miRagen Therapeutics NASDAQ: MGEN February 2020 1 Cautionary Note - - PowerPoint PPT Presentation

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miRagen Therapeutics NASDAQ: MGEN February 2020 1 Cautionary Note - - PowerPoint PPT Presentation

Restoring Biological Harmony for Patients with Debilitating Disease Restoring Biological Harmony for Patients with Debilitating Disease miRagen Therapeutics NASDAQ: MGEN February 2020 1 Cautionary Note Regarding Forward-Looking Statements


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Restoring Biological Harmony for Patients with Debilitating Disease Restoring Biological Harmony for Patients with Debilitating Disease

miRagen Therapeutics

NASDAQ: MGEN

February 2020

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Cautionary Note Regarding Forward-Looking Statements

This presentation contains forward-looking statements relating to Miragen Therapeutics, Inc., including statements about our plans to

  • btain funding, develop and commercialize our therapeutic candidates, our planned clinical trials, the timing of and our ability to obtain

and maintain regulatory approvals for our therapeutic candidates, the clinical utility of our therapeutic candidates and our intellectual property position. You can identify forward-looking statements by the use of forward-looking terminology including “believes,” “expects,” “may,” “will,” “should,” “seeks,” “intends,” “plans,” “pro forma,” “estimates,” or “anticipates” or the negative of these words and phrases or other variations of these words and phrases or comparable terminology. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. These statements involve substantial known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to be materially different from the information expressed or implied by these forward-looking statements. These forward-looking statements should not be relied upon as predictions of future events as we cannot assure you that the events or circumstances reflected in these statements will be achieved or will occur. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements that we make due to a number of important factors, including those risks discussed in “Risk Factors” and elsewhere in our Annual Report on Form 10-K for the year ended December 31, 2018 and our other reports filed with the U.S. Securities and Exchange Commission. The forward-looking statements in this presentation represent our views as of the date of this presentation. We anticipate that subsequent events and developments will cause our views to change. However, while we may elect to update these forward-looking statements at some point in the future, we have no current intention of doing so except to the extent required by applicable law. You should, therefore, not rely on these forward-looking statements as representing

  • ur views as of any date subsequent to the date of this presentation.

This presentation also contains estimates and other statistical data made by independent parties and by us relating to market size and

  • ther data about our industry. This data involves a number of assumptions and limitations, and you are cautioned not to give undue

weight to such estimates. In addition, projections, assumptions and estimates of our future performance and the future performance

  • f the markets in which we operate are necessarily subject to a high degree of uncertainty and risk.
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miRagen Therapeutics

  • Leading the development of what we believe

is the most advanced microRNA targeting therapeutics platform currently in development

  • Favorable safety and tolerability profile has

been observed in multiple product candidates

  • 3 clinical stage product candidates and a

recently unveiled preclinical program

  • Aims to advance multiple product candidates

through collaborations, while driving future expansion opportunities for the company

COBOMARSEN

  • miR-155 elevated blood cancers
  • Phase II (CTCL, ongoing)
  • Phase I (ATLL, ongoing)

REMLARSEN

  • Pathological fibrosis
  • Phase II (skin, ongoing)
  • Preclinical (ocular, Ph 1 ready)

MRG-110

  • Tissue repair and heart failure
  • Phase I (two completed clinical trials)
  • Phase II ready for intradermal

administration

MRG-229

  • Antifibrotic effects for systemic

applications

  • Lung, liver, and kidney (preclinical)

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Why microRNAs? microRNAs Regulate Network Biology to Maintain Homeostasis

  • microRNAs have been evolutionarily selected to

regulate networks of genes

  • microRNAs are dysregulated in many diseases
  • Dysregulation of microRNAs is associated with

alteration of downstream gene networks and disease

  • microRNA-targeted therapy is focused on disease

modification by restoring homeostasis to dysregulated processes

  • microRNA therapeutics are particularly suited for

complex, multigenic disorders

A

Conventional Therapies (Small molecules, Antibodies, siRNA, etc) Single molecule as target microRNA-based Therapies Network (pathway) as target

% INHIBITION 100 50

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miRagen Approach to Clinical Development

  • mPOC and target validation from in-

vitro to in-vivo disease models

  • Validate assays for translation to the

clinic

  • Incorporate mPOC endpoints such as

PD biomarker regulation into Ph I trials to confirm biological activity in humans

  • Identification of PD biomarker “genetic

fingerprint” for each miRNA modulator

  • Selectivity for disease specific

pathways

  • Chemical modification design

appears to blunt toxicity

  • Stable molecules
  • Infrequent dosing
  • No complex formulations
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Candidate (Target) Disease Area Pre-clinical Phase 1 Phase 2

Cobomarsen

(miR-155) Blood Cancers

Remlarsen

(miR-29) Pathologic Fibrosis

MRG-110

(miR-92) Tissue Repair

MRG-229

(miR-29) Pathologic Fibrosis Cutaneous T-cell Lymphoma (CTCL) Adult T-Cell Lymphoma/Leukemia Ocular Fibrosis Cutaneous Fibrosis Wound Healing Heart Failure Idiopathic Pulmonary Fibrosis

Anticipated 2020 Milestones

  • Phase I ATLL Data (released Jan 20)
  • MRG-229 Pre-clinical Data (2Q20)
  • Regulatory Guidance in ATLL (3Q20)
  • Phase 2 CTCL Topline Data (3Q20)
  • Phase 2 Cutaneous Fibrosis Data

(2H20)

The Most Advanced microRNA Targeting Pipeline

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Clinical Development Programs

Large microRNA Therapeutics Safety Database

COBOMARSEN REMLARSEN MRG-110

ROUTE OF ADMINISTRATION Intralesion, IV and Subcutaneous Intradermal Intradermal and IV DOSE 75-1200 mg Up to 14 mg Up to 1.5 mg/kg EXPOSURE* 68 patients (CTCL, ATLL, DLBCL, and CLL from Ph1 and CTCL SOLAR) for up to 2.2 Years 61 patients for up to 4 weeks 65 subjects for up to 3 weeks CLINICAL TRIALS*

  • CTCL – Phase 1 Completed (n=41)
  • CTCL – SOLAR Phase 2 Ongoing (n=10)
  • ATLL – Phase 1 Ongoing (n=13)
  • DLBCL, CLL – Phase 1 Enrollment Suspended (n=9)
  • NHV – Phase I Completed

(n=54)

  • Keloid – Phase 2 Enrollment

Complete (n=14)

  • NHV – Phase 1 ID SAD/MAD Completed

(n=42)

  • NHV – Phase 1 IV SAD Completed (n=49)

SAFETY*

  • Generally safe and well tolerated
  • No acute inflammatory toxicities
  • No significant abnormalities in liver, kidney or blood
  • No evidence of global immunosuppression (no

exaggerated pharmacology)

  • No evidence of metabolic or hematological toxicities
  • Generally safe and well tolerated
  • No negative effect on healing (no

exaggerated pharmacology)

  • Generally safe and well tolerated
  • No acute inflammatory toxicities
  • No significant abnormalities in liver, kidney
  • r blood
  • No injection site reactions
  • No evidence of distal angiogenesis (no

exaggerated pharmacology)

*data cut off of July 23,2019

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microRNA Dysregulation Can Be Associated with Poor Outcomes, Creating an Opportunity for microRNA Targeting Therapeutics

microRNA-155

  • Overexpression of miR-155 has been

associated with poor clinical outcomes in a variety of cancers

COBOMARSEN

  • A microRNA-155 inhibitor that has

demonstrated promising anticancer activity

  • By affecting multiple signaling pathways in

cancer, cobomarsen may provide long term benefit with few resistance mechanisms CTCL DLBCL CLL AML Burkitt’s Lymphoma Breast Cancer Lung Cancer Glioblastoma Colon Cancer Gastric Cancer ATLL Pancreatic Cancer Melanoma Neurofibromatosis Head & Neck Cancer PTCL Waldenstrom Macroglobulinemia

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  • For evaluable patients achieving a PR (n=12), the mean duration of response was 309 days at

the time of the 07/30/19 data cutoff

  • Cobomarsen was generally well-tolerated at all doses tested in CTCL subjects
  • Data from the Phase I trial helped the company to design ongoing Phase II clinical trial

Cobomarsen Phase 1 Clinical Trial Data Highlights

92% of the CTCL subjects in the systemic administration cohorts observed to have improvement in tumor burden as assessed by mSWAT score. 63% of subjects treated with cobomarsen administered as a 300 mg IV-infusion achieved a PR and 50% maintained the response for greater than four months (ORR4).

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SOLAR Phase 2 Clinical Trial

A Randomized, Open-Label, Parallel-group, Active Comparator, Global Trial in Patients with Stage IB-III Mycosis Fungoides (MF)

Primary Endpoint + Durable Skin Response Rate of Four Months (ORR4) Secondary Endpoints + Progression-free Survival in Skin

Follow until progression Open Label Randomized to: Cobomarsen IV Infusion vs. Vorinostat Randomize n~37 Cobomarsen N=~18 Vorinostat N=~18 Cobomarsen N=up to 43 Interim Analysis Vorinostat N=up to 43 Follow until progression Crossover to cobomarsen Follow until progression Potential to open additional Randomization EOS

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ATLL (Adult T-cell Leukemia/Lymphoma)

  • Adult T-cell leukemia/lymphoma (ATLL) is a

peripheral T-cell neoplasm caused by human T- lymphotrophic virus type 1 (HTLV-1)

  • HTLV-1 is correlated with the overexpression of miR-

155 during its lifecycle

  • Malignant transformation leading to ATLL occurs in

up to 7% of HTLV-1–infected individuals

  • The aggressive form of the disease is highly morbid,

with mean survival times of 4-10 months after diagnosis even with the best standard of care over the last two decades

Arch Pathol Lab Med 2014;138-282; Blood Advances, 2018 (march27); 2 (6)

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RESULTS Cobomarsen observed to have a favorable MST and PFS in Aggressive ATLL with Residual Disease, Compared to External Historical Cohort

Cobomarsen- Aggressive External Cohort All Aggressive External Cohort- Acute External Cohort- Lymphomatous n (papers) NA 12 8 8 n (patients) 6 3,739 3,369 3,369 MST (months) 26 7.4 6.8 10.4 PFS (months) 12.5 5.4

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Cobomarsen Appears to Decrease Expression of Cell Proliferation and Activation Biomarkers on ATL Cells

% K i-6 7 + 1 0 2 0 3 0 4 0 5 0

% K i-6 7 A T L C e lls

% o f C D 4 + C D 4 5 R A -C D 2 5 + /- % C C R 7 + 1 0 2 0 3 0 4 0 5 0 6 0 7 0

% C C R 7 + A T L C e lls

% o f C D 4 + C D 4 5 R A -C D 2 5 + /-

C 1 D 1 C 1 D 1 2 C 2 D 8 C 3 D 8 C 4 C 6 C 8 C 1 C 1 2 C 1 4 C 1 6

0 .0 0 .5 1 .0 1 .5

P ro life ra tio n In d e x A T L T u m o r C e lls

A v e ra g e F o ld C h a n g e o f % C e lls P o s itiv e fro m B a s e lin e

% K i-6 7 +

C 1 D 1 C 1 D 1 2 C 2 D 8 C 3 D 8 C 4 C 6 C 8 C 1 0 C 1 2 C 1 4 C 1 6

0 .0 0 .5 1 .0 1 .5

A c tiv a tio n M a rk e rs A T L T u m o r C e lls

A v e ra g e F o ld C h a n g e o f % C e lls P o s itiv e fro m B a s e lin e

% C D 6 9 + % H L A -D R +

BASELINE PROGNOSTIC BM COBOMARSEN TREATMENT

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miR-29 is an Anti-Fibrotic miRNA

Ocular Fibrosis Pulmonary Fibrosis Inflammatory Bowel Disease Liver Fibrosis Cardiac Fibrosis Tendinopathies Renal Fibrosis Cutaneous Fibrosis Osteoarthritis Dupuytren’s Contractures

miR-29 TGF-β + ECM Fibrosis miR-29 agonist TGF-β + ECM Fibrosis

X X

  • Reduced expression of miR-29 has been

implicated in the development and progression of a wide range of fibrosis indications

  • miR-29 inhibits TGF-β activity, EMT,

fibroblast-to-myofibroblast transition and ECM synthesis

  • miR-29 inhibits every step of the collagen

fibrillogenesis pathway

miRagen preclinical and/or clinical data + literature support Literature support

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Remlarsen: Reduces Fibroplasia Without Affecting Wound Healing

  • Remlarsen treatment appears to inhibit the

expression of dynamic and mechanistic biomarkers of fibrogenesis in humans

  • This appears to result in a significant

reduction in fibroplasia, a marker of scar tissue deposition

  • Normal regranulation and healing of the

wounds observed with treatment

  • Statistically significant reduction of

fibroplasia without affecting wound healing

  • Justifies further exploration for broad

applications in scar reduction

16 subjects (Additional 3 subjects did not have histology assessment performed) Hematoxylin and Eosin stain & assessment by a blinded pathologist

*

*Statistically significant (p=0.0086)

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Remlarsen: An Anti-Fibrotic in the Eye

  • Successful biodistribution to target cells in preclinical

studies

  • Retina with intravitreal injection
  • Cornea with topical administration
  • Compelling biomarker and antifibrotic activity in

preclinical studies

Unburned Cornea No Treatment Saline Treated Burned Cornea Remlarsen Treated Burned Cornea

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MRG-229: A Next-Gen miR-29 Mimic for Systemic Administration and Targeted Delivery in Systemic Fibrosis

In vitro Screening of Extensively Modified Mimics

  • Increased stability
  • Improved potency

Targeting Conjugates

  • Tissue/indication specific receptor targeting
  • Improved uptake via conjugates

Remlarsen (Parent Compound) Mechanism of Action Validated in Human Clinical Trials Optimized for Stability and Activity Optimized for Biodistibution and Delivery MRG-229 (Next Gen miR-29 mimic)

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MRG-229: Potent Antifibrotic Activity Observed in Preclinical Model of IPF

S a lin e /S a lin e B le o m y c in /S a lin e B le o m y c in /m iR -2 9 m im ic

2 4 6 8 1 0

T o ta l C o lla g e n Q u a n tific a tio n

% C o lla g e n

p<0.05

Bleomycin/Saline Bleomycin/MRG-229

Collagen stained blue Normal alveoli

213.23 µm 213.23 µm

Significantly Blocks Pulmonary Fibrosis in Bleomycin-Treated Mice

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MRG-229 Appears to Block Fibrosis in Human Precision-Cut Lung Slices

In collaboration with Naftali Kaminski And Maurizio Chioccioli

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miRagen Therapeutics

  • Leading the development of the most

advanced microRNA targeting therapeutics platform currently in development

  • Favorable safety and tolerability profile
  • bserved in multiple product candidates
  • 3 clinical stage product candidates and a

recently unveiled preclinical program

  • Aims to advance multiple product candidates

through collaborations, while driving future expansion opportunities for the company

3

Anticipated 2020 Milestones

  • Phase I ATLL Data (released Jan 20)
  • MRG-229 Pre-clinical Data (2Q20)
  • Regulatory Guidance in ATLL (3Q20)
  • Phase 2 CTCL Topline Data (3Q20)
  • Phase 2 Cutaneous Fibrosis Data

(2H20)

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Restoring Biological Harmony for Patients with Debilitating Disease Restoring Biological Harmony for Patients with Debilitating Disease

miRagen Therapeutics

NASDAQ: MGEN

February 2020