Direct acting anti-virals: the near future

Transcription

1 Direct acting anti-virals: the near future Heiner Wedemeyer Hannover Medical School Germany

2 Will IFN-free treatment be possible in the near future?

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? 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?

4 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?

5 HCV HIV HCV HBV

6 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

7 Vaccine Development for Hepatitis C Virus infection Torresi, Johnson & Wedemeyer, J Hepatol 2011

8 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

9 Early Treatment with Interferon alpha Monotherapy Leads to Cure in 9/10 Patients with Acute Hepatitis C Jaeckel E et al. N Engl J Med. 2001;345: Wiegand J et al. Hepatology. 2006;43: No Late Relapse! Wiegand J et al. Hepatology. 2004;40: Quality of T cell responses is associated with treatment response Wiegand J et al. Antiviral Therapy 2007

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

11 Can chronic HCV infection be cured without interferon alpha?

12

13 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

14 Patel & Heathcote, GUT 2010

15 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. EASL Abstract 1356

16 Can HCV be cured in the absence of a functional immune system?

17 PI + low dose Pol-Inh PI + Pol-Inh + IFNa Ohara et al., J Hepatol 2011

18 PI + low dose Pol-Inh PI + Pol-Inh + IFNa Ohara et al., J Hepatol 2011

19 PI + high dose Pol-Inh = Cure w/o IFNa in immunodeficient mice! Ohara et al., J Hepatol 2011

20 DAA combinations in clinical trials

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

22 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

23 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 +++ +/++ +/ (-) + (-) / /++ +/++ +/

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25 Individualized Treatment in 2018?

26 Individualized Treatment in 2014????

27 Interferon-free Combination Treatment Protease Inhi. Nukl. 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 ) Nukl. Polym. Inhib. PSI PSI 938 PSI 7977 BMS Non-Nuc NS5A Inh Ribavirin PSI RBV Alisporivir + RBV

28 Non-Nucs + Protease inhibitors

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

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

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

32 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

33 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

34 SOUND C2 Study: BI BI (+ RBV) IL28B and week 12 response

35 NS5A inhibitor + Protease inhibitor

36 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. EASL Abstract

37 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)

38 Cyclophilin inhibitor + RBV Pawlotsky et al., AASLD 2011, LB Poster

39 VITAL-1: Treatment arms ALV loading* RVR at W4 W12 W24 SVR12 SVR24 W6 ALV 1000 mg RVR ALV 1000 mg QD ALV 600 mg + RBV Continue on IFNfree or add-on IFN No RVR ALV 600 mg QD + PegIFN/RBV RVR ALV 600 mg + RBV No RVR ALV 600 mg + PegIFN/RBV Main objective: Proportion HCV RNA negative ALV 1000 mg QD ALV 600 mg QD + RBV ALV 800 mg QD + RBV ALV 800 mg + RBV RVR ALV 800 mg + RBV Effect of add-on IFN treatment No RVR ALV 600 mg + PegIFN/RBV ALV 600 mg + PegIFN RVR ALV 600 mg + PegIFN No RVR ALV 600 mg + PegIFN/RBV Exploratory: Safety of PegIFN-based treatment PegIFN + RBV PegIFN + RBV *Loading dose: ALV 600 mg BID for 1 week; RVR by LOQ (<25 IU/mL) after 4 weeks of treatment 39

40 Up to 50 half of patients on IFN-free treatment achieve undetectable RNA at week 6 Beyond Week 4, HCV RNA negative rates increase with IFN-free therapy ALV+RBV show higher responses Longer duration of ALV IFN-free treatment could achieve higher proportion with undetectable HCV RNA Viral response by <LOQ; Analysis for patients who had Week 12 HCV RNA assessment, patients with HCV RNA assessments missing at Week 12 are excluded 40

41 ALV IFN-free treatment is successful in maintaining HCV RNA negative response to Week 12 RVR patients on IFN free treatment Non-RVR patients with add-on IFN from week 6 IFN-free week 12 results: ALV100 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 RNA assessment, 41

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

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

44 Nucleos(t)ide Polym. Inhibitor + RBV

45 Ed Gane et al., AASLD 2011

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

47 Challenges?

48 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

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

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

51 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

52 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,.

53 Treatment of Hepatitis C /5