ABCs of Hepatitis C: What s New. The Long-Awaited New Era: Protease Inhibitors for HCV Genotype 1

Transcription

1 ABCs of Hepatitis C: What s New ACG Postgraduate Course Washington, DC October 30, 2011 Ira M. Jacobson, M.D. Vincent Astor Professor of Medicine Chief, Division of Gastronterology and Hepatology Medical Director, Center for the Study of Hepatitis C Weill Cornell Medical College The Long-Awaited New Era: Protease Inhibitors for HCV Genotype 1 >70% Genotype 1 Response-guided therapy (RGT) Side effects Resistance Drug-drug interactions April 27-28, 2011: FDA Advisory Panel voted 18-0 for approval of boceprevir and telaprevir Both drugs approved by FDA May 2011 (compensated liver disease) 1

2 Phase 3 Trials Telaprevir Naïve ADVANCE ILLUMINATE Experienced REALIZE Boceprevir Naïve SINT-2 Experienced RESPOND-2 ADVANCE: Treatment Naïve G1 Randomized, Double-Blind, Placebo-Controlled for Telaprevir 72 weeks T12 TVR + ervr + ervr-. T8 TVR + Pbo + ervr + ervr-. (control) Pbo + Weeks ervr = HCV RNA undetectable at week 4 and week 12 (Taqman v2.0) (T) TVR = telaprevir 750 mg q8h; Pbo = Placebo; (P) Peg-IFN = pegylated interferon alfa-2a ( kd) 1 µg/wk; (R) RBV = ribavirin 1,000 or 1,200 mg/da Jacobson IM, et al. N Engl J Med 2011;364:

3 ADVANCE: Rates T12 T8 100 P< Percent of patients with n/n = P< / / /361 Jacobson IM, et al. N Engl J Med 2011;364:25-16 ADVANCE: RVR and ervr Rates 100 T12 T8 rcent of patients with CV RNA undetectable Pe HC 90 Patients eligible to receive24weeks of total treatment n/n = / /364 34/ / /364 29/361 Week 4 (RVR) Weeks 4 and 12 (ervr) 3

4 ADVANCE: Rates by ervr Status Perc cent of patients with SV VR ervrn/n = T12 T8 189/ /207 28/29 82/151 79/ / week regimen ervr+ 48-week regimen Jacobson IM, et al. N Engl M Med 2011;364:25-16 Per rcent of patients with n/n = Rates in Subgroups T12 T8 226/ / /288 45/73 45/85 24/73 Black/African American Bridging Fibrosis or Cirrhosis Jacobson IM et al. N Engl J Med 2011;364:

5 ADVANCE: Discontinuation for Adverse Events D/C T12 T8 TVR/Placebo only 11% 7% 1% All therapy 10% 10% 7% (overall study) Jacobson IM, et al. N Engl J Med 2011;364:25-16 Rash Events During Telaprevir/Placebo Phase % of Patients with T12 T8 N=363 N=364 (control) N=361 Rash events Severe rash events Discontinuation of telaprevir/placebo only due to rash events Discontinuation of all study drugs due to rash events Rash was primarily eczematous and resolved upon cessation of therapy Severe rash was managed by sequentially discontinuing telaprevir, followed by ribavirin and, if indicated, peginterferon for continued progression Anorectal symptoms in ~29% with telaprevir Jacobson IM et al. N Engl J Med 2011;364:

6 Nadir Hemoglobin, Discontinuation for Anemia, and Median Hemoglobin Levels Hemoglobin nadir during TVR/Pbo Phase Median Hemoglobin % of Patients with T12 T8 N=363 N=364 N=361 Hemoglobin <10 g/dl Hemoglobin <8.5 g/dl Per protocol, anemia was to be managed with RBV dose modifications and ESAs were not allowed 1%, 3% and 1% of patients in T12, T8 and, respectively discontinued all drugs due to anemia events Median Hemoglobin (g/dl) TVR TVR. T12 (n=363) T8 ( (n=364) (control) (n=361) 4%, 2% and 0% of patients in T12, T8 and, respectively discontinued telaprevir/placebo only Jacobson IM, et al.n Engl J Med 2011;364: Weeks ILLUMINATE Study: Randomization of ervr Patients to 24 Versus 48 Weeks Phase 3 Treatment-naïve Genotype 1 T12/ Telaprevir (750 mg q8h) PegIFN + RBV PegIFN + RBV PegIFN Follow-Up + RBV With ervr PegIFN + RBV Follow-Up Follow-Up Without ervr PegIFN + RBV Follow-Up Week ervr (extended rapid virologic response): HCV RNA <25 IU/mL at weeks 4 and week 20. Sherman KE, et al. N Engl J Med 2011;365:

7 100 Rates: ILLUMINATE Δ 4.5% (2-sided 95% CI = -2.1% to +11.1%) ) Patients With (%) n/n= 388/5 149/162 1/1 76/118 23/100 ITT ervr+ ervr+ ervr- Other T1224 T12 T12 Sherman KE, et al. N Engl J Med 2011;365: REALIZE: Study Design (N=662) T12/ TVR + Pbo + Peg-IFN N=266 Peg-IFN + RBV Peg-IFN + RBV + RBV LI T12/ N=264 Pbo + Peg-IFN + RBV TVR + Peg-IFN + RBV Peg-IFN + RBV Pbo/ (control) N=132 Pbo + Peg-IFN + RBV Peg-IFN + RBV Weeks assessment Randomization was stratified by viral load and prior response. Stopping rules applied for TVR (Weeks 4, 6, and 8 for T12/; Weeks 8, 10 and 12 for LI T12/) and Peg-IFN/RBV (Weeks 12, 24, and 36 for T12/; Weeks 16, 24 and 36 for LI T12/) Peg-IFN: Peg-IFN alfa-2a = 1μg/week; RBV = mg/day; TVR = 750mg every 8 hours ClinicalTrials.gov identifier: NCT LI = lead-in; Pbo = placebo; TVR = telaprevir Zeuzem S, et al.easl:2011, Oral Presentation

8 REALIZE: in Prior Relapsers, Prior Partial Responders and Prior Null Responders Prior relapsers 86% Prior partial responders Prior null responders 56% (%) 31% T12/ LI T12/ Pbo/ T12/ LI T12/ Pbo/ T12/ LI T12/ Pbo/ n/n= 121/ /141 16/68 29/49 26/48 4/27 21/72 25/75 2/37 Zeuzem S, et al. N Engl J Med 2011;364: *p<0.001 vs Pbo/ REALIZE: by Baseline Fibrosis Stage and Prior Response Prior relapsers Prior partial responders Prior null responders Pooled T12/ Pbo/ (%) n/n= 144/167 12/38 53/62 2/15 48/57 2/15 34/47 3/17 10/18 0/5 11/32 1/5 24/59 1/18 15/38 0/9 7/50 1/10 Stage No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis Zeuzem S, et al. N Engl J Med 2011;364:

9 Control 48 P/R n = 363 SINT-2: Boceprevir in G1 Naïve CHC Week 4 Week 28 Week 48 Week 72 lead-in + Placebo TW 8-24 HCV RNA Undetectable t BOC RGT n = 368 lead-in + Boceprevir TW 8-24 HCV RNA Detectable + Placebo BOC/ n = 366 lead-in + Boceprevir Peginterferon (P) administered subcutaneously at 1.5 μg/kg once weekly, plus ribavirin (R) using weight-based dosing of 0-10 mg/day in a divided daily dose Boceprevir dose of 0 mg thrice daily Poordad F et al. NEJM 2011;364: SINT-2: and Relapse Rates (ITT) p < * Relapse Rate p = p < p = % Patients / / P/R BOC RGT BOC/ % Patients * / / P/R BOC RGT BOC/ Non-Black Patients Black Patients Poordad F, et al NEJM 2011; *(mitt in 47% vs 53%) 9

10 SINT-2 Study Outcomes Based on Week 4 Lead-In (Nonblack Patients) and HCV RNA at wk 4 >1 log 10 HCV RNA decline <1 log 10 HCV RNA decline (%) LI/B44/ (n=218/79) LI/B24/ (n=228/73) 5 (n=234/62) Poordad F, et al. NEJM 2011;364: (%) SINT-2: By Response Pattern (Non-Black) in Patients With Undetectable HCV RNA Between Weeks BOC RGT BOC/ in Patients With Undetectable HCV RNA At Least Once Between Weeks BOC RGT BOC/ 47% patients eligible for shortened treatment (44% of both cohorts combined) Adapted from Poordad F et al. NEJM 2011;364:

11 SINT-2: Safety Profile Over Entire Course of Therapy 48 n = 363 BOC RGT n = 368 BOC/ n = 366 Median treatment duration, days Deaths n = 4 n = 1 n = 1 Serious AEs 9% 11% 12% Discontinued due to AEs 16% 12% 16% Dose modification due to AEs 26% % 35% Hematologic parameters Hemoglobin (<10 to 8.5 g/dl / <8.5 g/dl) 26% / 4% 45% / 5% 41% / 9% Discontinuation due to anemia 1% 2% 2% Dose reductions due to anemia 13% 20% 21% Erythropoietin use 24% 43% 43% Mean (median) days of use 121 (109) 94 (85) 156 (149) Neutrophil count (<750 to 500/mm 3 / <500/mm 3 ) Other incremental AE is dysgeusia 14% / 4% 24% / 6% 25% / 8% Poordad F et al. NEJM 2011;364: RESPOND 2: G1 Relapsers & Partial Responders Control 48 P/R N = Week 4 Week 36 Week 48 Week 72 lead-in + Placebo Week 12 futility TW 8 HCV-RNA Undetectable BOC RGT N = 162 lead-in + Boceprevir TW 8 HCV-RNA Detectable/ TW 12 Undetectable + placebo BOC/ N = 161 lead-in + Boceprevir HCV-RNA measured by the Cobas TaqMan assay (Roche). Peginterferon alfa-2b (P) administered subcutaneously at 1.5 μg/kg once weekly, plus Ribavirin (R) using weight based dosing of 0-10 mg/day in a divided daily dose Boceprevir dose of 0 mg tid Bacon BR et al, NEJM 2011;364:

12 RESPOND-2 and Relapse Rates Intention to Treat Population % of Patients p < p < Relapse Rate BOC RGT BOC/ Difference in response in cirrhotics drove numerical differences Bacon BR et al, NEJM 2011;364: RESPOND-2 by Prior Response 100 B, boceprevir 0 mg TID; P, P, PEG IFN α-2b 1.5 µg/kg/wk; R, ribavirin 0 10 mg/d; RGT, response-guided therapy; (%) RGT 4/B /29 23/57 30/58 15/51 72/105 77/103 Partial Responder Relapser Bacon BR, et al. NEJM 2011;364:

13 Practical Guidelines Stopping Rules for Telaprevir Treatment Naïve & Experienced Week 4 HCV RNA >1000 IU/ml Week 12 HCV RNA >1000 IU/ml Week 24 HCV RNA detectable Stop Stop Stop all therapy all therapy all therapy 13

14 Response-Guided Therapy: Telaprevir Naives, relapsers ervr+ 24 weeks (T12/12) ervr- 48 weeks (T12/36) Nonresponders (Partial and null) 48 weeks (T12/36) Treatment-naïve patients with cirrhosis and ervr may benefit from additional 36 weeks of Telaprevir package insert Stopping Rules for Boceprevir Treatment Naïve & Experienced Week 12 Week 24 HCV RNA >100 IU/ml HCV RNA detectable Stop all therapy Stop all therapy 14

15 Response-Guided Therapy: Boceprevir Naives: 28 or 48 weeks total therapy HCV RNA undetectable at weeks 8, weeks (4/B24) HCV detectable at week 8, undetectable week weeks (4/B32/12) Relapsers, partial responders: 36 or 48 weeks total therapy HCV RNA undetectable weeks 8, weeks (4/B32) HCV RNA detectable week 8, undetectable week weeks (4/B32/12) Null responders: 48 weeks total therapy 48 weeks (4/B44) NOTE: Cirrhotics should be treated for 48 weeks (4/B44) (NO RGT) Consider 4/44 regimen for patients with poor IFN response at 4 wks Boceprevir Package Insert IL28B and Protease Inhibors Major increment in for naive T allele patients Studies differ re: degree of increased with TVR and BOC in naïve CC patients May fine tune discussion re: chance for and RGT in naïve patients Appears of limited practical value in nonresponders 15

16 Side Effect Management Anemia incremental decline in hgb (both PI s) With BOC and TVR, RBV dose reductions did not affect Role of epo? Await results of BOC study with epo vs RBV dose reduction For now, individualize treatment decisions Rash Can manage mild to moderate rash locally Topical steroids Antihistamines For severe rash: sequential d/c of meds (telaprevir first, then RBV + IFN if necessary) Differing Perspectives on HCV Resistance to Protease Inhibitors RESISTANCE (V36, T54, R155, A156) resistance Majority of PI treatment failure pts are left with resistant variants Some HCV variants are fit and can persist in the long term Theoretical impact on future regimens that incorporate PI s HCV doesn t appear to be archived Encouraging data re: clearance of variants from BOC + TVR studies Diverse pipeline decreases concern 16

17 Alfuzosin Contraindicated Drugs With Telaprevir & Boceprevir Common Denominator is interaction with CYP3A4 Interactions may occur via inhibition OR induction Rifampin Ergot derivatives Cisapride St. John s wort Lovastatin, simvastatin, atorvastatin (telaprevir) Sildenafil or tadalafil for PA hypertension Oral midazolam, triazolam Drosperinone (boceprevir) Consult package inserts for other established and potential drug-drug interactions; should be readily accessible in office Contraception During PI Therapy 2 methods of contraception required for all Rule re: no conception until 6 months after RBV completed remains in effect During active PI treatment phase, female patients must use 2 nonhormonal methods of contraception and for 2 weeks thereafter Decreased ethinyl estradiol exposure and increased drosperinone exposure 17

18 A Glimpse Into the Future of HCV Therapy Targets for New Hepatitis C Drugs Core E1 E2 P NS2 NS3 NS4A NS4B NS5A NS5B NS5A inhibitors Protease inhibitors BMS Polymerase GS-5885 Linear inhibitors ABT-267 Macrocyclic Cyclophilin Telaprevir Boceprevir ACH-1625 GS-9451 Danoprevir (RG7227) TMC BI BMS Vaniprevir MK-5172 Debio 025 SCY-635 Active site (nucleosides) Not all-inclusive Non-nucleosides Meracitabine IDX184 PSI-7977 ABT-333 ABT-072 GS 9190 ANA598 VX-222 Filibuvir BI

19 Nucleoside (RG7128) + Protease Inhibitor(RG7227) G1 Interferon-Naive and Null Responders RG mg BID + RG mg BID Nucleoside Protease polymerase inhibitor inhibitor Profound viral suppression, no breakthroughs Gane EJ, et al. Lancet 2010;376: The Study That Stole the Show : EASL 2011 NS5A + Protease Inhibitor + Peg IFN/RBV in Null Responders BMS ( mg QD) + BMS (0 mg BID) (n=11) BMS BMS PEG IFN/RBV (n=10) 24-week treatment Post treatment: Week 24: 24 - Dual: 36% (4/11, including 2/2 G1b, 2/9 G1a) - Quad: 100% (10/10) Proof of concept for curability of HCV without IFN Major potential for quad therapy in null responders (and others) Lok A, et al. EASL 2011, Berlin, O1356; 2. McPhee F, et al. EASL 2011, Berlin, P

20 Various Paradigms Being Developed Simultaneously IFN-free regimens PEG IFN + Ribavirin + Single DAA PIs Nucs NS5A Cyclophilin antagonist PEG IFN + Ribavirin + DAA-1 + DAA-2 Some trials involve more than one of these designs PEG IFN lambda being evaluated Proof of concept for curative potential of IFN-free regimens has been established; RBV may remain an important adjunct 20