: Will IFN-free treatment be possible? Heiner Wedemeyer Hannover Medical School Germany
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?
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?
HCV HIV HCV HBV
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
Long-Term follow-up after treatment of chronic hepatitis C: Long-term SVR in >98% of cases!
Can chronic HCV infection be cured without interferon alpha? YES: The proof-of-concept studies
HCV Cure by treatment with a PI + Pol.Inh. 3 Chimps 4 weeks combination MK7009 + MK0608 8 weeks monotherapy MK7009 1 Chimp with Sustained Virological Response! D. Olsen et al., Antimicrob Agents Chemother. 2011
Patel & Heathcote, GUT 2010
BMS-790052 + BMS-650032: AI447011 AI447011: phase IIa study of BMS-790052 plus BMS-650032, 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-790052 60 mg QD + BMS-650032 600 mg BID Follow-up SVR12 4/11 B n=10 BMS-790052 60 mg QD + BMS-650032 600 mg BID + PR Follow-up 10/10 Week 24 48 72 Lok A, et al. NEJM 2012
DAA combinations in clinical trials
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
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 +++ +/++ +/++ +-++ + (-) + (-) +-+++ +++ ++/+++ +++ +/++ +/++ +/++ +++ ++
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 790052 BMS 650032) Nuc. Polym. Inhib. PSI 7977 + PSI 938 PSI 7977 BMS790052 Non-Nuc NS5A Inh Ribavirin PSI 7977 + RBV Alisporivir + RBV
Non-Nucs + Protease inhibitors
Protease inhibitor GS 9256 + non-nuc-pol. Inhibitor tegobuvir Zeuzem et al., Hepatology 2011
Protease inhibitor GS 9256 + non-nuc-pol. Inhibitor tegobuvir + RBV Zeuzem et al., Hepatology 2011
Protease inhibitor GS 9256 + non-nuc-pol. Inhibitor tegobuvir + RBV + IFN Zeuzem et al., Hepatology 2011
28 days of treatment with BI 201335 (Prot. Inh) + BI 207127 (NNI) + Ribavirin 100000000 10000000 1000000 100000 10000 1000 100 0 4 8 12 16 20 24 28 32 36 40 44 Treatment day BI 207127 600 mg/ BI 201335/RBV BI 201335/ PegIFN/RBV Zeuzem et al., Gastroenterology 2011
SOUND C2 Study: BI 207127 + BI 201335 + RBV SVR data for 16 weeks of treatment Proportion of patients (%) 100 80 60 40 20 0 73 400 mg TID 600 mg TID 100 100 93 94 11/15 17/17 14 a /15 73 17/17 11/15 16 b /17 RVR EoT SVR Zeuzem et al., AASLD 2011, LB Poster
NS5A inhibitor + Protease inhibitor
BMS-790052 + BMS-650032: AI447011 AI447011: phase IIa study of BMS-790052 plus BMS-650032, 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-790052 60 mg QD + BMS-650032 600 mg BID No Cure in 7/11 patients!!! BMS-790052 60 mg QD + BMS-650032 600 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 2012 48 72
BMS-790052 + BMS-650032 10 Japanese patients all infected with HCV genotype 1b all null responder to prior IFN-based treatment 24 weeks of treatment 790052 (60mg once daily) 650032 (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)
Nucleos(t)ide Polym. Inhibitor + Protease Inhibitor
Combination of Danoprevir and RG7128 Protease inhibitor and nuc-pol-inh. Treatment duration: 14 Days Gane et al., Lancet 2010
Nucleos(t)ide Polym. Inhibitor + RBV
Ed Gane et al., AASLD 2011
PSI 7977 100% cure in HCV Genotyp 2/3 Patients!! Ed Gane et al., AASLD 2011
Challenges?
Challenges for IFN-free treatment regimens Resistance (difference between genotype 1a vs. 1b!) Pan-genotype activity
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: 881-889
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
Log 10 HCV RNA Change from Baseline (IU/mL) 1 0-1 -2-3 -4-5 -6 MK 5172: A protease inhibitor with pan-genotypic acitivity Placebo N=8 MK-5172 100 mg N=5 MK-5172 200 mg N=5 GENOTYPE 3 PATIENTS Dosing Complete MK-5172 400 mg N=5 MK-5172 600 mg N=5 MK-5172 800 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
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)
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
Challenges for IFN-free treatment regimens Resistance (difference between genotype 1a vs. 1b!) Pan-genotype activity how long to treat? Drug-Drug interactions
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
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
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,.
Treatment of Hepatitis C 2011 2014/5