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Best in Class Agents for Global HCV Eradication

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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 [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.
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