HER2 and we expect to initiate a Phase 1 clinical trial in mid-2022.

XMT‑1536:

We believe this target to be clinically validated via Genentech’s lifastuzumab vedotin, an ADC targeting NaPi2b utilizing the Seattle Genetics vc‑MMAE platform, which provided encouraging results in Phase 1 studies in ovarian cancer.maximum tolerated dose. The clinical study had a 41% confirmed objective response rate by response evaluation criteria in solid tumors (RECIST criteria), which was achieved without evidence of target-mediated toxicities. However, in a randomized Phase 2 study in platinum‑resistant ovarian cancer, lifastuzumab vedotin failed to demonstrate a statistically‑significant benefit to liposomal doxorubicin, the comparator, on the primary endpoint of progression free survival, or PFS, despite a numerically superior response rate and improvement in median progression‑free survival. Responses in NSCLC patients were also limited despite widespread expressionexpansion portion of the NaPi2b target in the Phase 1 patients. Genentech has since discontinued developmenttrial evaluated two doses, 36 mg/m2 and 43 mg/m2, up to a maximum of lifastuzumab vedotin. The validation of the NaPi2b target provided by these studies forms the basis of our rationale to

XMT‑1536the European Society for Medical Oncology and at company presentations to investors. These data were from the dose escalation and expansion portions of our UpRi Phase 1 trial, and they demonstrated encouraging clinical activity in heavily-pretreated patients with a safety profile differentiated from those of first generation ADCs. In August 2020, the FDA granted Fast Track Designation for UpRi for the treatment of patients with platinum-resistant high-grade serous ovarian cancer who have received up to three prior lines of systemic therapy or patients who have received four prior lines of systemic therapy regardless of platinum status. In January 2021 and in September 2021, we provided interim clinical data updates from our expansion cohort. The interim data presented in September 2021 was based on approximately 100 ovarian patients for efficacy analysis and an overall group of approximately 200 patients for safety evaluation. All of the data from these patients were from our ongoing Phase 1/2 clinical trial. These data supported UpRi’s clinically meaningful activity in heavily-pretreated ovarian cancer patients with an objective response rate, or ORR, of approximately 34%, including complete responses, in evaluable patients with high NaPi2b tumor expression. The data also showed that UpRi was generally well tolerated without the severe toxicities commonly seen with other ADCs such as neutropenia, ocular toxicities, or peripheral neuropathy. The most common grade 3 or higher adverse events reported in this heavily pretreated trial population included fatigue and transiently increased aspartate aminotransferase. Other adverse events of clinical interest included infrequent, generally low-grade pneumonitis that generally resolves with dose reduction, delay, discontinuation and treatment with steroids. Based on these safety and efficacy data and our population pharmacokinetics analyses of the overall group of approximately 200 patients administered UpRi as of the data cut off, we determined that the phase 2 recommended dose of UpRi is 36 mg/m2 up to a total dose of approximately 80mg. This is the dose that we are currently evaluating in UPLIFT. In November 2021, we announced that we had completed enrollment of a Phase 1, open label, multi‑center study. 1/2 dose escalation cohort of NSCLC adenocarcinoma patients. Based on the data collected from that cohort, we deprioritized further monotherapy development in NSCLC, instead focusing on developing UpRi in ovarian cancer.

There are two parts2022. The design of UP-NEXT was informed by discussions with the FDA and the Committee for Medicinal Products for Human Use, or CHMP. UP-NEXT could serve as a post-approval confirmatory trial, supporting the expansion of UpRi into earlier lines of therapy. We expect UP-NEXT to enroll platinum-sensitive ovarian cancer patients who have achieved a response or stable disease after platinum therapy. Eligible patients with BRCA mutation must have received prior treatment with poly adenosine diphosphate ribose polymerase, or PARP, inhibitor therapy. Additionally, eligible patients must have high NaPi2b tumor expression. In recognition of the unmet medical need and the lack of a standard of care for these patients, the trial will be randomized against placebo.

The dose escalation part of the study utilizes a modified 3+3 design. A Safety Review Committee will review the data after each dose cohort of three patients completes the DLT evaluation period and will recommend three patients be enrolled at the next dose level if a dose is reasonably well‑tolerated. After the first cycle, patients maythese treatment options, outcomes in metastatic breast cancer continue to receive XMT‑1536 until disease progression, provided the drug is well‑toleratedbe poor, and patients continue to derive clinical benefit in the opinionnew treatments that improve survival and quality of the investigator. Dose escalation started with a once every three week schedule which has been fully explored. Currently an evaluation of a once every four week regimen is ongoing.

Merck KGaA strategic research and development partnership

In June 2014, we entered into a collaboration agreement with Merck KGaA for the development and commercialization of ADC product candidates

Takeda XMT‑1522 strategic partnership

In January 2016, we entered into a collaboration agreement with Takeda (formerly in partnership with Millennium Pharmaceuticals, Inc.) for the development and commercialization of XMT‑1522. On January 2, 2019 we received a notice from Takeda that it was exercising its rights to terminate the Development Collaboration and Commercial License Agreement between the two parties for the global development and commercialization of XMT-1522. Takeda’s delivery of the notice followed discussions between the two parties whereby we mutually agreed to terminate the co-development collaboration for XMT-1522 following a strategic evaluation of the competitive environment for HER2-targeted therapies.  We are working with Takeda to wind down activities under the Development Collaboration and Commercial License Agreement. Through December 31, 2018, we have received an upfront payment of $13.3 million and milestone payments of $33.3 million under this agreement.

Takeda strategic research and development partnership

In March 2014, we entered into a collaboration agreement with Takeda (formerly in partnership with Millennium Pharmaceuticals, Inc.) for the development and commercialization of ADC product candidates utilizing Fleximer. On January 2, 2019, we received notice from Takeda stating that it was exercising its rights to terminate the Research Collaboration and Commercial License Agreement. Takeda’s delivery of the notice followed discussions between the two parties whereby they mutually agreed to discontinue the Research Collaboration and License Agreement. We are in the process of winding down activities under Research Collaboration and Commercial License Agreement. Through December 31, 2018, we have received an upfront payment of $24.8 million and milestone payments of $0.8 million under this agreement.

The current XMT-1592 supply chain utilizes the same vendors that we could use for commercialization with the exception of components necessary for the Synaffix bioconjugation technology, where the identification of a commercially capable vendor is ongoing. The current supply chains for XMT-1660 and XMT-2056 have several vendors in common, and based on what we know today, we believe we could use these vendors for commercialization purposes.

AIND, sponsors must submit a protocol for each clinical studytrial and any subsequent protocol amendments must be submitted to the FDA as part of the IND. An IND automatically becomes effective 30 days after receipt by the FDA, unless before that time the FDA raises concerns or questions related to aone or more proposed clinical study ortrials and places the studytrial on a clinical hold. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical studytrial may proceed. As a result, submission of an IND may not result in the FDA allowing clinical trials to commence.

proceed or recommence. Occasionally, clinical holds are imposed due to manufacturing issues that may present safety issues for the clinical trial subjects.

combined. Additional trials may also be required after approval.

as Phase 4 clinical studiestrials, may be conducted after initial marketing approval. These studiestrials are used to gain additional experience from the treatment of a larger number of patients in the intended therapeutic indication andtreatment group. In certain instances, the FDA may mandate the performance of Phase 4 clinical trials, such as to document averify clinical benefit in the case of products approved under accelerated approval regulations or when otherwise requestedregulations. Failure to exhibit due diligence with regard to conducting mandatory Phase 4 clinical trials could result in withdrawal of FDA approval for products.

approval before being implemented. The FDA’s regulations also require, among other things, the investigation and correction of any deviations from cGMP and the imposition of reporting and documentation requirements upon the sponsor and any third-party manufacturers involved in producing the approved product.

BLA pathway

Our ADC product candidatesdetermination to the applicant. Typically, an RTF will be based on administrative incompleteness, such as clear omission of information or sections of required information such that substantive and meaningful review is precluded. The FDA may request additional information rather than accept an application for filing. In this event, the application must be licensed viaresubmitted with the additional information. The resubmitted application is also subject to review before the FDA approval of a BLA under Section 351 ofaccepts it for filing.

Before approving the BLA, the FDA will inspect the facilities at which the biological product is manufactured and will not approve the product unless the facility is compliant with cGMPs. Additionally, the FDA will typically inspect one or more clinical study sites for compliance with GCP and integrity of the data supporting safety and efficacy.

During the approval process, therecommendations when making final decisions on approval.

On The FDA determines the basisrequirement for a REMS, as well as the specific REMS provisions, on a case-by-case basis. If the FDA concludes a REMS is needed, the sponsor of the FDA’s evaluation ofapplication must submit a proposed REMS and the BLAFDA will not approve the application without a REMS.

If

Fast track, breakthrough therapy and priority review designations

The FDA is authorized to designate certain products for expedited review if they are intended to address an unmet medical need in the treatment

First,new prescription product, the FDA may designate amanufacturer, the approved product for “fast track” review if it is intended for the treatment of a serious or life‑threatening disease or condition and it demonstrates the potential to address unmet medical needs for such disease or condition. For fast track products, sponsors may have greater interactions with the FDA, and the FDA may initiate review of sections of a fast track product’s BLA before the application is complete. This “rolling review” is available if the FDA determines, after preliminary evaluation of clinical data submitted by the sponsor, that a fast track product may be effective. The sponsor must also provide, and the FDA must approve, a schedule for the submission of the remaining information and the sponsor must pay applicable user fees.

Second, the FDA may designate a product as a breakthrough therapy if it is intended to treat a serious or life‑threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. The FDA may take certain actions with respect to breakthrough therapies, including holding meetings with the sponsor throughout the development process, providing timely advice to the product sponsor regarding development and approval, involving more senior staff in the review

products.

Once an approval is granted, the FDA may withdraw the approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in mandatory revisions to the approved labeling to add new

The FDA strictly regulates marketing, labeling, advertising and promotion of products that are placed•restrictions on the market. Such productsmarketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls;

Biosimilars and exclusivity

The Patient Protection and Affordable Care Act as amended bywas enacted in the Health CareUnited States and Education Reconciliation Act, signed into law on March 23, 2010, or the Health Care Reform Act, includes a subtitle calledincluded the Biologics Price Competition and Innovation Act of 2009, or the BPCIA. The BPCIA which createdamended the PHSA to create an abbreviated approval pathway for biological products shown to bethat are biosimilar to or interchangeable with an FDA‑licensedFDA-licensed reference biological product. Biosimilarity requiresTo date, the FDA has approved a showingnumber of biosimilars and the first interchangeable biosimilar product was approved on July 30, 2021 and a second product previously approved as a biosimilar was designated as interchangeable in October 2021.

the interchangeable biosimilar product, the FDA may not grant interchangeability status for any second biosimilar until one year after the first commercial marketing of the first interchangeable biosimilar product.

to be effective in the pediatric population studied. If reports of requested pediatric studies are submitted to and accepted by the FDA within the statutory time limits, whatever statutory or regulatory periods of exclusivity or patents that cover the product are extended by six months. Although this is not a patent term extension, it effectively extends the regulatory period during which the FDA cannot approve another application.

Review

Significant uncertainty exists asreplaced the prior Clinical Trials Directive 2001/20/EC. The new regulation aims at simplifying and streamlining the authorization, conduct and transparency of clinical trials in the European Union. Under the new coordinated procedure for the approval of clinical trials, the sponsor of a clinical trial to be conducted in more than one Member State of the coverage and reimbursement status of products approvedEuropean Union, or EU Member State, will only be required to submit a single application for approval. The submission will be made through the Clinical Trials Information System, a new clinical trials portal overseen by the FDAEMA and available to clinical trial sponsors, competent authorities of the EU Member States and the public.

cases, when a medicinal product is expected to be of a major public health interest, particularly from the point of view of therapeutic innovation. The timeframe for the evaluation of an MAA under the accelerated assessment procedure is of 150 days, excluding stop-clocks.

The containmentEMA-approved Pediatric Investigation Plan, or PIP, covering all subsets of healthcare costs alsothe pediatric population, unless the EMA has becomegranted a priority of federal, state and foreign governments and the prices of drugs and biologics have beenproduct-specific waiver, a focus in this effort. Governments have shown significant interest in implementing cost‑containment programs, including price controls, restrictions on reimbursement and requirements for substitution of generic products. Adoption of price controls and cost‑containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limitclass waiver or a company’s revenue generated from the sale of any approved products. Coverage policies and third‑party reimbursement rates may change at any time. Even if favorable coverage and reimbursement status is attaineddeferral for one or more productsof the measures included in the PIP. The respective requirements for all marketing authorization procedures are set forth in Regulation (EC) No 1901/2006, which is referred to as the Pediatric Regulation. This requirement also applies when a company wants to add a new indication, pharmaceutical form or route of administration for a medicine that is already authorized. The Pediatric Committee of the EMA, or PDCO, may grant deferrals for some medicines, allowing a company to delay development of the medicine in children until there is enough information to demonstrate its effectiveness and safety in adults. The PDCO may also grant waivers when development of a medicine in children is not needed or is not appropriate because (a) the product is likely to be ineffective or unsafe in part or all of the pediatric population; (b) the disease or condition occurs only in adult population; or (c) the product does not represent a significant therapeutic benefit over existing treatments for pediatric population. Before a marketing authorization application can be filed, or an existing marketing authorization can be amended, the EMA determines that companies actually comply with the agreed studies and measures listed in each relevant PIP.

United States, both marketing authorization holders and manufacturers of medicinal products are subject to comprehensive regulatory oversight by the EMA and the competent authorities of the individual EU Member States both before and after grant of the manufacturing and marketing authorizations. The holder of an EU marketing authorization for a medicinal product must, for example, comply with EU pharmacovigilance legislation and its related regulations and guidelines which entail many requirements for conducting pharmacovigilance, or the assessment and monitoring of the safety of medicinal products. The manufacturing process for medicinal products in the European Union is also highly regulated and regulators may shut down manufacturing facilities that they believe do not comply with regulations. Manufacturing requires a manufacturing authorization, and the manufacturing authorization holder must comply with various requirements set out in the applicable EU laws, including compliance with EU cGMP standards when manufacturing medicinal products and active pharmaceutical ingredients.

The downward pressure on healthcare costs in general, particularly prescription drugs and biologics, has become intense. As a result, increasingly high barriers are being erected to the entry of new products. In addition, in some countries, cross‑border imports from low‑priced markets exert competitive pressure that may reduce pricing within a country. Any country that has price controls or reimbursement limitations for products may not allow favorable reimbursementEuropean Union.

Our current and future arrangements with healthcare professionals, principal investigators, consultants, customers and third‑party payors are and will be subjectregulatory developments to various federal, state and foreign fraud and abuse laws and other healthcare laws and regulations. These laws and regulations may impact, among other things, our arrangements with third‑party payors, healthcare professionals who participatethose in our clinical research programs, healthcare professionals and others who purchase, recommend or prescribe our approved products and our proposed sales, marketing, distribution and education programs. The federal and state healthcare laws and regulations thatthe United States may affect our ability to operate include, without limitation,profitably commercialize our product candidates, if approved. In markets outside of the following:

Healthcare reform

Our revenueimposes numerous requirements on companies that process personal data, and operations could be affectedit imposes heightened requirements on companies that process health and other sensitive data, such as requiring in many situations that a company obtain the consent of the individuals to whom the sensitive personal data relate before processing such data. Examples of obligations imposed by changes in healthcare spendingthe GDPR on companies processing personal data that fall within the scope of the GDPR include providing information to individuals regarding data processing activities, implementing safeguards to protect the security and policy inconfidentiality of personal data, appointing a data protection officer, providing notification of data breaches and taking certain measures when engaging third-party processors.

Since its enactment, there have been judicialJanuary 1, 2021, the Medicines and Congressional challengesHealthcare products Regulatory Agency, or the MHRA, became responsible for supervising medicines and medical devices in Great Britain, comprising England, Scotland and Wales under domestic law whereas Northern Ireland continues to certain aspectsbe subject to EU rules under the Northern Ireland Protocol. The MHRA will rely on the Human Medicines Regulations 2012 (SI 2012/1916) (as amended), or the HMR, as the basis for regulating medicines. The HMR has incorporated into the domestic law the body of the Health Care Reform Act, and we expect there will be additional challenges and amendmentsEU law instruments governing medicinal products that pre-existed prior to the Health Care Reform Act inUnited Kingdom’s withdrawal from the future. The current Presidential administration and members of the U.S. Congress have indicated that they may continue to seek to modify, repeal or otherwise invalidate all, or certain provisions of, the Health Care Reform Act. Most recently, on December 22, 2017, the Tax Cuts and Jobs Act was enacted, which, among other things, removes penalties for not complying with the individual mandate to carry health insurance. It is uncertain the extent to which any such changes may impact our business or financial condition. We cannot predict the ultimate content, timing or effect of any changes to the Health Care Reform Act or other federal and state reform efforts. There is no assurance that federal or state healthcare reform will not adversely affect our business and financial results, and we cannot predict how future federal or state legislative, judicial or administrative changes relating to healthcare reform will affect our business.

In addition, other legislative changes have been proposed and adopted since the Health Care Reform Act was enacted. The Budget Control Act of 2011 includes provisions to reduce the federal deficit. The Budget Control Act, as amended, resulted in the imposition of 2% reductions in Medicare payments to providers which began in April 2013, and will remain in effect through 2024 unless additional Congressional action is taken. Any significant spending reductions affecting Medicare, Medicaid or other publicly funded or subsidized health programs that may be implemented and/or any significant taxes or fees that may be imposed on us, as part of any broader deficit reduction effort or legislative replacement to the Budget Control Act, could have an adverse impact on our results of operations.

Additional regulation

In addition to the foregoing, state and federal laws regarding environmental protection and hazardous substances, including the Occupational Safety and Health Act, the Resource Conservation and Recovery Act and the Toxic Substances Control Act, affect our business. These and other laws govern the use, handling and disposal of various biologic, chemical and radioactive substances used in, and wastes generated by, operations. If our operations result in contamination of the environment or expose individuals to hazardous substances, we could be liable for damages and governmental fines. Equivalent laws have been adopted in foreign countries that impose similar obligations.

European Union.

We also believe in protecting our unpatented trade secrets and know-how and continuing our technological innovation to develop our business and to maintain our competitive position.

XMT‑1536

Novel DNA Alkylators and Novel Scaffolds

Many of our competitors, either alone or with strategic partners, have substantially greater financial, technical and human resources than we do. Accordingly, our competitors may be more successful than us in obtaining approval for treatments and achieving widespread market acceptance, rendering our treatments obsolete or non‑competitive.non-competitive. Accelerated merger and acquisition activity in the biotechnology and biopharmaceutical industries may result in even more resources being concentrated among a smaller number of our competitors. These companies also compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical studytrial sites and patient registrationenrollment for clinical studiestrials and acquiring technologies complementary to, or necessary for, our programs. Smaller or early‑stageearly-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. Our commercial opportunity could be substantially limited in the event that our competitors develop and commercialize products that are more effective, safer, less toxic, more convenient or less expensive than our comparable products. In geographies that are critical to our commercial success, competitors may also obtain regulatory approvals before us, resulting in our competitors building a strong market position in advance of our products’ entry. We believe the factors determining the success of our programs will be the efficacy, safety and tolerability of our product candidates.

Legal proceedings

From time to time, we may be subject to various legal proceedings and claims that arise in the ordinary course