Adhera Therapeutics (ATRX) 8-K Marina Biotech Announces Changes to Board of Directors

Annual Shareholders Meeting

Company Update

14 July 2011

Exhibit 99.2

Forward Looking Statement

Statements made in this presentation may be forward-looking statements within the

meaning of Federal Securities laws that are subject to certain risks and uncertainties and

involve factors that may cause actual results to differ materially from those projected or

suggested. Factors that could cause actual results to differ materially from those in

forward-looking statements include, but are not limited to: (i) the ability of Marina Biotech to

obtain

additional

funding;

(ii)

the

ability

of

Marina

Biotech

to

attract

and/or

maintain

manufacturing, research, development and commercialization partners; (iii) the ability of

Marina

Biotech

and/or

a

partner

to

successfully

complete

product

research

and

development, including preclinical and clinical studies and commercialization; (iv) the ability

of Marina Biotech and/or a partner to obtain required governmental approvals; and (v) the

ability of Marina Biotech and/or a partner to develop and commercialize products that can

compete favorably with those of competitors. Additional factors that could cause actual

results to differ materially from those projected or suggested in any forward-looking

statements are contained in Marina Biotech’s most recent periodic reports on Form 10-K

and Form 10-Q which are filed with the Securities and Exchange Commission. Marina

Biotech assumes no obligation to update and supplement forward-looking statements

because of subsequent events.

2

Broad Nucleic Acid-Based Platform

Provides a Superior Drug Discovery Engine

Appropriate

therapeutic

approach

to

targets

not

typically

suited

to

small

molecule or monoclonal antibody therapeutics

Capitalizes on distinct endogenous intracellular processes for protein

down-regulation

Allows for a scientific and risk adjusted pursuit of a specific nucleic acid-

based therapeutic modality

Established regulatory path through FDA and EMA

Multiple nucleic acid-based therapeutics are in clinical development

Two such therapeutics have been approved

3

4

Pfizer and Nucleic Acid-based Therapeutics

Tacere

shRNA

(TT-033):  Three separate, expressed RNAi elements targeting the

conserved regions of the Hepatitis C virus entrapped in an AAV protein coat

$145 MM deal (upfront and milestone payments have been made through Feb

2010)

Quark

siRNA

(PF-04523655):  Chemically-modified, unformulated siRNA compound

targeting proprietary target, RTP-801, for the treatment of wet age-related

macular degeneration (wet-AMD) and diabetic macular edema (DME)

Terms

not

disclosed

but

Pfizer

upped

milestone

payments

in

March

2011

to

support extended Phase II trials

Santaris

:

LNA

chemistry

for

single-stranded

RNA-targeted

therapies

$17 MM upfront (included $10 MM in equity) in 2010; $14 MM in 2011 and up

to $600 MM in downstream milestones

ssRNA

Nucleic Acid Therapeutic “Toolbox”

Constructs

Dicer length siRNA

RISC length siRNA

microRNA mimetics

microRNA antagonists

miniRNAs

Single-stranded RNA/DNA

5

Chemistries

UNA –

Non-nucleotide acyclic

monomers –

greater flexibility

CRN –

nucleotide analogs with a

linker connecting the C2’

and C4’

Delivery

DiLA

2

–

Combinations of amino acid head-groups, spacers, and

alkyl chains (tails)

SMARTICLES –

Combinations of anionic and cationic lipids

E. Coli –

Non-pathogenic bacteria engineered to produce, deliver

and release interfering RNA mediators (shRNA) to targeted tissue

Conjugation –

Peptides, etc. (phage display library)

Critical Needs for a Broad Nucleic Acid-

Based Therapeutics Discovery Engine

Multiple

chemistries to construct single and double-stranded

oligonucleotides with suitable affinity, stability and minimization of off-

target activity

Unlocked Nucleotide Analogs (UNA)

Conformationally Restricted Nucleotides (CRN)

With

multiple

delivery

approaches

Multiple carriers ranging from saline to bacteria to liposomal

(DiLA

2

/SMARTICLES

®

)

Multiple routes of administration (oral, local and systemic)

Leading to multiple nucleic acid-based therapeutic approaches

Double-stranded RNAi-based therapeutics

Single-stranded oligonucleotide therapeutics

MicroRNA-based therapeutics

6

RNAi

RDNA+

/chi

Marina Biotech’s Nucleic Acid-based

Therapeutic Platform

7

“undruggable target”

for a specific

indication

ssRNA/DNA

dsRNA

antagomir

mimetic

CRN/RNA

+ delivery

CRN/RNA

UNA/CRN

+ delivery

CRN/RNA

+ delivery

CRN/RNA

Plasmid +

bacteria

UNA +

delivery

Molecular Target

Local/Systemic

Oral

mRNA

microRNA

tk

tau

muRNA/muRNA+

RNAi

RDNA

RNA

RNA+

chi

/mu

mu

Selection of a Nucleic Acid-based

Therapeutic Approach

Target, indication and patient phenotype determine the most appropriate

combination of technologies and thus the specific nucleic acid-based

modality(ies) to pursue in preclinical proof-of-concept

Determine target and intended biology

Specific mRNA(s) to down-regulate a specific protein(s)

microRNA to up-/down-regulate multiple mRNAs/proteins

For down-regulation, use a mimetic

For up-regulation, use an antagomir

Select delivery approach based on construct and site (tissue/organ)

tkRNAi

tauRNAi

DNA+

–

delivery

of

ssDNA/RNA

A

When appropriate, multiple technologies can be evaluated to determine

the best approach

8

–

delivery

of

shRNA

to

mucosal

epithelium

RNAi

–

delivery

of

dsRNA

in

a

liposomal

formulation

RNAi

RDNA

RNA+

–

delivery

of

ssDNA/RNA

or

dsRNA

RNA

/mu

RDNA+

–

delivery

of

ssDNA/RNA

chi

/chi

mu

transKingdom

RNAi Platform

9

“undruggable target”

for a specific

indication

Molecular Target

mRNA

(protein)

ssDNA/RNA

dsRNA

antagomir

mimetic

microRNA

CRN-RNA

+ delivery

CRN-RNA

UNA/CRN

+ delivery

CRN-RNA

+ delivery

CRN/RNA

Plasmid +

bacteria

UNA +

delivery

Local/Systemic

Oral

tk

RNAi

About transKingdom

RNA interference (tkRNAi™)

10

Non-pathogenic bacteria engineered to produce, deliver and release

interfering RNA mediators (shRNA) to targeted tissue

Efficient delivery to the epithelium of the gastrointestinal tract via oral

administration

Safe

and

well

tolerated

daily

dosing

of

up

to

10

11

cfu

(colony

forming

units) in non-human primates for 9 months

Phase 1b/2a clinical trial to treat Familial Adenomatous Polyposis

(FAP) –

a genetic pre-cancerous polyposis disease with orphan drug

status

Exclusive worldwide license from Beth Israel Deaconess Medical

Center/Harvard

Familial Adenomatous Polyposis (FAP)

Rare hereditary disease

Mutation in Adenomatous Polyposis Coli (APC) gene

Causes

dysregulation

and

accumulation

of

-catenin

Results in numerous colon polyps appearing in early

adolescence with potential for rapid disease progression

Clinical

drug

product,

CEQ508,

targets

-catenin

oncogene

Unmet medical need

~80,000 worldwide (orphan status)

Near 100% risk of colon cancer if untreated

Treatment options:

Surgical intervention (colectomy) is the only available treatment

to prevent colon cancer progression

No generally accepted pharmaceutical approach is available

U.S. FAP Market Potential: >$100 MM

Opportunities to expand into sporadic CRC, other polyposis syndromes and other

GI cancers

Potential for 4Q2014 launch and first RNAi drug to market

11

Actual and Potential Clinical, Regulatory

and Commercial Timelines

12

December 2009 –

IND granted in U.S.

September 2010 –

Patent grant in the EP protecting tkRNAi

December 2010 –

Received FDA Orphan Drug Designation

January 2011 –

Completed LTT study in Non-Human Primates

June 2011 –

Completed dosing in Cohort 1

1Q2012 –

Complete dose escalating phase of 1b/2a

Delayed dosing of Cohort 2 until 4Q2011

Remedying GMP-related issues not a safety issue

Informed the FDA of our decision to delay dosing

2Q2012 –

Complete stable dose phase of 1b/2a

4Q2013 –

Complete Pivotal Phase 2

3Q2014 –

Expedited/accelerated FDA review and approval

4Q2014 –

Launch –

first RNAi drug to market

RNAi Platform

13

“undruggable target”

for a specific

indication

ssDNA/RNA

dsRNA

mRNA

antagomir

mimetic

microRNA

CRN/RNA

+ delivery

CRN/RNA

UNA/CRN

+ delivery

CRN/RNA

+ delivery

CRN/RNA

Plasmid +

bacteria

UNA +

delivery

Molecular Target

RNAi

tau

Local/Systemic

Oral

tau

About tauRNA interference (tauRNAi)

14

Combination of highly active UsiRNA constructs and liposomal

delivery systems

UsiRNA –

Substitution of unlocked nucleobase analogs (UNA) within

siRNA; therapeutic use proprietary to Marina Biotech

DiLA

-

Di-Alkylated

Amino

Acids

for

liposomal-based

delivery;

novel

compounds proprietary to Marina Biotech

Smarticles -

Lipid-based amphoteric liposomes for oligonucleotide delivery

(in Phase I Clinical Trial by ProNAi via systemic delivery)

Pairing of the UsiRNA with the most appropriate liposomal delivery

system provides greater efficacy and specificity for RNAi

2

Publications on UsiRNAs and Systemic

and

Local

Delivery

with

DiLA

15

Mol Ther. 2011 Apr 19. (PMID:21505423)

An Amino Acid-based Amphoteric Liposomal Delivery System for Systemic Administration of

siRNA.

Adami RC, Seth S, Harvie P, Johns R, Fam R, Fosnaugh K, Zhu T, Farber K, McCutcheon M, Goodman TT, Liu Y, Chen Y, Kwang E,

Templin MV, Severson G, Brown T, Vaish N, Chen F, Charmley P, Polisky B, Houston ME Jr.

Marina Biotech, Inc., Bothell, Washington, USA.

Nucleic Acids Res. 2011 Mar 1;39(5):1823-32.

Improved specificity of gene silencing by siRNAs containing unlocked nucleobase analogs.

Vaish N, Chen F, Seth S, Fosnaugh K, Liu Y, Adami R, Brown T, Chen Y, Harvie P, Johns R, Severson G, Granger B, Charmley P,

Houston M, Templin MV, Polisky B.

Marina Biotech Inc., 3830 Monte Villa Parkway, Bothell, WA 98021, USA

Mol Ther. 2011 Mar 1. (PMID: 21364537)

RNAi-based Therapeutics Targeting Survivin and PLK1 for Treatment of Bladder Cancer.

Seth

S,

Matsui

Y,

Fosnaugh

K,

Liu

Y,

Vaish

N,

Adami

R,

Harvie

P,

Johns

R,

Severson

G,

Brown

T,

Takagi

A,

Bell

S,

Chen

Y,

Chen

F,

Zhu T, Fam R, Maciagiewicz I, Kwang E, McCutcheon M, Farber K, Charmley P, Houston Jr ME, So A, Templin MV, Polisky B.

Discovery Research and Pharmaceutical Development, Marina Biotech Inc., Bothell, Washington, USA

2

Marina Biotech/Debiopharm:

Bladder Cancer R&D Collaboration

Exclusive agreement for the research, development and

commercialization of Marina Biotech’s pre-clinical program

in bladder cancer

First agreement to license an RNAi-based therapeutic,

delivered with a lipid-

or liposomal-based formulation, to a

pharma company

Debiopharm is responsible for development and

commercialization of any products

Debiopharm will pay:

All research and development costs for the program

Up to $24 million based on predefined research and development

milestones

Royalties on sales of products

16

ssDNA/RNA Technology

17

“undruggable target”

for a specific

indication

ssDNA/RNA

dsRNA

mRNA

antagomir

mimetic

microRNA

CRN/RNA

+ delivery

CRN/RNA

UNA/CRN

+ delivery

CRN/RNA

+ delivery

CRN/RNA

Plasmid +

bacteria

UNA +

delivery

RDNA/     RDNA+

Molecular Target

Local/Systemic

Oral

chi

chi

Conformationally Restricted

Nucleotides (CRN)

CRNs

are

nucleotide

analogs

with

a

linker

connecting

the

C2’

and

C4’

carbons of ribose

CRN and LNA lock the ribose ring into a stable conformation and increase

the hybridization affinity to the mRNA or microRNA target

Distinguished

from

LNA

by

a

longer

linker

and

different

location

of

the

oxygen atom

Places the oxygen in an optimal position for stability and affinity

RNA                                        CRN               

LNA

18

CRN-Substitution Results in Less

Ribose Ring Puckering

19

CRNs are distinguished by a linker whose length results in less ribose

ring puckering

Conformation of CRN more closely resembles that found in RNA

CRN

LNA

Puckering of the ribose

ring at the 2’

carbon

Less Ribose Ring Puckering May Result

in Lower Structural Distortion

20

CRN substitution within an oligo may result in lower structural distortion

when hybridized to a complementary mRNA

Figure Adapted from Eichert et al.,

Nucleic Acid res. 2010 Oct 1 38(19):6729-36

RNA/CRN

Distortion of

Duplex Structure

The rigid structure imparted by multiple

LNA

substitutions

“stretches”

the

duplex

CRNs have greater flexibility by virtue of

the longer linker and would be expected

to maintain an overall structure similar to

an all-RNA structure

Therefore CRN substituted single-

stranded RNA/DNA may have promising

drug-like properties

Therapeutic Approaches Using CRN

Technology

21

mRNA Translational Blockers

Substitute CRN at ends of DNA-RNA hybrid compounds thus preserving

DNA in the interior and allowing interaction with RNAse H

microRNA Antagonists

Substitute CRN throughout strand to maximize hybridization affinity

Additional modifications (e.g., 2’O-methyl) can be included within the

construct for increased affinity and greater nuclease stability

= CRN

Advantages of CRN Technology

22

Increased affinity with CRN substitution maintains structural orientation

thus allowing for variable lengths

Standard 19-

to 22-mers

Greater number of substitutions in 14-

to 16-mers

Fully substituted 7-

to 9-mers targeting microRNA seed region

Delivery can be achieved with multiple formulations

Simple formulations (e.g., saline) can be used in many situations (liver,

lung, kidney, some tumors)

If

appropriate,

encapsulation

within

a

liposomal

formulation

for

systemic

or

local administration to certain tissues/organs

CRN-Related Therapeutic Modalities

Aptamers

Therapeutics

Diagnostics

Delivery/cell surface ligands

Exon skipping oligonucleotide

Minor/Major Groove Binders/Triplex forming oligonucleotides

Ribozymes

Splice junction inhibitors

Steric blockers

tRNA/tRNA suppressors

bridge (adapter molecule) between the mRNA and the protein

“Suppress”

the phenotypic effect of a coding mutation

23

Other Uses for CRN technology

Primer/Probes for PCR

qRT-PCR

5’

and 3’

RACE

Single, multiplex and allele specific PCR

Capture Probes

In

situ

hybridization/Fluorescence

in

situ

hybridization

SNP genotyping

Expression analysis

Monitor/identify exon skipping

Monitor/identify splice variants

Research/Diagnostics agents

Aptamers

Bacterial strain/virus identification

Single cell miRNA analysis

24

microRNA (miRNA) Technology

Local/Systemic

Oral

“undruggable target”

for a specific

indication

microRNA

mimetic

antagomir

UNA/CRN

+ delivery

CRN-RNA

+ delivery

CRN/RNA

mRNA

dsRNA

ssDNA/RNA

Plasmid +

bacteria

UNA +

delivery

CRN-RNA

+ Delivery

CRN-RNA

25

microRNA Mimetic Approach

Molecular Target

Local/Systemic

Oral

“undruggable target”

for a specific

indication

microRNA

mimetic

antagomir

UNA/CRN

+ delivery

CRN-RNA

+ delivery

CRN-RNA

mRNA

dsRNA

ssDNA/RNA

Plasmid +

bacteria

UNA +

delivery

CRN-RNA

+ delivery

CRN-RNA

26

mu

RNA+

microRNA Mimetic using UNA & CRN

27

MicroRNA mimetic -

dsRNA

Substitute with UNA and CRN

UNA –

increase nuclease resistance and decrease cytokine induction;

inhibition of passenger strand activity

CRN –

increase hybridization affinity; nuclease resistance

Additional modifications (e.g., 2’O-methyl) can be included within the

construct for nuclease stability

Duplex

construct

–

likely

to

require

delivery

for

most

indications

DiLA

2

-based

liposomes

or

Smarticles

(amphoteric

liposomes)

= CRN

= UNA

Delivery of a miR-34 Mimetic in a Smarticles

Formulation Inhibits Tumor Growth

Inhibition of Liver Cancer Biomarker

Alpha Feto Protein Levels

Inhibition of Tumor Growth

Tumor Weight (g)

miR-NC

miR-34

Untreat. Cont.           miR-NC                  miR-34

Smarticles

formulation

provided

effective

delivery

to

orthotopic

liver

tumors

Significant reduction in tumor growth and liver tumor specific biomarker

28

Local/Systemic

Oral

Molecular Target

“undruggable target”

for a specific

indication

microRNA

mimetic

antagomir

UNA/CRN

+ delivery

CRN-RNA

+ delivery

CRN/RNA

mRNA

dsRNA

ssDNA/RNA

Plasmid +

bacteria

UNA +

delivery

CRN-RNA

+ delivery

CRN-RNA

29

mu

RNA/

mu

RNA+

microRNA Antagonist using CRN

30

MicroRNA antagonists (Antimir) therapeutics

Substitute CRN throughout the strand to maximize the hybridization affinity

between antimir and the target microRNA

Allows for use of shorter length sequences

Additional modifications (e.g., phosphorothioate and 2’O-methyl) can be

included within the construct for nuclease stability and increase affinity

Delivery formulation

Simple formulations (e.g., saline) can be used as the vehicle for and can

be used as the vehicle in many situations

Encapsulation within a liposomal formulation for systemic or local

administration may be required for some tissues/organs

= CRN

CRNs Increase Antimir Activity

CRN substitution increases the activity of an Antimir with >90%

inhibition of luciferase activity

No activity against a scrambled target sequence (not shown)

31

Dual luciferase assay; Average of triplicate; HeLa cells co-transfected with psiCHECK2-miR21plasmid

% Luciferase (Renilla) Activity Remaining

Construct

0%

20%

40%

60%

80%

100%

miR-21

Antimir-21

Unmodified

Antimir-21

(CRN)

Antimir-21

(LNA)

5 nM

25 nM

5 nM

25 nM

5 nM

25 nM

5 nM

25 nM

Antimir Conc. (nM)

CRN-substituted Antimir

LNA-substituted Antimir

Unmodified Antimir

CRN-substituted

Antimir

is

highly

potent,

with

an

IC

50

of

0.2

nM

Similar potency for CRN-

and LNA-substituted versions

50% Inhibition

Dual luciferase assay; HeLa cells co-transfected with psiCHECK2-miR21plasmid;

Unmodified Antimir all RNA; CRN-substituted Antimir has DNA and P=S backbone

CRNs Increase Antimir Potency

32

Molecular Target

Local/Systemic

Oral

“undruggable target”

for a specific

indication

microRNA

mimetic

antagomir

UNA/CRN

+ delivery

CRN/RNA

+ delivery

CRN/RNA

mRNA

dsRNA

ssRNA/DNA

Plasmid +

bacteria

UNA +

delivery

CRN/RNA

+ delivery

CRN/RNA

Marina Biotech’s Nucleic Acid-based

Therapeutic Platform

33

tk

RNAi

tau

RNAi

chi

RDNA/

chi

RDNA+

mu

RNA+

mu

RNA/

Resourcing a Broad Discovery Engine

–

Funded

by

Marina

Biotech

Includes funding CEQ508 Phase 1b/2a Trial

–

Funded by outside sources

siRNA in liposomal delivery for local administration funded by Debiopharm

(Marina Biotech UsiRNA and liposomal delivery)

–

Funded

by

Marina

Biotech

and

outside

sources

ssDNA in liposomal delivery for systemic administration funded by ProNAi (ProNAi DNA

decoy in Marina Biotech delivery)

ssRNA/DNA in saline/liposomal delivery for systemic administration funded by Marina

Biotech

–

Funded

by

Marina

Biotech

and

outside

sources

microRNA mimetic in liposomal delivery for systemic administration funded by

Mirna Therapeutics (Mirna mimetic in Marina Biotech delivery)

microRNA antagonists in saline for systemic administration funded by Marina

Biotech

34

tk

RNAi

tau

RNAi

chi

RDNA/

chi

RDNA+

mu

RNA/

mu

RNA+

2010-2011 Achievements

Initiated patient dosing in an FAP Phase 1b/2a Clinical Trial and

completed dosing the first cohort

Established first ever partnership around a liposomal delivered

RNAi compound with Debiopharm for the development and

commercialization a bladder cancer therapeutic

Established use of CRNs within single-stranded oligonucleotides

including microRNA antagonists

Established broadest single-company nucleic acid-based drug

discovery engine in the industry

Published three scientific manuscripts in peer-reviewed journals

describing UsiRNA platform, DiLA2 delivery technology and pre-

clinical data from the bladder cancer program

35

Thank You

36