Pg. 1Confidential

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

Inhibition of corneal fibrosis with a miR-29 mimic

Corrie Gallant-Behm, PhD, MQARS

Oligonucleotide Therapeutics Society 14th Annual Meeting

October 1, 2018

Pg. 2

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 disease-relevant

pathways

▪ microRNA therapeutics particularly

suited for complex, multigenic disorders

Pg. 3

miR-29 Pathways and Systems Control

Growth factors

Collagen transcription/translation

Post-translational modification

& triple helix formation

N- and C-terminal cleavage

& secretion

Fibril cross-linking

Mature collagen fibrils

miR-29

Inflammation

TGF-b +

Diseased ECM

TGF-b2, TGF-b3, EGF, IGF2, IGFBP5,

PDGFA, PDGFC

COL1A1, 1A2, 3A1, 5A1, 5A2, 5A3,

6A4, 6A5, 6A6, 8A1, 8A2, 9A1,

11A1, 12A1, 14A1, 22A1, 28A1

HSP47, P4HA2, P4HA3, PLOD2

PCOLCE2

LOXL2

in vivo Validated Targets

Pg. 4

miR-29 Pathways and Systems Control

Remlarsen(MRG-201)(promiR-29)

Growth factors

Collagen transcription/translation

Post-translational modification

& triple helix formation

N- and C-terminal cleavage

& secretion

Fibril cross-linking

Mature collagen fibrils

TGF-b2, TGF-b3, EGF, IGF2, IGFBP5,

PDGFA, PDGFC

COL1A1, 1A2, 3A1, 5A1, 5A2, 5A3,

6A4, 6A5, 6A6, 8A1, 8A2, 9A1,

11A1, 12A1, 14A1, 22A1, 28A1

HSP47, P4HA2, P4HA3, PLOD2

PCOLCE2

LOXL2

in vivo Validated Targets

Pg. 5

Fibrotic Diseases in Which Reduced miR-29 Has Been Implicated

▪ Keloid scar. Phase 2 clinical trial ongoing: NCT03601052

▪ Hypertrophic scar. Phase 1 clinical trial complete: NCT02603224

▪ Scleroderma.

▪ Cardiac fibrosis.

▪ Pulmonary fibrosis – IPF, CTD-associated.

▪ Liver fibrosis – cirrhosis, NASH, viral.

▪ Kidney fibrosis – diabetic nephropathy, IgA.

▪ Retinal fibrosis.

▪ Glaucoma. Trabeculectomy bleb failure. Multiple opportunities in ophthalmology

▪ Fuch’s Endothelial Corneal Dystrophy.

Pg. 6

The Eye is a Preferred Target Organ for microRNA Therapeutics

▪ Delivery to multiple compartments of the eye, and via multiple routes of administration including injection and topical drops

▪ Stability due to reduced nuclease concentration enables long duration of action and infrequent dosing

▪ Reduced liability for toxicities due to local administration with limited systemic exposure

Pg. 7

Remlarsen Uptake in Alkali Burned Cornea

▪ Animal model: Rat alkali burn

▪ Distribution of Remlarsen (MRG-201) to all layers of the cornea, including corneal endothelium after drop administration

EpitheliumStroma

FITC-remlarsenDAPI

Pg. 8

▪ Uptake of remlarsen in alkali burned cornea is high, but diminishes after re-

establishment of the corneal epithelium and/or tear film post-burn

Remlarsen Uptake in Alkali Burned Cornea

0

2 0

4 0

6 0

8 0

1 0 0

1 0 0 01 5 0 02 0 0 02 5 0 03 0 0 0

m iR -2 9 b le v e ls in ra t c o rn e a

miR

NA

ex

pre

ss

ion

(fo

ld c

ha

ng

e)

* * * *

S a lin e : + + + +

R e m la rs e n : + + + +

2 4 h 4 8 h 4 D 7 D

C o n tr o l S a lin e D a y 1 0 D a y 1 4 D a y 2 1 D a y 2 8

0

5

1 0

1 5

m iR - 2 9 L e v e ls

miR

NA

ex

pre

ss

ion

(fo

ld c

ha

ng

e)

R e m la r s e n

14x

11x

1.7x

Pg. 9

Remlarsen as an Anti-Fibrotic in the Cornea

▪ Damage is reduced in remlarsen treated alkali burned eyes▪ Epithelium re-established more quickly

▪ Less damage to the stroma, decreased cellularity

▪ Reduced inflammation

Unburned corneaNo treatment Saline treated burned cornea Remlarsen treated burned cornea

Day 4

Pg. 10

Remlarsen as an Anti-Fibrotic in the Cornea

▪ Wound healing is accelerated in remlarsen treated alkali burned eyes▪ Epithelium re-established more quickly

▪ Reduced stromal thickness results

D a y 4 D a y 7 D a y 1 0 D a y 1 4

0

2 0

4 0

6 0

Ep

ith

eli

um

th

ick

ne

ss

(u

M)

S a lin e

M R G -2 0 1

T re a tm e n t e ffe c t a c ro s s a ll t im e s : p < 0 .0 0 1

p < 0 .0 1

D a y 4 D a y 7 D a y 1 0 D a y 1 4

0

1 0 0

2 0 0

3 0 0

Str

om

al

thic

kn

es

s (

uM

)T re a tm e n t e ffe c t a c ro s s a ll t im e s : p < 0 .0 5

p < 0 .0 5

Saline Remlarsen

Pg. 11

Remlarsen as an Anti-Fibrotic in the Cornea

▪ Scarring is reduced in remlarsen treated alkali burned eyes

Day 14

1 2 3 4 5Normal Scar

Unburned cornea

No treatment

Saline treated burned cornea

Remlarsentreated burned

cornea

0 .0 0

0 .2 5

0 .5 0

0 .7 5

1 .0 0

H a z in g /s c a r r in g

Pro

po

rti

on

of

sa

mp

les

* * *

10 14 21 28D a y :

R e m la rs e n : - + - + - + - +

Pg. 12

Remlarsen as an Anti-Fibrotic in the Cornea

▪ a-SMA staining is reduced by remlarsen treatment

Saline Remlarsen

Least stainingin cohort

Most stainingin cohort

a-smooth muscle actin

S a lin e R e m la r s e n

0

2 0 0

4 0 0

6 0 0

D a y 1 4

a

SM

A+

co

un

ts

S a lin e R e m la r s e n

0

5 0

1 0 0

1 5 0

2 0 0

D a y 2 8

a-S

MA

+ c

ou

nts

Pg. 13

▪ miR-29b PD biomarkers are repressed following twice daily remlarsen drop treatments

▪ Consistent in multiple studies

▪ Multiple collagens and pro-fibrotic factors are affected

Remlarsen Demonstrates Target Engagement in Cornea in vivo

S a lin e R e m la r s e n

0 .0

0 .5

1 .0

1 .5

D a y 7

mR

NA

Ex

pre

ss

ion

(Fo

ld C

ha

ng

e)

0.0350p =

S a lin e R e m la r s e n

0 .0

0 .5

1 .0

1 .5

D a y 1 0

mR

NA

Ex

pre

ss

ion

(Fo

ld C

ha

ng

e)

0.0003p =

S a lin e R e m la r s e n

0 .0

0 .5

1 .0

1 .5

D a y 1 4

mR

NA

Ex

pre

ss

ion

(Fo

ld C

ha

ng

e)

p < 0 .0 0 0 1

COL1A1

COL1A2

COL5A2

FN1

TGFB2

MMP2

Study 1 Study 2

Pg. 14

▪ miR-29b mimics are well taken up by a damaged/ulcerated cornea following drop

administration

▪ Remlarsen uptake is sustained in the alkali burn model until the corneal epithelium and

tear film are fully established post-burn

▪ Remlarsen treatment reduces the severity of alkali burn, accelerates repair vs. vehicle

▪ Remlarsen treatment reduces corneal hazing/scarring, decreases the corneal stromal

thickness, and reduces a-SMA staining post-burn

▪ Remlarsen engages its pharmacodynamic targets and reduces collagen/ECM

expression in vivo

▪ Remlarsen represents a potential therapeutic for corneal scarring regardless of the

etiology:

▪ Infectious keratitis, surgery, trauma, genetic disease

▪ Translatable to other compartments of the eye – trabecular meshwork, conjunctiva, retina, choroid

Conclusions