidentiality of our intellectual property, the value of our intellectual property could be materially adversely affected and our business would be harmed.

We seek to protect our intellectual property, in part, by confidentiality agreements with our employees, consultants, scientific advisors, contractors and collaborators. However, there can be no assurance that our intellectual property will not be disclosed or that competitors will not otherwise gain access to our intellectual property or independently develop

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substantially equivalent intellectual property. For example, if our confidential information were disclosed in violation of our confidentiality agreements, we may not be able to obtain adequate remedies for such breaches. We also seek to protect our intellectual property by maintaining physical security of our premises and physical and electronic security of our information technology systems, but it is possible that these security measures could be breached. If any of our intellectual property were to be lawfully obtained or independently developed by a competitor, we would have no right to prevent such competitor from using that intellectual property to compete with us, which could harm our business.

Risks Relating to our Business and Strategy

Our business may fail without a new equity incentive plan.

We depend heavily on equity incentives to retain the services of all of our personnel, without which we are not able to retain or hire qualified personnel or board members.  In particular, our independent board members receive no form of compensation for their services other than new equity incentives every year.  The 2008 Equity Plan expired in December 2017.  Furthermore, in 2017, shareholders rejected a proposal to renew an equity incentive plan. As a result, going-forward we are no longer able to grant new equity incentives to any of our personnel, including new potential hires and board members, until and unless shareholders approve a new equity incentive plan.  The loss of personnel and board members, and our potential inability to hire replacement personnel, will materially delay or disrupt our operations and will put us out of compliance with various legal standards and regulations for listed companies, all of which may force us to curtail or cease operations.

If we are not successful in attracting and retaining qualified personnel, we could experience delays in completing necessary clinical trials, in the regulatory approval process or in formulating, manufacturing, marketing and selling our potential products.

We depend on the services of our key personnel, including Remi Barbier, our Chairman, President and Chief Executive Officer. On February 14, 2017, Peter S. Roddy resigned, effective March 9, 2017, as Vice President, Chief Financial Officer and Secretary. Remi Barbier, President and Chief Executive Officer, has assumed the role of Principal Financial Officer until such time as a new Chief Financial Officer is appointed.

The loss of key personnel, including members of executive management as well as key bioengineering, product development, and technical personnel, could disrupt our operations and have an adverse effect on our business. We will need to hire additional qualified personnel with expertise in clinical research, preclinical testing, government regulation, formulation and manufacturing and sales and marketing. We compete for qualified individuals with numerous biopharmaceutical companies, universities and other research institutions. Competition for such individuals is intense, and our search for such personnel may not be successful. Attracting and retaining qualified personnel is critical to our success.

We have employees whose equity ownership in the Company could result in a substantial increase in personal wealth if the fair value of our common stock increases. Over time, this increase in personal wealth may make it more challenging to retain these employees.

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If third-party manufacturers of our drug candidates fail to devote sufficient time and resources to our concerns, or if their performance is substandard, our clinical trials and product introductions may be delayed and our costs may be higher than expected.

We have no manufacturing facilities and have limited experience in drug product development and commercial manufacturing. We lack the resources and expertise to formulate, manufacture or test the technical performance of our drug candidates. We rely on and expect to continue to rely on a limited number of experienced personnel and a small number of contract manufacturers and other vendors to formulate, test, supply, store and distribute drug supplies for our preclinical studies and clinical trials. Our reliance on a limited number of vendors exposes us to the following risks, any of which could delay our clinical trials, and, consequently, FDA approval of our drug candidates and commercialization of our products, result in higher costs, or deprive us of potential product revenues:

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Contract commercial manufacturers, their sub-contractors or other third parties we rely on and expect to rely on, may encounter difficulties in achieving the volume of production needed to satisfy preclinical and clinical needs or commercial demand, may experience technical issues that impact quality or compliance with applicable and strictly enforced regulations governing the manufacture of pharmaceutical products, and may experience shortages of qualified personnel to adequately staff production operations.parties;

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Our contract manufacturers could default on their agreements with usour competitors or other third parties might conduct research and development activities in countries where we do not have patent rights and then use the information learned from such activities to provide supplies or meetdevelop competitive products for sale in our requirements for commercialization of our products.major commercial markets;

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For certain of our drug candidates, the use of alternate manufacturers may be difficult because the number of potential manufacturers that have the necessary governmental licenses to produce narcotic products is limited. Additionally, the FDA and the DEA must approve any alternative manufacturer of our products before we may use the alternative manufacturer to produce our supplies.not develop additional proprietary technologies that are patentable;

·

Itthe patents of others may be difficult or impossible for us to find a replacement manufacturer on acceptable terms quickly, or at all. Our contract manufacturersharm our business; and vendors may not perform as agreed or may not remain in the contract manufacturing business for the time required to successfully produce, store and distribute our products.

·

If any contract manufacturer makes improvements in the manufacturing process for our products, we may choose not own,to file a patent in order to maintain certain trade secrets or know-how, and a third party may have to share, thesubsequently file a patent covering such intellectual property rights to such innovation.property.



Should any of these events occur, they could have a material adverse effect on our business, financial condition, results of operations, and growth prospects.

Risks Related to Our Business and Operations

The worldwide outbreak of an infectious disease, called COVID-19, may materially and adversely affect our business operations and our ability to conduct clinical studies.

A widespread outbreak of a novel infectious disease called Coronavirus Disease 2019, or COVID-19, has been declared by the World Health Organization to be a “public health emergency of international concern”; a national emergency by the President of the U.S; and a major disaster by several states in which we operate. This unprecedented spread of disease may affect our operations by causing a period of business disruption, including the potential interruption or halt of our clinical study activities and delays or disruptions in the supply of our products and product candidates, or the inability of our employees to continue their normal course of work due to disease, quarantine or leave requirements, or the possibility of legal claims and actions against us for claims of loss arising out of COVID-19. As a small company that operates with a limited number of employees, the impact of disease may disproportionately hurt our operations. Further, our business insurance may not provide coverage against economic loss or claims specifically tied to COVID-19 or any other disease.

COVID-19 presents many challenges that are without precedent. As such, we cannot presently assess or predict all current and potential uncertainties around the scope and severity of COVID-19 on our business operations with any meaningful precision. There is no assurance that COVID-19 will not have a material adverse impact on our future results. For example, the continued spread of COVID-19 could adversely impact our clinical study operations, including our ability to recruit and retain patients and principal investigators and site staff who, as healthcare providers, may have heightened exposure to COVID-19 if an outbreak occurs in their geography. COVID-19 could also negatively affect our manufacturing operations, which could result in delays or disruptions in the supply of our product candidates. A greater number of our employees working remotely during this outbreak of disease may expose us to greater risks related to cybersecurity and cyber-liability. Our study participants, vendors, employees, suppliers or others may allege they became sick due to our negligence. In addition, there could be a potential effect of a slowdown at FDA, which could result in delays of regulatory correspondence that are necessary for us to maintain or advance our product candidates in clinical studies. Further, the COVID-19 outbreak may adversely impact our ability to file on a routine and timely basis our obligations under federal securities laws, present new data at annual scientific meetings and professional conferences, reach out to institutional investors through in-person meetings, advance simufilam in a Phase 3 efficacy program, add an international component to our clinical studies, obtain additional financing as needed, engage in partnering discussions or conduct other activities necessary to the success of our business.

If we or any of the third parties with whom we engage were to experience shutdowns or other business disruptions related to COVID-19, our ability to conduct our business in the manner and on the timelines presently planned could be materially and negatively impacted, which could have a material adverse effect on our business, results of operations and financial condition. 

Our reliance on third parties for both the supply and manufacture of materials for our product candidates carries the risk that we will not have sufficient quality or quantities of such materials or product candidates, or that such supply will not

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be available to us at an acceptable cost, which could delay, prevent, or impair our development or commercialization efforts.

We do not have any manufacturing facilities. We currently rely on CDMOs for all of the manufacture of our materials for preclinical studies and clinical studies and expect to continue to do so for preclinical studies, clinical studies, and for commercial supply of any product candidates that we may develop. We currently have established relationships with several CDMOs for the manufacturing of our product candidates. We may be unable to establish any further agreements with CDMOs or to do so on acceptable terms. Even if we are able to establish agreements with third-party manufacturers, reliance on CDMOs entails additional risks, including:

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the possible breach of the manufacturing agreement by the third party;

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the possible termination or nonrenewal of the agreement by the third party at a time that is costly or inconvenient for us;

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reliance on the third party for regulatory compliance, quality assurance, safety, and pharmacovigilance and related reporting; and

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the inability to produce required volume in a timely manner and to quality standards.

Third-party manufacturers may not be able to successfully developcomply with cGMP regulations or commercialize potential drugsimilar regulatory requirements outside the U.S. Our failure, or the failure of our CDMOs, to comply with applicable regulations could result in clinical holds on our studies, sanctions being imposed on us, including fines, injunctions, civil penalties, delays, suspension or withdrawal of approvals, seizures, or recalls of product candidates for indications other than pain.or product candidates, operating restrictions, and criminal prosecutions, any of which could significantly and adversely affect supplies of our product candidates and harm our business, financial condition, results of operations, and growth prospects.



Our researchAny product candidates that we may develop may compete with other product candidates and products for access to manufacturing facilities. There are a limited number of manufacturers that operate under cGMP regulations and that might be capable of manufacturing for us.

Any performance failure on the part of our existing or future third-party manufacturers could delay clinical development activities include developmentor marketing approval. If any one of potential drugour current contract manufacturers cannot perform as agreed, we may be required to replace that manufacturer and may incur added costs and delays in identifying and qualifying any such replacement. Furthermore, securing and reserving production capacity with contract manufacturers may result in significant costs.

We also rely on third-parties for the supply of the raw materials required for the production of our product candidates, and we expect to continue to rely on third party manufacturers for indications other than pain. We have no historythe commercial supply of developing such drug candidates. We do not know whether any of our planned development activities will result in marketable products. We do not anticipate that our drugproduct candidates in these areas will reachfor which we obtain marketing approval. Our current and anticipated future dependence upon others for the market for at least several years, if at all.

Our employees and consultants are generally subject to confidentiality or other agreements with their former employers and they may inadvertently or otherwise violate those agreements.

Manymanufacture of our employees and consultants were previously employed at universities or biotechnology or pharmaceutical companies. While we require our employees and consultants to honor any agreements they may have entered into prior to working with us,product candidates we may be subject to claims that we inadvertently or otherwise used or disclosed trade secrets or other confidential information belonging to former employers. Failure to defend such claims could result in loss of valuable rights or personnel, which in turn could harm or prevent commercialization of our drug candidates. Successful defense against such claims can be expensive and might distract us from executing our strategies.

Law enforcement concerns over diversion of opioids and social issues around abuse of opioids may make the regulatory approval process and commercialization of our drug candidates very difficult.

Law enforcement agencies or regulatory agencies may apply policies that seek to limit the availability of opioids. Such effortsdevelop may adversely affect our future profit margins and our ability to commercialize any medicines that receive marketing approval on a timely and competitive basis.

We expect to grow the regulatory approvalsize and commercializationcapabilities of our drug candidates.organization, including accessing new physical facilities, and we may experience difficulties in effectively managing this growth.

As our development plans and strategies develop, we expect to add a significant number of additional managerial, operational, financial, and other personnel. Future growth will impose significant added responsibilities on members of management, including:

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identifying, recruiting, integrating, retaining, and motivating additional employees;

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leasing or purchasing additional physical facilities to accommodate our increasing employee headcount;

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managing our internal development efforts effectively, including the clinical and FDA review process for our current and future product candidates, while complying with our contractual obligations to contractors and other third parties;

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expanding our operational, financial and management controls, reporting systems, and procedures; and

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managing increasing operational and managerial complexity.



 

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Developments by competitors may render our products or technologies obsolete or non-competitive.

Alternative technologiesOur future financial performance and products are being developed to improve or replace the use of opioids for pain management, several of which are in clinical trials or are awaiting approval from the FDA. In addition, the active ingredients in nearly all opioid drugs are available in generic form. Drug companies that sell generic opioid drugs represent substantial competition. Many of these organizations competing with us have substantially greater capital resources, larger research and development staffs and facilities, greater experience in drug development and in obtaining regulatory approvals and greater manufacturing and marketing capabilities than we do. Our competitors may market less expensive or more effective drugs that would compete with our drug candidates or reach market with competing drugs before we are able to reach market with our drug candidates. These organizations also compete with us to attract qualified personnel and partners for acquisitions, joint ventures or other collaborations.

Business interruptions could limit our ability to operatecontinue to develop and, if approved, commercialize our business.product candidates will depend, in part, on our ability to effectively manage any future growth. Our management may also have to divert a disproportionate amount of its attention away from day-to-day activities in order to manage these growth activities.



Our operations, as well as thoseWe currently rely, and for the foreseeable future will continue to rely, in substantial part on certain independent organizations, advisors, and consultants to provide certain services. There can be no assurance that the services of these independent organizations, advisors, and consultants will continue to be available to us on a timely basis when needed, or that we can find qualified replacements. In addition, if we are unable to effectively manage our collaborators on whichoutsourced activities or if the quality or accuracy of the services provided by consultants is compromised for any reason, our clinical studies may be extended, delayed, or terminated, and we depend, are vulnerable to damage or interruption from computer viruses, human error, natural disasters, electrical and telecommunication failures, international acts of terror and similar events. We have not established a formal disaster recovery plan and our back-up operations and business interruption insurance may not be adequateable to compensate us for losses we may suffer. A significant business interruption could result in losses or damages incurred by us and require us to cease or curtail our operations.

Cyber-attacks or other failures in telecommunications or information technology systems could result in information theft, data corruption and significant disruptionobtain regulatory approval of our business operations.

We use information technology, computer systems and networks to process, transmit and store electronic information in connection withproduct candidates or otherwise advance our business activities. Cyber incidents, including deliberate attacks and attempts to gain unauthorized access to computer systems and networks, have increased in frequency, scope and sophistication in every industry. These threats pose a risk to the security of our systems and networks and the confidentiality, availability and integrity of our data, and may cause a disruption in our operations, harm our reputation and increase our stock trading risk.business. There can be no assurance that we will be successfulable to manage our existing consultants or find other competent outside contractors and consultants on economically reasonable terms, if at all.

If we are not able to effectively expand our organization by hiring new employees and expanding our groups of consultants and contractors, we may not be able to successfully implement the tasks necessary to further develop our product candidates and, accordingly, may not achieve our research, development, and commercialization goals.

Our internal computer systems, or those used by third parties on whom we rely, may fail or suffer other breakdowns, cyberattacks, or information security breaches that could compromise the confidentiality, integrity, and availability of such systems and data, result in preventing cyber-attacksmaterial disruptions of our development programs and business operations, risk disclosure of confidential, financial, or successfully mitigating their effects. Similarly, there can be no assurance thatproprietary information, and affect our third-party collaborators, distributorsreputation.

In the ordinary course of our business, we collect and store sensitive data, including legally protected patient health information, personally identifiable information about our employees, intellectual property, and proprietary business information. We manage and maintain our applications and data utilizing on-site systems. These applications and data encompass a wide variety of business-critical information including research and development information, commercial information and business and financial information. Despite the implementation of security measures, our internal computer systems and those of our current or future Clinical Research Organizations (CROs) and other contractors and consultants willmay be successfulvulnerable to damage from computer viruses and unauthorized access. As the cyber-threat landscape evolves, these attacks are growing in protecting our data that is stored on their systems. Afrequency, sophistication, and intensity, and are becoming increasingly difficult to detect. Such attacks could include the use of key loggers or other harmful and virulent malware, including ransomware or other denials of service, and can be deployed through malicious websites, the use of social engineering, and/or other means. If a breakdown, cyberattack, or destructionother information security breach were to occur and cause interruptions in our operations, it could result in a misappropriation of confidential information, including our intellectual property or financial information, and a material disruption of our development programs and our business operations. For example, the loss of clinical study data from completed, ongoing, or future clinical studies could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data. Likewise, we rely on our third-party research institution collaborators for research and development of our product candidates and other third parties for the manufacture of our product candidates and to conduct clinical studies, and similar events relating to their computer systems could also have a material adverse effect on our business. To the extent that any disruption or security breach were to result in a loss of, or damage to, our data or systems, or inappropriate disclosure of confidential, financial, or proprietary information, including data related to our personnel, we could incur liability or risk disclosure of confidential, financial, or proprietary information, and the further development and commercialization of our product candidates could be delayed. There can be no assurance that we and our business and prospects. In addition, we may suffer reputational harmcounterparties will be successful in efforts to detect, prevent, or face litigationfully recover systems or adverse regulatory action as a resultdata from all breakdowns, service interruptions, attacks, or breaches of cyber-attacks or other data security breaches and may incur significant additional expense to implement further data protection measures.

Unfavorable media coverage of opioid pharmaceuticalssystems that could negatively affect our business.

Opioid drug abuse receives a high degree of media coverage. Unfavorable publicity regarding, for example, the use or misuse of oxycodone or other opioid drugs, the limitations of ADFs, public inquiries and investigations into prescription drug abuse, litigation or regulatory activity could adversely affect our reputation. Such negative publicity could have an adverse effect on the potential size of the market for our drug candidates and decrease revenues and royalties, which would adversely affect our business and operations and/or result in the loss of critical or sensitive data, which could result in financial, results.legal, business, or reputational harm to us.



Our business involves environmental risks that may result in liability for us.

Risks Relating

In connection with our research and development activities, we, and our collaborators and vendors, are subject to Manufacturingfederal, state and local laws, rules, regulations and policies governing the use, generation, manufacture, storage, air emission, effluent discharge, handling and disposal of certain materials, biological specimens, chemicals and wastes. Although we believe that we comply with such applicable laws, regulations and policies in all material respects and have not been required to correct any material noncompliance, we may incur significant costs to comply with environmental and health and safety regulations in the future. Although we believe that our safety procedures for handling and disposing of controlled materials comply with the standards prescribed by state and federal regulations, accidental contamination or injury from these materials may occur.

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In the event of such an occurrence, we could be held liable for any damages that result and any such liability could exceed our resources.

Business disruptions and lack of appropriate levels of commercial insurance could seriously harm our future revenue and financial condition and increase our costs and expenses.

Our operations, and those of our third-party research institution collaborators, CROs, CDMOs, suppliers, and other contractors and consultants, could be subject to earthquakes, power shortages, telecommunications failures, water shortages, floods, hurricanes, typhoons, fires, extreme weather conditions, disease epidemics or pandemics, such as COVID-19, a novel coronavirus first detected in 2019, and other natural or man-made disasters or business interruptions, for which we are partly or entirely uninsured. In addition, we rely on our third-party research institution collaborators for conducting research and development of our product candidates, and they may be affected by government shutdowns or withdrawn funding. The occurrence of any of these business disruptions could seriously harm our operations and financial condition and increase our costs and expenses. We rely on third party manufacturers to produce and process our product candidates. Our ability to obtain clinical supplies of our product candidates could be disrupted if the operations of these suppliers are affected by a man-made or natural disaster or other business interruption.

Our day-to-day operations are located in a single office facility in Austin, Texas. Damage or extended periods of interruption to our corporate, development, or research facilities could cause us to cease or delay development of some or all our product candidates. Our insurance might not cover losses under such circumstances and our business may be seriously harmed by such delays and interruption.

Social media platforms present risks and challenges.

As social media continues to expand, it also presents us with new challenges. The inappropriate or unauthorized use of our confidential information on media platforms could cause brand damage or information leakage, which would cause legal or regulatory problems for us. In addition, negative, inappropriate or inaccurate posts or comments about us or our product candidates on social media internet sites could quickly and irreversible damage our reputation, brand image and goodwill. Further, the accidental or intentional disclosure of non-public sensitive information by our workforce or others through media channels could lead to information loss or could lead to legal or regulatory problems for us.

We expect to rely on third parties to conduct our studies and some aspects of our research, and such third parties may not perform satisfactorily, which could delay or harm our studies, research, and testing.

We substantially rely and expect to continue to rely on third parties, such as CROs, clinical data management organizations, medical institutions, and clinical investigators, to conduct some aspects of our research and preclinical testing and our clinical studies. Any of these third parties may terminate their engagements with us or be unable to fulfill their contractual obligations. If we need to enter into alternative arrangements, it will delay our product development activities.

Our reliance on these third parties for research and development activities reduces our control over these activities but does not relieve us of our responsibilities. For example, we remain responsible for ensuring that all of our clinical studies are conducted in accordance with the general investigational plan and protocols for the trial. Moreover, FDA requires us to comply with the norms of Good Clinical Practice (GCPs) for conducting, recording, and reporting the results of clinical studies to assure that data and reported results are credible, reproducible, and accurate and that the rights, integrity, and confidentiality of study participants are protected. We also are required to register ongoing clinical studies and post the results of completed clinical studies on a government-sponsored database within certain timeframes. Failure to do so can result in fines, adverse publicity, and civil and criminal sanctions.

If our third-party vendors do not successfully carry out their contractual duties, meet expected deadlines, or conduct studies in accordance with regulatory requirements or our stated protocols, we will not be able to obtain, or may be delayed in obtaining, marketing approvals for any product candidates we may develop and will not be able to, or may be delayed in our efforts to, successfully commercialize our product candidates. For example, one of our vendors failed to fully comply with certain Good Laboratory Practice (GLP) norms in its research facility, which required us to repeat a lab study at a different research site.

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We also rely on other third parties to label, store and distribute drug supplies for our clinical studies. Any performance failure on the part of our distributors, including with the shipment of any drug supplies, could delay clinical development or marketing approval of any product candidates we may develop or commercialization of our product candidates, producing additional losses and depriving us of potential product revenue.



We do not own any manufacturing facilities and we rely on third-party commercial drug manufacturers for clinical drug supply.



We do not own any manufacturing facilities. We plan to continue to outsource formulation, manufacturing and related activities.

We rely on a limited number of third-party suppliers to formulate, manufacture, fill, label, ship or store all of our drugproduct candidates. These suppliers must comply with current good manufacturing practices, or GMPcGMP, regulations enforced by the FDA and other government agencies, and DEA regulations, and are subject to ongoing periodic unannounced inspection, including preapproval inspections by the FDA and DEA and corresponding state and foreign government agencies to ensure

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strict compliance with cGMP and other government regulations and corresponding foreign standards. These manufacturers may subsequently be stopped from producing, storing, shipping or testing our drug products due to their non-compliance with federal, state or local regulations. We do not have control over our suppliers’ compliance with these regulations and standards.

If REMOXY is approved, our commercial suppliers may encounter difficulties in achieving high volumes of production to satisfy commercial demands.

We cannot control decisions by our suppliers that affect their ability or willingness to continue to supply us on acceptable terms, or at all.

We may not be able to replace a commercial supplier on commercially reasonable terms, or at all. Replacing any of our commercial suppliers would be expensive and time consuming.

Failure by any of our suppliers to perform as expected could delay or prevent commercialization of REMOXYour product candidates or result in shortages, cost overruns, or other problems and would materially harm our business.



We will relyare a small company with a limited number of employees. We are highly dependent on Durect as the sole source of certain excipientsour key personnel, and if we are not successful in REMOXY. Durect has limited experience manufacturing pharmaceutical productsattracting, motivating, and maintaining GMP-compliant operations. We currently do not have a long-term commercial supply agreement in place with Durect. We expect thatretaining highly qualified personnel, we and Durect will negotiate a supply agreement for these excipients. We may not be able to establish a commercial supply agreement on acceptable terms, or at all.successfully implement our business strategy.



If we receive marketing approval forOur ability to compete in the highly competitive biotechnology and commercially launch REMOXY, Durect may needpharmaceutical industries depends upon our ability to materially expand its manufacturing capacity. Durect may not be ableattract, motivate, and retain highly qualified managerial, scientific, and medical personnel. We are highly dependent on our management, particularly our Chief Executive Officer, Remi Barbier, and our scientific and technical personnel. The loss of the services provided by any of our executive officers, other key employees, and other scientific and medical advisors, and our inability to increase its manufacturing capacity for REMOXYfind suitable replacements, could result in a timely or economic manner, or at all. Moreover, significant scale updelays in the development of manufacturing will require additional validation studies, which are subject to FDA reviewour product candidates and approval. If Durect is unable to successfully increase the manufacturing capacity, at an acceptable cost or otherwise, and we are unable to establish alternative manufacturing capabilities, there may be a shortage in supply, which would harm our future revenues and cause our business to suffer.business.



If Durect failsCompetition for skilled personnel is intense and the turnover rate can be high, which may limit our ability to supply excipients to us, they may be in breach of their supply obligations. With or without a commercial supply agreement, Durect’s failure for any reason to supply these excipients, including failure resulting from Durect relying on sole source providers, could delay or prevent commercialization of REMOXY or result in shortages, delays, unexpected costs or other problemshire and would materially harm our business.

We expect to rely on Noramco as the sole source of the oxycodone in REMOXY. We currently do not have a long-term commercial supply agreement in place with Noramco. Effective July 1, 2016, Noramco is owned by SK Capital Partners, a private investment firm. We expect to negotiate with Noramco a commercial supply agreement to supply us with oxycodone. We may not be able to establish a commercial supply agreementretain highly qualified personnel on acceptable terms or at all. UntilWe expect that we may need to recruit talent from outside of our region in Austin, Texas, and doing so may be costly and difficult.

To induce valuable employees to remain at our company, in addition to salary and cash incentives, we have a commercial supply agreementprovided equity option grants that vest over time. The value to employees of these equity grants that vest over time may be significantly affected by movements in placeour stock price that are beyond our control and may at any time be insufficient to counteract more lucrative offers from other companies. Although we have employment agreements with Noramco,our key employees, these employment agreements provide for at-will employment, which means that any of our employees could leave our employment at any time, with or without notice. If we expectare unable to obtain oxycodone from Noramco via purchase orders. There can be no assurance that Noramco will accept our purchase ordersattract and incentivize quality personnel on acceptable terms, or at all. With or without a commercial supply agreement, Noramco’s failure for any reasonall, it may cause our business and operating results to supply us with oxycodone could delay or prevent commercialization of REMOXY or result in shortages, cost overruns or other problems that would materially harm our business.suffer.



We willmay need to identifycease our operations if we are unable to attract and retain key personnel.

We are engaged in developing early-stage technologies and will continue to do so for the foreseeable future.  Unlike larger organizations, we rely on a third-partyvery small number of highly skilled, and highly sought after, employees to manufacture commercial suppliescontinue the advancement of REMOXY. Withoutour development stage technologies. The knowledge and skills contributed by our key employees may be irreplaceable and the loss of a commercial manufacturer,key employee may cause substantial negative financial, operational and scientific consequences for our business.  As an example, our research grant awards from NIH depend in part on the continued participation of certain key employees, known as a Principal Investigator. The loss of a Principal Investigator may result in the loss of one or more research grant awards from NIH, which would have significant adverse effects on our ability to continue to conduct, conclude or fund our research programs in Alzheimer’s disease. Likewise, the intellectual property that is intended to protect our development stage technologies is still evolving and its evolution remains highly dependent on a small number of employees

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with specific expertise. The loss of a key employee may jeopardize our existing or pending intellectual property or may prevent us from accessing the technical information and knowledge necessary to extend our portfolio of intellectual property. Furthermore, we believe the adverse effects that may result from losing a key employee’s participation cannot be compensated with any specific insurance policies, such as “key person” or “business life” insurance. If we are not successful in retaining key employees, our business and financial condition will suffer, and we may need to cease our operations.

If our current research collaborators or scientific advisors terminate their relationships with us or develop relationships with a competitor, our ability to continue our business operations could be adversely affected.

We have relationships with research collaborators at academic and other institutions who conduct research at our request. These research collaborators are not our employees. As a result, we have limited control over their activities and, except as otherwise required by our collaboration agreements, can expect only limited amounts of their time to be dedicated to our activities. Our ability to discover drugs and biomarkers involved in human disease and validate and commercialize diagnostic tests will depend in part on the continuation of these collaborations. If any of these collaborations are terminated, we may not be able commercialize REMOXY. To date, we have not identified such third-party manufacturer and we may never find a viable source of commercial supplies of REMOXY. We expect to rely on such third party as the sole-source drug product manufacturer of REMOXY pursuant to a supply agreement.enter into other acceptable collaborations. In addition, to drug product manufacturing, this third-part manufacturer will need toour existing collaborations may not be responsiblesuccessful. Our research collaborators and scientific advisors may have relationships with other commercial entities, some of which could compete with us. Our research collaborators and scientific advisors sign agreements which provide for sourcing excipients in REMOXY other than those provided by the Durect Agreement. Failure for any reason to manufactureconfidentiality of our proprietary information and supply REMOXY could delay or prevent commercializationthe results of REMOXY or result in shortages, product recalls or withdrawals, delays or failures in product testing or delivery, cost overruns or other problems that would materially harmstudies conducted at our business.

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If we cannot formulate and scale-up additional dosage forms of REMOXY, the commercial opportunity for REMOXY might be diminished.

We plan to formulate and scale-up additional dosage forms of REMOXY.request. We may not, however, be able to successfully completemaintain the confidentiality of our formulation or scale-up activities or we may determine that the commercial opportunity for REMOXY in certain dosage forms is too limited to warrant further investment. If we are unsuccessful in our formulation or scale-up activities with REMOXY, our future revenue may be less than expected and our operations may suffer.

We rely solely on Durect to provide us with certain components of drug candidates and will continue to rely on Durect as the sole-source providerof these components.

We rely on Durect as the sole-source provider of certain components of REMOXYtechnology and other drug candidates designedconfidential information related to reduce the potential risksall collaborations. The dissemination of unintended use, and will rely solelyour confidential information could have a material adverse effect on Durect to produce commercial supplies of these components. Durect’s failure for any reason to provide these components or to achieve and maintain satisfactory manufacturing standards could result in product recalls or withdrawals, delays or failures in product testing or delivery, cost overruns or other problems that could materially harm our business.

Durect may encounter manufacturing difficulties involving production yields, quality control and quality assurance. Durect is subject to ongoing periodic unannounced inspection by the FDA and corresponding state and foreign agencies to ensure strict compliance with government regulations and corresponding foreign standards. We cannot control Durect’s compliance with these regulations and standards.

If we receive marketing approval for and commercially launch REMOXY, Durect may need to materially expand its manufacturing capacity. Durect may not be able to increase its manufacturing capacity for REMOXY in a timely or economic manner, or at all. Moreover, significant scale up of manufacturing will require additional validation studies, which are subject to FDA review and approval. If Durect is unable to successfully increase the manufacturing capacity for such components of REMOXY, at an acceptable cost or otherwise, and we are unable to establish alternative manufacturing capabilities, commercialization of REMOXY may be delayed, prevented or impaired or there may be a shortage in supply, which would harm our future revenues and cause our business to suffer.

We expect to rely on Noramco as the sole source of the oxycodone in REMOXY. 

We expect to rely on Noramco as the sole source of the oxycodone in REMOXY. We expect we and Noramco will negotiate a supply agreement to supply us with the oxycodone in REMOXY. Noramco’s operation is subject to regulation by the DEA and the Controlled Substances Act. Noramco’s failure for any reason to manufacture and supply us with the oxycodone in REMOXY could result in shortages, cost overruns or other problems that could materially harm our business.



Risks RelatingRelated to our Financial PositionCondition and Need for Financing

Our operating history may make it difficult for you to evaluate our business to date and to assess its future viability.

Our operations from our inception to date have been limited to organizing and staffing our company, acquiring, developing and securing our technology, undertaking preclinical studies and clinical trials of our drug candidates and forming collaborations. We have not yet demonstrated our ability to obtain regulatory approval, formulate and manufacture our drug candidates on a commercial scale or conduct sales and marketing activities. Consequently, any predictions you make about our future success or viability may not be as accurate as they could be if we had a longer operating history.Capital Requirements



We have a history ofincurred significant net losses in each period since our inception and expectanticipate that we will continue to incur substantialnet losses and negative operating cash flows for the foreseeable future.



AlthoughWe have incurred net losses in each reporting period since our inception, including a net loss of $6.3 million for the year ended December 31, 2020. As of December 31, 2020, we were profitable in some years in the past based on payments received pursuant to collaboration agreements and interest income, we have yet to generate any revenues from product sales. We havehad an accumulated deficit of $157 million$174.9 million.  

We have invested significant financial resources in research and development activities for product candidates. We do not expect to generate revenue from product sales for several years, if at December 31, 2017. Even if we succeed in developing and commercializing one or moreall. The amount of our drug candidates, wefuture net losses will depend, in part, on the level of our future expenditures and revenue. Moreover, our net losses may fluctuate significantly from quarter to quarter and year to year, such that a period-to-period comparison of our results of operations may not be a good indicator of our future performance.

We expect to continue to useincur significant cash resources in our operationsexpenses and higher operating losses for the foreseeable future.

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We anticipate that our expenses will increase substantially in the foreseeable future as we:

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continue to conductour research and discovery activities;

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advance our current and any future product candidates through preclinical studies and clinical trialsdevelopment;

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initiate and conduct additional preclinical, clinical, or other studies for our drugproduct candidates;

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work with our CDMO’s to scale up the manufacturing processes for our product candidates;

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seek regulatory approvals and marketing authorizations for our drugproduct candidates;

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develop, formulate, manufactureobtain, maintain, protect, defend and commercializeenforce our drugintellectual property portfolio;

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attract, hire, and retain qualified personnel;

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provide additional internal infrastructure to support our continued research and development operations and any planned commercialization efforts in the future;

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experience any delays or encounter other issues related to our operations; and

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meet the requirements and demands of being a public company.

Our prior losses and expected future losses have had and will continue to have an adverse effect on our stockholders’ equity and working capital. In any quarter, our operating results could be below the expectations of securities analysts or investors, which could cause our stock price to decline.

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We have broad discretion in the use of the net proceeds from any of our financing transactions and may not use them effectively.

We have broad discretion in the application of the net proceeds from our financing transactions, and investors will not have the opportunity to assess whether the net proceeds are being used appropriately. We could spend the net proceeds from offerings in ways that vary substantially from their intended use, do not improve our results of operations or enhance the value of our common stock. Our failure to apply these funds effectively could result in financial losses that could have a material adverse effect on our business, cause the price of our common stock to decline and delay the development of our product candidates. Pending their use, we may invest the net proceeds from our financing transactions in a manner that does not produce income or that loses value.

We have no product revenues and may never achieve revenues or profitability based on product revenues.

We have no products approved for commercial sale. To obtain revenues from the sales of our product candidates that are significant or large enough to achieve profitability, we must succeed, either alone or with third parties, in developing, obtaining regulatory approval for, manufacturing, and marketing product candidates with significant commercial value. This is a significant endeavor that few early-stage biopharmaceutical companies can successfully achieve. Our ability to generate revenue and achieve profitability depends on many factors, including:

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completing research and preclinical and clinical development of our product candidates;

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implement additional internal systemsobtaining regulatory approvals and develop new infrastructure;marketing authorizations for product candidates for which we successfully complete clinical development;

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acquire or in-license additionaldeveloping a sustainable and scalable manufacturing process for our product candidates, as well as establishing and maintaining commercially viable supply relationships with third parties that can provide adequate products or technologies, or expand the use ofand services to support clinical activities and commercial demand for our technology;product candidates;

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maintain, defendidentifying, assessing, acquiring, and/or developing new product candidates;

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negotiating favorable terms in any collaboration, licensing, or other arrangements into which we may enter;

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addressing any competing technological and expand the scopemarket developments;

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maintaining, protecting, expanding, and enforcing our portfolio of our intellectual property;property rights, including patents, trade secrets, and know-how; and

·

hire additionalattracting, hiring, and retaining qualified personnel.

 

We will needBecause of the numerous risks and uncertainties associated with drug development, we are unable to generate significant revenues to achieve and maintain profitability. If wepredict the timing or amount of our collaborators cannot successfully develop, obtain regulatory approval for and commercialize our drug candidates,expenses, or when we will not be able to generate such revenuesany meaningful revenue or achieve profitability in the future. Our failure to achieve or maintain profitability, would have a material adverse impact on the market priceif ever. In addition, our expenses could increase beyond our current expectations if we are required by FDA or foreign regulatory agencies to perform studies in addition to those that we currently anticipate, or if there are any delays in any of our common stock.clinical studies or the development of any of our product candidates.



If we cannot raiseWe may require additional capital to fund our operations and to complete the development of our product candidates. A failure to obtain this necessary capital on acceptable terms, or at all, could force us to delay, limit, reduce, or terminate our commercialization efforts, product development, or other operations.

Our operations have required substantial amounts of cash since inception, and we may be unableexpect our expenses to complete plannedincrease significantly in the foreseeable future. To date, we have financed our operations primarily through the sale of equity securities, research grants and payments received from prior third-party collaborations. Developing our product candidates and conducting clinical trialsstudies for the treatment of neurodegenerative diseases, including Alzheimer’s disease, will require substantial amounts of capital. We will also require a significant amount of capital to commercialize any or someapproved products.

As of December 31, 2020, we had cash and cash equivalents of $93.5 million. Subsequent to December 31, 2020, we completed a registered direct offering of our drug candidates or to pursue attractive business opportunities.

We have funded allcommon stock for net proceeds of our operations and capital expenditures with the proceeds from our public and private stock offerings, payments received under collaboration agreements and interest earnedapproximately $189.7 million. Based on our investments. We expectcurrent operating plan, we believe that our currentexisting cash and cash equivalents and marketable securities will be sufficient to meetfund our working capital and capital expenditure needsprojected operations for at least the next twelve12 months. However,Our estimate as to how long we expect our existing cash and cash equivalents to be available to fund our operations is based on assumptions that may prove inaccurate, and we could use our available capital resources sooner than we currently expect. In addition, changing circumstances may cause us to increase our spending significantly faster than we currently anticipate, and we may electneed to raise additional funds within such twelve-month period orspend more money than currently expected because of circumstances

61


beyond our control. We may need to raise additional funds thereafter andsooner than we anticipate if we choose to expand more rapidly than we presently anticipate.

We may require additional financingcapital for the further development of our product candidates. Additional capital may not be available when we need it, or on favorable terms ifacceptable to us or at all. EvenWe have no committed source of additional capital. If adequate capital is not available to us on a timely basis, we may be required to significantly delay, limit, reduce or terminate our research and development programs or the commercialization of product candidates, if we succeed in selling additional securitiesapproved, or be unable to raise funds,continue or expand our existing stockholders’ ownership percentage would be reducedoperations, or otherwise capitalize on our business opportunities, as desired, which could materially affect our business, financial condition, results of operations, and new investors may demand rights, preferences or privileges seniorgrowth prospects and cause the price of our common stock to those of existing stockholders. Ifdecline.

To the extent that we raise additional capital through the sale of equity or convertible debt securities, the ownership interest of our stockholders will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect your rights as a common stockholder. Debt financing, if available, such financings may involve agreements that include covenants that restrictlimiting or restricting our business activities.ability to take specific actions, such as incurring additional debt, making capital expenditures, or declaring dividends. If we raise additional capitalfunds through collaborations, strategic alliance and licensealliances, or licensing arrangements with pharmaceutical partners, we may have to trade ourrelinquish valuable rights to our technology, intellectual propertytechnologies, future revenue streams, research programs, or drugproduct candidates, to others in such arrangementsor grant licenses on terms that may not be favorable to us.



If we determine that we needGlobal credit and financial market conditions could negatively impact the value of our portfolio of cash equivalents and our ability to raise additional fundsmeet our financing objectives.

Our cash and cash equivalents are generally maintained in highly liquid investments with original maturities of 90 days or less at the time of purchase. While, as of the date of this filing, we are not successfulaware of any downgrades, material losses, or other significant deterioration in doing so, we may be unable to complete the clinical development of some or allfair value of our drug candidatescash equivalents since December 31, 2020, no assurance can be given that deterioration in conditions of the global credit and financial markets would not negatively impact our current portfolio of cash equivalents or our ability to seek or obtain FDA approvalmeet our financing objectives.

Risks Related to the Ownership of our drug candidates. Our Common Stock

We then could be forced to discontinue product development, enter intodo not know whether a relationship with an additional strategic partner earlier than currently intended, relinquish or license on unfavorable terms our rights to technologies or drug candidates that we would seeksufficient market will continue to develop ourselves or significantly delay, scale-back or curtailfor our operations.

Our forecast of the period of time through which our financial resources will be adequate to support our operations is a forward-looking statement and involves risks and uncertainties, and actual results could vary as a result of a number of factors, including the factors discussed elsewhere in this “Risk Factors” section. We have based this estimate on assumptions that may prove to be wrong, and we could utilize our available capital resources sooner than we currently expect.  

Risks Relating to an Investment in our Common Stock

Our stock price has been volatile and could experience a sudden decline in value.

Our common stock has experienced significant price and volume fluctuations and may continue to experience volatility in the future. You may not be able to sell your shares quickly or at the latest market price if trading in our stock is not active or the volume is low.

41


The following factors, in addition to other risk factors described in this section, may have a significant impact onwhat the market price of our common stock:stock will be, and, as a result, it may be difficult for investors to sell shares of our common stock.

If a market for our common stock is not sustained, it may be difficult to sell shares of our common stock at an attractive price or at all. We cannot predict the prices at which our common stock will trade. It is possible that in one or more future periods our results of operations and progression of our product pipeline may not meet the expectations of public market analysts and investors, and, as a result of these and other factors, the price of our common stock may fall.

The market price of our common stock has historically been highly volatile, and we expect it to continue to be volatile, which could result in substantial losses for investors who purchase our shares.

For example, the closing price of our common stock has fluctuated from a low of $2.04 to a high of $87.95 over the 12 months preceding the filing date of this Form 10-K. Some of the factors that may cause the market price of our common stock to fluctuate include:

·

resultsthe success of existing or delays in efforts to seek regulatory approval for REMOXY, and in preclinical studies and clinical trials for our other drug candidates;new competitive products or technologies;

·

publicity regarding products under development by us or others, including with respect to actual or potential medicalthe timing and results relating to such matters;of clinical studies for our current product candidates and any future product candidates that we may develop;

·

failure or discontinuation of any of our product development and research programs;

·

results of preclinical studies, clinical studies, or regulatory approvals of product candidates of our competitors, or announcements about new research programs or product candidates of technological innovationsour competitors;

·

regulatory or new commercial products by us or others;legal developments in the United States and other countries;

·

developments inor disputes concerning patent applications, issued patents, or other proprietary rights by us or others;

·

comments or opinions by securities analysts or major stockholders;

·

adverse media coverage related to opioid pharmaceuticals;

·

future sales of our common stock by existing stockholders;

·

developments with respect to potential merger and acquisition activity of companies with whom we have strategic alliances or other agreements;

·

regulatory developments or changes in regulatory guidance enacted by applicable governmental or other authorities;

·

litigation or threats of litigation;

·

economic and other external factors or other disaster or crises;rights;

·

the recruitment or departure of any of our officers, directors or key employees;personnel;

·

period-to-period fluctuationsthe level of expenses related to any of our research programs, clinical development programs, or product candidates that we may develop;

62


·

the results of our efforts to develop additional product candidates or products;

·

actual or anticipated changes in estimates as to financial results;results or development timelines;

·

announcement or expectationsexpectation of additional financing efforts;

·

changessales of our common stock by us, our insiders, or other stockholders;

·

variations in accounting practices;our financial results or those of companies that are perceived to be similar to us;

·

changes in the structure of the healthcare payment system;estimates or recommendations by securities analysts, if any, that cover our stock;

·

market conditions in the biopharmaceutical industry;

·

publication of research reports about us, our competitor or our industry, or positive or negative recommendations or withdrawal of research coverage by securities analysts;pharmaceutical and biotechnology sectors; and

·

limited daily trading volume.general economic, industry, and market conditions.



We are a smaller reporting companyIn recent years, the stock market in general, Nasdaq, and we cannot be certain if the reduced disclosure requirements applicablemarkets for early stage companies and pharmaceutical and biotechnology companies, has experienced significant price and volume fluctuations that have often been unrelated or disproportionate to smaller reporting companies will make our common stock less attractive to investors.

We are currently a “smaller reporting company” as definedchanges in the Securities Exchange Act of 1934, and are thus allowed to provide simplified executive compensation disclosures in our filings, are exempt from the provisions of Section 404(b)operating performance of the Sarbanes-Oxley Act requiring that an independent registered public accounting firm provide an attestation report on the effectiveness of internal control over financial reporting and have certain other reduced disclosure obligations with respect to our SEC filings. We will remain a “smaller reporting company” until the aggregate market value of our outstanding common stock held by non-affiliates as of the last business day our recently completed second fiscal quarter is $75 million or more. We cannot predict whether investors will find our common stock less attractive because of our reliance on any of these exemptions. If some investors find our common stock less attractive as a result, there may be a less active trading market for our common stock and our stock price may be more volatile.

We have in the past and may in the future fail to meet all applicable listing requirements, our common stock may be delisted from The Nasdaq Global Market, which could have an adverse impact on the liquidity and market price of our common stock.

Our commoncompanies whose stock is currently listed on The Nasdaq Global Market, which has qualitativeexperiencing those price and quantitative listing criteria. If we are unable to meet any of the Nasdaq listing requirements in the future, such as the corporate governance requirements, the minimum closing bid price requirement, the minimumvolume fluctuations. Broad market value of listed securities requirement, total assets and total revenues, net income from continuing operations, the number of publicly held shares or any other Nasdaq requirements. Nasdaq could determine to delist our common stock. A delisting of our common stock could adverselyindustry factors may seriously affect the market

42


liquidity of our common stock, decrease the market price of our common stock, adversely affect our ability to obtain financing for the continuationregardless of our operations and resultactual operating performance. Following periods of such volatility in the loss of confidence in our company. On November 16, 2016, we received notice from the Listing Qualifications Department of the Nasdaq Stock Market (the “Staff”) indicating that, for the previous 30 consecutive business days, the bid price for our common stock closed below the minimum $1.00 per share required for continued inclusion on The Nasdaq Global Market. The notification letter stated that we would be afforded 180 calendar days, or until May 15, 2017, to regain compliance with the minimum bid price requirement. In order to regain compliance, on May 4, 2017, our board of directors and stockholders approved the Charter Amendment to effect the Reverse Stock Split. On May 10, 2017, our common stock began trading on The Nasdaq Global Market on a split-adjusted basis at a ratio of 7-for-1. On May 24, 2017, we received a letter from the Staff indicating that we had regained compliance with the $1.00 minimum closing bid price requirement. Despite effecting the Reverse Stock Split, there can be no assurance that the market price per share of our common stock will remain in excess of the $1.00 minimum closing bid price requirement in the future. The continuing effect of the Reverse Stock Split on the market price of a company’s securities, securities class action litigation has often been brought against that company. Because of the potential volatility of our common stock cannotprice, we may become the target of securities litigation in the future. Securities litigation could result in substantial costs and divert management’s attention and resources from our business.

If we are unable to maintain effective internal controls, our business, financial position, and results of operations could be predicted with any certainty,adversely affected.

As a public company, we are subject to reporting and other obligations under the Securities Exchange Act of 1934, as amended (Exchange Act), including the requirements of Section 404 of SOX, which require annual management assessments of the effectiveness of our internal control over financial reporting.

The rules governing the standards that must be met for management to assess our internal control over financial reporting are complex and require significant documentation, testing and possible remediation to meet the detailed standards under the rules. During testing, our management may identify material weaknesses or deficiencies which may not be remedied in time to meet the deadline imposed by SOX. These reporting and other obligations place significant demands on our management and administrative and operational resources, including accounting resources.

Our management is responsible for establishing and maintaining adequate internal control over financial reporting. Our internal control over financial reporting is a process designed to provide reasonable assurance regarding the reliability of financial reporting and the historypreparation of similar stock split combinationsfinancial statements for companiesexternal purposes in like circumstances is varied.accordance with accounting principles generally accepted in the U.S. Any failure to maintain effective internal controls could have an adverse effect on our business, financial position, and results of operations.



Anti-takeover provisions in our charter documents and Delaware law may prevent or delay removal of incumbent management or a change of control.



Anti-takeover provisions of our amended and restated certificate of incorporation and amended and restated bylaws and Delaware law may have the effect of deterring or delaying attempts by our stockholders to remove or replace management, engage in proxy contests and effect changes in control. The provisions of our charter documents include:

·

a classified board so that only one of the three classes of directors on our boardBoard of directorsDirectors (the “Board”) is elected each year;

·

elimination of cumulative voting in the election of directors;

·

procedures for advance notification of stockholder nominations and proposals;

·

the ability of our board of directorsthe Board to amend our bylaws without stockholder approval; and

·

the ability of our board of directorsthe Board to issue up to 10,000,000 shares of preferred stock without stockholder approval upon the terms and conditions and with the rights, privileges and preferences as our board of directorsthe Board may determine.



In addition, as a Delaware corporation, we are subject to Delaware law, including Section 203 of the Delaware General Corporation Law. In general, Section 203 prohibits a Delaware corporation from engaging in any business combination with

63


any interested stockholder for a period of three years following the date that the stockholder became an interested stockholder unless certain specific requirements are met as set forth in Section 203.



These provisions, alone or together, could have the effect of deterring or delaying changes in incumbent management, proxy contests or changes in control.



Our shareChanges in our ownership is concentrated, andcould limit our officers, directors and principal stockholders can exert significant control over matters requiring stockholder approval.ability to utilize net operating loss carryforwards.



DueAs of December 31, 2020, we had aggregate federal net operating loss carryforwards of approximately $87.3 million, which begin to their combined stock holdings,expire in 2029. Under Section 382 of the Internal Revenue Code of 1986, as amended, changes in our officers, directors and principal stockholders (stockholders holding greater than 5%ownership may limit the amount of our common stock) acting collectivelynet operating loss carryforwards that could be utilized annually to offset our future taxable income, if any. This limitation would generally apply in the event of a cumulative change in ownership of our company of more than 50% within a rolling three-year period. Any such limitation may have thesignificantly reduce our ability to exercise significant influence over matters requiring stockholder approval includingutilize our net operating loss carryforwards and tax credit carryforwards. Any such limitation, whether as the electionresult of directors and approval of significant corporate transactions. In particular, Remi Barbier, our founder, Chairman of the Board of Directors, President and Chief Executive Officer, owns or controls a significant amount of the voting power of our outstanding capital stock. This concentration of ownership may delay or prevent a change in control of the Company and may make some transactions, including but not limited to any merger, consolidation, or sale of substantially all of our assets, more difficult or impossible to complete without the support of key stockholders.

Publicly available information regarding stockholders’ ownership may not be comprehensive because the SEC does not require certain large stockholders to publicly disclose their stock ownership positions.

If the fair value of our stock increases and outstanding Performance Awards vest, we expect to use substantial amounts of cash to fund employee tax liabilities.

We have Performance Awards outstanding. If these Performance Awards vest, we expect to issue our employees sharespast offerings, sales of our common stock net of statutory employment taxes. This net issuance results in fewer shares issued and usesby our cash to

43


fund these taxes. The use of cash could be substantially higher, depending on the fair valueexisting stockholders or additional sales of our common stock by us in the future could have a material adverse effect on our results of operations in future years. We have not completed a study to assess whether an ownership change for purposes of Section 382 has occurred, or whether there have been multiple ownership changes since our inception, nor do we plan to do so due to the date the Performance Awards vest. If our use of cash to fund these taxes is substantial, our cash balance could substantially declinesignificant costs and our stock price could also decline.complexities associated with such study.



We may in the future seeksell additional equity or debt securities to fund the cash usedour operations, and have outstanding securities exercisable for Performance Awards through the sale of our common stock. However, we may not be successful in selling shares of our common stock, to fund the cash used for Performance Awards. If the number of shares we sell to fund the cash used for Performance awards is significant, our stock price could decline.

Volatility in the stock prices of other companieswhich may contribute to volatility in our stock price.

The stock market in general, Nasdaq and the market for technology companies in particular, have experienced significant price and volume fluctuations that have often been unrelated or disproportionate to the operating performance of those companies. Further, there has been particular volatility in the market prices of securities of early stage life sciences companies. These broad market and industry factors may seriously harm the market price of our common stock, regardless of our operating performance. In the past, following periods of volatility in the market price of a company’s securities, securities class action litigation has often been instituted. A securities class action suit against us could result in substantial costs, potential liabilitiesdilution to our stockholders and the diversion of management’s attention and resources.

Our operating results may fluctuate from quarter to quarter and this fluctuation may causeimpose restrictions on our stock price to decline.

Our quarterly operating results have fluctuated in the past and are likely to fluctuate in the future. Factors contributing to these fluctuations include, among other items, the timing and enrollment rates of clinical trials for our drug candidates, our need for clinical supplies and the valuation of stock-based compensation. Thus, quarter-to-quarter comparisons of our operating results may not be not indicative of what we might expect in the future. As a result, in some future quarters our clinical, financial or operating results may not meet the expectations of securities analysts and investors and could result in a decline in the price of our stock.

If securities or industry analysts publish inaccurate or unfavorable research about our business or product candidates, our stock price could decline.

Securities or industry analysts publish research and reports about our business or product candidates. An analyst’s conclusions regarding prospects for product candidates in the biopharmaceutical industry can include judgments based on the limited publicly-available data. If one or more analysts issues unfavorable research about our business or our product candidates, including a downgrade of our common stock, the price of our stock may decline.

You may experience future dilution as a result of future equity offerings.business.



In order to raise additional capital to support our operations, we may in the future offersell additional shares of our common stock or other securities convertible into or exchangeable for our common stock. stock which could result in dilution our stockholders.

We cannot assure you that we will be able to sell shares or other securities in any other offering at a price per share that is equal to or greater than the price per share paid by investors in prior offerings, and investors purchasing our shares or other securities in the future could have rights superior to existing shareholders. The price per share at which we sell additional shares of our common stock or securities convertible into or exchangeable for our common Stockstock in future transactions may be higher or lower than the price per share in prior offerings.

There You may notalso be an active, liquid trading market for our common stock.

There is no guarantee that an active trading market fordiluted upon the exercise of outstanding stock options as of December 31, 2020 to purchase 2,817,504 shares of our common stock will be maintained on Nasdaq. Investorsat a weighted average price of $11.30 per share, and the future issuance of up to 252,188 compensatory equity awards authorized under our 2018 Omnibus Incentive Plan and up to 58,017 shares we may not be able to sell their shares quickly or at the latest market price if trading inunder our stock is not active.Employee Stock Purchase Plan.



Item 1B.Unresolved Staff Comments



None.

44




Item 2.Properties



We lease approximately 6,000 square feet of office space pursuant to a non-cancelable operating lease in Austin, TX that expires in December 2020.  We believe that our facilities are adequate and suitable for our current needs.April 30, 2024.



Item 3.Legal Proceedings



None.From time to time, we may become involved in litigation or other legal proceedings. We are not currently a party to any litigation or legal proceedings that, in the opinion of our management, are likely to have a material adverse effect on our business. Regardless of outcome, litigation can have an adverse impact on us because of defense and settlement costs, diversion of management resources, and other factors.



Item 4.Mine Safety Disclosures

Not applicable.



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PART II



Item 5.Market for Registrant's Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities

Market Price of Dividends of the Registrants Common Equity and Related Stockholder Matters



Our common stock is quoted on Nasdaq, under the symbol "PTIE."SAVA." The following table sets forth the high and low sales prices per share of our common stock as reported on Nasdaq for the periods indicated.



 

 

 

 

 

 

Sales Prices

 

High

 

Low

Fiscal 2016:

 

 

 

 

 

First Quarter

$

2.40

 

$

1.55

Second Quarter

$

2.63

 

$

1.95

Third Quarter

$

3.00

 

$

0.96

Fourth Quarter

$

1.04

 

$

0.51

Fiscal 2017:

 

 

 

 

 

First Quarter

$

9.31

 

$

3.71

Second Quarter

$

7.42

 

$

3.38

Third Quarter

$

4.30

 

$

3.10

Fourth Quarter

$

6.49

 

$

3.10



 

 

 

 

 



We currently expect to retain future earnings, if any, for use in the operation and expansion of our business and, notwithstanding our special nondividendnon-dividend distributions in December 2012 (of $0.75 per share of common stock totaling $34.0 million) and December 2010 (of $2.00 per share of common stock totaling $85.7 million), we have not paid and do not anticipate paying any cash dividends in the foreseeable future. As of January 12, 2018,25, 2021, there were approximately 4828  registered holders of record of our common stock.



Item 6.Selected Financial Data



Not applicable.

 

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Item 7.Management’s Discussion and Analysis of Financial Condition and Results of Operations



This discussion and analysis should be read in conjunction with our financial statements and accompanying notes included elsewhere in this report. Operating results are not necessarily indicative of results that may occur in future periods.



Overview



Pain Therapeutics,Cassava Sciences, Inc. develops proprietary drugs that offer significant improvementsis a clinical-stage biotechnology company. Our mission is to patientsdetect and healthcare professionals. We generally focus our drug development effortstreat neurodegenerative diseases, such as Alzheimer’s disease. Our novel science is based on disorders ofstabilizing – but not removing – a critical protein in the nervous system.brain.



Over the past 10 years, we have combined state-of-the-art technology with new insights in neurobiology to develop novel solutions for Alzheimer’s disease and other neurodegenerative diseases. Our expertise consists of developing new drug candidates and guiding these through various regulatory and development pathways in preparationstrategy is to leverage our unique scientific/clinical platform to develop a first-in-class program for their eventual commercialization. By necessity, the conduct of drug development is complex, lengthy, expensive and risky. The FDA has not yet established the safety or efficacy of our drug candidates.treating neurodegenerative diseases, such as Alzheimer’s.  



The following is a summary of our pipeline of drug assets:We currently have two clinical-stage biopharmaceutical assets under development:

·

our lead therapeutic product candidate is called simufilam, and it is a novel treatment for Alzheimer’s disease; and

·

our lead investigational diagnostic product candidate is called SavaDx, and it is a novel way to detect the presence of Alzheimer’s disease from a small sample of blood, possibly years before the overt appearance of clinical symptoms.



REMOXY ER (extended-release oxycodone capsules CII) – REMOXY, our lead drug candidate, is a proprietary abuse-deterrent, twice-daily, oral oxycodone to treat severe chronic pain.  We plan to resubmit the REMOXY NDA to the FDA, with Priority Review in Q1 2018.  We own exclusive rights to develop and commercialize REMOXY worldwide, with a sales royalty obligation to one of our technology partners.

FENROCK™ (transdermal fentanyl patch CII) – FENROCK is a proprietary, abuse-deterrent fentanyl skin patch to treat severe pain. This is an early-stage program that is substantially funded by a competitive research grant award from the National Institute on Drug Abuse (NIDA), the primary agency of the U.S. government for research on drug abuse. We own exclusive, worldwide rights to FENROCK, with no royalty obligations to any third party.

PTI-125 – PTI-125 is a proprietary small molecule drugOur scientific approach for the treatment of Alzheimer’s disease (AD).  seeks to simultaneously improve both neurodegeneration and neuroinflammation. We believe our ability to improve multiple vital functions in the brain represents a new, different and crucial approach to address Alzheimer’s disease.

Our lead therapeutic product candidate, simufilam, is a proprietary small molecule (oral) drug. Simufilam targets an altered form of a protein called filamin A (FLNA) in the Alzheimer’s brain. Published studies have demonstrated that the altered form of FLNA causes neuronal dysfunction, neuronal degeneration and neuroinflammation. 

We believe simufilam improves brain health by reverting altered FLNA back to its native, healthy conformation, thus countering the downstream toxic effects of altered FLNA. We have generated and published experimental and clinical evidence of improved brain health with simufilam. Importantly, simufilam is not dependent on clearing amyloid from the brain. Since simufilam has a unique mechanism of action, we believe its potential therapeutic effects may be additive or synergistic with that of other therapeutic candidates aiming to treat neurodegeneration.

Simufilam has demonstrated a multitude of beneficial effects in animal models of disease, including normalizing neurotransmission, decreasing neuroinflammation, suppressing neurodegeneration, and restoring memory and cognition. 

In 2017,2019, we completed a first-in-humansmall, first-in-patient, clinical-proof-of-concept, open-label Phase I2a study of simufilam in the U.S., with PTI-125.  This program is substantially funded by competitive research grant awardssubstantial support from the National Institutes of Health (NIH)Institute on Aging (NIA), the primary agencya division of the U.S. governmentNIH. Treatment with simufilam for biomedical research.  We own exclusive, worldwide rights to PTI-125, with no royalty obligations to any third party.28 days significantly improved key biomarkers of Alzheimer’s pathology, neurodegeneration and neuroinflammation (p<0.001).  Biomarkers effects were seen in all patients in both cerebrospinal fluid (CSF) and plasma.



PTI-125DXIn September 2020, – PTI-125 we announced final results of a Phase 2b study with simufilam in Alzheimer’s disease. In this clinical study funded by the NIH, Alzheimer’s patientstreated with 50 mg or 100 mg of simufilam twice-daily for 28 days showed statistically significant (p<0.05) improvements in CSF biomarkers of disease pathology, neurodegeneration and neuroinflammation, versusAlzheimer’s patients who took placebo. In addition, Alzheimer’s patientstreated with simufilam showed improvements in validated tests of episodic memory and spatial working memory,versus patients on placebo  (Effect Size 17-46%). Cognitive improvements correlated most strongly (R2=0.5) with decreases in levels of P-tau181.

In March 2020, we initiated a long-term open-label extension study to evaluate simufilam in patients with Alzheimer’s disease. This open-label, multi-center, extension study is intended to monitor the long-term safety and tolerability of simufilam 100 mg twice-daily for 12 or more months. The study’s initial target enrollment was approximately 100 patients with mild-to-moderate Alzheimer’s disease and, in February 2021, was increased to approximately 150 patients. This study uses the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog-11) to assess cognitive symptoms of

66


dementia and the Neuropsychiatric Inventory (NPI) to assess the presence and severity of dementia-related behavior. Both scales are widely used clinical tools in trials of Alzheimer’s disease.

On February 2, 2021, we announced results of the first of two preplanned interim analysis of our open-label study of simufilam. The first interim analysis summarizes clinical data at the midway point of enrollment, i.e., the first 50 patients who have completed at least 6 months of drug treatment. Patients’ cognition and behavior scores both improved following six months of simufilam treatment, with no safety issues. Six months of simufilamtreatment improved cognition scores by 1.6 points on ADAS-Cog11, a proprietary,10% mean improvement from baseline to month 6. In these same patients, simufilam also improved dementia-related behavior, such as anxiety, delusions and agitation, by 1.3 points on the Neuropsychiatric Inventory, a 29% mean improvement from baseline to month 6. 

Based on the interim results and inbound demand from Alzheimer’s patients and their caregivers, we announced significant changes to the open-label program, including an increase in the enrollment target by up to 50 additional patients, for a total target of approximately 150 patients. This study had enrolled approximately80 patients as of February 2021.

We expect to announce results of a second planned interim analysis on safety and cognition for our open-label study approximately mid-2021. The second interim analysis is intended to summarize clinical data on the first 50 patients who complete at least 12 months of open label drug treatment.

On February 22, 2021, we announced the successful completion of an End-of-Phase 2 (EOP2) meeting with the FDA for simufilam. Official EOP2 meeting minutes indicate we and the FDA agree on key elements of a pivotal Phase 3 clinical program in support of a New Drug Application (NDA) filing for simufilam in Alzheimer’s disease. We believe agreements reached during the EOP2 meeting show a clear path forward for advancing simufilam into Phase 3 studies. We expect to initiate a pivotal Phase 3 program with simufilam in Alzheimer’s disease in the second half of 2021.

Our diagnostic effort, called SavaDx, is an early-stage program focused on detecting the presence of Alzheimer’s disease from a small sample of blood, possibly years before the overt appearance of clinical symptoms. We are developing SavaDx as a fast, accurate and quantitative blood-based diagnostic/biomarkerinvestigational biomarker/diagnostic to detect and monitor Alzheimer's disease. The goal is to make the detection of Alzheimer’s disease (AD).  This clinical-stage program is substantially funded by competitive research grant awards from the NIH. as simple as getting a blood test. We own exclusive, worldwide rightsexpect to PTI-125DX, with no royalty obligations to any third party.initiate a validation/disease specificity study of SavaDx in 2021.

 



Financial Overview



We have yet to generate any revenues from product sales. We have an accumulated deficit of $157$174.9 million at December 31, 2017.2020. These losses have resulted principally from costs incurred in connection with research and development activities, salaries and other personnel-related costs and general corporate expenses. Research and development activities include costs of preclinical and clinical trialsstudies as well as clinical supplies associated with our drugproduct candidates. Salaries and other personnel-related costs include non-cash stock-based compensation associated with options and other equity awards granted to employees and non-employees. Our operating results may fluctuate substantially from period to period as a result of the timing of preclinical activities, enrollment rates of clinical trialsstudies for our drugproduct candidates and our need for clinical supplies.



We believe that our cash and cash equivalents at December 31, 2017,2020, will enable us to fund our operating expenses for at least the next 12 months. In addition, we willmay seek in the future to fund our operations through additional public or private equity or debt financings or other sources. However, we may be unable to raise additional funds or enter into such other arrangements when needed on favorable terms or at all. If we are unable to obtain financing or increasereach profitability, the related lack of liquidity will have a material adverse effect on our operations and future prospects.

46




We expect to continue to use significant cash resources in our operations for the next several years. Our cash requirements for operating activities and capital expenditures may increase substantially in the future as we:

·

initiate a large-scale manufacturing campaign for simufilam;

·

plan to initiate a Phase 3 program with simufilam

·

conduct other preclinical and clinical trialsstudies for our drugproduct candidates;

·

seek regulatory approvals for our drugproduct candidates;

67


·

develop, formulate, manufacture and commercialize our drugproduct candidates;

·

implement additional internal systems and develop new infrastructure;

·

acquire or in-license additional products or technologies, or expand the use of our technology;

·

maintain, defend and expand the scope of our intellectual property; and

·

hire additional personnel.



Product revenue will depend on our ability to receive regulatory approvals for, and successfully market, our drugproduct candidates. If our development efforts result in regulatory approval and successful commercialization of our drugproduct candidates, we will generate revenue from direct sales of our drugs and/or, if we license our drugs to future collaborators, from the receipt of license fees and royalties from sales of licensed products. We conduct our research and development programs through a combination of internal and collaborative programs. We rely on arrangements with universities, our collaborators, contract research organizationsCDMOs, CROs and clinical research sites for a significant portion of our product development efforts.



We focus substantially all our research and development efforts on research and development in the areas of neurology. The following table summarizes expenses by categorywhich have been reduced for research and development effortsreimbursements received for NIH grants (in thousands):





 

 

 

 

 



 

 

 

 

 



Years ended December 31,



2017

 

2016



 

 

 

 

 

Compensation

$

2,913 

 

$

3,561 

Contractor fees and supplies

 

3,989 

 

 

4,842 

Other common costs

 

713 

 

 

773 



$

7,615 

 

$

9,176 



 

 

 

 

 



 

 

 

 

 

 

 



 

 

 

 

 

 

 



 

Year ended

 



 

December 31,

 



 

2020

 

2019

 

Research and development expenses - gross

 

$

7,292 

 

$

6,297 

 

Less:  Reimbursement from NIH grants

 

 

4,239 

 

 

4,729 

 

 Research and development expenses - net

 

$

3,053 

 

$

1,568 

 



 

 

 

 

 

 

 



Research and development expenses include compensation, contractor fees and supplies as well as allocated common costs. Contractor fees and supplies generally include expenses for preclinical studies and clinical trialsstudies and costs for formulation and manufacturing activities. Other common costs include the allocation of common costs such as facilities. During the year ended December 31, 2020 and 2019, we received $4.2 million and $4.7 million from research grants from the NIH. These reimbursements were recorded as a reduction to our research and development expenses.



Our technology has been applied across certain of our portfolio of drugproduct candidates. Data, know-how, personnel, clinical results, research results and other matters related to the research and development of any one of our drugproduct candidates also relate to, and further the development of, our other drugproduct candidates. As a result, costs allocated to a specific drugproduct candidate may not necessarily reflect the actual costs surrounding research and development of that drugsuch product candidate due to cross application of the foregoing.



Estimating the dates of completion of clinical development, and the costs to complete development, of our drugproduct candidates would be highly speculative, subjective and potentially misleading. Pharmaceutical products take a significant amount of time to research, develop and commercialize. The clinical trialstudy portion of the development of a new drug alone usually spans several years. We expect to reassess our future research and development plans based on our review of data we receive from our current research and development activities. The cost and pace of our future research and development activities are linked and subject to change.

 

Critical Accounting Policies



The preparation of our financial statements in accordance with United StatesU.S. generally accepted accounting principles requires us to make estimates and assumptions that affect the reported amounts of assets, liabilities, revenues, expenses and interest income in our financial statements and accompanying notes. We evaluate our estimates on an ongoing basis, including those estimates related to agreements and research collaborations and investments.collaborations. We base our estimates on historical experience and various other assumptions that we believe to be reasonable under the circumstances, the results of which form the basis for making judgments about the carrying values of assets and liabilities that are not readily apparent from other sources. Actual results

 

4768


 

results may differ from these estimates under different assumptions or conditions. The following items in our financial statements require significant estimates and judgments:

·

Research Contract Costs and Accruals. The Company has entered into various research and development contracts with research institutions and other third-party vendors. These agreements are generally cancelable, and related payments are recorded as research and development expenses as incurred. The Company records accruals for estimated ongoing research costs. When evaluating the adequacy of the accrued liabilities, the Company analyzes progress of the studies including the phase or completion of events, invoices received and contracted costs. Significant judgments and estimates are made in determining the accrued balances at the end of any reporting period. Actual results could differ from the Company’s estimates. The Company’s historical accrual estimates have not been materially different from the actual costs.

·

2020 Cash Incentive Bonus Plan. In 2020, we established the 2020 Cash Incentive Bonus Plan (the “Plan”) to incentivize Plan participants. Awards under the Plan are accounted for as liability awards under ASC 718 “Stock-based Compensation”. The fair value of each potential Plan award will be determined once a grant date occurs and will be remeasured each reporting period. Compensation expense associated with the Plan will be recognized over the expected achievement period for each Plan award, when a Performance Condition is considered probable of being met. 

The Plan was established to promote the long-term success of the Company by creating an “at-risk” cash bonus program that rewards Plan participants with additional cash compensation in lockstep with significant increases in our market capitalization. The Plan is considered “at-risk” because Plan participants will not receive a cash bonus unless our market capitalization increases significantly and (1) we complete a merger or acquisition transaction that constitutes a sale of ownership of the Company or its assets (a Merger Transaction) or (2) the Compensation Committee of the Board (the Compensation Committee) determines the Company has sufficient cash on hand, as defined in the Plan, to render payment (each, a “Performance Condition”), neither of which may ever occur. Because of the inherent discretion and uncertainty regarding these requirements, we have concluded that a Plan grant date has not occurred as of December 31, 2020. No actual cash payments were authorized or made to participants under the Plan during the year ended December 31, 2020.

·

Stock-based compensation.Compensation. We recognize non-cash expense for the fair value of all stock options and other share-based awards. We use the Black-Scholes option valuation model to calculate the fair value of stock options, using the single-option award approach and straight-line attribution method. For options granted to employees and directors, we recognizeIt recognizes the resulting fair value as expense on a straight-line basis over the vesting period of each respective stock option, generally four years. For options granted to non-employees, we remeasure the fair value expense using Black-Scholes each reporting period.

We have granted share-based awards that vest upon achievement of certain performance criteria, or Performance Awards.performance awards. We multiply the number of Performance Awardsperformance awards by the fair market value of our common stock on the date of grant to calculate the fair value of each award. We estimate an implicit service period for achieving performance criteria for each award. We recognize the resulting fair value as expense over the implicit service period when we conclude that achieving the performance criteria is probable. We periodically review and update as appropriate our estimates of implicit service periods and determinations on achievement of the performance criteria. Performance Awardsawards vest and common stock is issued upon achievement of the performance criteria.

·

Income Taxes. We make estimates and judgments in determining the need for a provision The Company accounts for income taxes includingunder the estimationasset and liability method.  Deferred tax assets and liabilities are recognized for the estimated future tax consequences attributable to differences between the financial statement carrying amounts of our taxable income or loss for each full fiscal year.We haveexisting assets and liabilities and their respective tax bases.  Deferred tax balances are adjusted to reflect tax rates based on currently enacted tax laws, which will be in effect in the years in which the temporary differences are expected to reverse.  The Company has accumulated significant deferred tax assets that reflect the tax effects of net operating loss and tax credit carryovers and temporary differences between the carrying amounts of assets and liabilities for financial reporting purposes and the amounts used for income tax purposes. Realization of certain deferred tax assets is dependent upon future earnings, if any. We areearnings. The Company is uncertain as toabout the timing and amount of any future earnings. Accordingly, we offsetthe Company offsets these deferred tax assets with a valuation allowance. We may in the future determine that our deferred tax assets will likely be realized, in which case we will reduce our valuation allowance in the quarter in which such determination is made. If the valuation allowance is reduced, we may recognize a benefit from income taxes in our statement of operations in that period. We classify interest recognized in connection with our tax positions as interest expense, when appropriate.

69


The Company accounts for uncertain tax positions in accordance with ASC 740, “Income Taxes”, which clarifies the accounting for uncertainty in tax positions. These provisions require recognition of the impact of a tax position in the Company’s financial statements only if that position is more likely than not of being sustained upon examination by taxing authorities, based on the technical merits of the position. Any interest and penalties related to uncertain tax positions will be reflected as a component of income tax expense.



Recent Accounting Pronouncements



In August 2016,December 2019, the FABS issued ASU No. 2019-12, Income Taxes (Topic 740) Simplifying Accounting for Income Taxes as part of its initiative to reduce complexity in the accounting standards. The guidance amended certain disclosure requirements that had become redundant, outdated or superseded. Additionally, this guidance amends accounting for the interim period effects of changes in tax laws or rates, and simplifies aspects of the accounting for franchise taxes. The guidance is effective for annual periods beginning after December 15, 2020, and is applicable for the Company in fiscal 2021. Early adoption is permitted. The Company does not anticipate that this guidance will have a material impact on its consolidated financial statements.

In November 2018, the FASB issued ASU No. 2016-15,2018-18, Statement of Cash FlowsCollaborative Arrangements (Topic 230)808): Classification of Certain Cash ReceiptsClarifying the Interaction Between Topic 808 and Cash PaymentsTopic 606. .  This ASU providesThe amendments in this update provide guidance on statementhow to assess whether certain transactions between collaborative arrangement participants should be accounted for within the revenue recognition standard. The amendments in this update are effective for interim and annual periods for the Company beginning on January 1, 2020. The adoption of cash flows presentationthis guidance did not have a material impact on the Company’s financial statements.

In August 2018, the FASB issued ASU No. 2018-13,Fair Value Measurement (Topic 820) - Disclosure Framework - Changes to the Disclosure Requirements for eight specific cash flow issues where diversity in practice exists.  ThisFair Value Measurement (ASU 2018-13), which is designed to improve the effectiveness of disclosures by removing, modifying and adding disclosures related to fair value measurements. ASU2018-13 is effective for fiscal years beginning after December 15, 2017, and interim periods within those fiscal years.  The Company expects that the adoption will not have a material impact on its financial statements.

In February 2016, the FASB issued ASU No. 2016-02, Leases (Topic 842).  The core principle of Topic 842 is that a lessee should recognize the assets and liabilities that arise from leases.  For operating leases, a lessee is required to recognize a right-of-use asset and a lease liability, initially measured at the present value of the lease payments, in the statement of financial position.  This ASU is effective for fiscal years beginning after December 15, 2018,2019, including interim periods within those fiscal years. The Company is evaluating the effect that the adoption of this ASU will have on its financial statements.  The Company currently expects that its operating lease commitment will be subject to the new standard and recognized as right-of-use asset and operating lease liability upon adoption of ASU 2016-02, which will increase2018-13 did not have a material impact on the total assets and total liabilities that it reports relative to such amounts prior to adoption.Company’s financial statements.



Results of Operations



Research and Development Expense



Research and development expense consistsconsist primarily of costs of drug development work associated with our drugproduct candidates, including:

·

clinical studies,

·

preclinical testing,

·

clinical trials,

·

clinical supplies and related formulation and design costs, and

48


·

compensation and other personnel-related expenses.



Research and development expenses decreasedincreased to $7.6$3.1 million in 20172020 from $9.2$1.6 million in 2016,2019, representing a 95% increase. This increase was due primarily due to decreasescosts related to manufacture clinical trial supplies in REMOXY related expenses and non-cash Performance Award related expensesanticipation of launching a Phase 3 clinical program in the year ended 2017simufilam as well as lower NIH reimbursement compared to the same period in 2016.prior year.  We received a  $1.4NIH reimbursement of $4.2 million from research grantgrants in 2017 from the NIH that we2020 recorded as a reduction to our research and development expense, as compared to a $1.5$4.7 million research grant in 2016.2019.



Research and development expenses included non-cash stock-relatedstock-based compensation expenses of $1.2$0.5 million in 2017 compared to $1.8 million in 2016.both 2020 and 2019.



We expect research and development expense to fluctuateincrease over the next several yearsin future periods as we plan to hire new personnel, manufacture drug supply, continue our development efforts. We expect our development efforts to resultand launch a Phase 3 clinical program in our drug candidates progressing through various stages of clinical trials. Our research and development expenses may fluctuate from period to period due to the timing and scope of our development activities and the results of clinical trials and preclinical studies.simufilam.

70


 

General and Administrative Expense



General and administrative expense consistsexpenses consist of personnel costs, allocated expenses and other expenses for outside professional services, including legal, human resources, audit and accounting services. Personnel costs consist of salaries, bonus, benefits and stock-based compensation. Allocated expenses consist primarily of compensationfacility costs. We incur expenses associated with operating as a public company, including expenses related to compliance with the rules and regulations of the SEC and Nasdaq, additional insurance expenses, additional audit expenses, investor relations activities, SOX compliance expenses and other general corporate expenses.administrative expenses and professional services. General and administrative expense decreasedincreased to $4.3$3.7 million in 20172020 from $5.8$3.4 million in 20162019, representing a 10% increase. The increase was due primarily due to decreases in non-cash Performance Award relatedhigher insurance expenses and professional fees compared to the departure of our CFO in 2017 as compared in 2016.prior year, partially offset by lower non-cash stock-based compensation expense. 



General and administrative expenses included non-cash stock-relatedstock-based compensation expenses of $1.8$0.5 million in 20172020 compared to $2.6$0.8 million in 2016.

2019. We expect other general and administrative expense for 20182021 will be consistent with 2017.increase compared to 2020 due to higher operating costs such as insurance, office space and information technology related expenses.

Gain on Sale of Property and Equipment

During the year ended December 31, 2020, we sold surplus manufacturing equipment to an independent third party and received proceeds totaling $360,000. The original cost of the property and equipment was $892,000 and accumulated depreciation was $878,000, resulting in a gain on sale of property and equipment of $346,000 during the year ended December 31, 2020. There were no sales of property and equipment during the year ended December 31, 2019.

We do not expect any future gains on sales of property and equipment.



Interest Income



Interest and other income, net, was $38,000$112,000 in 20172020 compared to $107,000$328,000 in 2016.  We expect our interest income2019. The decrease was due primarily to a significant decrease in interest rates in 2020 compared to the future as we use cash to fund our operations.prior year.



Liquidity and Capital Resources



Since inception, we have financed our operations primarily through public and private stock offerings, payments received under collaborative agreements and interest earned on our investments. We intend to continue to use our capital resources to fund research and development activities, capital expenditures, working capital requirements and other general corporate purposes. As of December 31, 2017,2020, cash and cash equivalents totaled $93.5 million.

2021 Registered Direct Offering

On February 12, 2021, we completed a common stock offering pursuant to which certain investors purchased 4,081,633 shares of common stock at a price of $49.00 per share. Net proceeds of the offering were approximately $189.7 million after deducting offering expenses.

2020 Follow-on Public Offering

On November 13, 2020, we completed the sale of 9,375,000 shares of our common stock in an underwritten public offering at a price of $8.00 per share. We received net proceeds from the offering of approximately $70.3 million after deducting underwriting discounts and marketable securitiesoffering expenses.

Common Stock Warrants

In August 2018, we issued warrants to purchase up to an aggregate of 9.1 million shares of its common stock in conjunction with an offering of our common stock.

During 2019, we received proceeds of $5.9 million from the exercise of 4.6 million shares pursuant to warrants. During 2020, we received proceeds of $4.9 million from the exercise of 4.0 million shares pursuant to warrants. During 2021, we

71


received proceeds of $0.7 million from the exercise of an additional 0.6 million shares pursuant to warrants. There were $10.5no warrants outstanding following the 2021 exercises.

At the Market (ATM) Common Stock Issuance

On March 27, 2020, we established an at-the-market offering program (ATM) to sell, from time to time, shares of our common stock having an aggregate offering price of up to $100 million in transactions pursuant to a shelf registration statement that was declared effective by the U.S. Securities and Exchange Commission (the SEC) on May 5, 2020. We are obligated to pay a commission of 3.0% of the gross proceeds from the sale of shares of common stock in the offering. We are not obligated to sell any shares in the offering.

There were no common stock sales under the ATM during the year ended December 31, 2020.

NIH Research Grant Awards

Our research has been supported by NIH under multiple research grant awards. Strong, long-term support from NIH has allowed us to advance our two lead product candidates, simufilam and SavaDx, into clinical development.

In March 2020, we were awarded a supplemental research funding grant from NIH of up to $374,000.  In April 2020, we were awarded a research grant from NIH of up to $2.5 million. These new, non-dilutive research grants are intended to strengthen our clinical program of simufilam, our investigational drug to treat Alzheimer’s disease. All of our NIH research grant awards are paid out on a reimbursement basis and require milestone-based technical progress.

2020 Cash Incentive Bonus Plan Obligations

On August 26, 2020, the Board approved the 2020 Cash Incentive Bonus Plan (the Plan). The Plan was established to promote the long-term success of the Company by creating an “at-risk” cash bonus program that rewards Plan participants with additional cash compensation in lockstep with significant increases in the Company’s market capitalization. The Plan is considered “at-risk” because Plan participants will not receive a cash bonus unless the Company’s market capitalization increases significantly and certain other conditions specified in the Plan are met. Specifically, Plan participants will not be paid any cash bonuses unless (1) the Company completes a merger or acquisition transaction that constitutes a sale of ownership of the Company or its assets (a Merger Transaction) or (2) the Compensation Committee determines the Company has sufficient cash on hand, as defined in the Plan. Plan participants will be paid all earned cash bonuses in the event of a Merger Transaction.

The Company’s market capitalization, including all outstanding stock options,  was $89.4 million at the inception of the Plan on August 26, 2020. If the Company were to exceed a $5 billion market capitalization for no less than 20 consecutive trading days, and conditions noted above for payment are met, all Plan milestones would be deemed achieved, in which case total cash bonus awards would range from a minimum of $137.4 million up to a hypothetical maximum of $322.3 million.

The Company’s potential financial obligation to plan participants at December 31, 2020 totaled $7.3 million, based upon the achievement of one Plan milestone in the Company’s market capitalization. No actual cash bonus payments have been made to any Plan participant, as the Company has not yet satisfied all the conditions necessary for amounts to be paid under the Plan. Subsequent to December 31, 2020, the Company’s market capitalization increased substantially. These increases triggered the achievement of eight additional Plan milestones. Collectively, the achievement of such milestones could trigger potential Company obligations to Plan participants ranging from a minimum of $59.9 million up to a hypothetical maximum of $145.0 million, with exact amounts to be determined by the Compensation Committee.

No actual cash payments were made to participants under the Plan during the year ended December 31, 2020, or through the filing date of this Form 10-K.

Use of Cash



Net cash used in operating activities was $8.2$5.4 million for 2017 compared to $12.2the year ended December 31, 2020, resulting primarily from the net loss reported of $6.3 million and a gain on sale of property and equipment of $0.3 million, partially offset by non-cash stock-based compensation expense of $1.0 million and changes in operating assets and liabilities of $0.3 million.

72


Net cash used in operating activities was $2.5 million for 2019, resulting primarily from a $4.6 million net loss incurred partially offset by $1.3 million of non-cash stock-based compensation expense and $0.8 million from changes in 2016. The decrease was primarily due to lower researchoperating assets and development expenses during 2017 as compared in 2016.liabilities.



Net cash provided by investing activities during the year ended December 31, 2020 was $2.1 million in 2017 compared to net$360,000 for proceeds received from the sale of property and equipment.

Net cash used in investing activities was $18,000 for 2019 from purchases of $2.2computer equipment.

Net cash provided by financing activities during the year ended December 31, 2020 was $75.4 million consisting of $70.3 million proceeds from our follow-on public offering of common stock in 2016. Investing activities for both years consisted primarilyNovember 2020, $4.9 million proceeds from exercise of the purchasecommon stock warrants and maturities$0.3 million from exercise of marketable securities.stock options.



Net cash usedprovided by financing activities for 2019 was $0.3$5.8 million consisting of $5.9 million proceeds from exercise of common stock warrants partially offset by $0.1 million in 2016 resulting primarily from issuing sharesoffering expenses related the 2018 sale of our common stock to employees for vested Performance Awards net of statutory employment taxes.and warrants.



Realization of our deferred tax assets is dependent on future earnings, if any. We are uncertain about the timing and amount of any future earnings. Accordingly, we offset these net deferred tax assets with a valuation allowance.



We lease approximately 6,000 square feet of office space pursuant to a non-cancelable operating lease in Austin, TX that expires in 2020.April 2024. Future minimum lease payments are $0.3 million at December 31, 2017.as follows (in thousands):



We have license agreements that require us to make milestone payments upon the successful achievement of milestones, including clinical milestones. Our license agreements also require us to pay certain royalties to our licensors if we succeed in



49



 

 

 

For the year ending December 31,

 

 

 

2021

 

$

66 

2022

 

 

102 

2023

 

 

107 

2024

 

 

36 

Total future lease payments

 

$

311 



 

 

 


fully commercializing products under these license agreements. All of these potential future payments are cancelable as of December 31, 2017. Our formulation agreement with Durect Corporation obligates us to make certain milestone payments upon achieving clinical milestones and regulatory milestones.



We have an accumulated deficit of $157$174.9 million at December 31, 2017.2020. We expect our cash requirements to be significant in the future. The amount and timing of our future cash requirements will depend on regulatory and market acceptance of our drugproduct candidates and the resources we devote to researching and developing, formulating, manufacturing, commercializing and supporting our products. We believe that our current resources should be sufficient to fund our operations for at least the next 12 months. We may seek additional future funding through public or private financing within this timeframe,in the future, if such funding is available and on terms acceptable to us.



Off-balance Sheet Arrangements



As of December 31, 2017,2020, we did not have any relationships with unconsolidated entities or financial partnerships, such as entities often referred to as structured finance or special purpose entities, which would have been established for the purpose of facilitating off-balance sheet arrangements or other contractually narrow or limited purposes. In addition, we do not engage in trading activities involving non-exchange traded contracts. Therefore, we are not materially exposed to financing, liquidity, market or credit risk that could arise if we had engaged in these relationships. We do not have relationships or transactions with persons or entities that derive benefits from their non-independent relationship with us or our related parties.



Item 7A.Quantitative and Qualitative Disclosures about Market Risk



The primary objectivePursuant to Item 305(e) of our cash investment activitiesRegulation S-K, the information called for by Item 7A is to preserve principal while at the same time maximizing the income we receive from our investments without significantly increasing risk. Some of the securities that we invest in may be subject to market risk. This means that a change in prevailing interest rates may cause the principal amount of the investment to fluctuate. For example, if we hold a security that was issued with a fixed interest rate at the then-prevailing rate and the interest rate later rises, the principal amount of our investment will probably decline. A hypothetical 50 basis point increase in interest rates reduces the fair value of our available-for-sale securities at December 31, 2017 by approximately $2,000. To minimize this risk in the future, we intend to maintain our portfolio of cash equivalents and marketable securities in a variety of securities, including commercial paper, government and non-government debt securities and/or money market funds that invest in such securities. We have no holdings of derivative financial or commodity instruments. As of December 31, 2017, our investments consisted of investments in commercial paper, corporate notes and obligations or in money market accounts and checking funds with variable market rates of interest. We believe our credit risk is immaterial.not required.

73


 

Item 8.Financial Statements and Supplementary Data



INDEX TO FINANCIAL STATEMENTS





 

5074


 



Report of Independent Registered Public Accounting Firm



TheTo the Stockholders and the Board of Directors and Stockholders of Pain Therapeutics,Cassava Sciences, Inc.

Opinion on the Financial Statements

We have audited the accompanying balance sheets of Pain Therapeutics,Cassava Sciences, Inc. (the Company) as of December 31, 20172020 and 2016,2019, the related statements of operations, comprehensive income (loss), stockholders' equity and cash flows for each of the two years in the periodthen ended, December 31, 2017, and the related notes (collectively(collectively referred to as the “financial statements”). In our opinion, the financial statements present fairly, in all material respects, the financial position of the Company at December 31, 20172020 and 2016,2019, and the results of its operations and its cash flows for each of the two years in the periodthen ended, December 31, 2017, in conformity with U.S. generally accepted accounting principles.

Basis for Opinion

These financial statements are the responsibility of the Company's management. Our responsibility is to express an opinion on the Company’s financial statements based on our audits. We are a public accounting firm registered with the Public Company Accounting Oversight Board (United States) (PCAOB) and are required to be independent with respect to the Company in accordance with the U.S. federal securities laws and the applicable rules and regulations of the Securities and Exchange Commission and the PCAOB.



We conducted our audits in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit to obtain reasonable assurance about whether the financial statements are free of material misstatement, whether due to error or fraud. The Company is not required to have, nor were we engaged to perform, an audit of its internal control over financial reporting. As part of our audits we are required to obtain an understanding of internal control over financial reporting but not for the purpose of expressing an opinion on the effectiveness of the Company's internal control over financial reporting. Accordingly, we express no such opinion.



Our audits included performing procedures to assess the risks of material misstatement of the financial statements, whether due to error or fraud, and performing procedures that respond to those risks. Such procedures included examining, on a test basis, evidence regarding the amounts and disclosures in the financial statements. Our audits also included evaluating the accounting principles used and significant estimates made by management, as well as evaluating the overall presentation of the financial statements. We believe that our audits provide a reasonable basis for our opinion.



Critical Audit Matter

The critical audit matter communicated below is a matter arising from the current period audit of the financial statements that was communicated or required to be communicated to the audit committee and that: (1) relates to accounts or disclosures that are material to the financial statements and (2) involved our especially challenging, subjective, or complex judgments. The communication of the critical audit matter does not alter in any way our opinion on the financial statements, taken as a whole, and we are not, by communicating the critical audit matter below, providing a separate opinion on the critical audit matter or on the accounts or disclosures to which it relates.

75


Accrued Development Expenses

Description of

the Matter

As explained in Note 2 to the financial statements, the Company has various research and development contracts with research institutions and other third-party vendors, the costs under which are recorded as research and development expenses as incurred. The Company records an accrual for estimated ongoing research and development costs incurred but not yet billed at the end of each reporting period. At December 31, 2020, accrued development expense totaled $719,000, resulting primarily from patient clinical trials and ongoing drug manufacturing activities.

Auditing the Company’s accrued development expense was challenging because the accrual involved a higher degree of management judgment to estimate costs incurred for patient clinical trials and drug manufacturing activities at the end of the reporting period. An estimate of the costs incurred was necessary due to the long duration of the clinical trials, the progress of drug manufacturing activities, and the delayed timing of invoices received from third parties.

How We

Addressed the

Matter in Our

Audit

To evaluate the adequacy of the Company’s accrued development expense, our audit procedures included, among others, testing the accuracy and completeness of the underlying data used in the estimate, evaluating the significant assumptions used by management to estimate the accrual, and recalculating the accrual. To evaluate the significant assumptions (i.e., progress of patient clinical trials, progress of drug manufacturing activities), on a sample basis, we obtained external confirmation of key clinical trial contract terms and conditions directly from third parties, agreed information used in the estimate to the contracts with third parties and any amendments thereto, and corroborated the progress of clinical trials and drug manufacturing activities through inquiry of Company personnel who oversee research and development efforts. We also obtained and reviewed subsequent invoices received from third parties to corroborate the accrual at the end of the reporting period.

/s/ Ernst & Young LLP



We have served as the Company’s auditor since 2002.

Austin, Texas

February 6, 2018

March 23, 2021



 

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PAIN THERAPEUTICS, INC.

CASSAVA SCIENCES, INC.

CASSAVA SCIENCES, INC.

 

 

 

 

 

 

 

 

 

 

BALANCE SHEETS

BALANCE SHEETS

BALANCE SHEETS

(in thousands, except share and per share data)

(In thousands, except share and par value data)

(In thousands, except share and par value data)

 

 

 

 

December 31,

December 31,

 

2017

2016

2020

 

 

2019

 

 

 

 

 

 

 

 

 

 

 

ASSETS

ASSETS

ASSETS

Current assets:

 

 

 

 

 

 

 

 

 

 

Cash and cash equivalents

$

10,479 

$

16,615 

$

93,506 

 

$

23,081 

 

Marketable securities

 

 —

 

2,099 

Other current assets

 

184 

 

356 

 

488 

 

 

268 

 

Total current assets

 

10,663 

 

19,070 

 

93,994 

 

 

23,349 

 

Operating lease right-of-use assets

 

295 

 

 

90 

 

Property and equipment, net

 

156 

 

232 

 

11 

 

 

47 

 

Other assets

 

12 

 

 —

Total assets

$

10,831 

$

19,302 

$

94,300 

 

$

23,486 

 

 

 

 

 

 

 

 

 

 

 

LIABILITIES AND STOCKHOLDERS' EQUITY

LIABILITIES AND STOCKHOLDERS' EQUITY

LIABILITIES AND STOCKHOLDERS' EQUITY

Current liabilities:

 

 

 

 

 

 

 

 

 

 

Accounts payable

$

424 

$

303 

$

911 

 

$

453 

 

Accrued development expense

 

399 

 

27 

 

719 

 

 

777 

 

Accrued compensation and benefits

 

309 

 

335 

 

83 

 

 

58 

 

Operating lease liabilities, current

 

58 

 

 

90 

 

Other current liabilities

 

94 

 

 

 

Total current liabilities

 

1,132 

 

665 

 

1,865 

 

 

1,387 

 

Noncurrent liabilities

 

 —

 

 —

Operating lease liabilities, non-current

 

235 

 

 

 —

 

Total liabilities

 

1,132 

 

665 

 

2,100 

 

 

1,387 

 

Commitments and contingencies

 

 

 

 

Commitments and contingencies (Notes 7 and 8)

 

 

 

 

 

 

Stockholders' equity:

 

 

 

 

 

 

 

 

 

 

Preferred stock, $.001 par value; 10,000,000 shares authorized, none issued and outstanding

 

 —

 

 —

 

 —

 

 

 —

 

Common stock, $.001 par value; 120,000,000 shares authorized; 6,595,509 and 6,591,705

 

 

 

 

shares issued and outstanding at December 31, 2017 and 2016, respectively

 

 

Common stock, $.001 par value; 120,000,000 shares authorized; 35,237,987 and 21,841,810 shares issued and outstanding at December 31, 2020 and 2019, respectively

 

35 

 

 

22 

 

Additional paid-in capital

 

167,091 

 

164,118 

 

267,086 

 

 

190,664 

 

Accumulated other comprehensive income

 

 —

 

 —

Accumulated deficit

 

(157,399)

 

(145,488)

 

(174,921)

 

 

(168,587)

 

Total stockholders' equity

 

9,699 

 

18,637 

 

92,200 

 

 

22,099 

 

Total liabilities and stockholders' equity

$

10,831 

$

19,302 

$

94,300 

 

$

23,486 

 

 

 

 

 

 

 

 

 

 

 

See accompanying notes to financial statements.

 

5277


 





 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

PAIN THERAPEUTICS, INC.

CASSAVA SCIENCES, INC.

CASSAVA SCIENCES, INC.

 

 

 

 

 

 

 

 

 

 

 

STATEMENTS OF OPERATIONS

STATEMENTS OF OPERATIONS

STATEMENTS OF OPERATIONS

(in thousands, except per share data)

(In thousands, except per share data)

(In thousands, except per share data)

 

 

 

 

 

 

 

 

 

 

 

 

Years ended December 31,

 

Year ended December 31,

2017

 

2016

 

2020

 

2019

Operating expenses:

 

 

 

 

 

 

 

 

 

 

 

Research and development

$

7,615 

 

$

9,176 

Research and development, net of grant reimbursement

 

$

3,053 

 

$

1,568 

General and administrative

 

4,334 

 

 

5,781 

 

 

3,739 

 

 

3,391 

Gain on sale of property and equipment

 

 

(346)

 

 

 —

Total operating expenses

 

11,949 

 

 

14,957 

 

 

6,446 

 

 

4,959 

Operating loss

 

(11,949)

 

 

(14,957)

 

 

(6,446)

 

 

(4,959)

Interest income

 

38 

 

 

107 

 

 

112 

 

 

328 

Net loss

$

(11,911)

 

$

(14,850)

 

$

(6,334)

 

$

(4,631)

Net loss per share, basic and diluted

$

(1.82)

 

$

(2.28)

 

$

(0.24)

 

$

(0.27)

Shares used in computing net loss per share, basic and diluted

 

6,537 

 

 

6,520 

 

 

26,105 

 

 

17,412 

 

 

 

 

 

 

 

 

 

 

 

See accompanying notes to financial statements.

53




 

 

 

 

 



 

 

 

 

 

PAIN THERAPEUTICS, INC.



 

 

 

 

 

STATEMENTS OF COMPREHENSIVE INCOME (LOSS)

(in thousands)



 

 

 

 

 



 

 

 

 

 



Years ended December 31,



2017

 

2016

Net loss

$

(11,911)

 

$

(14,850)

Other comprehensive income (loss):

 

 

 

 

 

Net unrealized gains (losses) on marketable securities

 

 —

 

 

 —

Comprehensive loss

$

(11,911)

 

$

(14,850)



 

 

 

 

 



See accompanying notes to financial statements.





 

5478


 







 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

PAIN THERAPEUTICS, INC.



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

STATEMENTS OF STOCKHOLDERS' EQUITY

(in thousands)



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 

 

 

 

 

 

 

 

Accumulated

 

 

 

 

 

 



 

 

 

 

 

other

 

 

 

 

Total



Common stock

 

Additional

 

comprehensive

 

Accumulated

 

stockholders'



Shares

 

Par value

 

paid-in capital

 

income

 

deficit

 

equity

Balance at December 31, 2015

6,536,588 

 

 

 

 

159,998 

 

 

 —

 

 

(130,638)

 

 

29,367 

Non-cash stock-related compensation for:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stock options for employees

 —

 

 

 —

 

 

3,467 

 

 

 —

 

 

 —

 

 

3,467 

Stock options for non-employees

 —

 

 

 —

 

 

25 

 

 

 —

 

 

 —

 

 

25 

Performance Awards and related non-cash stock-related compensation

69,286 

 

 

 —

 

 

842 

 

 

 —

 

 

 —

 

 

842 

Performance Awards related to statutory taxes

(14,169)

 

 

 —

 

 

(214)

 

 

 —

 

 

 —

 

 

(214)

Other comprehensive loss

 —

 

 

 —

 

 

 —

 

 

 —

 

 

 —

 

 

 —

Net loss

 —

 

 

 —

 

 

 —

 

 

 —

 

 

(14,850)

 

 

(14,850)

Balance at December 31, 2016

6,591,705 

 

 

 

 

164,118 

 

 

 —

 

 

(145,488)

 

 

18,637 

Non-cash stock-related compensation for:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stock options for employees

 —

 

 

 —

 

 

2,954 

 

 

 —

 

 

 —

 

 

2,954 

Stock options for non-employees

 —

 

 

 —

 

 

19 

 

 

 —

 

 

 —

 

 

19 

Issuance of common stock pursuant to 7 to 1 Reverse stock split round up

3,804 

 

 

 —

 

 

 —

 

 

 —

 

 

 —

 

 

 —

Net loss

 —

 

 

 —

 

 

 —

 

 

 —

 

 

(11,911)

 

 

(11,911)

Balance at December 31, 2017

6,595,509 

 

$

 

$

167,091 

 

$

 —

 

$

(157,399)

 

$

9,699 



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CASSAVA SCIENCES, INC.



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

STATEMENTS OF STOCKHOLDERS' EQUITY

(in thousands)



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 

 

 

 

 

 

 

 

Accumulated

 

 

 

 

 

 



 

 

 

 

 

other

 

 

 

 

Total



Common stock

 

Additional

 

comprehensive

 

Accumulated

 

stockholders'



Shares

 

Par value

 

paid-in capital

 

income

 

deficit

 

equity

Balance at December 31, 2018

17,219,300 

 

$

17 

 

$

183,567 

 

$

 —

 

$

(163,956)

 

$

19,628 

Non-cash stock-based compensation for:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stock options for employees

 —

 

 

 —

 

 

1,287 

 

 

 —

 

 

 —

 

 

1,287 

Stock options for non-employees

 —

 

 

 —

 

 

 

 

 —

 

 

 —

 

 

Issuance costs from 2018 sale of common stock and warrants

 —

 

 

 —

 

 

(60)

 

 

 —

 

 

 —

 

 

(60)

Issuance of common stock pursuant to exercise of warrants

4,622,510 

 

 

 

 

5,861 

 

 

 —

 

 

 —

 

 

5,866 

Net loss

 —

 

 

 —

 

 

 —

 

 

 —

 

 

(4,631)

 

 

(4,631)

Balance at December 31, 2019

21,841,810 

 

$

22 

 

$

190,664 

 

$

 —

 

$

(168,587)

 

$

22,099 

Non-cash stock-based compensation for:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stock options for employees

 —

 

 

 —

 

 

961 

 

 

 —

 

 

 —

 

 

961 

Stock options for non-employees

 —

 

 

 —

 

 

27 

 

 

 —

 

 

 —

 

 

27 

Issuance of common stock pursuant to exercise of stock options

71,105 

 

 

 —

 

 

256 

 

 

 —

 

 

 —

 

 

256 

Issuance of common stock pursuant to exercise of warrants

3,950,072 

 

 

 

 

4,936 

 

 

 —

 

 

 —

 

 

4,940 

Common stock issued in conjunction with follow-on public offering, net of issuance costs

9,375,000 

 

 

 

 

70,242 

 

 

 —

 

 

 —

 

 

70,251 

Net loss

 —

 

 

 —

 

 

 —

 

 

 —

 

 

(6,334)

 

 

(6,334)

Balance at December 31, 2020

35,237,987 

 

$

35 

 

$

267,086 

 

$

 —

 

$

(174,921)

 

$

92,200 



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



See accompanying notes to financial statements.



 

5579

 


 

 



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

PAIN THERAPEUTICS, INC.

CASSAVA SCIENCES, INC.

CASSAVA SCIENCES, INC.

 

 

 

 

 

 

 

 

 

 

STATEMENTS OF CASH FLOWS

STATEMENTS OF CASH FLOWS

STATEMENTS OF CASH FLOWS

(in thousands)

(In thousands)

(In thousands)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Years ended December 31,

Year ended December 31,

2017

 

2016

2020

 

2019

Cash flows from operating activities:

 

 

 

 

 

 

 

 

 

 

Net loss

$

(11,911)

 

$

(14,850)

$

(6,334)

 

$

(4,631)

Adjustments to reconcile net loss to net cash used in operating activities:

 

 

 

 

 

 

 

 

 

 

Non-cash stock-based compensation

 

2,973 

 

 

4,334 

 

988 

 

 

1,296 

Depreciation and amortization

 

68 

 

 

58 

 

22 

 

 

58 

Non-cash net interest income

 

(2)

 

 

(8)

Gain on sale of property and equipment

 

(346)

 

 

 —

Changes in operating assets and liabilities:

 

 

 

 

 

 

 

 

 

 

Other current assets

 

172 

 

 

86 

 

(220)

 

 

(23)

Other non-current assets

 

(12)

 

 

12 

Operating lease right-of-use assets and liabilities

 

(2)

 

 

 —

Accounts payable

 

129 

 

 

(711)

 

458 

 

 

159 

Accrued development expense

 

372 

 

 

(867)

 

(58)

 

 

621 

Accrued compensation and benefits

 

(26)

 

 

(288)

 

25 

 

 

(3)

Other current liabilities

 

85 

 

 

Net cash used in operating activities

 

(8,237)

 

 

(12,234)

 

(5,382)

 

 

(2,514)

Cash flows from investing activities:

 

 

 

 

 

 

 

 

 

 

Purchases of property and equipment

 

 —

 

 

(75)

 

 —

 

 

(18)

Purchases of marketable securities

 

(399)

 

 

(4,141)

Sales of marketable securities

 

400 

 

 

 —

Maturities of marketable securities

 

2,100 

 

 

2,050 

Net cash provided (used in) investing activities

 

2,101 

 

 

(2,166)

Proceeds from sale of property and equipment

 

360 

 

 

 —

Net cash provided by (used in) investing activities

 

360 

 

 

(18)

Cash flows from financing activities:

 

 

 

 

 

 

 

 

 

 

Cash used for statutory taxes for net exercise of Performance Awards

 

 —

 

 

(214)

Deferred financing costs

 

 —

 

 

(70)

Net cash used in financing activities

 

 —

 

 

(284)

Net decrease in cash and cash equivalents

 

(6,136)

 

 

(14,684)

Issuance costs from 2018 sale of common stock and warrants

 

 —

 

 

(60)

Proceeds from exercise of stock options

 

256 

 

 

 —

Proceeds from exercise of common stock warrants

 

4,940 

 

 

5,866 

Proceeds from follow-on public offering, net of issuance costs

 

70,251 

 

 

 —

Net cash provided by financing activities

 

75,447 

 

 

5,806 

Net increase in cash and cash equivalents

 

70,425 

 

 

3,274 

Cash and cash equivalents at beginning of period

 

16,615 

 

 

31,299 

 

23,081 

 

 

19,807 

Cash and cash equivalents at end of period

$

10,479 

 

$

16,615 

$

93,506 

 

$

23,081 

 

 

 

 

 

 

 

 

 

 



See accompanying notes to financial statements.

 

5680


 

 

PAIN THERAPEUTICS,CASSAVA SCIENCES, INC.

NOTES TO FINANCIAL STATEMENTS

 

1.  General and Liquidity



Cassava Sciences, Inc. (the Company), formerly known as Pain Therapeutics, Inc., develops proprietary drugsproducts that offer significant improvements to patients and healthcare professionals. WeThe Company generally focus our drugfocuses its product development efforts on disorders of the nervous system, such as chronic pain.system.



On November 16, 2016, we received a letter from the Listing Qualifications staff of Nasdaq (the “Staff”) notifying us that, for the previous 30 consecutive business days, the bid price for our common stock had closed below the minimum $1.00 per share requirement (the “Minimum Price Requirement”) under Nasdaq’s Listing Rule 5450(a)(1) for continued listing on The Nasdaq Global Market. In accordance with Nasdaq Listing Rule 5810(c)(3)(A), if during the 180 calendar days following the date of the notification, or prior to May 15, 2017, the closing bid price of our common stock is at or above $1.00 for a minimum of 10 consecutive business days, the Staff will provide us with written confirmation of compliance. On May 24, 2017, we received a letter from the Staff indicating that we had regained compliance with the $1.00 minimum closing bid requirement following completion of the reverse stock split described below.Coronavirus Disease 2019 (COVID-19)



On May 4, 2017, following stockholder approval, our boardThe recent, widespread outbreak of directors approved a reverse stock split at a ratio of 7-for-1. On May 4, 2017, we filed with the Secretary of State of the State of Delaware a Certificate of Amendment tonovel infectious disease called Coronavirus Disease 2019, or COVID-19, has not significantly impacted the Company’s Amendedoperations or financial condition as of March 23, 2021. However, this pandemic has created a dynamic and Restated Certificateuncertain situation in the national economy. The Company continues to closely monitor the latest information to make timely, informed business decisions and public disclosures regarding the potential impact of Incorporation to effect the 7-for-1 reverse stock splitpandemic on its operations and financial condition. The scope of our outstanding shares of common stock. The number of outstanding shares of common stockpandemic is unprecedented and its long-term impact on the date of the reverse split was reduced from 46.1 million to 6.6 million shares. Our common stock began trading on the Nasdaq Global Market on a split-adjusted basis when the market opened for trading on May 10, 2017. As a result, all common stock share amounts included in these consolidatedCompany’s operations and financial statements have been retroactively reduced by a factor of seven, and all common stock per share amounts have been increased by a factor of seven, with the exception of our common stock par value.condition cannot be reasonably estimated at this time.



Liquidity 



The Company has incurred significant net losses and negative cash flows since inception, and as a result has an accumulated deficit of $157$174.9 million at December 31, 2017. We expect our2020. The Company expects its cash requirements to be significant in the future. The amount and timing of ourits future cash requirements will depend on regulatory and market acceptance of our drugthe Company’s product candidates and the resources we devoteit devotes to researching and developing, formulating, manufacturing, commercializing and supporting ourits products. WeThe Company may seek additional future funding through public or private financing within this timeframe,in the future, if such funding is available and on terms acceptable to us.

the Company. There are no assurances that additional financing will be available on favorable terms, or at all. However, management believes that the current working capital position will be sufficient to meet the Company’s working capital needs for at least the next 12 months.

 

2.  Summary of Significant Accounting Policies



Use of Estimates



The preparation of financial statements in conformity with accounting principles generally accepted in the United States of America requires that management make estimates and assumptions that affect the reported amounts of assets and liabilities and disclosure of contingent assets and liabilities at the date of the financial statements and the reported amount of revenue earned and expenses incurred during the reporting period. Actual results could differ from those estimates.



Proceeds from Grants



In 2017, we2020, the Company received $1.4$4.2 million of reimbursement from the National Institutes of Health and National Institute on Drug Abuse and $4.7 million in research grants from the NIH and NIDA and $1.5 million in 2016.  We record2019. The Company records the proceeds from the grantthese grants as a reductionreductions to ourits research and development expenses.



Cash and Cash Equivalents Marketable Securities and Concentration of Credit Risk



We investThe Company invests in cash and cash equivalents and, in the past, marketable securities. We considerThe Company considers highly-liquid financial instruments with original maturities of three months or less to be cash equivalents. Our marketable securitiesHighly liquid investments that are considered cash equivalents include interest-bearing financial instruments, generally consistingmoney market accounts, money market funds and certificates of corporate or governmentdeposit. The carrying value of cash equivalents approximates fair value due to the short-term maturity of these securities.



57


OurThe Company’s investment policy allows for investments in marketable securities with active secondary or resale markets, establishes diversification and credit quality requirements and limits investments by maturity and issuer. We maintain ourThe Company maintains its investments at one financial institution.



A change in prevailing interest rates may cause the fair value of the investment to fluctuate. We do not recognize an impairment charge related to this type of fluctuation because the fluctuation is temporary and eliminated by the time an investment matures. We would recognize an impairment charge if and when we determine that a decline in the fair value below the amortized cost of an investment is other-than-temporary. We consider various factors in determining whether to recognize an impairment charge, including any adverse changes in the investees’ financial condition, how long the fair value has been below the amortized cost and whether it is more likely than not that we would elect to or be required to sell the marketable security before its anticipated recovery.

 

We may elect to sell marketable securities before they mature. We hold these investments as “available for sale” and include these investments in our Balance Sheets as current assets, even though the contractual maturity of a particular investment may be beyond one year.81


 

Fair Value Measurements



We report ourThe Company reports its cash equivalents and marketable securitiescash equivalents at fair value as Level 1, Level 2 or Level 3 using the following inputs:

·

Level 1 includes quoted prices in active markets. We baseThe Company bases the fair value of money market funds and U.S. treasury securities on Level 1 inputs.

·

Level 2 includes significant observable inputs, such as quoted prices for identical or similar investments, or other inputs that are observable and can be corroborated by observable market data for similar securities. We useThe Company uses market pricing and other observable market inputs obtained from third-party providers. We useIt uses the bid price to establish fair value where a bid price is available. We baseThe Company bases the fair value of our marketable securitiesits certificates of deposit, if any, on Level 2 inputs.

·

Level 3 includes unobservable inputs that are supported by little or no market activity. We doThe Company does not have any investments where the fair value is based on Level 3 inputs.



We include unrealized gains or lossesIf a financial instrument uses inputs that fall in different levels of the hierarchy, the instrument will be categorized based upon the lowest level of input that is significant to the fair value calculation. A certificate of deposit totaling $13.0 million at December 31, 2019 was included within cash equivalents as a Level 2 input. The fair value of the remainder of cash and cash equivalents, including money market accounts, was based on our investments as Accumulated other comprehensive income (loss) in the Stockholders’ equity section of our Balance Sheets. We include changes in net unrealized gains or losses in our Statements of Comprehensive Income (Loss). We would recognize significant realized gainsLevel 1 inputs at December 31, 2020 and losses on a specific identification basis as other income in our Statements of Operations.2019.



Business Segments



We reportThe Company reports segment information based on how weit internally evaluateevaluates the operating performance of ourits business units, or segments. OurThe Company’s operations are confined to one business segment: the development of novel drugs.drugs and diagnostics.



Stock-based Compensation 



We recognizeThe Company recognizes non-cash expense for the fair value of all stock options and other share-based awards. We useThe Company uses the Black-Scholes option valuation model to calculate the fair value of stock options, using the single-option award approach and straight-line attribution method. For options grantedThis model requires the input of subjective assumptions including expected stock price volatility, expected life and estimated forfeitures of each award. These assumptions consist of estimates of future market conditions, which are inherently uncertain, and therefore, are subject to employees and directors, we recognizemanagement's judgment. The Company recognizes the resulting fair value as expense on a straight-line basis over the vesting period of each respective stock option, generally four years. For options granted to non-employees, we remeasure the fair value expense using Black-Scholes each reporting period.



We haveThe Company has granted share-based awards that vest upon achievement of certain performance criteria, or Performance Awards. We multiplyperformance awards. The Company multiplies the number of Performance Awardsperformance awards by the fair market value of ourits common stock on the date of grant to calculate the fair value of each award. We estimateIt estimates an implicit service period for achieving performance criteria for each award. We recognizeThe Company recognizes the resulting fair value as expense over the implicit service period when we concludeit concludes that achieving the performance criteria is probable. WeThe Company periodically reviewreviews and updateupdates as appropriate ourits estimates of implicit

58


service periods and conclusions on achieving the performance criteria. Performance Awardsawards vest and common stock is issued upon achievement of the performance criteria.



82


Net Loss per Share



Basic net loss per share is computed on the basis of the weighted-average number of common shares outstanding for the reporting period. Diluted net loss per share is computed on the basis of the weighted-average number of common shares outstanding plus dilutive potential common shares outstanding using the treasury-stock method. Potential dilutive common shares consist of outstanding equity awards and warrants. There is no difference between the Company’s net loss and comprehensive loss. The numerators and denominators in the calculation of basic and diluted net loss per share were as follows (in thousands)thousands, except net loss per share data):



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Years ended December 31,

 

Year ended December 31,

2017

 

2016

 

2020

 

2019

Numerator:

 

 

 

 

 

 

 

 

 

 

 

Net loss

$

(11,911)

 

$

(14,850)

 

$

(6,334)

 

$

(4,631)

Denominator:

 

 

 

 

 

 

 

 

 

 

 

Shares used in computing net loss per share, basic and diluted

 

6,537 

 

 

6,520 

 

 

26,105 

 

 

17,412 

Net loss per share, basic and diluted

$

(1.82)

 

$

(2.28)

 

$

(0.24)

 

$

(0.27)

Dilutive common shares excluded from net loss per share, diluted

 

2,497 

 

 

2,535 

 

 

 

 

 

 

 

 

 

 

 

Dilutive common stock options excluded from net loss per share, diluted

 

 

2,145 

 

 

2,932 

Common stock warrants excluded from net loss per share, diluted

 

 

554 

 

 

4,504 

 

 

 

 

 

 



WeThe Company excluded weighted equity awards and warrants outstanding to purchase common stock from the calculation of diluted net loss per share because the effect of including these shares in this calculation would be anti-dilutive.

 

Fair Value of Financial Instruments

Financial instruments include cash and cash equivalents, accounts payable and accrued liabilities. The estimated fair value of financial instruments has been determined using available market information or other appropriate valuation methodologies. However, considerable judgment is required in interpreting market data to develop estimates of fair value; therefore, the estimates are not necessarily indicative of the amounts that could be realized or would be paid in a current market exchange. The effect of using different market assumptions and/or estimation methodologies may be material to the estimated fair value amounts. The carrying amounts of cash and cash equivalents, accounts payable and accrued liabilities are at cost, which approximates fair value due to the short maturity of those instruments.

Research Contract Costs and Accruals

The Company has entered into various research and development contracts with research institutions and other third-party vendors. These agreements are generally cancelable, and related payments are recorded as research and development expenses as incurred. The Company records accruals for estimated ongoing research costs. When evaluating the adequacy of the accrued liabilities, the Company analyzes progress of the studies including the phase or completion of events, invoices received and contracted costs. Significant judgments and estimates are made in determining the accrued balances at the end of any reporting period. Actual results could differ from the Company’s estimates. The Company’s historical accrual estimates have not been materially different from actual costs.

Incentive Bonus Plan

In 2020, the Company established the 2020 Cash Incentive Bonus Plan (the “Plan”) to incentivize Plan participants.  Awards under the Plan are accounted for as liability awards under ASC 718 “Stock-based Compensation”. The fair value of each potential Plan award will be determined once a grant date occurs and will be remeasured each reporting period. Compensation expense associated with the Plan will be recognized over the expected achievement period for each Plan award, when a Performance Condition is considered probable of being met.  See Note 8 for further discussion of the Plan.

Leases

83


The Company recognizes assets and liabilities that arise from leases. For operating leases, the Company is required to recognize a right-of-use asset and a lease liability, initially measured at the present value of the lease payments, in the statements of financial position. As the Company`s leases do not provide an implicit rate, it uses its incremental borrowing rate based on the information available at the commencement date in determining the present value of lease payments. Lease expense for lease payments is recognized on a straight-line basis over the lease term.

Income Taxes



We make estimates and judgments in determining the need for a provisionThe Company accounts for income taxes includingunder the estimationasset and liability method. Deferred tax assets and liabilities are recognized for the estimated future tax consequences attributable to differences between the financial statement carrying amounts of our taxable income or loss for each full fiscal year.

We haveexisting assets and liabilities and their respective tax bases.  Deferred tax balances are adjusted to reflect tax rates based on currently enacted tax laws, which will be in effect in the years in which the temporary differences are expected to reverse. The Company has accumulated significant deferred tax assets that reflect the tax effects of net operating loss and tax credit carryovers and temporary differences between the carrying amounts of assets and liabilities for financial reporting purposes and the amounts used for income tax purposes. Realization of certain deferred tax assets is dependent upon future earnings. We areThe Company is uncertain about the timing and amount of any future earnings. Accordingly, we offsetthe Company offsets these deferred tax assets with a valuation allowance.



We mayThe Company accounts for uncertain tax positions in accordance with ASC 740, “Income Taxes”, which clarifies the accounting for uncertainty in tax positions. These provisions require recognition of the impact of a tax position in the future determineCompany’s financial statements only if that certain deferredposition is more likely than not of being sustained upon examination by taxing authorities, based on the technical merits of the position. Any interest and penalties related to uncertain tax assetspositions will likely be realized, in which case we will reduce our valuation allowance in the period in which such determination is made. If the valuation allowance is reduced, we may recognizereflected as a benefit fromcomponent of income taxes in our Statement of Operations in that period.

We classify interest recognized pursuant to our deferred tax assets as interest expense, when appropriate.expense.



Recent Accounting Pronouncements



WeThe Company reviewed recently issued accounting pronouncements and plan to adopt those that are applicable to us. We doit, and does not expect the adoption of these pronouncements to have a material impact on ourits financial position, results of operations or cash flows.



In August 2016,December 2019, the FABS issued ASU No. 2019-12, Income Taxes (Topic 740) Simplifying Accounting for Income Taxes as part of its initiative to reduce complexity in the accounting standards. The guidance amended certain disclosure requirements that had become redundant, outdated or superseded. Additionally, this guidance amends accounting for the interim period effects of changes in tax laws or rates and simplifies aspects of the accounting for franchise taxes. The guidance is effective for annual periods beginning after December 15, 2020, and is applicable for the Company in fiscal year 2021. Early adoption is permitted. The Company does not anticipate that this guidance will have a material impact on its consolidated financial statements.

In November 2018, the FASB issued ASU No. 2016-15,2018-18, Statement of Cash FlowsCollaborative Arrangements (Topic 230)808): Classification of Certain Cash ReceiptsClarifying the Interaction Between Topic 808 and Cash PaymentsTopic 606. .  This ASU providesThe amendments in this update provide guidance on statementhow to assess whether certain transactions between collaborative arrangement participants should be accounted for within the revenue recognition standard. The amendments in this update are effective for interim and annual periods for the Company beginning on January 1, 2020. The adoption of cash flows presentationthis guidance did not have a material impact on the Company’s financial statements.

In August 2018, the FASB issued ASU No. 2018-13,Fair Value Measurement (Topic 820) - Disclosure Framework - Changes to the Disclosure Requirements for eight specific cash flow issues where diversity in practice exists.  ThisFair Value Measurement (ASU 2018-13), which is designed to improve the effectiveness of disclosures by removing, modifying and adding disclosures related to fair value measurements. ASU2018-13 is effective for fiscal years beginning after December 15, 2017, and2019, including interim periods within those fiscal years. The Company expects that the adoption willof ASU 2018-13 did not have a material impact on itsthe Company’s financial statements.

 

In February 2016, the FASB issued ASU No. 2016-02, Leases (Topic 842).  The core principle of Topic 842 is that a lessee should recognize the assets and liabilities that arise from leases.  For operating leases, a lessee is required to recognize a right-of-use asset and a lease liability, initially measured at the present value of the lease payments, in the statement of financial position.  This ASU is effective for fiscal years beginning after December 15, 2018, including

59


interim periods within those fiscal years.  The Company is evaluating the effect that the adoption of this ASU will have on its financial statements.  The Company currently expects that its operating lease commitment will be subject to the new standard and recognized as right-of-use asset and operating lease liability upon adoption of ASU 2016-02, which will increase the total assets and total liabilities that it reports relative to such amounts prior to adoption.

3.  Collaboration Agreements

Durect Corporation

We have an exclusive, worldwide Development and License Agreement, or the Durect Agreement, with Durect to use a patented controlled-release technology that forms the basis for REMOXY. Under the terms of the Durect Agreement, we are solely responsible for clinical development, Durect is responsible for furnishing suitable laboratory facilities, equipment and personnel during pre-clinical phases of development and we and Durect are jointly responsible for certain pre-clinical activities.  We reimburse Durect’s expenses and have made milestone payments based on the achievement of certain clinical or regulatory milestones.

4.  Cash and Cash Equivalents and Marketable Securities

Cash, cash equivalents and marketable securities held as available-for-sale consisted of the following (in thousands):



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



Cash, Cash Equivalents and Marketable Securities



Amortized Cost

 

Unrealized Gains

 

Unrealized Losses

 

Estimated Fair Value

 

Accrued Interest

 

Total Value

December 31, 2017

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Cash

$

158 

 

$

 —

 

$

 —

 

$

158 

 

$

 —

 

$

158 

Cash equivalents

 

10,321 

 

 

 —

 

 

 —

 

 

10,321 

 

 

 —

 

 

10,321 

Total cash and cash equivalents

$

10,479 

 

$

 —

 

$

 —

 

$

10,479 

 

$

 —

 

$

10,479 

Reported as:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Cash and cash equivalents

$

10,479 

 

 

 —

 

 

 —

 

$

10,479 

 

$

 —

 

$

10,479 

Marketable securities

 

 —

 

 

 —

 

 

 —

 

 

 —

 

 

 —

 

 

 —



$

10,479 

 

$

 —

 

$

 —

 

$

10,479 

 

$

 —

 

$

10,479 

Maturities:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Matures in one year or less

$

10,479 

 

$

 —

 

$

 —

 

$

10,479 

 

$

 —

 

$

10,479 

Matures one to three years

 

 —

 

 

 —

 

 

 —

 

 

 —

 

 

 —

 

 

 —



$

10,479 

 

$

 —

 

$

 —

 

$

10,479 

 

$

 —

 

$

10,479 



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

December 31, 2016

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Cash

$

1,434 

 

$

 —

 

$

 —

 

$

1,434 

 

$

 —

 

$

1,434 

Cash equivalents

 

12,783 

 

 

 —

 

 

 —

 

 

12,783 

 

 

 —

 

 

12,783 

Commercial paper

 

4,497 

 

 

 —

 

 

 —

 

 

4,497 

 

 

 —

 

 

4,497 

Total cash and cash equivalents

$

18,714 

 

$

 —

 

$

 —

 

$

18,714 

 

$

 —

 

$

18,714 

Reported as:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Cash and cash equivalents

$

16,615 

 

 

 —

 

 

 —

 

$

16,615 

 

$

 —

 

$

16,615 

Marketable securities

 

2,099 

 

 

 —

 

 

 —

 

 

2,099 

 

 

 —

 

 

2,099 



$

18,714 

 

$

 —

 

$

 —

 

$

18,714 

 

$

 —

 

$

18,714 

Maturities:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Matures in one year or less

$

18,714 

 

$

 —

 

$

 —

 

$

18,714 

 

$

 —

 

$

18,714 

Matures one to three years

 

 —

 

 

 —

 

 

 —

 

 

 —

 

 

 —

 

 

 —



$

18,714 

 

$

 —

 

$

 —

 

$

18,714 

 

$

 —

 

$

18,714 



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

To date we have not recorded any impairment charges on marketable securities related to other-than-temporary declines in market value.

60


Our assets measured at fair value were (in thousands):



 

 

 

 

 

 

 

 

 

 

 



 

 

 

 

 

 

 

 

 

 

 



Level 1

 

Level 2

 

Level 3

 

Total

December 31, 2017

 

 

 

 

 

 

 

 

 

 

 

Cash and cash equivalents

$

10,479 

 

$

 —

 

$

 —

 

$

10,479 

Commercial paper

 

 —

 

 

 —

 

 

 —

 

 

 —



$

10,479 

 

$

 —

 

$

 —

 

$

10,479 

December 31, 2016

 

 

 

 

 

 

 

 

 

 

 

Cash and cash equivalents

$

14,217 

 

$

 —

 

$

 —

 

$

14,217 

Commercial paper

 

 —

 

 

4,497 

 

 

 —

 

 

4,497 



$

14,217 

 

$

4,497 

 

$

 —

 

$

18,714 



 

 

 

 

 

 

 

 

 

 

 

5.  Property and Equipment



PropertyThe Company’s property and equipment includesinclude furniture and equipment with a purchase value of $1.0 million at December 31, 2017 and 2016.equipment. Depreciation is recognized using the straight-line method over the expected life of the property and equipment. Accumulated

84


During the year ended December 31, 2020, the Company sold surplus manufacturing equipment to an independent third party and received proceeds totaling $360,000. The original cost of the property and equipment was $892,000 and accumulated depreciation was $0.8 million at$878,000, resulting a gain on sale of property and equipment of $346,000 during the year ended December 31, 20172020. There were no sales of property and $0.7 million atequipment during year ended December 31, 2016.2019.

 

6.4.  Stockholders' Equity and Stock-Based Compensation



Preferred Stock



OurThe Company’s Board of Directors (the “Board”) has the authority to issue preferred stock in one or more series and to fix the rights, preferences, privileges, restrictions and the number of shares constituting any series or the designation of the series.



2021 Registered Direct Offering

On February 12, 2021, the Company completed a common stock offering pursuant to which certain investors purchased 4,081,633 shares of common stock at a price of $49.00 per share. Net proceeds of the offering were approximately $189.7 million after deducting offering expenses.

2020 Follow-on Public Offering

On November 13, 2020, the Company completed the sale of 9,375,000 shares of Cassava common stock in an underwritten public offering at a price of $8.00 per share. The Company received net proceeds from the offering of $70,251,000 after deducting underwriting discounts and offering expenses.

Common Stock Warrants

In August 2018, the Company issued warrants to purchase up to an aggregate of 9.1 million shares of its common stock in conjunction with an offering of its common stock. 

During 2020, the Company received proceeds of $4.9 million from the exercise of 4.0 million shares pursuant to warrants. During 2019, the Company received proceeds of $5.9 million from the exercise of 4.6 million shares pursuant to warrants.

Subsequent to December 31, 2020, the Company received proceeds of $0.7 million from the exercise of an additional 0.6 million shares pursuant to warrants. There were no warrants outstanding following the 2021 exercises.

Warrants outstanding as of December 31, 2020 and 2019 were as follows:



 

 

 

 

 

 

 

 



 

 

 

 

 

Number of Shares Outstanding under Warrant



 

 

 

 

 

December 31,

Issuance Date

 

Expiration Date

 

Exercise Price Per Share

 

2020

 

2019



 

 

 

 

 

 

 

 

August 17, 2018

 

February 17, 2021

 

1.25 

 

554,019 

 

4,496,116 

August 17, 2018

 

February 17, 2021

 

1.59 

 

 —

 

7,975 



 

 

 

 

 

554,019 

 

4,504,091 



 

 

 

 

 

 

 

 

At the Market (ATM) Common Stock Issuance

On March 27, 2020, the Company established an at-the-market offering program (ATM) to sell, from time to time, shares of Company common stock having an aggregate offering price of up to $100 million in transactions pursuant to a shelf registration statement that was declared effective by the U.S. Securities and Exchange Commission (the SEC) on May 5, 2020. The Company is obligated to pay a commission of 3.0% of the gross proceeds from the sale of shares of common stock in the offering. The Company is not obligated to sell any shares in the offering.

85


There were no common stock sales under the ATM during the year ended December 31, 2020.

2008 Equity Incentive Plan



Under ourthe Company’s 2008 Equity Incentive Plan, or 2008 Equity Plan, ourits employees, directors and consultants received share-based awards, including grants of stock options and Performance Awards. Our Board of Directors or a designated Committee of the Board is responsible for administration of the 2008 Equity Plan and determined the terms and conditions of each option granted, consistent with the terms of the plan.performance awards. The 2008 Equity Plan expired in December 2017. Share-based awards generally expire ten years from the date of grant.



2018 Equity Incentive Plan

In  January 2018, the Company’s Board approved the Company’s 2018 Omnibus Incentive Plan (the 2018 Plan). The Company’s Board or a designated Committee of the Board is responsible for administration of the 2018 Plan and determined the terms and conditions of each option granted, consistent with the terms of the 2018 Plan. The Company’s employees, directors, and consultants are eligible to receive awards under the 2018 Plan, including grants of stock options and performance awards. Share-based awards generally expire ten years from the date of grant. The 2018 Plan provides for issuance of up to 1,000,000 shares of common stock, par value $0.001 per share under the 2018 Plan, subject to adjustment as provided in the 2018 Plan.

When stock options or Performance Awardsperformance awards are exercised net of the exercise price and taxes, the number of shares of stock issued is reduced by the number of shares equal to the amount of taxes owed by the award recipient and that number of shares are cancelled. WeThe Company then use ouruses its cash to pay tax authorities the amount of statutory taxes owed by and on behalf of the award recipient.



61


Stock Options



The following summarizes information about stock option activity during 2017:2020:





 

 

 

 

 

 

 

 

 

 

 



 

 

Number of Options

 

Weighted Average Exercise Price

 

Weighted Average Remaining Contractual Term

 

Aggregate Intrinsic Value



 

 

 

 

 

 

 

In years

 

In millions



Outstanding as of December 31, 2016

 

2,435,249 

 

$

25.19

 

4.8

 

$

 —



Options granted

 

1,026,410 

 

$

3.68

 

 

 

 

 



Options exercised

 

 —

 

$

 —

 

 

 

 

 



Options forfeited/canceled

 

(479,504)

 

 

31.73

 

 

 

 

 



Outstanding as of December 31, 2017

 

2,982,155 

 

$

16.74

 

6.2

 

$

0.4



Vested and expected to vest at December 31, 2017

 

2,982,155 

 

$

16.74

 

6.2

 

$

0.4



Exercisable at December 31, 2017

 

1,757,688 

 

$

24.02

 

4.1

 

$

 —



 

 

 

 

 

 

 

 

 

 

 



 

 

 

 

 

 

 

 

 

 

 



 

 

Number of Options

 

 

Weighted Average Exercise Price

 

Weighted Average Remaining Contractual Term

 

Aggregate Intrinsic Value



 

 

 

 

 

 

 

In years

 

In millions



Outstanding as of December 31, 2019

 

3,210,965 

 

$

12.27 

 

6.05

 

$

4.2



Options granted

 

60,000 

 

 

7.25 

 

 

 

 

 



Options exercised

 

(71,105)

 

 

3.60 

 

 

 

 

 



Options forfeited/canceled

 

(382,356)

 

 

20.31 

 

 

 

 

 



Outstanding as of December 31, 2020

 

2,817,504 

 

 

11.30 

 

5.60

 

$

6.4



Vested and expected to vest at December 31, 2020

 

2,817,504 

 

 

11.30 

 

5.60

 

$

6.4



Exercisable at December 31, 2020

 

2,167,633 

 

$

13.86 

 

4.85

 

$

3.7



 

 

 

 

 

 

 

 

 

 

 



The following summarizes information about stock options at December 31, 20172020 by a range of exercise prices:





 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 

 

 

 

 

 

Options outstanding

 

Options exercisable



 

 

 

 

 

 

 

 

Weighted

 

 

 

 

 

 

 

 



 

 

 

 

 

 

 

 

average

 

Weighted

 

 

 

Weighted



 

 

 

 

 

 

Number of

 

remaining

 

average

 

Number of

 

average



Range of exercise prices

 

outstanding

 

contractual

 

exercise

 

vested

 

exercise



From

 

To

 

options

 

life (in years)

 

price

 

options

 

price



$

3.24

 

$

4.09

 

933,200 

 

9.8

 

$

3.59

 

46,458 

 

$

3.25



$

4.10

 

$

15.61

 

620,243 

 

7.5

 

$

11.63

 

345,168 

 

$

12.51



$

16.31

 

$

23.38

 

628,411 

 

3.9

 

$

19.05

 

597,399 

 

$

19.16



$

23.59

 

$

35.00

 

656,841 

 

2.9

 

$

30.41

 

626,841 

 

$

30.24



$

36.40

 

$

53.55

 

143,460 

 

3.4

 

$

51.66

 

141,822 

 

$

51.82



 

 

 

 

 

 

2,982,155 

 

6.2

 

$

16.74

 

1,757,688 

 

$

24.02



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 

 

 

 

 

 

Options outstanding

 

Options exercisable



 

 

 

 

 

 

 

 

Weighted

 

 

 

 

 

 

 

 



 

 

 

 

 

 

 

 

average

 

Weighted

 

 

 

Weighted



 

 

 

 

 

 

Number of

 

remaining

 

average

 

Number of

 

average



Range of exercise prices

 

outstanding

 

contractual

 

exercise

 

vested

 

exercise



From

 

To

 

options

 

life (in years)

 

price

 

options

 

price



$

0.95

 

$

1.88

 

659,688 

 

8.4

 

$

1.47

 

251,613 

 

$

1.31



$

3.24

 

$

4.09

 

812,094 

 

6.7

 

$

3.51

 

643,377 

 

$

3.48



$

4.10

 

$

13.09

 

598,462 

 

5.0

 

$

10.89

 

525,383 

 

$

11.42



$

14.21

 

$

35.00

 

619,599 

 

2.8

 

$

24.02

 

619,599 

 

$

24.02



$

36.40

 

$

53.55

 

127,661 

 

0.7

 

$

51.72

 

127,661 

 

$

51.72



 

 

 

 

 

 

2,817,504 

 

5.6

 

$

11.30

 

2,167,633 

 

$

13.86

86




We useThe Company uses Black-Scholes to estimate the fair value of options granted. Black-Scholes considers a number of factors, including the market price of ourthe Company’s common stock. For options granted to employees and directors, weIt used certain factors to value each stock option granted, which resulted in a weighted average fair value of options granted during 20172020 and 2016,2019, as follows:







 

 

 

 



 

2017

 

2016



Volatility

79% to 83%

 

72%



Risk-free interest rates

2% to 2.4%

 

1% to 2%



Expected life of option

7 years

 

7 years



Dividend yield

zero

 

zero



Forfeiture rate

zero

 

zero



Weighted average fair value of stock options granted

$2.74

 

$1.60



 

 

 

 



 

 

 

 



 

2020

 

2019



Volatility

123% to 139%

 

118% to 119%



Risk-free interest rates

0.46% to 0.78%

 

1.7% to 2.5%



Expected life of option

7 years

 

7 years



Dividend yield

zero

 

zero



Forfeiture rate

zero

 

zero



Weighted average fair value of stock options granted

$6.69

 

$1.60



 

 

 

 



Volatility is based on reviews of the historical volatility of ourthe Company’s common stock. Risk-free interest rates are based on yields of U.S. treasury notes in effect at the date of grant. Expected life of option is based on actual historical option exercises. Dividend yield is zero because we dothe Company does not anticipate paying cash dividends in the foreseeable future. We estimate forfeitures and adjust this estimate periodically based in part on the extent to which actual forfeitures differ from our estimates.

For options granted to non-employees, we estimate the fair value of stock options granted using factors similar to those used for stock options granted to employees and directors and appropriate for the terms underlying the stock options granted to non-employees. We re-measure the compensation expense for options granted to non-employees each reporting period.

62




As of December 31, 2017, we expect2020, the Company expects to recognize compensation expense of $5.3$1.5 million related to non-vested options held by employees and directorsequity plan participants over the weighted average remaining recognition period of 3.22.1 years.

Subsequent to December 31, 2020, there were 20,385stock options exercised resulting in proceeds to the Company totaling $169,000.



Performance Awards



The following summarizes information about Performance Awardperformance award activity during 2017:2020:





 

 



 

Number of Performance Awards

Outstanding as of December 31, 20162019

 

222,060138,055 

Granted

 

 —

Vested Performance Awardsperformance awards

 

 —

Forfeited/Canceled

 

(69,720)

 —

Outstanding as of December 31, 20172020

 

152,340138,055 



 

 



If and when outstanding Performance Awardsperformance awards vest, wethe Company would recognize $2.5$2.3 million in non-cash stock-based compensation expense. These Performance Awardsperformance awards expire between 2022 and 2026.



Stock-Based Compensation Expense



The following summarizes information about non-cash stock-based compensation expense, in thousands:





 

 

 

 

 



 

 

 

 

 



Years ended December 31,



2017

 

2016



 

 

 

 

 

Research and development

 

 

 

 

 

Vesting of stock options

$

1,205 

 

$

1,313 

Vesting of Performance Awards

 

 —

 

 

438 



 

1,205 

 

 

1,751 

General and administrative

 

 

 

 

 

Vesting of stock options

 

1,768 

 

 

2,179 

Vesting of Performance Awards

 

 —

 

 

404 



 

1,768 

 

 

2,583 

Total non-cash stock-based compensation expenses

 

 

 

 

 

Vesting of stock options

 

2,973 

 

 

3,492 

Vesting of Performance Awards

 

 —

 

 

842 



$

2,973 

 

$

4,334 



 

 

 

 

 



 

 

 

 

 

 

 



 

 

 

 

 

 

 



 

Year ended

 



 

December 31,

 



 

2020

 

2019

 

Research and development

 

$

453 

 

$

542 

 



 

 

 

 

 

 

 

General and administrative

 

 

535 

 

 

754 

 



 

 

 

 

 

 

 

Total non-cash stock-based compensation expense

 

$

988 

 

$

1,296 

 



 

 

 

 

 

 

 

 

Non-cash stock-related compensation expense related to vesting of Performance Awards was associated with the resubmission of the NDA for REMOXY.

 

87


7.

5.  Employee 401(k) Benefit Plan



We haveThe Company has a defined-contribution savings plan under Section 401(k) of the Internal Revenue Code. The plan covers substantially all employees. Employees are eligible to participate in the plan the first day of the month after hire and may contribute up to the current statutory limits under Internal Revenue Service regulations. The 401(k) plan permits usthe Company to make additional matching contributions on behalf of all employees. Through December 31, 2017, we have2020, the Company has not made any matching contributions to the 401(k) plan.

 

63


8.6.  Income Taxes



U.S. Tax Reform

On December 22, 2017, legislation commonly known as the Tax Cuts and Jobs Act, or the Act, was signed in to law. The Tax Act, among other changes, reduces the U.S. federal corporate tax rate from 35% to 21%, requires taxpayers to pay a one-time transition tax on earnings of certain foreign subsidiaries that were previously tax deferred and creates new taxes on certain foreign sourced earnings.  On December 31, 2017, the Company did not have any foreign subsidiaries and the international aspects of the Tax Act are not applicable.

In connection with the initial analysis of the impact of the Tax Act, the Company remeasured certain deferred tax assets and liabilities based on the rates at which they are expected to reverse in the future, which is generally 21%. The remeasurement of the Company's deferred tax balance was primarily offset by application of its valuation allowance.      The Company is still in the process of analyzing the impact to the Company of the Tax Act. Where the Company has been able to make reasonable estimates of the effects for which its analysis is not yet complete, the Company has recorded provisional amounts. Where the Company has not yet been able to make reasonable estimates of the impact of certain elements, the Company has not recorded any amounts related to those elements and has continued accounting for them in accordance with ASC 740 on the basis of the tax laws in effect immediately prior to the enactment of the Tax Act.

We did not provide for income taxes in 20172020 and 20162019 because weit had a net operating loss for tax purposesbook and federal taxable losses in those years and the tax benefit that would have resulted from the statutory ratepre-tax losses was fully offset by a change in the valuation allowance.

The reconciliation of the statutory federal income tax rate to the Company’s effective tax rate for the years ended December 31, 2020 and 2019 was as follows:



 

 

 

 

 

 

 

 

 

 



 

 

 

 

 

 

 

 

 

 



 

 

 

 

Year ended December 31,

 

 



 

 

 

 

2020

2019

 

 

Tax at federal statutory rate

 

 

 

 

21.0 

%

 

21.0 

%

 

State tax, net of federal benefit

 

 

 

 

 —

 

 

 —

 

 

Share-based compensation

 

 

 

 

(42.8)

 

 

(2.4)

 

 

Research and development credits

 

 

 

 

1.6 

 

 

0.6 

 

 

Change in valuation allowance

 

 

 

 

20.2 

 

 

(19.2)

 

 

Effective income tax rate

 

 

 

 

 —

%

 

 —

%

 



 

 

 

 

 

 

 

 

 

 



Deferred tax assets and valuation allowance



Deferred tax assets reflect the tax effects of net operating loss and tax credit carryforwards and temporary differences between the carrying amounts of assets and liabilities for financial reporting purposes and the amounts used for income tax purposes. We reduced ourThe Company’s deferred taxes assets at December 31, 2017 for2020 and 2019 were valued at the reduced corporate tax rate toof 21% in recently enacted tax legislations.  We offset our. The Company offsets its deferred tax assets by a valuation allowance because we areit is uncertain about the timing and amount of any future profits. Significant components of ourits deferred tax assets are as follows (in thousands):



 

 

 

 

 

 

 

 

 

 

December 31,

December 31,

2017

 

2016

2020

 

2019

Deferred tax assets:

 

 

 

 

 

 

 

 

 

 

Net operating loss carryforwards

$

15,600 

 

$

22,300 

$

18,333 

 

$

17,110 

Stock-related compensation

 

5,300 

 

 

9,100 

Research & development credit carryforwards

 

6,400 

 

 

6,200 

Share-based compensation

 

3,230 

 

 

5,817 

Research and development credit carryforwards

 

6,687 

 

 

6,587 

Other

 

200 

 

 

200 

 

264 

 

 

237 

Total deferred tax assets:

 

28,514 

 

 

29,751 

Valuation allowance

 

(28,447)

 

 

(29,725)

Net deferred tax assets:

 

67 

 

 

26 

Deferred tax liabilities:

 

 

 

 

 

Property and equipment

 

(5)

 

 

(7)

Operating lease right-of-use assets

 

(62)

 

 

(19)

Total deferred tax liabilities:

 

(67)

 

 

(26)

Net deferred tax asset / (liability):

$

 —

 

$

 —

 

27,500 

 

 

37,800 

 

 

 

 

 

Valuation allowance

 

(27,500)

 

 

(37,800)

$

 —

 

$

 —

 

 

 

 

 



As of the beginning of 2017, we increased both our net operating loss carryforwards and our valuation allowance by $0.9 million when we adopted ASU 2016-09 for certain tax deductions associated with stock option transactions greater than the stock-related compensation expense in our financial statements.

88


The valuation allowance decreased by $10.3$1.3 million in 20172020. The valuation allowance decreased by $2.4 million due to a write down of the share-based compensation deferred tax asset and is offset in part by a $1.1 million increase due to additional book losses during the year. The valuation allowance increased by $3.6$0.9 million in 2016. 2019 due to additional book losses during the year.



OurThe Company’s pre-tax net operating loss carryforwards of $74$87.3 million are federal, and expireof which $74.1 million expires between 2029 and 2036.2039 and $13.2 million carries forward indefinitely. As of December 31, 2017, we2020, the Company had federal research and development tax credits of approximately $10.7$11.1 million, which expire in the years 2023 through 2036.  2040.  

Unrecognized tax benefits

As of December 31, 2020 and 2019, the Company has unrecognized tax benefits related to tax credits of $4.5 million and $4.4 million, respectively. None of the unrecognized tax benefits as of December 31, 2020, if recognized, would impact the effective tax rate due to the valuation allowance and no interest or penalties have been recognized. A reconciliation of the beginning and ending balance of unrecognized tax benefits is as follows (in thousands):



 

 

 

 

 



 

 

 

 

 



 

Year ended December 31,



2020

 

2019

Beginning balance

$

4,400 

 

$

4,400 

Additions based on tax positions related to the current year

 

100 

 

 

 —

Ending balance

$

4,500 

 

$

4,400 



 

 

 

 

 

As of December 31, 2020, there were no unrecognized tax benefits that we expect would change significantly over the next 12 months.

The Company files U.S. and Texas income tax returns. In the United States, the statute of limitations with respect to the federal income tax returns for tax years after 2016 are open to audit; however, since the Company has net operating losses, the taxing authority has the ability to review tax returns prior to the 2017 tax year and make adjustments to these net operating loss carryforwards. We are not under audit in any taxing jurisdiction at this time.

7.  Leases and Commitments

Right-of-use Asset and Liability

The Company has a single non-cancelable operating lease for approximately 6,000 square feet of office space in Austin, Texas, which is used for the development of novel products. On September 4, 2020, the Company entered into a lease amendment that extended the lease termination date to April 30, 2024 and set new rental rates effective as of January 1, 2021. Future lease payments are (in thousands).



 

 

 



 

 

 

For the year ending December 31,

 

 

 

2021

 

$

66 

2022

 

 

102 

2023

 

 

107 

2024

 

 

36 

Total future lease payments

 

 

311 

Less: imputed interest

 

 

(18)

Total

 

$

293 



 

 

 

Rent expense was $0.1 million for the year ended December 31, 2020 and 2019.



 

6489


 

 

Unrecognized tax benefitsThe Company recorded a right-of-use asset and lease liability of $316,000 as a result of the lease modification in September 2020. The Company utilized a discount rate of 3.25% for the modified lease to determine the present value of the future lease payments, which approximated the Company’s incremental borrowing rate in September 2020. There were no right-of-use assets exchanged for operating lease liabilities during the year ended December 31, 2019.



We have unrecognized tax benefits related to tax credits. We added to our unrecognized tax benefits in 2017Cash paid for operating lease liabilities totaled $99,000 and 2016 as follows (in thousands):$95,000 during the years ended December 31, 2020 and 2019, respectively.





 

 

 

 

 



 

 

 

 

 



2017

 

2016

Beginning balance

$

4,200 

 

$

4,000 

Additions based on tax positions related to the current year

 

100 

 

 

200 

Ending balance

$

4,300 

 

$

4,200 



 

 

 

 

 

9.  Leases andOther Commitments



We lease approximately 6,000 square feet of office space pursuant to a non-cancelable operating lease in Austin, TX that expires in December 2020. Future minimum lease payments are (in thousands).



 

 

 

 

 

 

 

 

 

 

 

 



 

 

 

 

 

 

 

 

 

 

 

 



 

2018

 

2019

 

2020

 

Total

Minimum lease payments

 

$

91 

 

$

95 

 

$

99 

 

$

285 



 

 

 

 

 

 

 

 

 

 

 

 

We believe that our facilities are adequate and suitable for our current needs. Rent expense was $0.1 million both in 2017 and 2016.

We conduct ourThe Company conducts its product research and development programs through a combination of internal and collaborative programs that include, among others, arrangements with universities, contract research organizations and clinical research sites. We haveIt has contractual arrangements with these organizations, however these contracts are cancelable on thirty days’ notice and ourthe Company’s obligations under these contracts are largely based on services performed.



The Company is dependent on contract development and manufacturing organizations for the manufacture of all our materials for clinical studies.

Note 8. 2020 Cash Incentive Bonus Plan

On August 26, 2020, the Board approved the Plan. The Plan was established to promote the long-term success of the Company by creating an “at-risk” cash bonus program that rewards Plan participants with additional cash compensation in lockstep with significant increases in the Company’s market capitalization. The Plan is considered “at-risk” because Plan participants will not receive a cash bonus unless the Company’s market capitalization increases significantly and certain other conditions specified in the Plan are met. Specifically, Plan participants will not be paid any cash bonuses unless (1) the Company completes a merger or acquisition transaction that constitutes a sale of ownership of the Company or its assets (a Merger Transaction) or (2) the Compensation Committee of the Board (the Compensation Committee) determines the Company has sufficient cash on hand, as defined in the Plan. Because of the inherent discretion and uncertainty regarding these requirements, the Company has concluded that a Plan grant date has not occurred as of December 31, 2020. Plan participants will be paid all earned cash bonuses in the event of a Merger Transaction.

The Company’s market capitalization for purposes of the Plan is determined based on either (1) the Company’s closing price of one share on the Nasdaq Capital Market multiplied by the total issued and outstanding shares and options to purchase shares of the Company or (2) the aggregate consideration payable to security holders of the Company in a Merger Transaction. This constitutes a market condition under applicable accounting guidance.   

The Plan triggers a potential cash bonus each time the Company’s market capitalization increases significantly, up to a maximum $5 billion in market capitalization. The Plan specifies 14 incremental amounts between $200 million and $5 billion  (each increment, a “Valuation Milestone”). Each Valuation Milestone triggers a potential cash bonus award in a pre-set amount defined in the Plan. Each Valuation Milestone must be achieved and maintained for no less than 20 consecutive trading days for Plan participants to be eligible for a potential cash bonus award. Approximately 59% of each cash bonus award associated with a Valuation Milestone is subject to adjustment and approval by the Compensation Committee. Any amounts not awarded by the Compensation Committee are no longer available for distribution.

If the Company were to exceed a $5 billion market capitalization for no less than 20 consecutive trading days, all Valuation Milestones would be deemed achieved, in which case cash bonus awards would range from a minimum of $137.4 million up to a hypothetical maximum of $322.3 million. Payment of cash bonuses is deferred until such time as (1) the Company completes a Merger Transaction, or (2) the Compensation Committee determines the Company has sufficient cash on hand to render payment (each, a “Performance Condition”), neither of which may ever occur. Accordingly, there can be no assurance that Plan participants will ever be paid a cash bonus that is awarded under the Plan, even if the Company’s market capitalization increases significantly.

The Plan is accounted for as a liability award. The fair value of each Valuation Milestone award will be determined once a grant date occurs and will be remeasured each reporting period. Compensation expense associated

90


with the Plan will be recognized over the expected achievement period for each of the 14 Valuation Milestones, when a Performance Condition is considered probable of being met.   

On October 13, 2020, the Company achieved the first Valuation Milestone. Subsequently, the Compensation Committee approved a potential cash bonus award of $7.3 million in total for all Plan participants, subject to future satisfaction of a Performance Condition. However, no compensation expense has been recorded since no grant date has occurred and no Performance Conditions are considered probable of being met. There is no continuing service requirement for Plan participants once the Compensation Committee approves a cash bonus award.

Subsequent to December 31, 2020, the Company achieved eight additional Valuation Milestones triggering potential Company obligations to all Plan participants from a minimum of $59.9 million up to a hypothetical maximum of $145.0 million, to be determined by the Compensation Committee and contingent upon future satisfaction of a Performance Condition.

No actual cash payments were authorized or made to participants under the Plan during the year ended December 31, 2020.



 

6591


 

 

 

Item 9.Changes in and Disagreements with Accountants on Accounting and Financial Disclosure



None.



Item 9A.Controls and Procedures



Evaluation of disclosure controls and procedures.



Our management, with the participation of our Chief Executive Officer and our Chief Financial Officer, evaluated the effectiveness of our disclosure controls and procedures as of the end of the period covered by this Annual Report on Form 10-K. Based on this evaluation, our Chief Executive Officer (as Principle Executiveand our Chief Financial Officer and Principal Financial Officer)hashave concluded that our disclosure controls and procedures are effective to ensure that information we are required to disclose in reports that we file or submit under the Securities Exchange Act of 1934, as amended, is recorded, processed, summarized and reported within the time periods specified in the Securities and Exchange Commission, or SEC, rules and forms and that such information is accumulated and communicated to management as appropriate to allow timely decisions regarding required disclosures.



Management’s annual report on internal control over financial reporting. We areOur management is responsible for establishing and maintaining adequate internal control over our financial reporting. We haveOur management has assessed the effectiveness of internal control over financial reporting as of December 31, 2017.2020. Our assessment was based on criteria set forth by the Committee of Sponsoring Organizations of the Treadway Commission, or COSO, in Internal Control-Integrated Framework (2013 Framework).



Our internal control over financial reporting is a process designed to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for external purposes in accordance with generally accepted accounting principles. Our internal control over financial reporting includes those policies and procedures that:



(1)

pertain to the maintenance of records that, in reasonable detail, accurately and fairly reflect our transactions and dispositions of our assets;

(2)

provide reasonable assurance that transactions are recorded as necessary to permit preparation of financial statements in accordance with generally accepted accounting principles, and that our receipts and expenditures are being made only in accordance with authorizations of our management and board of directors; and

(3)

provide reasonable assurance regarding prevention or timely detection of unauthorized acquisition, use, or disposition of our assets that could have a material effect on the financial statements.



Because of its inherent limitations, internal control over financial reporting may not prevent or detect misstatements. Also, projections of any evaluation of effectiveness to future periods are subject to the risk that controls may become inadequate because of changes in conditions, or that the degree of compliance with the policies or procedures may deteriorate.



Based on the COSO criteria, we believe our internal control over financial reporting as of December 31, 20172020 was effective.

This Annual Report on Form 10-K does not include an attestation report of our independent registered public accounting firm regarding internal control over financial reporting.  Management’s assessment of the effectiveness of our internal control over financial reporting as of December 31, 2020, was not subject to attestation by our independent registered public accounting firm pursuant to rules of the SEC that permit a smaller reporting company to provide only management’s report in the Company’s Annual Report on Form 10-K.



Changes in internal control over financial reporting.



As previously announced,on February 14, 2017, Peter S. Roddy resigned, effective March 9, 2017, as Vice President, Chief Financial Officer and Secretary. Remi Barbier, President and Chief Executive Officer,There was no change in our internal control over financial reporting that occurred during the quarter ended December 31, 2020 that has assumed the role of Principal Financial Officer until such time as a new Chief Financial Officermaterially affected, or is appointed.reasonably likely to materially affect, our internal control over financial reporting. 

92


Item 9B.Other Information



None.

 

66


PART III



Item 10.Directors and Executive Officers and Corporate Governance



The information regarding our directors, executive officers, director nomination process and the audit committee of our board of directorsthe Board is incorporated by reference from "Directors and Executive Officers" in our Proxy Statement for our 20182021 Annual Meeting of Stockholders.



Section 16(a) Beneficial Ownership Reporting Compliance



Section 16(a) of the Securities Exchange Act of 1934, as amended requires our executive officers and directors and persons who own more than ten percent (10%) of a registered class of our equity securities to file reports of ownership and changes in ownership with the SEC. Executive officers, directors and greater than ten percent (10%) stockholders are required to furnish us with copies of all Section 16(a) forms they file. We believe all of our executive officers and directors complied with all applicable filing requirements during 2017.2020.



Code of Ethics



We have adopted a Code of Ethics that applies to all of our directors, officers and employees, including our principal executive officer principal financial officer and principal accountingfinancial officer. We publicize the Code of Ethics through posting the policy on our website, http://www.paintrials.com.www.cassavasciences.com. We will disclose on our website any waivers of, or amendments to, our Code of Ethics.



Item 11.Executive Compensation



The information required by this Item is incorporated by reference from our definitive Proxy Statement referred to in Item 10 above where it appears under the heading "Executive Compensation and Other Matters."



Item 12.Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters



The information required by this Item regarding security ownership of certain beneficial owners and management is incorporated by reference from our definitive Proxy Statement referred to in Item 10 above where it appears under the heading "Security Ownership of Certain Beneficial Owners and Management."



The following table summarizes the securities authorized for issuance under our equity compensation plans as of December 31, 2017:



 

 

 

 

 

 

 



 

Number of
Securities to be
Issued Upon
Exercise of
Outstanding
Options, Warrants
and Rights

 

 

Weighted Average
Exercise Price of
Outstanding
Options,
Warrants
and Rights

 

Number of Securities
Remaining Available
for Future Issuance
Under Equity
Compensation
Plans

Equity compensation plans approved by stockholders

 

3,134,495 

 

$

15.92 

 

58,017 

Equity compensation plans not approved by stockholders

 

 —

 

 

 —

 

 —



 

3,134,495 

 

$

15.92 

 

58,017 



 

 

 

 

 

 

 

2020:







 

 

 

 

 

 

 

 



 

Number of
Securities to be
Issued Upon
Exercise of
Outstanding
Options, Warrants
and Rights

 

 

Weighted Average
Exercise Price of
Outstanding
Options,
Warrants
and Rights

 

Number of Securities
Remaining Available
for Future Issuance
Under Equity
Compensation
Plans

 

Equity compensation plans approved by stockholders

 

2,955,559 

(1)

$

10.77 

(2)

310,205 

(3)

Equity compensation plans not approved by stockholders

 

 —

 

 

 —

 

 —

 



 

2,955,559 

 

$

10.77 

 

310,205 

 



 

 

 

 

 

 

 

 



(1)

Includes outstanding stock options and awards for 2,220,871 shares of our common stock under the 2008 Plan and 734,688 shares of our common stock under the 2018 Plan.

 

6793


 

 

(2)

Includes the weighted average stock price for outstanding stock options of $14.54 under the 2008 Plan and $2.11 for the 2018 Plan.

(3)

Represents 252,188 shares of our common stock for the 2018 Plan and 58,017 for the Employee Stock Purchase Plan. No future awards shall occur under the 2008 Plan.

Item 13.Certain Relationships and Related Transactions and Director Independence



The information required by this Item is incorporated by reference from our definitive Proxy Statement referred to in Item 10 above where it appears under the heading "Certain Relationships and Related Transactions."



Item 14.Principal Accountant Fees and Services



The information required by this Item is incorporated by reference from our definitive Proxy Statement referred to in Item 10 above where it appears under the heading Principal Accountant Fees and Services.”

 



 

6894


 

 

PART IV



Item 15.Exhibits and Financial Statement Schedules



(a)The following documents are filed as part of this Form 10-K:

(1)Financial Statements (included in Part II of this report):

Report of Independent Registered Public Accounting Firm

Balance Sheets

Statements of Operations

Statements of Comprehensive Income

Statements of Stockholders' Equity

Statements of Cash Flows

Notes to Financial Statements

(2)Financial Statement Schedules:

All financial statement schedules are omitted because the information is inapplicable or presented in the notes to the financial statements.

(3)Management Contracts, Compensatory Plans and Arrangements.  

Management contracts, compensatory plans and arrangements are indicated by the symbol “*” in the applicable exhibits listed in Item 15(b), below.



(b)Exhibits



The exhibits listed below are filed as part of this Form 10-K other than Exhibit 32.1, which shall be deemed furnished.



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Incorporated by Reference

 

 

 

 

 

 

Incorporated by Reference

 

 

Exhibit
No.

Exhibit
No.

 

Description

 

Form

 

Filing
Date

 

Exhibit
No.

 

Filed
Herewith

Exhibit
No.

 

Description

 

Form

 

Filing
Date

 

Exhibit
No.

 

Filed
Herewith

3.1

 

 

Amended and Restated Certificate of Incorporation.

 

10-Q

 

7/29/2005

 

3.1

 

 

 

 

Amended and Restated Certificate of Incorporation.

 

10-Q

 

7/29/2005

 

3.1

 

 

3.2

 

 

Amended and Restated Bylaws.

 

10-Q

 

4/24/2013

 

3.2

 

 

 

 

Certificate of Amendment of Restated Certificate of Incorporation.

 

8-K

 

5/8/2017

 

3.1

 

 

3.3

 

 

Amended and Restated Certificate of Incorporation

 

8-K

 

5/8/2017

 

3.1

 

 

 

 

Certificate of Amendment of Restated Certificate of Incorporation.

 

10-K

 

3/29/2019

 

3.3

 

 

3.4

 

 

Amended and Restated Bylaws of Cassava Sciences, Inc.

 

8-K

 

12/11/2020

 

3.1

 

 

4.1

 

 

Specimen Common Stock Certificate.

 

10-Q

 

7/29/2005

 

4.1

 

 

 

 

Specimen Common Stock Certificate.

 

10-Q

 

8/12/2019

 

4.1

 

 

4.2

 

 

Description of Registrant’s Securities.

 

10-K

 

3/26/2020

 

4.2

 

 

4.3

 

 

Form of Common Stock Purchase Warrant.

 

8-K

 

8/20/2018

 

4.1

 

 

4.4

 

 

Form of Wainwright Warrant.

 

8-K

 

8/20/2018

 

4.2

 

 

10.1

*

 

Form of Indemnification Agreement between Pain Therapeutics and each of its directors and officers.

 

S-1

 

3/14/2000

 

10.1

 

 

*

 

Form of Indemnification Agreement between Registrant and each of its directors and officers.

 

S-1

 

3/14/2000

 

10.1

 

 

10.3

*

 

Employment Agreement dated October 23, 2001, between Registrant and Nadav Friedmann, PhD. M.D. 

 

10-K

 

3/22/2002

 

10.5

 

 

10.4

+

 

Development and License Agreement dated December 19, 2002 between Registrant and DURECT Corporation and Southern Biosystems, Inc.

 

10-K

 

2/24/2006

 

10.10

 

 

10.2

*

 

Employment Agreement, dated October 23, 2001, between Registrant and Nadav Friedmann, PhD. M.D. 

 

10-K

 

3/22/2002

 

10.5

 

 

10.5

+

 

Amendment dated December 15, 2005 to Development and License Agreement dated December 19, 2002 between Registrant and DURECT Corporation and Southern Biosystems, Inc.

 

10-K

 

2/24/2006

 

10.11

 

 

*

 

Employment Agreement, dated July 1, 1998 and amended December 17, 2008, between Registrant and Remi Barbier.

 

10-K

 

2/13/2009

 

10.12

 

 

10.6

*

 

2000 Employee Stock Purchase Plan, as amended and restated.

 

10-Q

 

7/29/2010

 

10.1

 

 

10.7

*

 

Amendment Number 1 to the 2008 Equity Incentive Plan.

 

10-Q

 

8/1/2013

 

10.1

 

 

10.8

*

 

Amendment No. 2 to Employment Agreement between Registrant and Remi Barbier.

 

10-Q

 

8/1/2013

 

10.2

 

 

10.9

 

 

Lease Agreement, dated as of February 14, 2011 between Registrant and StoneCliff Office, L.P.

 

10-Q

 

4/27/2011

 

10.1

 

 

10.10

*

 

First Amendment to Lease Agreement, dated September 21, 2011.

 

10-K

 

2/9/2012

 

10.20

 

 

10.11

*

 

Employment Agreement dated July 1, 1998 and amended December 17, 2008 between Registrant and Remi Barbier.

 

10-K

 

2/13/2009

 

10.12

 

 

 

 

Second Amendment to Lease Agreement, dated as of April 3, 2014 between Registrant and StoneCliff Office, L.P. 

 

10-Q

 

8/6/2014

 

10.1

 

 

10.12

*

 

2000 Employee Stock Purchase Plan, as amended and restated.

 

10-Q

 

7/29/2010

 

10.1

 

 

 

 

Third Amendment to Lease Agreement, dated as of November 3, 2017 between Registrant US REIF Eurus Austin, LLC dba StoneCliff Building as successor in interest to StoneCliff Office, L.P.

 

10-K

 

2/6/2018

 

10.17

 

 

10.13

 

 

Lease agreement, dated as of February 14, 2011 between Registrant and StoneCliff Office, L.P.

 

10-Q

 

4/27/2011

 

10.1

 

 

 

 

Fourth Amendment to Lease Agreement, dated September 4, 2020 between Registrant US REIF Eurus Austin, LLC dba StoneCliff Building as successor in interest to StoneCliff Office, L.P.

 

8-K

 

9/10/2020

 

10.1

 

 

10.14

*

 

Amendment Number 1 to the 2008 Equity Incentive Plan.

 

10-Q

 

8/1/2013

 

10.1

 

 

*

 

2018 Omnibus Incentive Plan.

 

8-K

 

5/11/2018

 

10.1

 

 

10.15

*

 

Amendment No. 2 to Employment Agreement between Registrant and Remi Barbier.

 

10-Q

 

8/1/2013

 

10.2

 

 

10.16

 

 

Second Amendment to Lease Agreement, dated as of April 8, 2014 between Registrant and StoneCliff Office, L.P. 

 

10-Q

 

8/6/2014

 

10.1

 

 

10.17

 

 

Third Amendment to Lease Agreement, dated as of November 3, 2017 between Registrant US REIF Eurus Austin, LLC dba StoneCliff Building as successor in interest to StoneCliff Office, L.P.

 

 

 

 

 

 

 

X

23.1

 

 

Consent of Independent Registered Public Accounting Firm.

 

 

 

 

 

 

 

X

 

6995


 

 

24.1

Power of Attorney (included in the signature page to this report).

X

31.1

Certification of Principal Executive Officer pursuant to Section 302 of the Sarbanes-Oxley Act of 2002.

X

32.1

Certifications of the Chief Executive Officer and the Chief Financial Officer pursuant to 18 U.S.C. Section 1350, as adopted pursuant to Section 906 of the Sarbanes-Oxley Act of 2002.

X

101.INS

XBRL Instance Document.

X

101.SCH

XBRL Taxonomy Extension Schema Document.

X

101.CAL

XBRL Taxonomy Extension Calculation Linkbase Document.

X

101.DEF

XBRL Taxonomy Extension Definition Linkbase Document.

X

101.LAB

XBRL Taxonomy Extension Labels Linkbase Document.

X

101.PRE

XBRL Taxonomy Extension Presentation Linkbase Document.

X

* Management contract, compensatory plan or arrangement.

+ Portions of this Exhibit are subject to a confidential treatment order.

10.15

 

 

Form of Securities Purchase Agreement, dated August 15, 2018, by and between Registrant and the purchasers named therein.

 

8-K

 

8/20/2018

 

10.1

 

 

10.16

 

 

Agreement between Registrant and H.C. Wainwright & Co., dated August 15, 2018.

 

8-K

 

8/20/2018

 

10.2

 

 

10.17

 

 

Sales Agreement, Dated March 27, 2020, between Registrant and SVB Leerink LLC.

 

S-3

 

3/27/2020

 

1.1

 

 

10.18

*

 

Cassava Sciences, Inc. 2020 Cash Incentive Bonus Plan

 

8-K

 

9/1/2020

 

10.1

 

 

10.19

 

 

Underwriting Agreement, dated November 13, 2020

 

8-K

 

11/13/2020

 

1.1

 

 

10.20

*

 

Employment Agreement, executed on October 9, 2018, by and between Registrant and Eric Schoen.

 

8-K

 

10/11/2018

 

10.1

 

 

10.21

*

 

Employment Agreement, executed on January 1, 2020, by and between Registrant and Dr. James Kupiec.

 

8-K

 

1/6/2021

 

10.1

 

 

23.1

 

 

Consent of Independent Registered Public Accounting Firm.

 

 

 

 

 

 

 

X

24.1

 

 

Power of Attorney (included in the signature page to this report).

 

 

 

 

 

 

 

X

31.1

 

 

Certification of Principal Executive Officer pursuant to Section 302 of the Sarbanes-Oxley Act of 2002. 

 

 

 

 

 

 

 

X

31.2

 

 

Certification of Principal Financial Officer pursuant to Section 302 of the Sarbanes-Oxley Act of 2002. 

 

 

 

 

 

 

 

X

32.1

 

 

Certifications of the Chief Executive Officer and the Chief Financial Officer pursuant to 18 U.S.C. Section 1350, as adopted pursuant to Section 906 of the Sarbanes-Oxley Act of 2002.

 

 

 

 

 

 

 

X

101.INS

 

 

XBRL Instance Document.

 

 

 

 

 

 

 

X

101.SCH

 

 

XBRL Taxonomy Extension Schema Document.

 

 

 

 

 

 

 

X

101.CAL

 

 

XBRL Taxonomy Extension Calculation Linkbase Document.

 

 

 

 

 

 

 

X

101.DEF

 

 

XBRL Taxonomy Extension Definition Linkbase Document.

 

 

 

 

 

 

 

X

101.LAB

 

 

XBRL Taxonomy Extension Labels Linkbase Document.

 

 

 

 

 

 

 

X

101.PRE

 

 

XBRL Taxonomy Extension Presentation Linkbase Document.

 

 

 

 

 

 

 

X

* Management contract, compensatory plan or arrangement.

 

 

 

 

 

 

 

 



 

 

 

 

 

 

 

 



(c)Financial Statement Schedules



All financial statement schedules are omitted because the information is inapplicable or presented in the notes to the financial statements.



Item 16.Form 10-K Summary



The Company has elected not to includedinclude summary information.



 

7096


 

 

SIGNATURES



Pursuant to the requirements of Section 13 or 15(d) of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned, thereunto duly authorized.



(Principal Executive

 

 



Pain Therapeutics,Cassava Sciences, Inc.

 



(Registrant)



 



/s/ REMI BARBIER

 



Remi Barbier,



Chairman of the Board of Directors,



President and Chief Executive Officer



 



Dated: February 6,  2018March 23, 2021



POWER OF ATTORNEY



KNOW ALL PERSONS BY THESE PRESENTS, that each person whose signature appears below constitutes and appoints Remi Barbier his true and lawful attorneys-in-fact, with full power of substitution, for him in any and all capacities, to sign any amendments to this Annual Report on Form 10-K and to file the same, with exhibits thereto and other documents in connection therewith, with the Securities and Exchange Commission, hereby ratifying and confirming all that each of said attorneys-in-fact or their substitute or substitutes may do or cause to be done by virtue hereof.



Pursuant to the requirements of the Securities Exchange Act of 1934, this report has been signed below by the following persons on behalf of the registrant and in the capacities and on the dates indicated.





 

 

 

 



 

 

 

 

Signature 

 

Title

 

Date



 

 

 

 

/s/  REMI BARBIER

 

President, Chief Executive Officer and

 

February 6, 2018March 23, 2021

Remi Barbier

 

Chairman of the Board of Directors

 

 



 

(Principal Executive Officer)

/s/  ERIC J. SCHOEN

Chief Financial Officer and

March 23, 2021

Eric J. Schoen

(Principal Financial Officer)

 

 



 

 

 

 

/s/  NADAV FRIEDMANN, PH.D., M.D.

 

Chief Operating and Medical Officer

 

February 6, 2018March 23, 2021

Nadav Friedmann, Ph.D., M.D.

 

and Director

 

 



 

 

 

 

/s/  ROBERT Z. GUSSIN, PH.D.

 

Director

 

February 6, 2018March 23, 2021

Robert Z. Gussin, Ph.D.

 

 

 

 



 

 

 

 

/s/  MICHAEL J. O'DONNELL, ESQ.

 

Director

 

February 6, 2018March 23, 2021

Michael J. O'Donnell, Esq.

/s/  SAIRA RAMASASTRY

Director

February 6, 2018

Saira Ramasastry

 

 

 

 



 

 

 

 

/s/  SANFORD R. ROBERTSON

 

Director

 

February 6, 2018March 23, 2021

Sanford R. Robertson

 

 

 

 



 

 

 

 

/s/  PATRICK SCANNON, M.D,M.D., PH.D.

 

Director

 

February 6, 2018March 23, 2021

Patrick Scannon, M.D., Ph.D.

 

 

 

 



 

 

 

 





 

7197