Our experience with NIH/SMARTT resources to bring PepducinsTM from the bench-into-the-clinic

Athan Kuliopulos, MD PhD, CEO, Oasis Pharmaceuticals

19th Annual HHS SBIR/STTR Conference Milwaukee, WI

! November 7, 2017 Overview

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" The Company

1. Overview and background of Oasis Pharmaceuticals

N Oasis Pharmaceuticals

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O Pepducin Pipeline

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Athan Kuliopulos, MD PhD, CEO • Inventor of Pepducin™ technology • Founder, CEO of Oasis Pharmaceuticals, LLC, 2013-present • Founder, CSO of Ascent Therapeutics, 2007-2010 • Raised $21M (A) from Novartis Option fund, HCV, TVM, plus additional funding ($10M) and partnerships with Novartis, J&J, and other Pharma • PI of NIH/NHLBI P50 to develop a PAR1 pepducin PZ-128 (currently enrolling PCI patients in a multi-center Phase 2 study) Lidija Covic, PhD, CSO • Co-Inventor of Pepducin™ technology • Founder, CSO of Oasis Pharmaceuticals, LLC, 2013-present • Founded Ascent/Anchor: SAB Member John Amedio, PhD, VP Chemistry and Manufacturing • CMC for therapeutics including PZ-128 • VP, Manufacturing and Chemistry, Seaside Therapeutics, Ziopharm Richard Looby, Director of Chemistry • Expert in pepducin design and synthesis Dana Minnick, PhD Regulatory Toxicology, IND-enabling studies, FDA Interactions Clinical Team: NASH CRN-Dr. Manal Abdelmalek, MD, Hepatologist, Duke Medical Center IPF-Dr. Steven Nathans, MD, Chief Pulmonary Medicine, Inova, VA AD-Dr. Alice Gottlieb, MD, Dermatologist-in-Chief, Tufts University School of Medicine 6 Pepducin technology

2.PAR2-a difficult-to drug receptor: Solution: Pepducin technologyTM

] Protease-Activated Receptor-2 (PAR2)

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G!"# + G! + "# GDP GTP PepducinTM Technology

Pepducin Lipopeptide structure:

GPCR 1. Synthetic Peptide • 7-19 amino acid fragment of GPCR intracellular loop • Nature-engineered specificity

2. Hydrophobic moiety • Cell-penetrating / membrane tethering lipid (e.g., palmitate)

3. Screened PAR2-derived pepducins • Identified PZ-235 Sevigny et al PNAS (2011) 108:8491-6

` PAR2 Antagonist: Rational Design of PZ-235

• Based on the PAR2 receptor structural model

• Pharmacologic data identified key residues (red and blue) important in eliminating PAR2 receptor constitutive (ligand independent) activity -$B",/./%0)*(-$B", -G;"NS

-$B" -$B"

!R PD-PK

Pepducins are stable and have long half-lives in plasma

t1/2~4-6h

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Into fibrosis-prone Organs, e.g. lung, liver, kidney

PAR2 pepducin has long tissue half-life and is widely distributed

!" Opportunity: Large Unmet Medical Need in IPF

• Two approved oral drugs sold at high cost Nintedanib (Ofev) Boehringer Ingelheim Pirfenidone (Esbriet) Roche • Limited benefit with high potential side effects • IPF market to surpass $1 Billion in 2017

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13 Summary of effort in IPF

• Product: OA-235c Lead Clinical Candidate Idiopathic Pulmonary Fibrosis (IPF)

• Identified OA-235c as a protease-resistant lipopeptide • SubQ injectable developed for systemic administration; aerosol delivery is a long-term goal • PK conducted in mouse and dog showing high AUC and sustained drug levels in plasma

• Milestones completed in partnership with NHLBI SMARTT program • Dose-escalation dog safety study • CV (GLP) dog pharmacology-tox study • Genotox panel (GLP) • AMES • Mouse micronucleus study (up to 200 mg/kg) • Chromosomal abnormality (Clastogenic)

• Remaining IND-enabling studies - funding pending

!O Summary of efforts in NASH

• Product: OA-235i Lead Clinical Candidate

• Nonalcoholic steatohepatitis (NASH) • Currently no approved treatments for NASH except for life style change and antioxidants

• Major milestones accomplished: • Identified OA-235i with 25-fold higher potency • SubQ injectable developed for daily-to-weekly administration • PK conducted in mouse, rat, dog showing high AUC and sustained drug levels in target tissue-namely liver • 28 day rat and 7 day dog completed showing high therapeutic safety margin • Pre-IND meeting held with FDA and identified regulatory pathway through IND and phase 1 trial • Additional indication is kidney fibrosis

• Expected IND in mid-2018 for NASH (funding secured) • First-in-human trial in NHV and NASH subjects in late-2018 (funding secured): single and multi-dose ascending study to be done at Duke Medical Center

!S Future earning Projections for entire market

!a Competition in NASH

$GILD(ACC) $BMS(FGF-21) Majority of experimental Limited number of anti-fibrotic agents agents target steatosis

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Normal NASH Fibrotic/Cirrhotic Liver Coagulation proteases Liver Inflammatory proteases

protease Activated cleavage PAR2 PAR2 TF in Cirrhotic liver

Stellate Cell Proliferative Myofibroblast LX-2 Proliferation/ERK signaling PAR2-ab Extracellular matrix deposition 2o-ab Production of inflammatory Cytokines

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"! Timeline for Completion of IND/Phase 1 for OA-235i in NASH

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Q3 Phase 1 2016 Phase 1 GLP tox/safety IND complete FDA preIND initiation meeting completion

FPFV Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 2017 2018 2019

"" Utilizing the NHLBI SMARTT Program

3. Developing a PAR1 pepducin from bench-to-Phase 2 clinical trials and beyond

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• Interruption of oxygen supply to the heart • Causes death of the heart muscle • A leading cause of death in both men and women • Patients with ACS treated with PCI/stent and anti-platelet agents

QTV CVD deaths vs. cancer deaths by age (United States) NHLBI

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! M9,*+(NNNB([4\(M,&+/;*(U";9(P-5L>NV2@-(%$(*;,#7+(@2)(06+/?"/F(A+'9,/"*:*_ Center of Hemostasis and Thrombosis Research at Tufts and NHLBI / RTI / SRI

SMARTT 36

Opened IND

"a Protease-Activated Receptor-1 (PAR1)

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!!HA&@/6)23(#&H@IA MMP1 cleaves PAR1 extracellular domain at a novel site

R Trivedi et al. Cell 137, 332–343 (2009) [ ' H I ! Bound inhibitors have extended conformations K

! Modeled hexapeptide aligns closely with bound Inhibitors P%

Modeled from MMP1 and MMP8-peptide inhibitor complexes: Lovejoy (1999) Nat Struct Biol; Bode (1994) EMBO Can one develop an inhibitor against PAR1 that will prevent both MMP1 and thrombin platelet activation?

H@IA !!HA R45$81"% H@IA

R45$81"% Identification of PZ-128 as an anti-PAR1 Pepducin To block both thrombin and MMP1 activation

MMP1

Zhang et al. Circulation (2012) 126:83-91 On-state of PAR1-modeled from KobilkaKobilka’s’s "2AR-Gs complex (Noble prize)

PZ-128: blocks PAR1 From Coupling with

32 Bringing PZ-128 from concept to Phase II clinical trials- Entirely sponsored by NHLBI Translational Programs

Preclinical development: RC2, SMARTT Generate pepducin leads and validate Manufacture 50 g cGMP material, 2-species efficacy and specificity in platelets IND-enabling GLP safety, toxicity studies In vitro In vivo Month: 0 6 8 10 12 16 24 Human platelets Start

Initiate 7-day Pre-IND 7-day pepducin Selective Guinea pig and Monkey meeting Guinea pig Tox, Screening Inhibition Baboon efficacy Tox, at other safety of PAR1 Safety FDA (SRI and RTI) cGMP synthesis 2+ year stability initiated

Clinical development: P50 TRIP-Program Phase I: 32 CAD Phase II: !200 PCI patients Year: 3 4-5 6 8 patients (Multi-center)

Safety (bleeding), FDA DSMB assessments FDA Finish First-in- Efficacy Signal: 30, 90 day Endpoints IND Human Dose escalation IND Whew! Safety, tolerability, PK, PD MACE anti-platelet efficacy Exploratory Efficacy (Troponin, TAT, MMP1, etc) 2016 Results: Pharmacokinetics

35 Anti-platelet efficacy is rapid and prolonged

n=4 PAR1 Platelet aggregation as a PD measure of efficacy Results: Safety

- There were no effects on ECG, hematologic or clinical chemistry parameters

38 Pathway from concept to Phase II clinical trials- Entirely sponsored by NHLBI Translational Programs

Preclinical development: RC2, SMARTT Generate pepducin leads and validate Manufacture 50 g cGMP material, 2-species efficacy and specificity in animals IND-enabling GLP safety, toxicity studies In vitro In vivo Month: 0 6 8 10 12 16 24 Human platelets Start

Initiate 7-day Pre-IND 7-day pepducin Selective Guinea pig and Monkey meeting Guinea pig Tox, Screening Inhibition Baboon efficacy Tox, at other safety of PAR1 Safety FDA (SRI and RTI) cGMP synthesis 2+ year stability initiated

Clinical development: P50 TRIP-Program Phase I: 32 CAD Phase II: ~100 PCI patients Year: 3 4-5 6 8 patients (Multi-center) Safety (bleeding), Efficacy Signal: 30, 90 day Endpoints FDA First-in- DSMB assessments FDA Start MACE IND Human Dose escalation IND P3 in 2018 Safety, tolerability, PK, PD Exploratory Efficacy Pending anti-platelet efficacy (Troponin, TAT, MMP1, etc) Funding N=536 Acknowledgements:

Oasis- Lidija Covic (CSO), John Amedio (VP CMC)

NIH & NHLBI Funding- STTR/SBIR, RC2, TRIP Andrei L. Kindzelski, MD, PhD, Keith Hoots MD, Pablo Cure MD, Yves Rosenberg MD

SMARTT Program: Traci Mondoro, Ray Ebert, Patricia Noel, Sonia Skarlatos (NHLBI), Diana Severynse- Stevens, Sudie Rowshan (RTI) / Hanna Ng (SRI)

Center of Hemostasis and Thrombosis Research, Tufts

!Boston Team !Oregon Primate Center Kuliopulos/Covic Labs: Jim Baleja Andrew Bohm Dan Cox

Paul Gurbel, MD Inova Kevin Bliden & Jeff Rade, MD Andras Gruber Carey Kimmelstiel, MD Susan Turner (OHSU) Udaya Tantry (Inova, VA) Director, Interventional Cardiology, Tufts UMass