DIA Oligonucleotide-Based Therapeutics Conference

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1 DIA Oligonucleotide-Based Therapeutics Conference North Bethesda MD October 25-27

2 Translating PD Biomarkers From Preclinical Studies to Clinical Trials: MRG-201, an Oligonucleotide Mimic of mir- 29, Inhibits Collagen Expression and Reduces Fibroplasia in Cutaneous Wounds Corrie L. Gallant-Behm, Ph.D. October 26, 2017

3 Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to DIA, its directors, officers, employees, volunteers, members, chapters, councils, Communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. DIA and the DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners.

4 microrna Therapeutics Regulate Systems Biology to Modify Disease microrna-targeted therapy is focused on disease modification by restoring homeostasis to dysregulated processes micrornas regulate complex biological systems microrna-targeted therapies are intrinsically focused on diseaserelevant pathways microrna therapeutics particularly suited for complex, multigenic disorders

5 Regulating Systems Biology to Modify Disease mir-29 is an Anti-Fibrotic microrna TGF-b + Diseased ECM Inflammation

6 A mir-29 Positive Feedback Loop in Fibrosis Homeostasis Scar Formation Injury mir-29 TGFβ, PDGF EGF IGF Matrix

7 Therapeutic Hypothesis MRG-201 restores homeostasis by modulating the positive feedback loops that maintain the fibrotic phenotype Homeostasis promir-29 TGFβ, PDGF EGF IGF Matrix

8 Reduced mir-29 Has Been Implicated in Multiple Fibrotic Diseases Keloid scar Hypertrophic scar Scleroderma Cardiac fibrosis Pulmonary fibrosis IPF, CTD-associated Liver fibrosis cirrhosis, NASH, viral Kidney fibrosis diabetic nephropathy, IgA Retinal fibrosis, corneal fibrosis

9 mir-29 as a Therapeutic in Cutaneous Fibrosis Keloids Preclinical models mpoc Human Volunteer Wound Repair Hypertrophic Scars Drug Placebo Cutaneous Scleroderma Safety, PK, Target Engagement (PD)

10 Gene Expression Profiling and PD Biomarker Identification Reciprocally regulated genes identified: mir-29b mimic antimir-29 Functional Annotation (GO terms) ECM: Collagen Extracellular matrix Function: Skin development Epidermis development Ectoderm development Cellular homeostasis Adhesion/cell signaling Signal peptide Cell adhesion Cation binding/transport Cell behavior Cell differentiation Apoptosis Structure: Nuclear lumen RNA: RNA processing ncrna processing mrna splicing Helicase

11 P B S 1.9 m g 3.9 m g 7.7 m g 1 g m ir -2 9 m im ic **** 5.5 m m R N A e x p re s s io n (fo ld c h a n g e ) m R N A e x p re s s io n (fo ld c h a n g e ) m R N A e x p r e s s io n (fo ld c h a n g e ) P B S 7.7 m g m g m g m ir -2 9 m im ic C O L 1 A 1 C O L 1 A 2 C O L 3 A 1 C O L 5 A 3 C O L 1 1 A **** P B S 0.4 m g 1 g m ir -2 9 m im ic ****.0 m m R N A e x p re s s io n (fo ld c h a n g e ) 1.5 **** U N T 2 u M 1 0 u M m ir -2 9 m im ic C O L 1 A 2 C O L 3 A 1 ELN F S T L 1 LBR P R IC K L E 1 T G F B 3 C O L 1 A 1 C O L 1 A 2 C O L 3 A 1 M M P 2 T G F B 2 C O L 1 A 1 C O L 1 A 2 C O L 3 A 1 C O L 1 1 A 1 E L N T G F B 2 Regulation of ECM Genes by MRG-201

12 Downregulation of mir-29 and Overexpression of mir-29 Target Genes in Keloids and Skin Scars

13 MRG-201: First-In-Human Phase 1 Study in Healthy Volunteers Four part study: Part A - Incision only, no drug; establish kinetics of expression of PD biomarkers Objectives: Part B Intradermal MRG-201 in intact skin; 6 dose levels ( mg); single administration Part C Intradermal MRG-201 in incised skin; single ascending dose (SAD); 3 dose levels (4, 7, 14 mg) Part D Intradermal MRG-201 in incised skin; multiple ascending dose (MAD); 3x/week for 2 weeks; 3 dose levels (4, 7, 14 mg) Part D4 Intradermal MRG-201 at one end of skin incision; 3x/week for 2 weeks; 14 mg dose level. Biopsy both treated and untreated ends of incision. Primary: Investigate the safety and tolerability of intradermal MRG-201 Secondary: Characterize the pharmacokinetic profile of MRG-201 Exploratory: Pharmacodynamic profile of MRG-201 in skin mir-29 level following incision

14 Clinical Trial MRG Part A: Establish Kinetics of PD Gene Expression mir-29 qpcr Nanostring Incision Biopsy Biopsy RNA Day 1 Day 9 Day 16

15 mir-29 Expression Decreases and mir-29 Direct Target Expression Increases Following Incision mir-29 Quantity Genes significantly regulated in incised vs. intact skin (BH p-value <0.01) n s M F A P 2 m ir -2 9 C o p y N u m b e r P e r C e ll F o ld C h a n g e v s. u n w o u n d e d C O L 3 A 1 C O L 5 A 2 C O L 1 A 2 T G F B 3 M M P 2 F S T L 1 E L N C O L 5 A 3 T G F B 2 N E D D 4 L S N X 2 7 S D C 4 C O L 1 A 1 C O L 1 1 A 1 C Y T L 1 G I M A P 7 P R I C K L E 1 L B R I T G A 3 N U M B 0 U n in c is e d D a y 9 In c is io n D a y 1 6 In c is io n D a y 9 D a y 1 6

16 Parts B/C/D: Safety, Tolerability and PK in Intact Skin and Skin Incisions, PD target engagement Normal healthy volunteers Single and multiple ascending dose (N=3/cohort) mg MRG-201 injected intradermally Part B: Intact skin Safety/tolerability only, no biopsies Part C: Incised skin, single administration Biopsy 24h after treatment for PD Part D: Incised skin, multiple administration (6 doses over 2 weeks) Biopsy 24h after final administration for PD Line or Incision Drug Line or Incision Placebo RESULTS Dosing and follow-up complete All doses well tolerated up to the maximally deliverable dose No significant injection site reactions Low systemic exposure of full length MRG-201 for all subjects with many samples below limit of quantitation Treated skin biopsy biodistribution assessments (dual probe hybridization assay) showed concentrations ranging from 12 to 200 g/g tissue Pharmacodynamic biomarker data demonstrate target engagement with single and multiple administration of MRG-201

17 MRG-201 Mechanistic Proof-of-Concept in Human Incised Skin Evidence of PD activity (mpoc) after single administration of MRG-201 Validation of preclinical PD biomarkers in human incised skin SINGLE DOSE

18 MRG-201 Treatment Significantly Blunts Fibroplasia in Human Incised Skin Multiple Ascending Dose Cohorts D1-D3 D e p th /W id th (m m ) o r A r e a (m m 2 ) p = S a lin e M R G S a lin e M R G S a lin e M R G W id t h D e p th A r e a F ib r o p la s ia

19 MRG-201 Target Engagement Corresponds to Impact on Fibroplasia Multiple Ascending Dose Cohorts D1-D3 * These subjects had no or minimal detectable fibroplasia (<2mm 2 ) in either saline or MRG-201 treated incisions

20 MRG-201 Target Engagement Corresponds to Impact on Fibroplasia Multiple Ascending Dose Cohorts D1-D3

21 mir-29 as a Therapeutic in Cutaneous Fibrosis Keloids Preclinical models mpoc Human Volunteer Wound Repair Hypertrophic Scars Drug Placebo Cutaneous Scleroderma Safety, PK, Target Engagement (PD)

22 MRG-201 Pharmacodyamic Biomarkers Translate to Multiple Fibrotic Indications TGFB2 Nedd4l Prickle1 Faim2 COL5A3 Gimap7 Cacna1g Colec11 ELN Mfap2 COL5A2 COL1A1 COL3A1 COL11A1 TGFB3 Fstl1 COL1A2 Cytl1 MMP2 Sdc4 Snx27 Itga3 Numb Lbr MRG-201 antimir-29 Day 9 Day 16 SSc skin SSc lung IPF lung Mouse skin vs. vehicle Human skin incision vs. unwounded Human disease tissue vs. normal tissue

23 Conclusions MRG-201 represses expression of genes associated with extracellular matrix production MRG-201 PD biomarker genes are conserved across species Endogenous mir-29 and MRG-201 PD biomarker genes are inversely expressed in cutaneous incisions in normal healthy volunteers, indicating a role for mir-29 in fibrosis development/ progression MRG-201 regulates PD biomarkers and reduces fibroplasia in skin incisions, demonstrating mechanistic proof-of-concept MRG-201 has therapeutic potential in reducing cutaneous fibrosis such as keloids, hypertrophic scars, cutaneous scleroderma MRG-201 PD biomarkers are conserved in other diseases including IPF and SSC-ILDs, indicating therapeutic potential in additional fibrotic conditions

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