Les Inhibiteurs de Protéase du VHC
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1 Les Inhibiteurs de Protéase du VHC Pr Jean-Michel Pawlotsky National Reference Center for Viral Hepatitis B, C and delta Department of Virology & INSERM U955 Henri Mondor Hospital University of Paris-Est Créteil, France
2 Chronic Hepatitis C million chronically infected patients worldwide 1 st cause of chronic liver disease and of hepatocellular carcinoma 1 st indication for liver transplantation in industrialized areas
3 Worldwide HCV Prevalence
4 (Simmonds P., et al., Hepatology 2006) HCV Genotypes
5 Standard-of-Care (EU label) Genotype 1 Genotype 2,3 Genotype 4, 5, 6 PegIFN + ribavirin 48 weeks PegIFN + ribavirin 24 weeks PegIFN + ribavirin 48 weeks
6 SVR Rates in Pivotal Trials PEG-IFN-α2a+ribavirin (Fried et al) PEG-IFN-α2a+ribavirin (Hadziyannis et al) PEG-IFN-α2b+ribavirin (Manns et al) 76% 84% 82% 46% 52% 42% Genotype 1 Genotypes 2/3 (Manns et al, Lancet 2001 ; Fried et al, N Engl J Med 2002 ; Hadziyannis et al, Ann Intern Med 2004)
7 HCV protease inhibitors
8 (Popescu & Dubuisson, Biol Cell 2009;102:63-74) HCV Life Cycle
9 NS3/4A Protease Inhibitors (Raney et al., J Biol Chem 2010:285: )
10 Median HCV RNA Change from Baseline (Log 10 IU/mL) Telaprevir Resistance Study Time (Days) Placebo VX mg q8h VX mg q12h (Reesink HW, et al. Gastroenterology 2006;131: )
11 Amino Acid Substitutions Associated with PI Resistance Asp168 Arg155 Ala156 Thr54 Val36 (Pawlotsky J-M, Ther Adv Gastroenterol 2009;2: )
12 New Standard-of-Care for HCV Genotype 1 Boceprevir Telaprevir Pegylated IFN- + Ribavirin
13 Telaprevir
14 Telaprevir Label HCV Genotype 1 Triple combination PegIFN- 2a: 180 g/wk; or PegIFN- 2b: 1.5 g/kg/wk Ribavirin: g/d Telaprevir 375mg: 750 mg tid (every 7-9 hours with food/fat) Treatment schedule Telaprevir: starts at day 0 Response-guided therapy
15 Response-Guided Therapy Peg-IFN + Ribavirin + Telaprevir Treatment-naive or responderrelapser Partial responder or null-responder W0 W4 W12 W24 W36 W48 W72
16 Response-Guided Therapy Peg-IFN + Ribavirin + Telaprevir ervr: undetectable HCV RNA at weeks 4 and 12 Treatment-naive or responderrelapser TVR + PR PR Follow-up: 24 weeks HCV RNA detectable at weeks 4 and/or 12 but 1000 UI/mL PR Follow-up: 24 weeks Partial responder or null-responder W0 W4 W12 W24 W36 W48 W72
17 Response-Guided Therapy Peg-IFN + Ribavirin + Telaprevir ervr: undetectable HCV RNA at weeks 4 and 12 Treatment-naive or responderrelapser TVR + PR PR Follow-up: 24 weeks HCV RNA detectable at weeks 4 and/or 12 but 1000 UI/mL PR Follow-up: 24 weeks Partial responder or null-responder TVR + PR PR Follow-up: 24 weeks W0 W4 W12 W24 W36 W48 W72
18 Futility Rules Peg-IFN + Ribavirin + Telaprevir HCV RNA >1000 IU/mL at W4 or W12 HCV RNA detectable (>10-25 IU/mL) at W24
19 % patients with SVR ADVANCE Rx-naive, Gen 1, Telaprevir % T12/PR N=363 P< % T8/PR N=364 P< % PR N=361 (Jacobson et al., N Engl J Med 2011;364: )
20 Patients With Undetectable HCV RNA (%) REALIZE Rx-experienced, Gen 1, Telaprevir % 88% P<0.01 vs placebo T12/PR48 Lead-in/T12/PR48 PR48 (control) 60 59% 54% 40 24% 29% 33% 20 15% 5% 0 Prior relapse (Zeuzem et al., N Engl J Med 2011;364: ) Prior partial response Prior null-response
21
22
23 Severe Cutaneous Adverse (SCAR) Reactions with Telaprevir SCAR Acute generalized exanthematous pustulosis (AGEP) and Erythema Multiforme Major (EMM) Drug rash/reaction with eosinophilia and systemic symptoms (DRESS) Toxic epidermal necrolysis (TEN) and Stevens- Johnson Syndrome (SJS) 3 cases suggestive of SJS ((of which 1 case considered not related to telaprevir, onset 11 weeks after telaprevir discontinuation) 11 cases suggestive of DRESS ( Committees/Meeting Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM pdf)
24 CUPIC-Telaprevir SAEs Exposure and SAEs TVR (n=176) Median exposure to telaprevir 85.0 days Severe adverse events (SAE) 90 (51%)* Discontinuations due to SAEs 21 (12%) Deaths 3 (1.7%) *228 SAEs in 90 patients (Hézode et al., HepDart 2011)
25 CUPIC-Telaprevir Clinical SAEs Clinical SAEs TVR (n=176) Grade 3/4 rash Grade 3 SCAR 12 (6.8%) 0 (0%) Grade 3/4 infection 6 (3.4%) Other grade 3/4 SAEs 92 (52%) (Hézode et al., HepDart 2011)
26 CUPIC-Telaprevir Biological Adverse Events Biological adverse events TVR (n=176) Anemia Grade 2 (8.0-<10,0 g/dl) 58 (33%) Grade 3/4 (<8,0 g/dl) 23 (13%) EPO use 96 (55%) Transfusion 32 (18%) Neutropenia Grade 3 (500-<1000/mm 3 ) 20 (11%) Grade 4 (<500/mm 3 ) 2 (1%) G-CSF use 5 (3%) Thrombocytopenia Grade 3 (25,000-<50000) 26 (15%) Grade 4 (<25000) 12 (7%) (Hézode et al., HepDart 2011)
27 Boceprevir
28 Boceprevir Label HCV Genotype 1 Triple combination PegIFN- 2b: 1.5 g/kg/wk; or PegIFN- 2a: 180 g/wk Ribavirin: g/d Boceprevir 200 mg: 800 mg tid (every 7-9 hours with food) Treatment schedule Lead-in: 4 weeks Boceprevir: starts at week 4 Response-guided therapy
29 Response-Guided Therapy Peg-IFN + Ribavirin + Boceprevir Treatment naive patients (excluding F4) Treatmentexperienced patients (excluding nullresponders and F4) F4 patients and null-responders
30 Response-Guided Therapy Peg-IFN + Ribavirin + Boceprevir W0 W4 W8 W12 W24 W28 W36 W48 Undetectable HCV RNA at week 8 Treatment naive patients (excluding F4) PegIFN/ RBV Boceprevir Boceprevir + PegIFN/RBV Detectable HCV RNA at week 8 Boceprevir + PegIFN/RBV PegIFN/RBV Treatmentexperienced patients (excluding nullresponders and F4) F4 patients and null-responders
31 Response-Guided Therapy Peg-IFN + Ribavirin + Boceprevir W0 W4 W8 W12 W24 W28 W36 W48 Undetectable HCV RNA at week 8 Treatment naive patients (excluding F4) PegIFN/ RBV Boceprevir Boceprevir + PegIFN/RBV Detectable HCV RNA at week 8 Boceprevir + PegIFN/RBV PegIFN/RBV Treatmentexperienced patients (excluding nullresponders and F4) W0 W4 W12 W24 W36 W48 PegIFN RBV Boceprevir Boceprevir + PegIFN/RBV PegIFN/RBV F4 patients and null-responders
32 Response-Guided Therapy Peg-IFN + Ribavirin + Boceprevir W0 W4 W8 W12 W24 W28 W36 W48 Undetectable HCV RNA at week 8 Treatment naive patients (excluding F4) PegIFN/ RBV Boceprevir Boceprevir + PegIFN/RBV Detectable HCV RNA at week 8 Boceprevir + PegIFN/RBV PegIFN/RBV Treatmentexperienced patients (excluding nullresponders and F4) F4 patients and null-responders W0 W4 W12 W24 W36 W48 PegIFN RBV Boceprevir Boceprevir + PegIFN/RBV PegIFN/RBV W0 W4 W12 W24 W48 PegIFN RBV Boceprevir Boceprevir + PegIFN/RBV
33 Futility Rules Peg-IFN + Ribavirin + Boceprevir HCV RNA 100 IU/mL at W12 HCV RNA detectable (>10-25 IU/mL) at W24
34 % patients with SVR SPRINT-2 SVR (non-black) P< % 68% BOC/RGT N=368 BOC/PR48 N=366 P< % 48P/R N=363 (Poordad et al., N Engl J Med 2011;364: )
35 Patients With Undetectable HCV RNA (%) RESPOND-2 SVR 100 BOC/RGT 80 69% 75% BOC/PR48 48P/R (control) 60 52% 40 29% 40% 20 7% 0 Prior relapse Prior partial response (Bacon et al., N Engl J Med 2011;364: )
36 % patients Anemia with Boceprevir in Phase II/III Clinical Trials BOC/RGT BOC/PR48 PR % 41% 26% Hemoglobin <10 to 8.5 g/dl 5% 9% Hemoglobin <8.5 g/dl 4% ( Committees/Meeting Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM pdf)
37 CUPIC-Boceprevir SAEs Exposure and SAEs BOC (n=134) Median exposure to boceprevir 84.0 days Severe adverse events (SAE) 39 (29%)* Discontinuations due to SAEs 8 (6%) Deaths 1 (1%) *85 SAEs in 39 patients (Hézode et al., HepDart 2011)
38 CUPIC-Boceprevir Clinical SAEs Clinical SAEs BOC (n=134) Grade 3/4 rash Grade 3 SCAR 0 (0%) 0 (0%) Grade 3/4 infection 0 (0%) Other grade 3/4 SAEs 43 (32%) (Hézode et al., HepDart 2011)
39 CUPIC-Boceprevir Biological Adverse Events Biological adverse events BOC (n=134) Anemia Grade 2 (8.0-<10,0 g/dl) 41 (31%) Grade 3/4 (<8,0 g/dl) 8 (6%) EPO use 70 (52%) Transfusion 8 (6%) Neutropenia Grade 3 (500-<1000/mm 3 ) 10 (7%) Grade 4 (<500/mm 3 ) 5 (4%) G-CSF use 7 (5%) Thrombocytopenia Grade 3 (25,000-<50,000) 8 (6%) Grade 4 (<25,000) 3 (2%) (Hézode et al., HepDart 2011)
40 Future HCV therapies
41 (Popescu & Dubuisson, Biol Cell 2009;102:63-74) HCV Life Cycle
42 NS3/4A Protease Inhibitors (Raney et al., J Biol Chem 2010:285: )
43 Antiviral Efficacy of NS3/4A Protease Inhibitors Drug Phase Dose Duration Median/mean log HCV RNA reduction Telaprevir (Janssen) Approved 750 mg q8h 14 days -4.4 Boceprevir (Merck) Approved 400 mg tid 7 days -1.6 TMC435 (Janssen) III 200 mg qd 7 days -4.1 Danoprevir (RG7227, Roche) II 200 mg q8h 14 days -3.8 Vaniprevir (MK-7009, Merck) II 700 mg bid 8 days -4.7 BI (BI) II 240 mg qd 14 days -4.0 Narlaprevir (Merck) II 400 mg bid 7 days -4.2 Asunaprevir (BMS) II 300 mg bid 3 days -3.3 ABT-450/r (Abbott) II 200 mg qd 3 days -4.1 GS-9451 (Gilead) I 400 mg qd 3 days -3.5 MK-5172 (Merck) I 400 mg qd 7 days -5.4
44 HCV RNA-Dependent RNA Polymerase (RdRp) Catalytic Site
45 Nucleoside/Nucleotide Analogue Inhibitors of HCV RdRp Drug Phase Dose Duration Median/mean log HCV RNA level reduction Mericitabine (RG7128, Roche) II 1500 mg bid 14 days -2.7 GS-7977 (Gilead) II 400 mg qd 3 days -3.7 INX-189 (Inhibitex) Ib 100 mg qd 7 days -2.5 IDX184 (Idenix) II 100 mg qd 3 days -0.7
46 Non-Nucleoside Inhibitors (NNI) NNI site A (Thumb/fingertips) Indoles Benzimidazoles NNI site C (Palm) Benzothiadiazine (A ) Acyl-pyrrolidine Proline sulfonamide Acrylic acid derivatives A B C D C NNI site B (Thumb) Phe derivatives Thiophene-COOH Dihydroxypirones Pyranoindoles (HCV371) NNI site D (R200 hinge) Benzofurans (HCV086, HCV796)
47 Non-Nucleoside Inhibitors of HCV RdRp (NNIs) Drug Phase Dose Duration Median/mean log HCV RNA reduction Tegobuvir (Gilead) II 40 mg bid 8 days -1.4 Filibuvir (Pfizer) II 300 mg bid 8 days -2.1 Setrobuvir (Roche) II 800 mg bid 3 days -2.9 BI (BI) II 800 mg q8h 3 days -3.1 ABT-333 (Abbott) II 600 mg bid 2 days -1.5 VX-222 (Vertex) Ib 750 mg bid 3 days -3.7
48 HCV Replication Complex (Membranous Web) (Moradpour et al., Nature Rev Microbiol 2007;5:453-63)
49 NS5A Protein
50 Antiviral Efficacy of NS5A Inhibitors Drug Phase Dose Duration Median/mean log HCV RNA reduction Daclatasvir (BMS) II 10 mg qd 1 day -3.2 PPI-461 (Presidio) Ib 100 mg qd 3 days -3.7 GS-5885 (Gilead) Ib 30 mg qd 3 days -3.3
51 Cyclophilins Cyclophilin A
52 Antiviral Efficacy of Cyclophylin Inhibitors Drug Phase Dose Duration Median/mean log HCV RNA reduction Alisporivir (DEBIO-025) II 1200 mg bid 14 days -3.6 SCY-465 Ib 900 mg qd 15 days -2.2
53 GS Ribavirin 12 weeks Treatment-naive, gen 2/3 10/10 SVR12 Null-responder, gen 1 6/8 relapses (Gane et al., AASLD 2011; Gilead press release, February 17, 2012)
54 Daclatasvir (NS5A) + Asunaprevir (PI) SVR N=11 Daclatasvir + Asunaprevir 2/9 genotype 1a 2/2 genotype 1b N=10 Daclatasvir + Asunaprevir SVR 9/10 genotype 1b (Lok et al., N Engl J Med 2012;366:216-24; Chayama 2012;55:742-8)
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