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Are (exogenous) interferons really necessary?

Are (exogenous) interferons really necessary?. Peter Ferenci Medical University of Vienna. Effect of interferon on experimental vaccinia and herpes-simplex virus infections in rabbits' eyes. CANTELL K , TOMMILA V. Lancet. 1960 Sep 24;2(7152):682-4.

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Are (exogenous) interferons really necessary?

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  1. Are (exogenous) interferons really necessary? Peter Ferenci Medical University of Vienna

  2. Effect of interferon on experimental vaccinia and herpes-simplex virus infections in rabbits' eyes. CANTELL K, TOMMILA V. Lancet. 1960 Sep 24;2(7152):682-4 Treatment ofchronic non-A,non-B hepatitiswithrecombinant human alphainterferon. A preliminaryreportJH Hoofnagle, KD Mullen, DB Jones, V Rustgi, A Di Bisceglie, M Peters, JG Waggoner, Y Park, and EA Jones Volume 315:1575-1578December 18, 1986

  3. Role of interferon-alfa in treatment of hepatitis? • Mode of action • immune-modulatory (dose dependent!) • antiviral • antiproliferative • IFN-sensitivity • IL28B • Nullresponse….

  4. Time Course of VirologicalResponse to IFN Therapy in Patients With CHC 100% Inhibition of viral replication HCV RNA Immune system elimination of infected cells Induction phase Maintenance phase Detection limit 0% 14–28 Days ? Ferenci P 1999 1stdose

  5. NK cellsand response to IFN therapy in patients with CHC Ahlenstiehl et al, Gastroenterology 2011

  6. HCV Life Cycle and DAA Targets Receptor bindingand endocytosis Transportand release Fusion and uncoating ER lumen Virionassembly (+) RNA LD LD LD Translation andpolyprotein processing Membranousweb RNA replication NS3/4 protease inhibitors ER lumen NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside NS5A* inhibitors *Role in HCV life cycle not well defined Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

  7. A n=8/0 Naive 500 mg BID MCB P/R (Peg-IFN + RBV) 100 mg TID DNV 100 mg TID DNV n=8/0 500 mg BID MCB B n=8/2 500 mg BID MCB 500 mg BID MCB 100 mg TID DNV 200 mg TID DNV 1000 mg BID MCB 100 mg TID DNV 1000 mg BID MCB 200 mg TID DNV D n=8/4 1000 mg BID MCB 600 mg BID DNV E n=8/2 TF (non-null) 1000 mg BID MCB 900 mg BID DNV F n=8/2 TF (null) 1000 mg BID MCB 900 mg BID DNV G n=8/2 Naive INFORM-1 study: proof of concept study, combination of a PI (danoprevir, DNV) with the polymerase inhibitor mericitabine (MCB) 1d 4d 7d 14d 48w Active/placebo C n=16/2 TF = IFN-treatment failures Gane EJ et al. Lancet 2010

  8. 1 0 –1 –2 –3 –4 –5 –6 0 2 4 6 8 10 12 14 Median change from baseline by treatment groupCohorts B–G MCB (mg BID) / DNV (mg) Placebo 500 BID / 100 TID 1000 BID / 100 TID 500 BID / 200 TID 1000 BID / 200 TID 1000 BID / 600 BID (pEVR) 1000 BID / 900 BID (TF - Null) 1000 BID / 900 BID (Naive) Median Log10 HCV RNA Change from Baseline (IU/mL) Days Gane EJ et al. Lancet 2010

  9. 7 6 5 4 3 2 1 Naive and Null Responders with a BID Oral Regimen of RG7128 and RG7227 100 88 90 RG7128 1000 mg BID + RG7227 900 mg BID 80 70 63 60 Median Log10 HCV RNA (IU/mL) 50 50 TF - Nulls 40 Naives 30 25 20 Naives Naives Nulls Nulls 10 Limit of Detection 0 <LLOD <LLOQ 1 3 5 7 9 11 13 Days Gane et al, Lancet 2010

  10. GS-9256 + Tegobuvir Alone, With RBV, or With PegIFN/RBV in GT1 Tx-Naive Patients • Phase II study of tegobuvir (GS-9190), an NS5B nonnucleoside polymerase inhibitor, and GS-9256, an NS3 protease inhibitor as part of HCV therapy Wk 48 Wk 4 PR*(n = 16) GS-9256 75 mg BID +Tegobuvir 40 mg BID(n = 16)† Treatment-naive patients with GT1 HCV Part A GS-9256 75 mg BID +Tegobuvir 40 mg BID + RBV*† (n = 15) PR*(n = 15) Part B(nonrandomized) GS-9256 75 mg BID +Tegobuvir 40 mg BID + PR* (n = 15) PR*(n = 15) *PegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day. †PegIFN/RBV started early if virologic breakthrough. Zeuzem S, et al. AASLD 2010. Abstract LB-1.

  11. GS-9256 + Tegobuvir Alone, With RBV, or With PegIFN/RBV: Virologic Response Tegubovir requires both pegIFN and RBV program terminated due to safety issues Zeuzem S, et al. AASLD 2010. Abstract LB-1.

  12. Telaprevir 1125 mg bid VX-222 100 mg bid* Telaprevir 1125 mg bid VX-222 400 mg bid* Telaprevir 1125 mg bid Peg-IFN alfa-2a VX-222 100 mg bid* RBV Peg-IFN alfa-2a RBV Telaprevir 1125 mg bid VX-222 400 mg bid* Peg-IFN alfa-2a RBV ZENITH: telaprevir (PI) + VX-222 (NNI) ± Peg-IFN/RBV in treatment-naive G1 patients Week 0 12 A N=18 B N=29 RVR2-guided Week 36 C N=29 D N=30 * Based on a 10 day healthy volunteer DDI study; when combined with telaprevir,VX-222 doses of 100 mg and 400 mg provide VX-222 plasma exposures equivalent to 250 mg and 750 mg bid. DDI = drug-drug interaction; NNI = non-nucleoside inhibitor; Peg-IFN = peginterferon alfa; PI = protease inhibitor; RBV = ribavirin Nelson D, et al. AASLD 2011. Abstract LB-14.

  13. Telaprevir 1125 mg bid VX-222 100 mg bid* Telaprevir 1125 mg bid VX-222 400 mg bid* Telaprevir 1125 mg bid Peg-IFN alfa-2a VX-222 100 mg bid* RBV Peg-IFN alfa-2a RBV Telaprevir 1125 mg bid VX-222 400 mg bid* Peg-IFN alfa-2a RBV ZENITH: telaprevir (PI) + VX-222 (NNI) ± Peg-IFN/RBV in treatment-naive G1 patients Week 0 12 A N=18 • DUAL regimens terminated B N=29 RVR2-guided Week 36 C N=29 D N=30 * Based on a 10 day healthy volunteer DDI study; when combined with telaprevir,VX-222 doses of 100 mg and 400 mg provide VX-222 plasma exposures equivalent to 250 mg and 750 mg bid. Nelson D, et al. AASLD 2011. Abstract LB-14.

  14. Telaprevir 1125 mg bid VX-222 100 mg bid* Telaprevir 1125 mg bid VX-222 400 mg bid* Telaprevir 1125 mg bid Peg-IFN alfa-2a VX-222 100 mg bid* RBV Peg-IFN alfa-2a RBV Telaprevir 1125 mg bid VX-222 400 mg bid* Peg-IFN alfa-2a RBV Telaprevir 1125 mg bid VX-222 400 mg bid* RBV ZENITH: telaprevir (PI) + VX-222 (NNI) ± Peg-IFN/RBV in treatment-naive G1 patients Week 0 12 A N=18 • DUAL regimens terminated B N=29 RVR2-guided Week 36 C N=29 D N=30 * Based on a 10 day healthy volunteer DDI study; when combined with telaprevir,VX-222 doses of 100 mg and 400 mg provide VX-222 plasma exposures equivalent to 250 mg and 750 mg bid. E/F (E G1b N=23; F G1a N=23) Enrolment complete Nelson D, et al. AASLD 2011. Abstract LB-14.

  15. ZENITH: telaprevir + VX-222 ± Peg-IFN/RBV SVR12 data SVR12, % 24 29 27 30 9 11 14 15 15 13 • No patient in either QUAD arm experienced viral breakthrough. However, 2 patients relapsed in Arm C (7%) and 2 patients (including 1 patient who received only 1 week of treatment) in Arm D (7%) Nelson D, et al. AASLD 2011. Abstract LB-14.

  16. MATTERHORN: study design N= 420 (70 pts/arm) IFN free: MCB 1000mg + DNVr 100/100mg + R A1 F/U Stratification by: • IL28B (CC, CT, TT) • G1a/1b Cohort A:PartialResponders Triple: DNVr 100/100mg + P/R A2 F/U Quad: MCB 1000mg + DNVr100/100mg + P/R A3 F/U IFN free: MCB 1000mg + DNVr 100/100mg + R B1 F/U Cohort B: Null Responders Quad: MCB 1000mg + DNVr100/100mg + P/R B2 F/U Quad: MCB 1000mg + DNVr100/100mg + P/R P/R B3 F/U 12 24 48 72 weeks Phase 2, randomized within cohort, open-label, parallel study of 2 cohorts

  17. MATTERHORN: study design GT1a N= 420 (70 pts/arm) IFN free: MCB 1000mg + DNVr 100/100mg + R A1 F/U Stratification by: • IL28B (CC, CT, TT) • G1a/1b Cohort A:PartialResponders Triple: DNVr 100/100mg + P/R A2 F/U Quad: MCB 1000mg + DNVr100/100mg + P/R A3 F/U GT1a IFN free: MCB 1000mg + DNVr 100/100mg + R B1 F/U Cohort B: Null Responders Quad: MCB 1000mg + DNVr100/100mg + P/R B2 F/U Quad: MCB 1000mg + DNVr100/100mg + P/R P/R B3 F/U 12 24 48 72 weeks Phase 2, randomized within cohort, open-label, parallel study of 2 cohorts

  18. Phase 2b SOUND-C2: BI201335 (PI) + BI207127 (NNI) ± RBV in treatment naive G1 patients BI207127 600 mg tid Follow-up • Randomization stratified by HCV subtype (G1a vs G1b) and IL28B genotype (rs12979860 CC vs non-CC) • 52% of patients were male, 98% White, 38% G1a, 85% had baseline HCV RNA ≥800,000 IU/mL, 10% had compensated cirrhosis, and 25% had IL28B genotype CC BI201335 120 mg qd RBV BI207127 600 mg tid Follow-up BI201335 120 mg qd RBV BI207127 600 mg tid Naive, CHC, G1 N=362 BI201335 120 mg qd RBV BI207127 600 mg bid Follow-up BI201335 120 mg qd RBV BI207127 600 mg tid Follow-up BI201335 120 mg qd Randomization 0 16 28 40 Weeks Zeuzem S, et al. AASLD 2011. Abstract LB-15

  19. SOUND-C2: preliminary SVR in treatment Arm A (16 week treatment duration, BI201335 + BI207127 + RBV in treatment naive G1 patients) (n=81) Proportion of patients (%) Zeuzem S, et al. AASLD 2011. Abstract LB-15

  20. BMS-790052 + BMS-650032 Alone or With PegIFN/RBV in GT1 Null Responders • Open-label, randomized, placebo-controlled phase IIa trial • BMS-790052: NS5A polymerase 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. NEJM 2012.

  21. HCV RNA Levels in Groups A and B. Lok AS et al. N Engl J Med 2012;366:216-224

  22. 0

  23. BMS-790052/BMS-650032 in Japanese G1bnull responders: virological response • 1 subject discontinued at Week 2; HCV RNA was undetectable after 24 weeks’ follow-up • No apparent association between detection of baseline RAVs and virological outcome Patients (%) RVR cEVR EOTR SVR12 SVR24 LLOQ = lower limit of quantification (15 IU/mL); RAV = resistance-associated variants Chayama K, et al. Hepatology 2011; DOI:10.1002/hep.24724.

  24. PSI-7977 ELECTRON: PSI-7977 + RBV study design for treatment-naive G2/3 • Treatment-naive, non-cirrhotic, age ≥18 years • HCV RNA >50,000 IU/mL • Allowed concurrent methadone use • Stratified by HCV genotype and IL28B genotype • Randomized 1:1:1:1 into IFN sparing or IFN-free PSI-7977 + RBV + Peg-IFN N=10 PSI-7977 + RBV + Peg-IFN PSI-7977 + RBV N=10 SVR12 PSI-7977 + RBV + Peg-IFN PSI-7977 + RBV N=10 PSI-7977 + RBV N=10 4 8 12 24 Weeks GaneEJ, et al. AASLD 2011. Abstract 34

  25. PSI-7977 ELECTRON: IFN-free PSI-7977 + RBV achieves 100% SVR12 GaneEJ, et al. AASLD 2011. Abstract 34

  26. CYCLOPHILIN A IS ESSENTIAL FOR HCV REPLICATION AND IS INHIBITED BY ALISPORIVIR Replication of new viral RNA Inhibition of replication NS2 NS2 ALISPORIVIR CypA CypA NS3 NS3 NS4B NS4B NS5B NS5B NS5A NS5A Gallay PA. Clin Liver Dis2009;13:403–417

  27. Phase 2b VITAL-1: alisporivir IFN-free therapy in G2/3 treatment-naive patients Screening Randomization Loading 1 week RVR HCV RNA EVR EOTR SVR12 SVR24 ALV1000 ALV 600 mg bid ALV 1000 mg qd ALV 600 mg qd+ RBV 400 mg bid + Peg-IFN sc weekly ≥25 IU/mL ≥25 IU/mL ≥25 IU/mL ≥25 IU/mL ALV 600 mg bid + RBV 400 mg bid ALV600R ALV 600 mg qd + RBV 400 mg bid ALV 600 mg qd+ RBV 400 mg bid + Peg-IFN sc weekly ALV 600 mg bid + RBV 400 mg bid ALV800R ALV 800 mg qd + RBV 400 mg bid ALV 600 mg qd+ RBV 400 mg bid + Peg-IFN sc weekly ALV 600 mg bid + Peg-IFN sc weekly ALV-P ALV 600 mg qd + Peg-IFN 180 mg sc weekly ALV 600 mg qd+ RBV 400 mg bid + Peg-IFN sc weekly PR RBV 400 mg bid + Peg-IFN 180 mg sc weekly BL 1 4 6 12 24 36 48 Week Viral response defined by HCV RNA < 25 IU/mL; sc = subcutaneous injection Pawlotsky JM, et al. AASLD 2011. Abstract LB-11

  28. Phase 2b VITAL-1: ALV IFN-free treatment maintains HCV RNA negative response to week 12 RCR patients On IFN-free treatment Non-RCR patients with Add-on IFN from week 6 100% 100 100 98% 92% 80 80 ALV 1000 mg (n=22) ALV 1000 mg (n=55) ALV 600 mg + RBV (n=49) ALV 600 mg + RBV (n=30) 60 60 Proportion of patients (%) Proportion of patients (%) ALV 800 mg + RBV (n=51) ALV 800 mg + RBV (n=37) 40 40 20 20 0 0 0 0 2 2 4 4 6 6 8 8 10 10 12 12 Week Week IFN-free week 12 results: ALV1000 26%; ALV800R 37%; ALV600R 41% Add-on IFN to non-RVR patients shows rapid response Viral response by <LOQ; Analysis for patients who had Week 12 HCV RNAassessment Pawlotsky JM, et al. AASLD 2011. Abstract LB-11

  29. Summary IFN-free therapy • All combinations in early development • SVR close to 100% in G1b • SVR 100% Genotype 2/3 patients • RBV required • Shortening of treatment • role of IL28B Polymorphisms?

  30. Outlook IFN-free therapy • If no new safety signals are detected IFN-free therapy of hepatitis C may became reality in 2015

  31. Outlook IFN-free therapy and we have reached the “holy grail” of hepatology • If no new safety signals are detected IFN-free therapy of hepatitis C may became reality in 2015

  32. NK cells in HCV infectionand response to IFN therapy in patients with CHC

  33. NK cellsand response to IFN therapy in patients with CHC Ahlenstiehl et al, Gastroenterology 2011

  34. cellular response to HCV infection IFN production HCV IFN receptor virusactivated kinase IRF-3 IRF-7 IFN responding genes antiviral proteins

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