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AASLD 2010 HCV Feedback

AASLD 2010 HCV Feedback. October 29 - November 2, 2010 Boston, Massachusetts Dr Allister J Grant Consultant Hepatologist Leicester Liver Unit. Boceprevir and Telaprevir. Boceprevir, a potent inhibitor of HCV NS3 protease Telaprevir, a potent inhibitor of HCV NS3/4A protease

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AASLD 2010 HCV Feedback

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  1. AASLD 2010 HCV Feedback October 29 - November 2, 2010 Boston, Massachusetts Dr Allister J Grant Consultant Hepatologist Leicester Liver Unit

  2. Boceprevir and Telaprevir Boceprevir, a potent inhibitor of HCV NS3 protease Telaprevir, a potent inhibitor of HCV NS3/4A protease Both being tested in combination with standard-of-care peginterferon alfa-2/ ribavirin in phase III studies in chronic HCV infection • Trials reported at AASLD 2010 • Boceprevir • SPRINT-2: naive GT1 patients • RESPOND-2: nonresponder GT1 patients • Telaprevir • ADVANCE: naive GT1 patients • ILLUMINATE: response-guided therapy in naive GT1 patients

  3. SPRINT-2: Boceprevir + PegIFN/RBV in G1 Tx-Naive Patients • Phase III, Randomized, placebo-controlled trial Wk 28 Wk 72 Wk 48 Wk 4 RVR† PR*(n = 316, 52) BOC + PR*(n = 316 nonblack, 52 black) Follow-up PR* Follow-up No RVR Treatment-naive patients withgenotype 1 HCV (2 cohorts: N = 938 nonblack and 159 black) PR*(n = 311,55) BOC + PR*(n = 311 nonblack, 55 black) Follow-up PR*(n = 311 nonblack, 52 black) PR*(n = 311, 52 ) Follow-up *BOC 800 mg q8h; pegIFN alfa-2b 1.5 µg/kg/wk; weight-based RBV 600-1400 mg/day. †Undetectable HCV RNA at Wk 4 of BOC treatment (ie, at Wk 8) and at all subsequent assays. Poordad F, et al. AASLD 2010. Abstract LB-4.

  4. SPRINT-2: Response Rates According to Race 4-wk PR + response-guided BOC + PR 4-wk PR + 44 weeks BOC + PR 48-wk PR Nonblack Patients Black Patients 100 100 P < .0001 P = .044 80 80 68 67 P = .004 60 60 53 Patients (%) Patients (%) 42 40 40 40 23 23 20 20 17 14 9 12 8 213 125 18 37 22 3 6 2 n = 211 21 29 12 0 0 Relapse SVR Relapse SVR Poordad F, et al. AASLD 2010. Abstract LB-4.

  5. SPRINT-2: Response Rates • >1 log drop in VL at wk 4: • 82% SVR for both B/PR arms • <1log drop in VL at wk 4: • 28% SVR in RGT (response guided therapy) • 38% SVR in 44BOC/PR • PCR neg at week 4 and 8 • 97% SVR in RGT (47% of patients) • 98% SVR in 44BOC/PR

  6. RESPOND-2: Boceprevir in G1 Prior Non-responders to PegIFN/RBV Phase III, Randomised Wk 36 Wk 48 Wk 8 Wk 4 BOC+ PR* PR* If detectable at Wk 8 Follow-up† BOC + PR* PR*(n = 162) Follow-up† Treatment-experienced patients with GT1 HCV (N = 403) PR*(n = 161) BOC + PR* Follow-up† PR*(n = 80) Follow-up† *BOC 800 mg TID; pegIFN alfa-2b 1.5 µg/kg/wk; weight-based RBV 600-1400 mg/day. †Follow-up for 24 wks after completion of therapy. Bacon BR, et al. AASLD 2010. Abstract ♯216.

  7. RESPOND-2: SVR Rates According to Treatment Arm and Prior Response 4-wk PR + response-guided BOC + PR (n = 162) P < .0001 vs control (both arms) 100 4-wk PR + 44-wk BOC + PR (n = 161) 80 48-wk PR (n = 80) 75 69 66 59* 60 52 SVR (%) 40 40 29 21 20 72/105 77/103 15/51 23/57 30/58 95/ 162 107/161 17/80 7 2/29 0 Overall PreviousNonresponders PreviousRelapsers Bacon BR, et al. AASLD 2010. Abstract 216.

  8. PROVE 1: Combination of Telaprevir with PegIFN/Ribavirin significantly increases SVR in treatment-naïve patients with HCV Genotype 1 Wk 12 Wk 24 Wk 48 24-wk follow-up 12-Wk Arm TVR* + PegIFN/RBV† (n = 17) 24-wk follow-up Treatment-naive patients infected with genotype 1 HCV (N = 250) PegIFN/RBV* 24-Wk ArmTVR*+ PegIFN/RBV† (n = 79) 24-wk follow-up 48-Wk Arm TVR* + PegIFN/RBV† (n = 79) PegIFN/RBV* 24-wk follow-up 48-Wk Control ArmPegIFN/RBV†+ Placebo (n = 75) PegIFN/RBV* *1250 mg loading dose of TVR administered on Day 1, then 750 mg 3 times daily.†PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

  9. PROVE 1: Results 12-wk TVR + pegIFN/RBV (n = 17) 100 12-wk TVR + 24-wk pegIFN/RBV (n = 79) 12-wk TVR + 48-wk pegIFN/RBV (n = 79) 80 Control (n = 75) 67‡ 61† 60 Patients (%) 41 40 35 33 23 20 6 2 0 SVR Relapse N/A, not applicable. *P < .001 vs control. †P = .02 vs control. ‡P = .002 vs control. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

  10. Frequency of undetectable HCV RNA levels during and after treatment 12% 14% McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

  11. T12/PR24 vs T12/PR48 McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

  12. PROVE 1: Conclusions Coadministration of a 12-week course of TVR with 24 or 48 weeks of pegIFN/RBV significantly increased SVR rates in treatment-naive patients infected with genotype 1 HCV vs 48 weeks of pegIFN/RBV alone Coadministration of TVR also resulted in higher rate of RVR and lower relapse rate compared with pegIFN/RBV TVR coadministration increased rate of treatment discontinuation due to adverse effects, predominantly rash McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

  13. Prove 3 24 vs 48wks of T/PR in patients with G1 previously treated with PEG IFN/ RBV- Week 4 non-response - <1log decline in control arm or detectable HCV in TPR arms *P < .001 vs control. †P = .024 vs control. ‡P = .297 vs control. §P = .029 vs control. McHutchison JG, et al. AASLD 2009. Abstract 66, NEJM 2010.

  14. ADVANCE: Telaprevir + PegIFN/RBV in G1 Tx-Naive Patients • Phase III, Randomized, placebo-controlled trial Wk 24 Wk 72 Wk 48 Wk 12 Wk 8 TVR + PR*(n = 364) eRVR†: PR* Follow-up PR* Follow-up Treatment-naive patients with genotype1 HCV (N = 1088) TVR + PR*(n = 363) eRVR†: PR* Follow-up PR* Follow-up PR*(n = 361) Follow-up *TVR 750 mg q8h; pegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day. †eRVR: extended rapid virologic response = undetectable HCV RNA at Wks 4 and 12. Jacobson IM, et al. AASLD 2010. Abstract 211.

  15. ADVANCE: 1088 Treatment naïve G1 patients randomised: TPV/PEG/RBV x8 weeks then PEG /RBV x16 weeks (T8/PR24) TPV/PEG/RBV x12 weeks then PEG /RBV x12 weeks (T12/PR24) PEG/RBV x48 weeks (PR48) RESULTS: Jacobson I AASLD ♯211 Kiefer T AASLD LB-11

  16. ILLUMINATE: Response-Guided Telaprevir + PegIFN/RBV in G1 Naive Pts • Phase III Open-label, randomized trial, ITT analysis Wk 12 Wk 20 Wk 24 Wk 48 Wk 72 TVR + PR* PR* PR*(n = 162) Follow-up eRVR† Treatment-naive patients with GT1 HCV (N = 540) PR*(n = 160) Follow-up No eRVR† PR*(n = 218) Follow-up *TVR 750 mg q8h; pegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day. †eRVR: extended rapid virologic response = undetectable HCV RNA at Wks 4 and 12. Sherman KE, et al. AASLD 2010. Abstract LB-2.

  17. ILLUMINATE: Overall SVR Rates 100 92 88 80 72 60 SVR (%) 40 20 140/160 n/N = 388/540 149/162 0 Overall 24-wk therapy 48-wk therapy Patients With eRVR Sherman KE, et al. AASLD 2010. Abstract LB-2.

  18. ILLUMINATE: • Adverse Events • Anaemia <8.5 • 9% in TPV • 2% in PR • 0.6% DC • Fatigue (1.1% DC) • Rash • Eczematous rash in 37% • 7% severe rash • Pruritis • Nausea • Overall discontinuation rate 17% • In first 12 weeks there was: • 7% DC of all drugs • 12% DC of Telaprevir

  19. Interferon Free Therapy? BMS-790052 + BMS-650032 Alone or With PegIFN/RBV in G1 Null Responders • Open-label, randomized, placebo-controlled phase IIa trial • BMS-790052: NS5A polymerase inhibitor • BMS-650032: NS3 protease inhibitor Wk 72 Wk 24 BMS-790052 60 mg QD + BMS-650032 600 mg BID(n = 11) Follow-up Prior null responders with GT1 HCV (N = 21) BMS-790052 60 mg QD + BMS-650032 600 mg BID + PR*(n = 10) Follow-up *PegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day. Lok A, et al. AASLD 2010. Abstract LB-8.

  20. Wk 12 Interim Analysis BMS-790052 + BMS-650032 BMS-790052 + BMS-650032 + PR 100 90 80 64 60 60 60 46 Patients (%) 36 40 20 7/11 6/10 4/11 6/10 5/11 9/10 0 RVR eRVR cEVR • All viral breakthroughs occurred in patients with GT1a Lok A, et al. AASLD 2010. Abstract LB-8.

  21. Other Protease/Polymerase Inhibitors • TMC435- NS3/4a Protease inhibitor (PILLAR Trial) • Phase IIa , G1 Naive • Once Daily • 12-24 weeks Rx +PR48 • SVR 91%-98% (4 vs12 wks ) • Daneprovir • RG7227 phase II, in G1 naive patients (ATLAS trial) • 88% to 92% of patients achieved cEVR when combined with pegIFN/RBV vs 43% with SOC • Vaniprevir- NS3/4a Protease Inhibitor • MK-7009 phase IIa study G1 naive patients without cirrhosis • Significantly higher when combined with pegIFN/RBV vs SOC • RVR: 67% to 84% vs 5% Fried M, et al. AASLD 2010. Abstract LB-5. Terrault N, et al. AASLD 2010. Abstract 32. Manns MP, et al. AASLD 2010. Abstract 82

  22. HCV Pharmacogenetics • GWAS used patients from IDEAL and Muir Studies • 1137 samples on patients with SVR • SNP’s rs12979860 on Chr 19 strongly associated with SVR & localised to IL28β SVR % Thomas DL, et al. Nature. 2009;461:798-801.

  23. Regional Distribution of IL28B rs12979860 CC Genotype Thomas DL, et al. Nature. 2009;461:798-801.

  24. IL28β Associations in Patients With Hepatitis C • IL28β polymorphisms associated with • Higher SVR rates[1] • Higher RVR rates[2] • Higher HCV RNA[3] • Higher LDL levels[4] • Higher baseline ALT levels[5] • Higher rate of spontaneous viral clearance[6] 1. Ge D, et al. Nature. 2009;461:399-401. 2. Mangia A, et al. AASLD 2010. Abstract 897. 3. Liu L, et al. AASLD 2010. Abstract 231. 4. Saito H, et al. AASLD 2010. Abstract 732. 5. Thompson AJ, et al. AASLD 2010. Abstract 1893. 6. Thomas DL, et al. Nature. 2009;461:798-801.

  25. And if time

  26. ♯214:Maintenance PEG IFN to prevent HCC • Extended FU from HALT-C trial • 1084 patients 6.1-8.7yr FU • 88 HCC (20 clinical HCC) • No difference between Rx and Control at 3/5/7yr • Subgroup analysis • Cirrhotics who had PEG for >2 years- marginal benefit A Lok et al AASLD 2010, Abstract 214

  27. EXTEND Trial:Long Term FU of PROVE 1-3 patients • 3 yr FU of T/PR treated patients • 123 patients who had SVR’s from previous studies • 122/123 had durable SVR (99%) • 79 patients without SVR analysed for resistance and after 22 mo 89% reverted to wild type S Zeuzem et al AASLD 2010 , Abstract 227

  28. ♯213: Effect of SVR on all cause mortality • Dept of Veterans Affairs Data Registry • 23000 patients • 16800 with post Rx RNA , SVR rate 44% • 52% smokers, 20% DM, 15% COPD, 12% CAD, 26% alcohol, 36% depression • 1535 died (median 3.7yrs) G3 No SVR G1,2 No SVR Mortality G1,2,3 with SVR Time

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