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] 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 • Oral, 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 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 Infections 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 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 VRTX’s Incivek & MRK’s Victrelis approved Following GS-7977 data, “ Patients warehousing themselves” GS-7977 BI 207127 GILD’s sofosbuvir (GS-7977) likely approved for all genotypes VX-135 BMS 791325 BMY’s daclatasvir, JNJ’s TMC-435 likely approved GILD’s single-pill combo (GS-7977+5885) IDX184 Setrobuvir 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 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 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 § 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 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.