(olix) intro kotra 혁신기술 수출상담회

Accelerate Drug Development

using oligonucleotides

www.olixpharma.com

KOTRA 혁신기술 수출상담회 2017

The Next Generation Nucleic Acid Therapeutics

OliX Pharmaceuticals

Executive Summary •

OliX is a biotechnology company developing therapeutics against a variety of diseases, based on the ground-breaking technology regulating the expression of diseasecausing genes via RNA interference (RNAi) mechanism.

•

RNAi technology, one of a gene based drug recognized as the third drug development platform after small molecule and protein (antibody) drugs, is changing the paradigm of therapeutic development.

•

Based on the cutting edge technology, OliX is the only Asian RNAi therapeutics company having own proprietary RNAi structure and securing “freedom-to-operate”.

•

OliX is focusing on developing drugs against locally treatable diseases such as skin/eye/lung to develop many drugs with small development cost and time.

•

OliX will become the 1st RNAi company in Asia conducting clinical trials based on its own platform technology. By 2020, OliX will become Top 3 oligotherapeutic company and No. 1 oligotherapeutic company in skin, ocular and pulmonary diseases in the world.

This material is non-confidential but may not be reproduced or distributed without the written consent of OliX Pharmaceuticals, Inc.

2

OliX Introduction

Business Field CEO Established Location

Oligonucleotide + Xelerate use oligonucleotide technologies to accelerate drug development

Employees

Oligonucleotide (RNAi) Therapeutics Dong-ki Lee, Ph.D. 2010 Suwon, Korea 28 people (18 in R&D) • $9M in VC funding raised in 2014-15

Financing

• Past and ongoing grants totaling >$5M • $8M in VC funding raised in April, 2016

3

OliX Introduction  Management Name

Position

Dong-ki Lee/ Founder

CEO

Shin-Young Park/ Vice President

Career / Education • •

Ph.D. Cornell Univ.

Professor, Sungkyunkwan Univ.

(Global Research Laboratory (GRL) for RNAi Medicine)

Regulatory Affair

• • •

Ph.D. (Pharmacy), Seoul National Univ.

Diplomate of American Board of Toxicologist (DABT), USA Korea Institute of Toxicology (KIT)

David Lee/ Executive Director

Strategic & Clinical Development

• •

B.A. KAIST • MBA, Sejong-Syracuse Univ.

Janssen Korea/Pfizer Korea/Olympus Korea/Molnlycke Health Care

Sun Woo Hong/ Director

CSO

• •

Ph.D. POSTECH Research Professor, Dongguk Univ.

Muhnho La/ Director

Business Development

• •

Ph.D. Korea Advanced Institute of Science & Technology (KAIST) Samyang Biopharm, Principal Researcher

Younghee Kim/ Director

Pharmacology & Preclinical Development

• •

Ph.D. Gyeongsang National Univ.

Assistant Professor, Univ. of Virginia

Sangjin Lee/ Director

CFO

• •

B.A. Seoul National Univ.

Korea Investment Partners/Samil PwC

4

OliX Introduction  Scientific Advisory Board Name

Current Position •

Professor, Vice Chair for Research and Director of the Center for Advanced Vision Science at Univ. of Virginia, School of Medicine

Ophthalmology (Macular Degeneration)

•

Distinguished Professor, Stanford University, School of Medicine

Gene therapy, RNAi Therapeutics, miRNA

• •

Distinguished Professor, Cornell University Member, National Academy of Sciences

Gene Expression, oligotherapeutics

• •

Senior Director, R&D Alliance Management, Sanofi Scientific Managing Director, COMPACT Consortium, Innovative Medicine Initiative

Oligotherapeutics, Biopharmaceuticals

Jayakrishna Ambati

Mark Kay

John Lis

Ekkehard Leberer

Expertise

5

RNA interference



received the 2006 Nobel Prize in Physiology or Medicine



is developed as therapeutics to silence disease-causing genes



gene silencing can be achieved by chemically synthesized RNAi triggering molecules



can silence “undruggable” (cannot be targeted by small molecules or biologics) genes

6

RNAi/Oligonucleotide Drugs: In Clinics and Approved Mipomersen (antisense, Ionis):

Hyperlipidemia → FDA approved (2013)

Eteplirsen (Exon skipping, Sarepta) : Duchenne muscular dystrophy → FDA approved (2016) Nusinersen (antisense, Ionis):

Spinal Muscular Atrophy → FDA approved (2016)

ALN-TTR02 (RNAi, Alnylam):

TTR Amyloidosis → expecting FDA NDA submission (2017)

RNAi Therapeutics - Clinical Development (2016) Stage

Phase III

Phase II

Modified from Roots Analysis (2015)

Drug

Type of Molecule

Indication

Administration

Company

Patisiran (ALN-TTR02)

siRNA

TTR Amyloisosis (FAP)

IV

Alnylam

QPI1002

siRNA

DGF

IV

Quark Pharmaceuticals

QPI1007 / RQ1007

siRNA

NAION

IV

Quark Pharmaceuticals

Vigil (formerly FANG)

shRNA

Ovarian Cancer

ID

Gradalis

ALN-AAT

siRNA

AATD

IV

Arbutus

ANL-AT3

siRNA

Hemophilia A or B

SC

Alnylam

ALN-CC5

siRNA

PNH

SC

Alnylam

ALN-PCSsc

siRNA

Hypercholesterolemia

SC

Alnylam

ANL-RSV01

siRNA

Respiratory Syncytial Virus

Nasal Spray

Alnylam

Atus027

siRNA

Pancreatic Cancer

IV

Silence Therapeutics

Cal-1

ddRNAi

HIV/AIDS

Benitec Biopharma

DCR-MYC

siRNA

HCC

Miravirsen (SPC3649)

miRNA

Hepatitis C

IV

Santaris

Dicerna

ND-L02-s021

siRNA

Liver Fibrosis

Quark Pharmaceuticals

PF-655

siRNA

DME; AMD

Pfizer / Quark

7

Key Challenges for RNAi Therapeutics Development In vivo delivery: achieving effective and safe down-regulation of diseasecasing genes in selected organ(s) and cell type(s) OliX’s solution: 1) cell-penetrating RNAi molecules (cpRNA; capable to cross cellular membrane without additional delivery vehicles), with 2) local (direct) administration routes IP: accessing FTO (freedom-to-operate) and securing protection for therapeutic RNAi molecules OliX’s solution: proprietary RNAi technologies 1) asymmetric RNAi (asiRNA) molecule configurations, with 2) cell-penetrating moieties (cpRNA)

8

OliX Proprietary Configurations for RNAi Molecules Conventional Configuration

19 bp

Sense (Passenger)

siRNA

Antisense (Guide)

5’

3’

3’

5’

Original structure (Tuschl) published in 2001

OliX Proprietary Structures asiRNA Sense (Passenger) Antisense (Guide)

• •

lasiRNA

15-16 bp 5’

3’

3’

5’

Comparable potency, reduced non-specific effects PCT/KR2008/007530 - issued in Korea, Europe, Japan, Australia & China - under review in USA

cp-asiRNA

5’ Increased potency, reduced non-specific effects PCT/KR2011/006632 - issued in Korea, Japan - under review in USA, Europe, China & Canada

Contains cell-penetrating moiety PCT/KR2013/004463 - issued in Korea - under review in USA, Europe, Japan & China

• •

3’ 5’

• •

3’

3’

tiRNA

5’ 3’

5’

• •

15-16 bp

15-16 bp

Iincreased cell penetrating capacity, multiple targets PCT/KR2010/000678 - issued in Korea, Europe, Japan - under review in USA

bg-asiRNA • •

Minimized side effects with bulge structure PCT/KR2010/007771 - issued in Korea, USA

9

OliX Technology for Therapeutics cp-asiRNA (cell penetrating asymmetric siRNA) : no delivery vehicles required for intracellular delivery

Cell Targeting Moiety

5’

3’

3’

5’

Chemical modifications (base)

Chemical modifications (linker)

[Dose Dependency]

mRNA*

protein*

(%)

(%)

100

100

80

80

60

60

40

40

20

20

0

Cell only

0.3

0.5

1

3

5 (μM)

cp-asiRNA

0

[Specificity]

Western Blot Target protein Housekeeping Cell only

Target Nonspecific specific cp-asiRNA

Cell only

Target Nonspecific specific cp-asiRNA

*normalized by housekeeping gene

10

cp-asiRNA: Robust Cellular Uptake Nuclei/Lysotracker/Cy3 cp-asiRNA

cp-asiRNA is spontaneously and efficiently taken up by various mammalian cell types

11

cp-asiRNA Development process 1. asiRNA design / synthesis 2. 1st round screening (in vitro mRNA level analysis)

4. cp-asiRNA design/synthesis (chemical modification) 5. cp-asiRNA efficacy analysis and optimization Target mRNA level (%)

3 months for lead candidates

3. 2nd round screening (in vitro protein level analysis)

100

*

*

50

← OLX301 (34kD) 0 0M4PS 4M4PS 0M4PS 4M4PS 0M4PS 4M4PS 0M4PS 4M4PS S-0M-P-C Ctrl

S-8M-P-C

MyD88-45 OLX301-45

S-0M-P-C

S-8M-P-C

← β-actin

MyD88-46 OLX301-46

6. Select cp-asiRNA for in vivo efficacy test

12

cp-asiRNA in vitro efficacy Cell penetration independent of cell type

TF

cp-asiRNA IB (uM)

TF

TF

cp-asiRNA IB (uM)

cp-asiRNA IB (uM)

TF

3

2

1

0.3

3

2

1

0.3

asiRNA

cp-asiRNA

NT

L2K

3

2

1

0

0.3

0

asiRNA

0 cp-asiRNA

25

0

NT

25

L2K

25 3

50

25 2

50

1

50

0.3

75

50

asiRNA

100

75

cp-asiRNA

100

75

NT

100

75

L2K

100

asiRNA

PANC1 125

NT

CAPAN1 125

cp-asiRNA

AGS 125

L2K

MDA-MB-231 125

cp-asiRNA IB (uM)

Dose response analysis

IC50= 275.7nM

[OLX104B] Relative mRNA level

Relative mRNA level

[OLX301A]

IC50= 22.37 nM

* IC50: half maximal inhibitory concentration

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OliX Approach to Therapeutic Indications Eye OLX301 : Age-related Macular Degeneration

Skin OLX101 : Hypertrophic Scar OLX102 : Skin Brightening OLX103 : Atopic Dermatitis OLX104 : Androgenic Alopecia OLX105 : Anti-Wrinkle OLX106 : Diabetic Ulcer

Lung OLX201 : Idiopathic Pulmonary Fibrosis

Others OLX401 : Neuropathic Pain OLX701 : Liver Fibrosis

Lung Fibrosis

OLX201

Retinal Fibrosis

OLX301D

Liver Fibrosis

OLX701

• Seeking opportunity in vision-related QoL

Wet/Dry AMD

OLX301A

Wet AMD

OLX301B, C

• Leveraging benefit of easily accessible tissue

Pharmaceutical

OLX103, 104

Cosmeceutical

OLX102, 105

“CTGF” Franchise

• Expanding OLX101 to other fibrotic diseases

Eye Disease Skin Disease

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OLX101-CTGF: Anti-scar •

Wound repair frequently results in scar formation - In extreme cases: Hypertrophic scars or Keloids

•

No approved drug in market

•

Global scar treatment market: $ 15 B in 2015*

•

Minimized risk of failure by selecting clinically proven target gene

•

Potentially faster entry to the Asian market than competitors

Competitors Developer (drug)

Target

Drug

Status

Excaliard (EXC-001)

CTGF

antisense

PhaseⅡ

Rxi (Rx109)

CTGF

siRNA

PhaseⅡ

* “Global Scar treatment Market Size, Share, Development, Growth and Demand Forecast to 2022” P&S Market Research 2016 - Including Post-Surgical Scars, Acne Scars, Contracture Scars, Stretch Marks, Keloid and Hypertrophic Scars

•

Licensed out to Hugel (Territory: Asia)

•

Government Grant (KDDF) for preclinical study and IND Approval

• Preclinical study completed (efficacy achieved, no toxicity reported) • IND Approved in Jan. 2017 (KFDA) • Plans to file EU IND in 2017

* Korean drug manufacturer specialized in botulinum toxin and hyaluronic acid filler products (www.hugel.co.kr)

15

OLX101-CTGF: Anti-scar In vivo KD efficacy

J Invest Dermatol. 2016 Nov;136(11):2305-2313.

• CTGF mRNA/protein knockdown normalized to GAPDH • Intradermal injection in rat skin • SC cp-asiCTGF: cp-asiRNA with scrambled sequence • OLX101 showed better in vivo KD efficacy when compared with Rx109 and with Excaliard in mouse skin (in-house preliminary study)

Therapeutic effect (histological analysis) • Excision wound in rat skin • SC cp-asiCTGF: cp-asiRNA with scrambled sequence • MTS: Masson’s trichrome staining - red arrow: excision site

• •

KFDA IND approved Planning EU IND 16

OLX201-CTGF: Idiopathic Pulmonary Fibrosis •

Scarring of lung tissue is a chronic, irreversible fatal disease

•

70,000 IPF patients in the US and EU

•

About 30,000–35,000 new patients emerging every year

•

Annual Potential IPF Market: $ 900M (‘15), $ 3.2B (‘25E)*

•

Currently, there is no cost-effective therapeutics for the IPF

* “Opportunity Analyzer: Idiopathic Pulmonary Fibrosis – Opportunity Analysis and Forecast to 2025” GlobalData Healthcare 2016

A*STAR (Singapore) – KHIDI (Korea) Joint Grant Call ($1.8 M for 3 yrs)

•

2nd year result (‘15. Oct. ~ ‘16. Sep.) - Proof of concept in animal disease model using intratracheal administration - In vivo knock-down of CTGF and downstream genes - Therapeutic effect was shown by reduced fibrotic area in lung and hydroxyproline assay

•

3rd year plan (‘16. Oct. ~ ‘17. Sep.) - Therapeutic efficacy study with inhalable formulation

17

OLX201-CTGF: Idiopathic Pulmonary Fibrosis Therapeutic effect (Immunohistopathology) CTGF

H&E

MT

SR

w/o BLM

BLM only

BLM/OLX201 low dose H&E: Hematoxylin & Eosin BLM/OLX201 high dose

MT: Masson’s Trichrome SR: Sirius Red

Therapeutic effect (fibrotic area, representative figure)

w/o BLM

BLM only

BLM/OLX201 high dose

BLM/OLX201 low dose

18

OLX301A: wet AMD & dry AMD •

The leading cause of severe vision loss in over age 60

•

Two types: wet AMD (10%) & dry AMD (90%)

•

Global wet AMD market: $ 7.65B in 2015*

•

No approved drug in dry AMD - Vitamin regimen is current standard of care

•

Estimated dry AMD market: $ 6.58B at 2025*

•

98% of wet AMD patients were reported the onset of dry AMD in seven years**  Unmet medical need for a drug that can treat both wet and dry AMD

* “Macular Degeneration (AMD) and Other Retinal Diseases: World Drug Industry and Market 2016-2026” Visiongain 2016 ** Ophthalmology. 2012 Jul;119(7):1388-98., Ophthalmology. 2013 Nov;120(11):2292-9.

•

Collaboration with Jayakrishna Ambati, MD (Univ. of Virginia) •

World-renowned researcher in the field of macular degeneration

•

Developed animal models for development of novel therapeutics to prevent and treat AMD

•

Identified the molecular mechanisms underlying the development of AMD for the first time

•

Showed that siRNA having shorter duplex (similar to OliX’s asiRNA) is better suited to ocular diseases (Mol Ther. 2012 Jan; 20(1): 101–108.)



Decrease of CNV volume in laser-induced CNV mouse model - Comparable to Lucentis 19

OLX301A: wet AMD & dry AMD Therapeutic effect (wet AMD, CNV) cpLuc

OLX301A

Lucentis

OLX301A/ Lucentis

Therapeutic effect (dry AMD, ZO1-stained RPE)

Normal

PBS

Low dose

High dose

Advanced form of Dry AMD (GA*) model

No toxicity @ 10X therapeutic dose (Representative image)

* GA: Geographic Atrophy

20

OLX102 : Skin Brightening •

Freckles and age spots result from localized melanin pigmentation

•

Estimated global market: $10B, Expected to grow to $24B by 2020*

•

The largest market for skin brightening is in Asia, in particular China, Jpan, India and Korea

* “The Global Skin Lighteners Market Trends, Drivers & Projections.” Global Industry Analysts, 2015

OLX102 Development Status

Negative Control

OLX102

melanocyte

 Target Gene : Tyrosinase  Registered in ICID** and ready for clinical tests  Cosmeceutical Product Development for Skin brightening ** ICID : International Cosmetic Ingredient Dictionary managed by Personal Care Products Council (US)

21

OLX103: Atopic Dermatitis 

AD affects more than 10% of children and 1-3% of adults more common in younger children



Global market in 2014 : $4B By 2020, expected to grow to $5.2B*



No cure for AD yet, although treatments may reduce the severity

* “Atopic Dermatitis – Global Drug Forecast and Market Analysis to 2022”, Global Data 2013

OLX103 Development Status OUT side



Government grant awarded (SMBA*) in 2015

 

OLX103A : Target for Inflammation-related gene OLX103B and C : Target for Itching-related gene

Trigger

Impaired Barrier OLX103A

IN side Inflammation

 

Lead molecule selected; Animal POC study in progress Delivery formulation being developed

Scratch

Itch

OLX103B OLX103C

*Small and Medium Business Administration

22

OLX104 : Alopecia 

In Korea, continuous growth of alopecia population  from 50 M in 2002 to 100 M in 2013, including potential alopecia population



Korea’s market size : $ 3 B estimated



In China, 0.1 B Alopecia patients estimated*



Functional hair loss managing products, like shampoos and conditioners, black powders, and wigs are market leading products to prevent alopecia

* KOTRA Global Window 2014

Problems with Existing Treatments Finasteride side effects - malignant prostate cancer, sexual dysfuction, glow, weight loss, bond density loss, etc

Advantage of OliX RNAi Tech. 

Minimization of systemic exposure and internal organ influence from local administration and properties of OliX asiRNA



Safe and effective DDS Technology

Dutasteride side effects - increased male breast cancer prevalence → Serious side effects from systemic exposure and internal organ influence

23

OLX104 : Delivery by Motorized Microneedle

Needle penetration into the skin

Dispersion of ingredient

Regeneration

Development Strategy • Effective delivery to target site by motorized microneedle • Regulatory perspectives* Probe

• Ingredient (OLX104): cosmetic category (RNA) • Device: general commodity (< 0.25mm of penetration depth)

Device

* According

to Korean regulations

24

OLX105 : Anti-Wrinkle 

Skin wrinkle, a fold, ridge or crease in the skin, typically appears as a result of aging processes



Global anti-aging market to be worth US $191.7 Billion in 2019 with CAGR of 7.8% between 2013 and 2019*

* “ Anti-aging Market - Global Industry Analysis, Size, Share, Growth, Trends and Forecast, 2013 - 2019”, Transparency Market Research 2014

Development Status  Target Gene : MMP1  OLX105 as a cosmeceutical product, mainly targeting Asia cosmetic market (Japan, China and Korea)  Lead identified  Fast regulatory pathway for cosmeceutical development Fast development time using the OliX's proprietary RNAi platform

25

OLX401 : Neuropathic Pain 

A complex, chronic pain state that usually is accompanied by tissue injury



Common causes are from diabetes, shingles, HIVassociated pain, multiple sclerosis, post-stroke pain and cancer



The market is expected to grow to $ 5.2 Billion by 2018 (major 7 countries, Research and Markets)



Lack of efficacy and frequent incidence of side effects associated with current treatment options. (NSAID, Opioids)



Novel therapeutic approaches are actively undergoing now



Topical Admin. has advantages in efficacy and safety (reduced systemic exposures)

Development Status  Currently, a lead identification completed and animal efficacy study in progress

26

Thank You. Questions? 경기도 수원시 영통구 대학 4로 17 에이스광교타워1 1014호 #1014 Gwanggyo Ace Tower1, 17 Daehak 4-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 16226, Republic of Korea TEL : +82-31-779-8408 / FAX : +82-31-779-8499 www.olixpharma.com

This material is non-confidential but may not be reproduced or distributed without the written consent of OliX Pharmaceuticals, Inc.