The HCV pipeline: Will IFN-free treatment be possible? Heiner Wedemeyer. Hannover Medical School Germany

Transcription

1 : Will IFN-free treatment be possible? Heiner Wedemeyer Hannover Medical School Germany

2 Interferon-free regimens to treat hepatitis C What should be the goal of interferon-free treatment regimens: Sustained suppression of viral replication or cure of HCV infection? Can chronic HCV infection be cured without interferon alpha? Which DAA combinations have already been studied in clinical trials? What will be the major challenges for interferon-free treatment regimens?

3 Interferon-free regimens to treat hepatitis C What should be the goal of interferon-free treatment regimens: Sustained suppression of viral replication or cure of HCV infection?

4 HCV HIV HCV HBV

5 Immune Control of HCV Is Possible! Spontaneous clearance of acute hepatitis C in 10%-50% of cases HCV-specific T-cell responses are associated with recovery from acute hepatitis C Interferon alpha monotherapy is highly effective if HCV infection is treated early

6 Long-Term follow-up after treatment of chronic hepatitis C: Long-term SVR in >98% of cases!

7 Can chronic HCV infection be cured without interferon alpha? YES: The proof-of-concept studies

8 HCV Cure by treatment with a PI + Pol.Inh. 3 Chimps 4 weeks combination MK MK weeks monotherapy MK Chimp with Sustained Virological Response! D. Olsen et al., Antimicrob Agents Chemother. 2011

9 Patel & Heathcote, GUT 2010

10 BMS BMS : AI AI447011: phase IIa study of BMS plus BMS , with or without PegIFN/RBV, for 24 weeks in HCV genotype-1 null responders A n=11 Cure of HCV-infection w/o IFNa!! BMS mg QD + BMS mg BID Follow-up SVR12 4/11 B n=10 BMS mg QD + BMS mg BID + PR Follow-up 10/10 Week Lok A, et al. NEJM 2012

11 DAA combinations in clinical trials

12 IFN-free DAA combination therapies Entry-Inhibitors TLR-Agonists Therapeutic Vaccine Other IFNs PEG-IFN lambda Ribavirin NS5A-Inhibitors Protease- Inhibitors Cyclophillin Inhibitors Polymeraseinhibitors NI NNI

13 DAAs against HCV in clinical development Protease-Inhibitors 2nd wave vs. 2nd generation Polymerase Inhibitors Non-nucleos(t)ides Polymerase Inhibitors nucleos(t)ides NS5A Inhibitors Cyclophilin Inhibitors Potency Pan-genotype efficacy Resistance Barrier Potency Pan-genotype efficacy Resistance Barrier Potency Pan-genotype efficacy Resistance Barrier Potency Pan-genotype efficacy Resistance Barrier Potency Pan-genotype efficacy Resistance Barrier +++ +/++ +/ (-) + (-) / /++ +/++ +/

14 Interferon-free Combination Treatment Protease Inhi. Nuc. Polym. Inh. Non-Nuc NS5A Inhib Cyclophilin Inhibitors Protease Inhi. Mericitabine Danoprevir Several trials +/-RBV (e.g. BI, Gilead) Several trials (e.g. BMS BMS ) Nuc. Polym. Inhib. PSI PSI 938 PSI 7977 BMS Non-Nuc NS5A Inh Ribavirin PSI RBV Alisporivir + RBV

15 Non-Nucs + Protease inhibitors

16 Protease inhibitor GS non-nuc-pol. Inhibitor tegobuvir Zeuzem et al., Hepatology 2011

17 Protease inhibitor GS non-nuc-pol. Inhibitor tegobuvir + RBV Zeuzem et al., Hepatology 2011

18 Protease inhibitor GS non-nuc-pol. Inhibitor tegobuvir + RBV + IFN Zeuzem et al., Hepatology 2011

19 28 days of treatment with BI (Prot. Inh) + BI (NNI) + Ribavirin Treatment day BI mg/ BI /RBV BI / PegIFN/RBV Zeuzem et al., Gastroenterology 2011

20 SOUND C2 Study: BI BI RBV SVR data for 16 weeks of treatment Proportion of patients (%) mg TID 600 mg TID /15 17/17 14 a / /17 11/15 16 b /17 RVR EoT SVR Zeuzem et al., AASLD 2011, LB Poster

21 NS5A inhibitor + Protease inhibitor

22 BMS BMS : AI AI447011: phase IIa study of BMS plus BMS , with or without PegIFN/RBV, for 24 weeks in HCV genotype-1 null responders A n=11 B n=10 Cure of HCV-infection w/o IFNa!! BMS mg QD + BMS mg BID No Cure in 7/11 patients!!! BMS mg QD + BMS mg BID + PR Follow-up Follow-up SVR12 4/11 10/10 Week 24 Genotype 1a: cure in 2/9 patients Genotype 1b: cure in 2/2 patients Lok A, et al. NEJM

23 BMS BMS Japanese patients all infected with HCV genotype 1b all null responder to prior IFN-based treatment 24 weeks of treatment (60mg once daily) (600/200 mg twice daily) 9 patients completed treatment: 9/9 SVR12 1 patient stopped after 2 weeks: SVR Chayama et al., Hepatology 2011 (epub ahead of print)

24 Nucleos(t)ide Polym. Inhibitor + Protease Inhibitor

25 Combination of Danoprevir and RG7128 Protease inhibitor and nuc-pol-inh. Treatment duration: 14 Days Gane et al., Lancet 2010

26 Nucleos(t)ide Polym. Inhibitor + RBV

27 Ed Gane et al., AASLD 2011

28 PSI % cure in HCV Genotyp 2/3 Patients!! Ed Gane et al., AASLD 2011

29 Challenges?

30 Challenges for IFN-free treatment regimens Resistance (difference between genotype 1a vs. 1b!) Pan-genotype activity

31 Telaprevir has some antiviral efficacy against HCV genotype 2 but not against genotype 3 Genotype 2 Genotype 3 Telaprevir Monotherapy Telaprevir Monotherapy Foster G et al, Gastroenterology 2011; 141:

32 Boceprevir has some antiviral efficacy against HCV genotype 2 and genotype 3 4 pts. Genotype 3 2 pts. Genotype 2 Silva M et al, APASL 2011

33 Log 10 HCV RNA Change from Baseline (IU/mL) MK 5172: A protease inhibitor with pan-genotypic acitivity Placebo N=8 MK mg N=5 MK mg N=5 GENOTYPE 3 PATIENTS Dosing Complete MK mg N=5 MK mg N=5 MK mg N=5 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 12 Day 15 Time Petry et al. AASLD 2011

34 Other classes of DAAs with proven activity against HCV genotypes 2 & 3 Nucleos(t)idic polymerase inhibitors e.g. PSI 7977: 10/10 patients with SVR after 12 weeks of PSI7977/Ribavirin therapy (no PEG-IFNa) (Gane et al., AASLD 2011) Cyclophilin inhibitors e.g. Alisporivir: 32-49% of patients HCV-RNA negative after 6 weeks of Alisporivir +/-RBV therapy (Pawlotsky et al., AASLD 2011)

35 Challenges for IFN-free treatment regimens Resistance (difference between genotype 1a vs. 1b!) Pan-genotype activity how long to treat? 8w vs. 12w vs. 16w. vs. 24w vs. xx vs. maintenance therapy

36 Challenges for IFN-free treatment regimens Resistance (difference between genotype 1a vs. 1b!) Pan-genotype activity how long to treat? Drug-Drug interactions

37 Challenges for IFN-free treatment regimens Resistance (difference between genotype 1a vs. 1b!) Pan-genotype activity how long to treat? Drug-Drug interactions Toxicity Anemia Rash

38 Challenges for IFN-free treatment regimens Resistance (difference between genotype 1a vs. 1b!) Pan-genotype activity how long to treat? Drug-Drug interactions Toxicity Drug burden / adherence to therapy

39 Challenges for IFN-free treatment regimens Resistance (difference between genotype 1a vs. 1b!) Pan-genotype activity how long to treat? Drug-Drug interactions Toxicity Drug burden / adherence to therapy role of host genes, decompensated liver disease, liver transplantation, dialysis, costs, substance user,.

40 Treatment of Hepatitis C /5