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 [email protected] Introducon: Hepas 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: + peg-INF-α + Protease Inhibitors – Treatment complicated – coinfecon even more complicated – Side effects, subopmal efficacy, genotype-dependent, injectable

• Oral, direct acng anvirals (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 One size fits all

♦ Once 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

60,000 40.0 Cost of Non-Treatment 35.0 50,000 Average Per Patient Cost 30.0 40,000 25.0

30,000 20.0

15.0 20,000 10.0

10,000 Average Per Patient Cost ($000s) Cumulative Cost of Non-Trmt ($Ms) 5.0

- - 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’”

Bob Dylan

“The times, they have changed’”

Market Will See An Influx of New Drugs Over the Next Few Years

QD BID TID

ABT-450 = Nucleos(t)ide Polymerase Inhibitor

ACH-1625 = NS5a Inhibitor

BI 201335 GS-9256 = Protease Inhibitor

TMC435 = Non-nucleos(t)ide Polymerase Inhibitor

MK-5172 ABT-333

Narlaprevir VRTX’s Incivek & MRK’s Victrelis approved Following GS-7977 data, “ Patients warehousing themselves” GS-7977 BI 207127 GILD’s (GS-7977) likely approved for all genotypes

VX-135 BMS 791325 BMY’s , JNJ’s TMC-435 likely approved

GILD’s single-pill combo (GS-7977+5885) IDX184 likely approved

Daclatasvir Tegobuvir ABT’s all-oral DAA combination Other all-oral likely approved possible approvals: ACHN (PI/NS5a) GS-5885 VX-222 Bristol’s all-oral DAA triple VRTX (VX-135) combination likely approved IDIX (nuc/NS5a) ABT-267 ABT-072

ACH-3102 Mericitabine 2011 2012 2013 2014 2015 2016 2017 2018 2019

6 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 Other all-oral likely approved possible approvals: ACHN (PI/NS5a) Bristol’s all-oral DAA triple VRTX (VX-135) combination likely approved IDIX (nuc/NS5a)

2011 2012 2013 2014 2015 2016 2017 2018 2019

Source: UBS research Changing Nucleoside Landscape for HCV

RS-27 (U/C-like) RS-28 (U/C-like) In development (RFSP) DAPD-PD1 (A/G-like) Preclinical On hold with FDA DAPN-PD2 (A/G-like) (RFSP) Development status unknown Preclinical RG7128 (C & U) (Roche/PSI) Development discontinued Phase 2b

GS-7977 (U-like) IDX184 (G) & IDX-19368 (Gilead/PSI) (G) (Idenix) Phase 3 Phase 2b Clinical hold/abandoned

ALS-2200 (U) IDX20963 (U) (Vertex/Alios) (Idenix) Phase 2a Preclinical hold

BCX-5191 (Biocryst) Preclnical PSI-661 (G) RG7348 NM-283 (C) ALS-2158 (Gilead/PSI) (Roche-Ligand) (Idenix) (Vertex/Alios) Preclinical Phase I stopped GI toxicity Phase 1 GS-6620 PSI-938 (G) INX-189 (G) RG7432 TMC649128 (Gilead) R1626 (C) MK-0608 (A) (Gilead/PSI) (BMS/Inhibitex) (Roche) (Medivir) Phase 1 (Roche) (Merck) Phase 1 Phase 2a Safety issues Phase I stopped Preclinical Insufficient activity Suboptimal PK/ activity Liver toxicity Cardiotoxicity 8 Drug Discovery Algorithm for Nucs For HIV, HBV and HCV: Fail fast - Fail cheap

Reducing the risk - the path of least Design & Synthesis resistance Kin & pol Cell-based Testing Enzyme (Mechanism) Cytotoxicity Spectrum HITS Antiviral Spectrum Different Cell Lines Mitochondria (Activity/Toxicity) NIH Test (confirm) Bone Marrow

Intracellular Pharmacology Toxicology & Stability

Compound Pharmacokinetics in rats/monkeys/dogs Scale-up

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

O O CH CH3 3 O NH O NH H C O H3C O 3 N P O N P O N O N O H Sp H Rp CH3 O O CH3 O O O O CH3 CH3 HO F HO F

PSI-7976 PSI-7977 (Sofosbuvir)

HCV 1b replicon: EC90 = 7.5 µM (WT); HCV 1b replicon: EC90 = 0.42 µM (WT); > 100 µM (S282T); 1.3 µM (S96T) 7.8 µM (S282T); 0.11 µM (S96T) 11 Diastereomericaly Pure Nucleotide Phosphoramidates for HCV* O CH 3 O NH H C O 3 N P O H N O PSI-7977 CH3 O O O CH3 Sp isomer HO F

HCV 1b replicon: EC90 = 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 log10 decline in viral load with 88% of patients reaching undetectability (<15 IU/mL) after 14 days. • *Summarized in part from: 1) J Org 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 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

SOF + RBV SOF + GS-5885 + RBV HCV RNA < 15 UI/mL Treatment-naïve Null responder Treatment-naïve Null responder (n = 25) (n = 10) (n = 25) (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)

EOT 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, Ongoing IFN-free trials

§ + BI-207127 ( - 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 Gilead Sofosbuvir nuc NS5A inhibitors (GS-7977; 400 mg QD) (GILD-5885 or 5816; 25-100 mg QD)

Bristol Myers Squibb BI-201335 PI or NS5A inhibitor TMC-435 PI (BMS-790052; Daclatasvir (120 mg or 75 mg QD) 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 – DONE • Null-responders – DONE • Co-infected with HIV or HBV – ALMOST DONE • non-GT1, especially GT3 – DONE • IFN intolerant or contraindicated - DONE • Cirrhosis • Bleeding disorders (hemolysis) • Pediatrics & transplant subjects • Opiate 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

One prodrug provides two active metabolites that are incorporated by HCV polymerase as G- and A-like NTP analogs.

DAPN TP

DAPN-PD1 Inhibition of • Increased potency or NS5B and Chain • Reduced resistance DAPN-PD2 Termination! • Pan-genotypic activity • Prodrug metabolite not toxic (food additive & coloring agent) 2’-C-Me-G TP

Schinazi et al., Patent WO 2012/158811 19 Pan-Genotypic Activity (EC50, 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 EC50 ranging from 0.08-0.39 µM. 20 Addressing Toxicity

BMS acquired Inhibitex in 2012

Me INX-189 (BMS-986094) O 2’-C-methyl-GTP O Me N N O N O HN P O N NH2 O O CH3 HO OH

Phase II clinical: • 9 paents suffered heart and kidney toxicity • Trial halted aer paent 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 The effect of prodrug group choice on potency cell types and assays and toxicity

Cytotoxicity, CC (µM) Huh-7 50 EC , Compound Base 50 CC , µM 50 MTS, Huh-7 > 100 µM 1° human > 100 DAPN Prodrug 1 G/A-like 0.26 > 10 lymphocytes CEM > 100 DAPN Prodrug 2 G/A-like 0.9 > 10

Vero > 100 INX-189 G-like 0.006 0.8 PC3 (human prostate > 100 cancer cell line) GADPH > 100 Thymidine uptake > 100

22 Mitochondrial Toxicity with DAPN Prodrugs

CC50 (µM) in HepG2 cells Lacc acid levels (% of ß-acn-control) + SD

mtDNA ß-acn DNA 1 µM 10 µM 50 µM DAPN > 50 > 50 43 + 3.2 56 + 6.5 90 + 14 Prodrug 1 DAPN > 100 > 100 90 + 5.1 81 + 0.1 80 + 3.0 Prodrug 2

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 Although both compounds share the same toxicity was observed active metabolite, the choice of prodrug for DAPN prodrugs 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 Only ~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 Egypan 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 COST Gattexa $295,000/year Kalydecoa $294,000/year Juxtapida $200,000-$300,000/year Elelysoa $150,000/year Iclusiga,b $115,000/year Zaltrapb $11,000/month Cometriqa,b $9,900/month Kyprolisb $9,550/month Stivargaa,b $9,350/month Inlytab ~$8,900/month Bosulifa,b $8,200/month Erivedgeb $7,500/month Xtandib $7,450/month a Drug for orphan disease b Cancer treatment

SOURCE: 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 COI: I am a founder & shareholder of Idenix & RFS Pharma LLC