HCV Pipeline: The Next 18 Months Michael W. Fried, MD

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1 HCV Pipeline: The Next 18 Months Michael W. Fried, MD Professor of Medicine Director, UNC Liver Center University of North Carolina at Chapel Hill

2 Michael W. Fried, MD Commercial Disclosures Grants/Research Support Genentech, Merck, Vertex, Janssen, Bristol-Myers Squibb, Anadys, Abbott, Gilead Consultant: Genentech, Janssen, Vertex, Merck, Novartis, Abbott, Janssen, Gilead, Idenix Stock/Shareholder: None Speakers Bureau: None Other Financial Support: NIH Grants

3 Great Bridges of the World

4 Triple Therapy is a Bridge to All Oral Regimens Why is/was the Triple Therapy Bridge important? Provided highly effective first generation regimens Provided info about toxicity of DAAs against the known background of PEG/RBV AE profile Provided clinical information about viral resistance and clues about potentially effective oral combinations Provided a safety net for testing new DAAs in POC studies Taught us what to aspire for in next generation therapies

5 Walking, Before You Can Run QUAD Regimens Protease Inhibitor NS5A Inhibitor QUAD Regimens PEG-± + RBV QUAD Regimens Nucleotide Polymerase Inhibitor Non-Nuc Polymerase Inhibitor All-Oral Regimens PEG-lambda + RBV + NS5A Inhibitor

6 HCV Treatment Regimens by 2015 Estimated U.S. Approval Geno Regimen Population Studied in Phase III 4Q P/R + Simeprevir Naïve/Relapsers 4Q P/R + Sofosbuvir Naive Off Label 1 Simeprevir + Sofosbuvir Only phase II data Unknown 1 P/R + Faldeprevir Naïve and treatment experienced 4Q Sofosbuvir/Ledipasvir/RBV Naïve and treatment experienced 4Q and 3 Sofosbuvir + RBV Naïve and treatment experienced 4Q Q ABT450/r + ABT333+ ABT RBV Naïve and treatment experienced 4Q Asunaprevir+ Daclatasvir + NNI Naive Unknown All Peg-Lambda, MK-5172 (PI), VX135 (Nuc) Multiple other potential combinations and classes Ongoing

7 Simeprevir (TMC435) + PEG/RBV: Phase III QUEST-1/QUEST-2: Treatment-naïve, Genotype 1 Q1: n=264 Q2: n=257 TMC mg + PEG/RBV PEG/RBV RGT No? PEG + RBV RGT Yes? Post-Treatment F/U Q1: n=130 Q2: n=134 Placebo + PEG/RBV PEG/RBV RGT* Week QUEST-1: 30% F3-F4 QUEST-2: 22% F3-F4 RGT duration in TMC435 arms; End treatment at Week 24, if HCV RNA <25 IU/mL detectable/undetectable at W4 and <25 IU/mL undetectable at W12 (all others continued PegIFN/RBV up to 48 W) Jacobson et al. EASL 2013; Manns et al. EASL 2013

8 Simeprevir (TMC435) + PEG/RBV: Phase III QUEST-1 and QUEST-2: Treatment-naïve, Genotype 1 100% 80% % SVR12 60% 40% 20% 85% Met RGT TMC435 PEG/RBV 91% 80% 81% n=394 n=391 50% 50% 0% QUEST-1 QUEST-2 85%-93% qualified for shorter duration of therapy AEs, including rash and anemia, similar to placebo and c/w phase II studies Mild and reversible increase in bilirubin with TMC435 Lower response rates in cirrhosis, genotype 1a (Q80K) Jacobson et al. EASL 2013; Manns et al. EASL 2013

9 Simeprevir (TMC435) + PEG/RBV: Phase III QUEST-1: Impact of Subtype and Fibrosis Stage TMC435 PEG/RBV F0-F2 F3 F4 100% 80% 60% 40% 20% 0% 90% 71% 49% 52% Geno 1a Geno 1b 100% 80% 60% 40% 20% 0% 83% 78% 58% TMC435 60% 26% 29% PEG/RBV SVR: G1b > G1a SVR: F0-2 > F4 Jacobson et al. EASL 2013;

10 Simeprevir (TMC435) + PEG/RBV: Phase III QUEST-1: Differences in SVR12 Between Treatment Groups

11 Sofosbuvir + PEG + RBV: Phase III NEUTRINO Study (Geno 1,4,5,6) Phase III registration trial Regimen: SOF 400mg/d + PEG 180mics/wk +RBV mg/d for 12 weeks Predefined historical control = 60% as comparator Participant characteristics (n=327): Geno 1: 89% (n=292) Cirrhosis: 17% (n=56) AE in >20%: Fatigue, Nausea, Headache, Insomnia, Dizziness 5 premature discontinuations due to AE Press release, Gilead Feb 2013

12 Sofosbuvir + PEG + RBV: Phase III NEUTRINO Study (Geno 1,4,5,6) 100% 80% 100% 90% Sofosbuvir + P/R x 12 wks 89% 97% 80% 60% 40% 20% 10% 0% EOT ITT SVR12 Relapse Geno 1 Geno 4,5,6 Cirrhosis n=327 n= Lawitz et al NEJM 2013

13 Unexpected Path to All-Oral Regimen (Off-Label) PEG RBV Sofosbuvir (NUC) RBV PEG RBV Simeprevir (PI)

14 Sofosbuvir + Simeprevir +/-RBV Interim Analysis: COSMOS Genotype 1, Prior null responders, F0-F2 0nly Simeprevir 150 mg QD + Sofosbuvir 400 mg QD + RBV x12 weeks (n = 27) SVR4 SVR8 96 (26/27) 96 (26/27) Simeprevir 150 mg QD + Sofosbuvir 400 mg QD x12 weeks (n = 14) 93 (13/14) 93 (13/14) Lawitz E, et al. CROI Weeks 12 No anemia in dual therapy arm (11% with RBV) No grade 3/4 AE or treatment discontinuations

15 Sofosbuvir + RBV: Phase III POSITRON Study (Geno 2,3) 100% 100% Sofosbuvir + RBV x 12 wks 93% 80% 78% 60% 61% 61% 40% 20% 0% EOT ITT SVR12 Geno 2 Geno 3 Cirrhosis *All treatment-naïve, IFN-ineligible G3 Cirrhosis = 21% (3/14) G3 Non-cirrhosis= 68% (57/84) SOF 400mg qd + RBV mg/d x 12 weeks Jacobson et al, EASL 2013

16 Sofosbuvir + RBV vs PEG + RBV in Genotype 2,3: Phase III (FISSION) SOF + RBV Peg-IFN + RBV SVR12 (%) /59 44/54 10/11 8/13 89/145 99/139 13/38 11/37 No cirrhosis Cirrhosis No cirrhosis Cirrhosis *All treatment-naïve, GT 2 GT 3 SOF 400mg qd + RBV mg/d x 12 weeks vs PEG + RBV x 24 weeks

17 Sofosbuvir + RBV in Genotype 2,3 12 wks vs 16 weeks: FUSION SOF + RBV 12 weeks SOF + RBV 16 weeks SVR12 (%) /26 23/23 6/10 7/9 14/38 25/40 5/26 14/23 No cirrhosis Cirrhosis 0 No cirrhosis Cirrhosis GT 2 GT 3 Nelson et al, EASL 2013

18 Sofosbuvir (NI) + Ledipasvir (NS5A) + RBV Genotype 1 HCV: ELECTRON Interim analysis of nonrandomized phase II ELECTRON study SVR12 outcomes with sofosbuvir + RBV previously reported No serious AEs related to study drugs AE profile consistent with RBV toxicity profile Wk 12 SVR12, % (n/n) Treatment naïve (n = 25) Null responders (n = 10) Treatment naïve (n = 25) Null responders (n = 10) Sofosbuvir + RBV Sofosbuvir + RBV Sofosbuvir + Ledipasvir + RBV Sofosbuvir + Ledipasvir + RBV 84 (21/25) 10 (1/10) 100 (25/25) 100 (9/9) 1. Gane E, et al. CROI Abstract 41LB. 2. Gane EJ, et al. AASLD Abstract 229

19 AVIATOR Study: ABT-450/r, ABT-267 (NS5A), ABT-333 (NNI) +/- RBV in Non-cirrhotic, Naïve and Null Responders No. Patients SVR 12 % SVR 24 * % VBT/Relapse / / / / / / / / / 0 Kowdley et al.easl patients relapsed between SVR 12 and SVR 24.

20 AVIATOR Study: Grade 3 or Grade 4 Laboratory Abnormalities (12- and 24-week Arms of 3 DAA + RBV) Grade 3 event, n Pooled (N =247) 3 DAAs + RBV Treatment-Naïve (N =159) Null Responders (N = 88) ALT >5x 20x ULN AST >5x 20x ULN Alkaline Phosphatase >3x 20x ULN Total bilirubin > 3x 10xULN Hemoglobin < g/dl Grade 4 event, n ALT > 20x ULN AST > 20x ULN Alkaline Phosphatase > 20x ULN Total bilirubin > 10x ULN Hemoglobin < 6.5 g/dl Kowdley KV, et al. Presented at: EASL: The International Liver Congress Note: Value must also be more extreme than the baseline value

21 AVIATOR Study: Most Common Adverse Events with the12- and 24-week arms of 3 DAA + RBV The majority of adverse events were mild 3 DAAs + RBV Event, % Total (N =247) Treatment-Naïve (N =159) Null Responders (N = 88) Headache Fatigue Nausea Insomnia Diarrhea

22 Faldaprevir (PI) + PEG/RBV Treatment Naïve, GT SVR12 (%) / / /261 Placebo FDV 120 mg FDV 240 mg Enrollment in Europe and Japan FDV + PR x 12 weeks + PR x 12 weeks by RGT FDV 120mg: SVR G1b=84% vs G1a=69% Ferenci et al, EASL 2013

23 Phase IIb COMMAND Study: Daclatasvir (NS5A) + PegIFN/RBV in Treatmentnaive GT1 or GT4 12 Wks DCV + P/R, then those with protocol-defined response rerandomized to triple therapy through Wk 24 or placebo + P/R through Wk 24 SVR12, % DCV 20 mg QD + P/R DCV 60 mg + P/R Placebo + P/R 20 n/n = 95/ / 26/ / / / 56 GT 1 GT 1a GT 1b GT 4 32/ 41 27/ 31 5/ 16 8/ 12 12/ 12 3/ 6 Hezode C, et al. AASLD 2012.

24 DCV + SOF in Telaprevir or Bocepevir / PR Failures: Virologic Response HCV RNA < LLOQ (% patients) N = * Week 2 Week 4 EOT SVR 4 SVR 12 DCV + SOF DCV + SOF + RBV Missing 41 adult HCV GT1-infected patients who had virologic non-response during prior treatment with TVR or BOC + PEG-IFN/RBV (PR) were treated with: Daclatasvir (DCV): 60 mg QD NS5A replication complex inhibitor Sofosbuvir (SOF): 400 mg QD NS5B nucleotide inhibitor with or without RBV for 24 weeks of therapy Demographics: 1a (83%), IL28b non-cc (98%), Non-cirrhotic (100%) Sulkowski et al, EASL 2013

25 PEG-Lambda + RBV + Daclatasvir or Asunaprevir* 100% 80% 60% 90% 84% 91% 91% 73% 73% 76% 75% L/R/DCV L/R/ASV 40% 20% 0% PDR RVR* ervr* SVR12* PEG-Lambda 180 mics/week + RBV weight-based + DCV 60mg/d or ASV 200mg/bid x24wks PDR (Protocol Defined Response): HCV RNA <LLOQ at Wk 4 and <LLOD at Wk 12; ~90% G1 patients treated with lambda/rbv + DCV or ASV achieved PDR and qualified for shortened duration (24 wk) Reduced efficacy in G1a vs 1b, DCV = 65% vs 93%; ASV 67% vs 91% Less hematologic toxicity than PEG-2a ALT and bilirubin elevations (6%) in ASV arm Vierling et al. AASLD 2012, Boston, #LB-9

26 MK-5172 (PI) + P/R x 24 Weeks for Genotype 1, Treatment Naive Patients (%) Dose finding study, RGT criteria (n=136) MK5172 +P/R x 12 wks + P/R x 12 wks: if HCV RNA TND at week 4 High rates of RVR and SVR MK-5172 doses >200mg associated with hepatotoxicity TND RVR TD (<LOD) Patients (%) SVR N= MK 100 mg + PR MK 200 mg + PR MK 400 mg + PR Marcellin P, et al. AASLD 2012 MK 800 mg + PR BOC + PR RGT 20 N= MK 100 mg + PR MK 200 mg + PR MK 400 mg + PR MK 800 mg + PR BOC + PR RGT

27 Everson GT, et al. Presented at: EASL: The International Liver Congress 2013; April 24-28, 2013; Amsterdam, The Netherlands. Abstract IFN- and RBV-free: Daclatasvir (DCV), Asunaprevir (ASV), and BMS Phase 2 randomized study, treatment-naïve, HCV GT1, non-cirrhotic patients (N=32) SVR > 90%: Similar with either 12 or 24 weeks of treatment and with 75 mg or 150mg dose of BMS

28 ALS-2200 (VX-135) in Treatmentnaïve G1-4 with Cirrhosis Median Change From Baseline After 7 Days of Treatment (Log10 IU/mL) Genotype 1, 3, 4 Genotype 1 Genotype 3, Genotype 1, Cirrhotic Placebo ALS mg ALS mg + RBV ALS-2200, nucleotide HCV polymerase inhibitor Phase 1, viral kinetic study, N=44 Marcellin P, et al. Presented at: EASL: The International Liver Congress

29 So What Will the Next 6-12 Months Look Like? Over the next 6-9 months for GT 1: PEG + RBV + Simeprevir PEG + RBV + Sofosbuvir Over the next 6-9 months for GT 2,3 Sofosbuvir + RBV Genotype 2- highly effective Genotype 3/ G3 cirrhosis suboptimal response (?add PEG) Off label combination of available DAA classes Simeprevir + Sofosbuvir + RBV for GT1

30 HCV Pipeline: The Next 18 Months Highly effective regimens will shorten treatment duration Cirrhosis and genotypes 1a and 3 are more difficult to treat and represent the stress test for new agents Ribavirin may still be important in all-oral regimens DAAs effective in P/R combination have a high chance of success when combined with other DAA classes in all-oral regimens Complete transition to all-oral regimens by Q PEG/RBV backbone may still be needed in QUAD regimens for difficult to cure populations