EASL and The Future of HCV Treatment

Transcription

1 EASL and The Future of HCV Treatment Douglas T. Dieterich, M.D Professor of Medicine Division of Liver Diseases, Gastroenterology and Infectious Diseases Department of Medicine Mount Sinai School of Medicine New York, New York P-1

2 Case Discussions Miles 64y/o successful garment executive with HCV for >30 years Treated with IFN TIW and RBV :partial responder in 1990 s Declined therapy with Peg in 2001 Cirrhosis and HCC 2005 : RFA successful Declined therapy in 2005 (DAA s coming) Declined therapy with DAA in 2011 (IFN Free) 2013 HCC in portal vein now getting palliative Y90 and sorafenib

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4 DAAs as Components of New Treatment Paradigm for Hepatitis C Peg-IFN + RBV (SOC) IFN-based 1 DAA + SOC 2 DAAs + SOC Prospect of shorter treatment duration for a greater proportion of patients IFN-free? IFN-free? ~ Time DAA=direct-acting antiviral; SOC=standard of care (Peg-IFN + RBV)

5 Evolving Treatment Landscape of Direct Acting Anti- Viral Agents Others NS5A inhibitor DAA combinations MSD Idenix GSK IFN lamba (BMS) Alisporivir cyclophilins AZD07259 NSSA (AZN) Presidio Enanta BMS NSSA (BMS) Vertex Gilead Vertex Roche Daclatasvir (BMS) MK5172 (MSD) GS9256 (Gilead) BMS BI Abbott Preclinical Phase I Phase II Phase III Approved ABT450/r (ABT) Protease inhibitors Boceprevir (MSD) Telaprevir (J&J/Vertex) Simeprevir (J&J/Tobizer) Faldaprivir (BI) Vaniprevir (MSD) Asunaprevir (BMS) Danoprevir Sovaprevir (Achillion) (Roche/Intermune) BI Mericitabine (Roche/Pharmasset) Sofosbuvir (Gilead) Tegobuvir (Gilead) Setrobuvir (Roche) VX222 (Vertex) BI (BI) Nuc- Polymerase inhibitors R0622 (Roche) Medivir (Tibotec) GL59393 (GSK) Biocryst BMS (nuc/non-nuc BMS)) ABT333. ABT7072 (ABT) IDX375 (Idenix/NVS) Non Nuc- Polymerase inhibitors DAA = direct-acting anti-viral agents. 5

6 The first all-oral combination therapies of NUC+NS5A and PI+non-NUC are expected to reach the market in 2013 Single agents PI NUC NS5A Non-NUC Combinations Incivek (Vertex) and Victrelis (Merck) launched in 2011 Second generation PIs MK-7009 (Merck) TMC435 (JNJ) GS7977 (Gilead) First oral NUC Second wave BI-335 (BI) BMS-032 (BMS) GS5885 (Gilead) BMS-052 (BMS) ABT-450 (Abbott) ABT-072 (Abbott) All Phase II with expected launch in 2016 ACH-1625 (Achillion) GS9256, GS9451 (Gilead) VX-135 (Vertex) BMS-393 (BMS) IDX-719 (Idenix) ABT-333 (Abbott) BI-7127 (BI) GS9190 (Gilead) RG7227 (Roche) MK-5172 (Merck) RG7128 (Roche) ABT-267 (Abbott) 6805 (GSK) BMS-325 (BMS) RG7790 (Roche) VX-222 (Vertex) 8742 (Merck) 668, 461 (Presidio) GS9669 (Gilead) Third wave ACH-2684 (Achillion) 3102, 2928 (Achillion) TMC-055 (JNJ) IDX-963 (Idenix) 239 (Novartis) IDX-437 (Idenix) 383 (BioCryst) NUC+NS5A Non-NUC+PI NUC+PI Single agent First all-oral combinations GS7977+GS5885 (NUC+NS5A, Gilead) ABT-450+ABT-072 (PI+non-NUC, Abbott) VX (Vertex, GSK) GS9256+GS9190 (Gilead) BI-335 and BI-7127 (BI) VX-135+TMC435 (Vertex, JNJ) RG7128+RG7227 (Roche) VX-135+GSK-6805 (Vertex, GSK) Idenix s combo is expected to launch in 2017 NS5A+PI+ non-nuc Combination ABT-267+ABT-450+ABT-333 (Abbott) BMS-052+BMS-032+BMS-325 (BMS) Idenix NS5A-PI combo (+/- NUC and/or non-nuc) 2013 Source: L.E.K. interviews and analysis

7 Patients achieving SVR (%) All genotypes Genotype 1 Genotype 2/ *Range of values reported; lower bar represents lower value; Weeks 78 Peg-IFN IFN + ribavirin IFN monotherapy Peg-IFN + ribavirin Peg-IFN + ribavirin + PI Fig. 2 Updated from Manns MP et al: Nature Reviews Drug Discovery, 2007

8 virions SR-BI SR-BI Blocker ITX-5061 (1) mir122 CD81 Anti mir122 agents Miravirsen (2) ribosome CLDN1 endosome OCLN Nucleus NS3/4A PI s Boceprevir (4) Telaprevir (4) Simeprevir (3) Faldaprevir (3) Asunaprevir (3) ABT-450 (3) Danoprevir (2) GS-9451 (2) MK-5172 (2) ACH-2684 (1) NS2 NS3/4A ER NS5B NS5A Lipid droplets CypA Viral RNA Cyclophilin A inhibitors Alisporivir (3/hold) SCY-635 (2) NS5A inhibitors Daclatasvir (3) GS-5885 (3) ABT-267 (3) PPI-668 (1) Polymerase inhibitors Nucleosides Sofosbuvir (3) Mericitabine (2) VX-135 (1) Non-nucleosides ABT-333 (3) BI (3) ABT-072 (2) BMS (2) GS-9669 (2) Setrobuvir (2) VX-222 (2) Fig. 3A

9 specific drugs Boceprevir Telaprevir ABT-333 ABT-450/r Other GS-5885 Other ABT-267 Other Faldaprevir Other Asunaprevir Other Daclatasvir Other Simeprevir Other Other Sofosbuvir pre non-specific drugs PEG-Alpha Ribavirin NS3/4A PI Nucleoside NS5B inhibitor NS5A inhibitor Non-Nuc NS5B inhibitor PEG-Lambda Non-specific agent Fig. 4

10 Daclatasvir (NS5A inhibitor) + Asunaprevir (PI) ± PR in null responders: phase IIa study CHC, G1, null responder to PR, no cirrhotics, N=21 Daclatasvir 60 mg qd plus Asunaprevir 600 mg bid Daclatasvir 60 mg qd + Asunaprevir 600 mg bid plus PR 0 Study weeks 24 Randomisation Null response defined as <2 log 10 decline in HCV RNA following 12 weeks of treatment with PR Lok A, et al. EASL 2011, oral

11 Virologic Response before and after treatment * NS5A+PI QUAD 20 0 RVR ervr cevr EOTR SVR 12 SVR 24 Group A: 4(2/9 GT1a and 2/2 GT1b) patients achieved SVR12 and SVR24 Group B; 10/10 achieved SVR12 and 9 had SVR24 1 patient had HCVRNA<LLQ at post treatment week 24, and undetectable 35 d later

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13 The world changed again in November 2011 in San Francisco : Electron

14 ELECTRON 100% concordance of SVR12 with SVR24 Time Wk Sofosbuvir RBV 12 weeks PEG Sofosbuvir RBV 8 weeks PEG Sofosbuvir RBV 4 weeks PEG Sofosbuvir RBV NO PEG n %<LOD n %<LOD n %<LOD n %<LOD 2 9/ /8 88 8/9 89 8/ / / / / / / / / / / / / SVR4 11/ / / / SVR8 11/ / / / SVR12 11/ / / / SVR24 6/ / / /4 100 Gane EJ, et al. 62nd AASLD; San Francisco, CA; November 4-8, Abst. 34.

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16 On Treatment Viral Suppression

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18 Once-Daily Sofosbuvir Plus Ribavirin Given for 12 or 24 Weeks in Treatment-Naïve Patients With HCV Infection: the QUANTUM Study

19 ATOMIC Study Design Day 1 Wk 12 Wk 24 Group A N = 52 SOF + PEG + RBV GT 1 Group B N = 125* SOF + PEG + RBV GT 1, 4, 6 Group C N = 155 SOF + PEG + RBV SOF (n = 75) SOF + RBV (n = 75) GT 1 Non-cirrhotic, treatment-naïve patients with HCV genotype 1 were randomized 1:2:3 into open-label arms HCV RNA analyzed by TaqMan HCV Test 2.0 (LOD: 15 IU/mL) *Of the 125 patients enrolled in Arm B, 11 were genotype 4 and five were genotype 6 Five of the 155 patients were not re-randomized at Week 12 Hassanein T, et al. 63rd AASLD; Boston, MA; November 9-13, Abst. 230.

20 Patients with HCV RNA <LOD (%) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 90% of Patients Achieved SVR12: Sofosbuvir + PEG + RBV 12-Week Regimen 94% 98% 98% 99% 97% 99% 94% 94% 93% 90% 92% 91% SOF+PEG+RBV 12 Wks Week 4 EOT SVR4 SVR12 SOF+PEG+RBV 24 Wks SOF+PEG+RBV Wks 11 patients (1 in the 12 Wk group) who achieved SVR12 were subsequently lost to follow-up resulting in SVR24 rate of 88% with 12 weeks of treatment No relapse after SVR12 was seen in any group Hassanein T, et al. 63rd AASLD; Boston, MA; November 9-13, Abst. 230.

21 Sofosbuvir Phase 3 Programs: GT2/3 FISSION Genotype 2/3 (naïve) Study Weeks N=256 N=243 Sofosbuvir 400mg QD + RBV Peg-IFN + RBV SVR12 SVR12 POSITRON Genotype 2/3 (IFN ineligible/intolerant) N=207 N=71 Sofosbuvir 400mg QD + RBV Sofosbuvir placebo + RBV placebo SVR12 SVR12 FUSION Genotype 2/3 (treatment-experienced) N=103 N=98 Sofosbuvir 400mg QD + RBV Sofosbuvir 400mg QD + RBV SVR12 SVR12

22 FISSION SVR12 Results: Patients Achieving SVR12 (%) 100% 80% 60% 40% 20% Treatment naive GT 2/3 P <0.001* Primary Endpoint 67% 67% 97% 78% 63% 56% SOF+RBV12 Wks Peg-IFN+RBV 24 Wks 47% 38% 0% 170/ / 243 Overall GT2 GT3 Cirrhosis 1 on-treatment virologic failure in SOF+RBV arm due to nonadherence Most common AEs occurring in 10% subjects were fatigue, headache, nausea, insomnia, and dizziness (all more common in PEG+RBV arm) Press Release. These data are available in press release format only, have not been peer reviewed, may be incomplete, and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data.

23 POSITRON SVR12 Results: GT 2/3 IFN Intolerant/Unwilling 100% 93% Patients Achieving SVR12 (%) 80% 60% 40% 20% n/n = 0% 78% 161/ % 61% Overall GT2 GT3 Cirrhosis SVR12 rate in placebo recipients was 0% No on-treatment virologic failure in SOF+RBV arm (all relapses) Most common AEs occurring in 10% subjects were fatigue, nausea, headache, insomnia, pruritus, and anemia Press Release. These data are available in press release format only, have not been peer reviewed, may be incomplete, and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data.

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25 Patients Achieving SVR12 (%) FUSION SVR12 Results: Treatment experienced GT 2/3 100% 94% 12 Weeks SOF+RBV 86% 16 Weeks SOF+RBV 80% 60% 40% 20% 0% 50% 50/ % 69/ 95 62% 30% 31% Overall GT2 GT3 Cirrhosis No on-treatment virologic failure (all relapses) Most common AEs occurring in 15% subjects were fatigue, headache, insomnia, nausea Press Release. These data are available in press release format only, have not been peer reviewed, may be incomplete, and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data. 66%

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27 Treatment With Sofosbuvir + Peginterferon + Ribavirin for 12 Weeks Achieves 90% SVR12 in Treatment-Naïve Genotype 1, 4, 5, and 6 HCV-Infected Patients: The NEUTRINO Study

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32 ELECTRON: Genotype 1 Cohorts Week 0 Week 4 Week 8 Week 12 n = 25 n = 10 SOF + RBV (treatment-naïve) SOF + RBV (null responders) 84% SVR12 10% SVR12 n = 25 n = 10 SOF + GS RBV (treatment-naïve) SOF + GS RBV (null responders) 32

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34 Chronic HCV GT 2/3 (N = 44) Daclatasvir + Sofosbuvir with or without Ribavirin in HCV genotype 1, 2 or 3 n = 16 n = 14 n = 14 Group B: SOF 400 mg QD 7 d, then Follow-up DCV 60 mg QD + SOF 400 mg QD Group D: DCV 60 mg QD + SOF 400 mg QD Group F: DCV 60 mg QD + SOF 400 mg QD + RBV Follow-up Follow-up Week 24 SVR 4 SVR 12 SVR 24 SVR 48 n = 15 Group A: SOF 400 mg QD 7 d, then DCV 60 mg QD + SOF 400 mg QD Follow-up n = 14 Group C: DCV 60 mg QD + SOF 400 mg QD Follow-up Chronic HCV GT 1a/1b (N = 126)* n = 15 n = 41 Group E: DCV 60 mg QD + SOF 400 mg QD + RBV Group G: DCV 60 mg QD + SOF 400 mg QD Follow-up Follow-up n = 41 Group H: DCV 60 mg QD + SOF 400 mg QD + RBV Follow-up Week 12 SVR 4 SVR 12 SVR week groups (G and H) were enrolled and independently randomized after 24-week groups (A, C, and E) RBV: mg/d, weight-based (GT 1); 800 mg/d (GT 2/3). SVR 48 Sulkowski M, et al. 63rd AASLD; Boston, MA; November 9-13, Abst. LB-2.

35 HCV RNA < LLOQ (% Patients) 100 Genotype 2/3: Virologic Response During and N = After Treatment (mitt) Week 4 EOT a SVR 4 SVR 12 SVR 2 4 B: SOF LI + DCV D: DCV + SOF F: DCV + SOF + RBV Missing % of patients with HCV RNA < LLOQ-TND Group B: 1 patient (GT3) relapsed; NS5A-A30K polymorphism (associated with DCV resistance) detected at baseline and PT Week 4. 1 patient (GT3) met protocol definition of virologic breakthrough; added pegifn alfa/rbv achieved SVR 24 Group F: 2 lost to follow-up after EOT; 1 returned at PT Week 24 with HCV RNA < LLOQ-TND a End-of-treatment (EOT) includes patients who discontinued early, with last visit considered EOT; TD, target detected; TND, target not detected. Sulkowski M, et al. 63rd AASLD; Boston, MA; November 9-13, Abst. LB-2.

36 Genotype 1: Virologic Response During and After Treatment,12- and 24-Week Groups (mitt) A: SOF LI + DCV HCV RNA < LLOQ (% patients) C: DCV + SOF E: DCV + SOF + RBV G: DCV + SOF (12-wk) H: DCV + SOF + RBV (12-wk) Missing N = % of patients with HCV RNA < LLOQ-TND 12-week Groups (G and H) Week 4 EOT a SVR 4 SVR 12 SVR 24 2 patients missing at PT Week 4 both achieved SVR 12 ; 1 patient undetectable at PT Week 2 and with HCV RNA detected at PT Week 4 (not confirmed) achieved SVR patients have reached PT Week 12 all 68 have achieved SVR 12 a End-of-treatment (EOT) includes patients who discontinued early, with last visit considered EOT. Sulkowski M, et al. 63rd AASLD; Boston, MA; November 9-13, Abst. LB-2.

37 Sustained Virologic Response With Daclatasvir Plus Sofosbuvir ± Ribavirin (RBV) in Chronic HCV Genotype (GT) 1-Infected Patients Who Previously Failed Telaprevir (TVR) or Boceprevir (BOC) HCV RNA < LLOQ (% patients) N = Week 2 Week 4 EOT SVR 4 SVR 12 * 1 patient missing at post-treatment (PT) Week 12: HCV RNA was undetectable at PT Week 4 and at PT Week 24 (preliminary) /41 patients have reached PT Week 24; all have achieved SVR * DCV + SOF DCV + SOF + RBV Missing

38 Virologic Response by Presence or Absence of Baseline NS3 Polymorphisms Patients with NS3 polymorphisms, n V36M-R155K 6 R155K 3 V36L-R155K 1 T54S-R155K 1 T54S-V55I-R155K 1 V36M 1 V36M-V55I 1 V36M-V55A-R155K 1 V36M-R155K-I170T 1 V36A 1 V55A 1 Median change in HCV RNA (log 10 IU/mL) First dose NS3 polymorphisms (n=19) No NS3 polymorphisms (n=22) Study Day V170T 1

39 ABT450/r (PI) + ABT267 (NS5A)+/- ABT333 (NNI) +- RBV in Treatment and Prior Null Responders N 80 Regimen/Duration ABT-450 ABT-267 ABT-333 RBV ABT-450/r Dose (QD) 150/100 Treatment-naïve ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 ABT-333 ABT-450 ABT-267 ABT-333 RBV 150/ /100,200/ / /100,150/ ABT-450 ABT-267 ABT-333 RBV 100/100,150/100 Wk 0 Wk 8 Wk 12 Wk 24 Null Responder ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 ABT-333 RBV 200/ /100,150/ /100,150/100 ABT mg QD; ABT mg BID; RBV weight-based mg daily dose divided BID All patients to be followed through 48 weeks post-treatment Kowdley K, et al. 63rd AASLD; Boston, MA; November 9-13, Abst. LB-1.

40 SVR12 Rates (ITT) for 8- and 12-Week Arms Percentage of patients (ITT) achieving SVR Naïve RBV 8 Week Naïve RBV Naïve RBV Naïve RBV-free Naïve RBV 12 Week Null RBV Null RBV 12 Week 88,6 85,4 89,9 88,5 Treatment-naϊve Patients 97,4 88, N=80 N=41 N=79 N=79 N=79 N=45 N=45 8 weeks 12 weeks 12 weeks ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 RBV Null Responders Kowdley K, et al. 63rd AASLD; Boston, MA; November 9-13, Abst. LB-1.

41 Simeprevir (TMC435) with peginterferon/ribavirin for chronic HCV genotype 1 infection in treatment-naïve patients: results from QUesT-1, Phase III

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43 COSMOS: Sofosbuvir + Simeprevir ± RBV in GT1 Null- Responders Phase IIa Study: Sofosbuvir 400 mg QD + Simeprevir 150 mg QD ± RBV x 12 wks SVR 8wks (%) /27 13/14 RBV + RBV - Lawitz et al., CROI 2013, Abstract 155LB

44 2013 Simeprevir filed NDA in US in March Sofosbuvir filed NDA in US April 4 FDA meeting tentatively October 24,25 SMV PDUFA Date November 28 SOF PDUFA Date December 6 Will you use these two together off label? Will insurers pay for it?

45 Lonestar Press Release Treatment Duration Weeks Population numbers SVR % SVR weeks SOF+LDV 8 G1 naive 19/ SOF+LDV RBV 8 G1 naive 21/ SOF+LDV 12 G1 naive 19/ SOF+LDV 12 G1 experienced 18/ SOF+LDV RBV 12 G1 experienced 20/

46 New Nucs

47 Second Generation NS5As

48 The Future (as I see it) PEG/RBV PI+PEG+RBV PI 2 +PEG+RBV 40 % Nuc + P/R For G 1 Nuc + RBV For G 2/3 DAA 1 + DAA 2 + RBV

49 A Potential Evolution Scenario HCV Therapy for Genotype 1 Sustained Virologic Response in G1 (SVR) % 35% ribavirin % + PEG-IFN Estimated 65-70% + Pol Inhibitor or Prot Inhibitor +/- Estimated 85-90% + Pol Inhibitor + Prot Inhibitor Oral immune modulators Other direct antivirals All Oral Therapy 1st Stage 2nd Stage 3rd Stage 4th Stage 5th Stage 6th Stage present