Best in Class Agents for Global HCV Eradication

Best in Class Agents for Global HCV Eradication Raymond F. Schinazi, PhD, DSc Frances Winship Walters Professor Director, Scientific Working Group on Viral Eradication, Emory University CFAR/VAMC University of Miami Emory Institute for Drug Discovery Boston June 27, 2013 rschina@emory.edu

Introduc)on: Hepa))s C Virus and Treatment ~170 million infected with HCV worldwide (USA: 2.7-3.9 million) Six different genotypes worldwide Chronic disease leads to liver cirrhosis and cancer No latency hence curable Virus dynamic Standard of care: Ribavirin + peg- INF- α + Protease Inhibitors Treatment complicated coinfecuon even more complicated Side effects, subopumal efficacy, genotype- dependent, injectable ral, direct acung anuvirals (DAA): NS5B, Entry, Protease, NS5A, Cyclophilins, microrna, etc. Nucleoside Analog Inhibitors (NAI) are Best in Class: High potency Pan- genotypic High barrier to resistance Low pill burden and orally bioavailable 2

Ultimate Goal For HCV Therapy ne size fits all nce a day oral Rx - Easier for doctors & patients Pan-genotypic No clinical resistance No response guided therapy Short duration 12 weeks or less Safe with no or manageable side effects High cure rates - Lowers cost to healthcare Suitable for all populations at low cost

Analysis of Treatment Costs of HCV Infections 60,000 40.0 Cumulative Cost of Non-Trmt ($Ms) 50,000 40,000 30,000 20,000 10,000 Cost of Non-Treatment Average Per Patient Cost 35.0 30.0 25.0 20.0 15.0 10.0 5.0 Average Per Patient Cost ($000s) - 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021-4 Source: UBS research, Milliman 2009 report

HCV Therapies: Changing Landscape Advances for Unmet Medical Needs The times, they are a-changin The times, they have changed Bob Dylan

Market Will See An Influx of New Drugs ver the Next Few Years QD BID TID ABT- 450 Asunaprevir Telaprevir = Nucleos(t)ide Polymerase Inhibitor ACH- 1625 Danoprevir Boceprevir = NS5a Inhibitor BI 201335 GS- 9256 = Protease Inhibitor TMC435 Vaniprevir = Non- nucleos(t)ide Polymerase Inhibitor MK- 5172 ABT- 333 Narlaprevir Filibuvir GS- 7977 BI 207127 VX- 135 BMS 791325 VRTX s Incivek & MRK s Victrelis approved Following GS- 7977 data, Patients warehousing themselves GILD s sofosbuvir (GS- 7977) likely approved for all genotypes BMY s daclatasvir, JNJ s TMC- 435 likely approved IDX184 Setrobuvir GILD s single- pill combo (GS- 7977+5885) likely approved Daclatasvir GS- 5885 ABT- 267 Tegobuvir VX- 222 ABT- 072 ABT s all- oral DAA combination likely approved Bristol s all- oral DAA triple combination likely approved ther all- oral possible approvals: ACHN (PI/NS5a) VRTX (VX- 135) IDIX (nuc/ns5a) 6 2011 2012 2013 2014 2015 2016 2017 2018 2019 ACH- 3102 Mericitabine Source: UBS research

Market Time Lines: Shaping the Future VRTX s Incivek & MRK s Victrelis approved Following GS- 7977 data, Patients warehousing themselves GILD s sofosbuvir (GS- 7977) likely approved for all genotypes BMY s daclatasvir, JNJ s TMC- 435 likely approved GILD s single- pill combo (GS- 7977+5885) likely approved ABT s all- oral DAA combination likely approved Bristol s all- oral DAA triple combination likely approved ther all- oral possible approvals: ACHN (PI/NS5a) VRTX (VX- 135) IDIX (nuc/ns5a) 2011 2012 2013 2014 2015 2016 2017 2018 2019 Source: UBS research

Changing Nucleoside Landscape for HCV DAPD-PD1 (A/G-like) DAPN-PD2 (A/G-like) (RFSP) Preclinical RS-27 (U/C-like) RS-28 (U/C-like) (RFSP) Preclinical RG7128 (C & U) (Roche/PSI) Phase 2b In development n hold with FDA Development status unknown Development discontinued GS-7977 (U-like) (Gilead/PSI) Phase 3 IDX184 (G) & IDX-19368 (G) (Idenix) Phase 2b Clinical hold/abandoned ALS-2200 (U) (Vertex/Alios) Phase 2a IDX20963 (U) (Idenix) Preclinical hold BCX-5191 (Biocryst) Preclnical RG7348 (Roche-Ligand) Phase I stopped R1626 (C) (Roche) Safety issues RG7432 (Roche) Phase I stopped MK-0608 (A) (Merck) Preclinical TMC649128 (Medivir) Insufficient activity PSI-661 (G) (Gilead/PSI) Preclinical GS-6620 (Gilead) Phase 1 Suboptimal PK/ activity NM-283 (C) (Idenix) GI toxicity PSI-938 (G) (Gilead/PSI) Phase 1 Liver toxicity ALS-2158 (Vertex/Alios) Phase 1 INX-189 (G) (BMS/Inhibitex) Phase 2a Cardiotoxicity 8

Drug Discovery Algorithm for Nucs For HIV, HBV and HCV: Fail fast - Fail cheap Reducing the risk - the path of least resistance Cytotoxicity Spectrum Different Cell Lines Mitochondria Bone Marrow Design & Synthesis Cell-based Testing HITS (Activity/Toxicity) Kin & pol Enzyme (Mechanism) Antiviral Spectrum NIH Test (confirm) Intracellular Pharmacology Toxicology & Stability Compound Scale-up Pharmacokinetics in rats/monkeys/dogs Efficacy in small animal model (Combo) Clinical Candidate

PSI-6130 is metabolized to two active NTP of HCV Polymerase Murakami, Schinazi et al, AAC: 51, 503-9, 2007

Activity of Diastereomericaly Pure Nucleotide Phosphoramidates H 3 C CH 3 CH 3 N H P Rp H F NH N CH3 H 3 C CH 3 CH 3 N H P Sp H F NH N CH3 PSI- 7976 HCV 1b replicon: EC 90 = 7.5 µm (WT); > 100 µm (S282T); 1.3 µm (S96T) PSI- 7977 (Sofosbuvir) HCV 1b replicon: EC 90 = 0.42 µm (WT); 7.8 µm (S282T); 0.11 µm (S96T) 11

Diastereomericaly Pure Nucleotide Phosphoramidates for HCV * H 3 C CH 3 CH 3 N H P H F N NH CH3 PSI-7977 Sp isomer HCV 1b replicon: EC 90 = 0.42 µm (WT), 7.8 µm (S282T mutant), 0.11 µm (S96T mutant). In a 28 day Phase IIa clinical study of genotype 1 treatment-naïve HCV patients dosed in combination with peg IFN/RBV at 100 mg, 200 mg, and 400 mg: RVR rates of 88%, 94%, and 93% respectively. 14 day monotherapy of genotype 1 treatment-naïve HCV patients showed an average of -5.0 log 10 decline in viral load with 88% of patients reaching undetectability (<15 IU/mL) after 14 days. * Summarized in part from: 1) J rg Chem. 2011 Sep 14. [Epub ahead of print], Synthesis of Diastereomerically Pure Nucleotide Phosphoramidates. Ross BS, Reddy PG, Zhang HR, Rachakonda S, Sofia MJ.; 2) J. Med. Chem. 2010, 53, 7202-7218, Discovery of a β-d-2-deoxy-2-α-fluoro-2-β-c-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus. Sofia MJ, Bao D., Chang W, et al. and Antivir. Chem. Chemoth. 2011, 22, 23-49, Nucleotide prodrugs for HCV therapy. Sofia MJ.

Sofosbuvir (NS5B) + GS 5885 (NS5A) + RBV HCV RNA < 15 UI/mL Treatment-naïve (n = 25) SF + RBV Null responder (n = 10) SF + GS-5885 + RBV Treatment-naïve (n = 25) Null responder (n = 9) Week 1 8/25 (32) 1/10 (10) 11/25 (44) 0/9 (0) Week 2 17/25 (68) 7/10 (70) 22/25 (88) 4/9 (44) Week 4 25/25 (100) 10/10 (100) 25/25 (100) 8/9 (89) ET 25/25 (100) 10/10 (100) 25/25 (100) 9/9 (100) SVR4 22/25 (88) 1/10 (10) 25/25 (100) 9/9 (100) SVR12 21/25 (84) 1/10 (10) 25/25 (100) 9/9 (100) Gane et al. AASLD 2012 Press Release, 7 January 2013, gilead.com,

ngoing IFN-free trials Faldaprevir + BI- 207127 (Deleobuvir - Boehringer- Ingelheim) ABT- 450/r + ABT- 333 ± ABT- 267 ± RBV (AbbVie) 5D Sofosbuvir + GS- 5885 ± RBV (Gilead) Sofosbuvir + GS- 5885 + RBV (Gilead) (G2 and G3) Asunaprevir + daclastavir + BMS- 791325 (BMS)

Inter/Intra-Company Combinations Good Example: Two Molecules QD (Truvada-like for HCV) GILD/PSI Sofosbuvir nuc (GS-7977; 400 mg QD) Gilead NS5A inhibitors (GILD-5885 or 5816; 25-100 mg QD) BI-201335 PI or TMC-435 PI (120 mg or 75 mg QD) Bristol Myers Squibb NS5A inhibitor (BMS-790052; Daclatasvir 20 mg QD) AASLD 2012: 7977+5885+ Riba = 100% SVR4

The Game is not over v Assuming Sofosbuvir (PSI/GS-7977) is approved by Q4 2013; new IND are behind by < 3 years. v Gilead may be able to treat at most half a million people per year. With only 1.5 2 MM people treated over 3 yrs, there is still majority of the world and US market available. v > 60 MM people who can pay will be available for treatment v No pan-genotypic regimen has advanced to Phase 3. No effective combo for cirrhotic yet 16

There are still other opportunity: Shift in focus to difficult to treat persons Several unmet needs remain: DAA/PR failures DNE Null-responders DNE Co-infected with HIV or HBV ALMST DNE non-gt1, especially GT3 DNE IFN intolerant or contraindicated - DNE Cirrhosis Bleeding disorders (hemolysis) Pediatrics & transplant subjects piate substitution therapy Too few Tx persons to come to any definitive conclusion Real World Adapted from A. Kwang

Three Waves of DAA Treatments with Sofosbuvir Leading to Cure Tsunamis Sofosbuvir as a single DAA plus Riba Sofosbuvir/NS5a or PI for genotype 1 Final regimen, short in duration, one size fits all that is pangenotypic and SVR rates > 90% in the real world (nuc as backbone + PI/NS5a or two nucs or perhaps one v potent nuc).

Novel Multi-metabolite Prodrug Approach for HCV Inhibition ne prodrug provides two active metabolites that are incorporated by HCV polymerase as G- and A-like NTP analogs. DAPN TP DAPN-PD1 or DAPN-PD2 2 -C-Me-G Inhibition of NS5B and Chain Termination! TP Increased potency Reduced resistance Pan-genotypic activity Prodrug metabolite not toxic (food additive & coloring agent) Schinazi et al., Patent W 2012/158811 19

Pan-Genotypic Activity (EC 50, µm) of DAPN-PD1 Versus Wild-Type/Mutant HCV Strains gt5a (chimera) gt4a (chimera) gt3a (chimera) gt2b (chimera) gt2a gt1b P495A gt1b M414I gt1b C316Y:C445F gt1b C316Y gt1b S282T gt1b NS3 R155K gt1b gt1a NS5a Y93H gt1a 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 Excellent activity across 14 strains with EC 50 ranging from 0.08-0.39 µm. 20

Addressing Toxicity BMS acquired Inhibitex in 2012 INX- 189 (BMS- 986094) Me Me N N HN P N N NH 2 CH 3 H H 2 - C- methyl- GTP Phase II clinical: 9 pauents suffered heart and kidney toxicity Trial halted aoer pauent death Potential sources of toxicity: Prodrug group, byproducts, metabolites or drug as a whole (too much NTP formed in wrong compartment) 21

Assessment of DAPN Prodrug Cytotoxicity Cytotoxicity with various cell types and assays Cytotoxicity, CC 50 (µm) MTS, Huh- 7 > 100 1 human lymphocytes > 100 CEM > 100 Vero > 100 PC3 (human prostate cancer cell line) > 100 GADPH > 100 Thymidine uptake > 100 The effect of prodrug group choice on potency and toxicity Compound Base EC 50, µm Huh-7 CC 50, µm DAPN Prodrug 1 G/A-like 0.26 > 10 DAPN Prodrug 2 G/A-like 0.9 > 10 INX-189 G-like 0.006 0.8 22

Mitochondrial Toxicity with DAPN Prodrugs CC 50 (µm) in HepG2 cells LacUc acid levels (% of ß- acun- control) + SD mtdna ß- acun DNA 1 µm 10 µm 50 µm DAPN Prodrug 1 DAPN Prodrug 2 > 50 > 50 43 + 3.2 56 + 6.5 90 + 14 > 100 > 100 90 + 5.1 81 + 0.1 80 + 3.0 Parent > 50 > 50 100 + 13 140 + 2.0 90 + 4.5 INX- 189 3.4 < 1 190 + 20 ND ND 3TC > 10 > 10 ND 91 + 2.5 ND ddc < 10 < 10 ND 220 + 11 ND No mitochondrial toxicity was observed for DAPN prodrugs Although both compounds share the same active metabolite, the choice of prodrug can impact both potency and cytotoxicity 23

Conclusions DAPN prodrugs represent new investigational compounds against HCV Potent and non-toxic in several cell culture systems Novel prodrug produced non-toxic metabolite (food additive) No mitochondrial toxicity or lactic acid increase (below 100) Choice of prodrug reduces cytotoxicity when compared to INX-189 Two active metabolites were observed intracellularly: Prodrug group may modulate ratio of active metabolites 2 -C-methyl-GTP metabolite acts as a G analog DAPN-TP metabolite acts as an A analog Combined delivery of nucleotide analogs with different viral RNA incorporation profiles may be synergistic and prevent selection of mutant viruses Advanced toxicological studies with a DAPN prodrug is proceeding towards an IND in 1Q2014 24

DAPN-PD Additional Highlights v DAPN-PDs exhibit prolonged stability in gut (SGF) and intestine (SIF) similar to GS-7977. v In human microsomes, DAPN-PD rapidly metabolized suggesting high liver exposure. v DAPN-PD2 is a more lipophilic and more metabolically stable follow-up prodrug of DAPN-PD1. It has similar potency to DAPN-PD1 in the HCV 1b replicon assay with no toxicity in Huh-7, CEM, human PBM, or Vero cells. v The phosphorous diastereomers of DAPN-PD2 are equipotent in vitro; thus, no need to separate diastereomers resulting in >significant cost savings in manufacturing. v 1 kg of non-gmp DAPN-PD1 and DAPN-PD2 parent nucleoside prepared (97.4% pure). v Extensive exploration of nucleoside prodrugs and unique IP portfolio.

.The US and EU are nly ~15% (11 MM) of the Total Worldwide HCV Population (170 MM) 170MM People HCV Infected Worldwide Source: Pharmasset/Idenix Investor Relations Slide Deck. 26

Egypt s Burden: HCV prevalence is nearly 5x greater in Egypt than many other countries Source: Yahia M. A uniquely EgypUan epidemic. Nature 2011; 474: S12- S13. 27

Never forget the need for assistance to the Developing World Before After HCV shows no visible scars like HIV that inspire the public to advocate solutions 28

Near future with effective oral agents Who to screen? Who to treat first? Modifird: piceh.org

What is a life worth: Sticker shock New drugs for cancer and rare diseases come with big price tags HCV causes cancer! DRUG Gattex a Kalydeco a Juxtapid a Elelyso a Iclusig a,b Zaltrap b Cometriq a,b Kyprolis b Stivarga a,b Inlyta b Bosulif a,b Erivedge b Xtandi b a Drug for orphan disease CST $295,000/year $294,000/year $200,000-$300,000/year $150,000/year $115,000/year $11,000/month $9,900/month $9,550/month $9,350/month ~$8,900/month $8,200/month $7,500/month $7,450/month b Cancer treatment SURCE: Chemical & Engineering News, February 4, 2013

The ultimate benefit of cures for HCV will not be measured by the costs they avoid, but by the lives they save Supported by NIH, CFAR, and the Department of Veterans Affairs CI: I am a founder & shareholder of Idenix & RFS Pharma LLC