Future HCV Treatment: Interferon-sparing. Ed Gane NZ Liver Transplant Unit

Transcription

1 Future HCV Treatment: Interferon-sparing Combination DAA therapy Ed Gane NZ Liver Transplant Unit

2 % SV VR (cure e) Protease Inhibitor plus Peg-IFN/RBV Triple Therapy in Treatment-Naïve Gt1 ADVANCE p Phase py III Telaprevir Study SPRINT-2 Phase III Boceprevir Study Triple Therapy new Standard-of-Care 100% 100% But limited efficacy in many populations: 75% 50% White patients only 1. IFN contraindicated, 75% not tolerated 69% 75% 68% 67% 2. Non-1 HCV genotype 3. Null responders to Peg-IFN/RBV 44% 50% 40% 4. Nonresponders to Triple Therapy % SV VR (cure e) 25% 25% 0% 0% SOC TVR8+PR RG 24wks TVR12+PR RG 24wks Jacobson I, et al. Hepatology 2010; 52: 427A SOC BCV+PR 48wks BCV+PR RG-24wks Poordad F, et al. Hepatology 2010; 52: LB4

3 What about Combining two Direct Antivirals? The INFORM-1 Study Combination therapy with a nucleoside polymerase (RG7128) and protease inhibitor (danoprevir) in HCV EJ Gane, SK Roberts, CA Stedman, PW Angus, B Ritchie, R Elston, D Ipe, PN Morcos, I Najera, T Chu, MM Berrey, WZ Bradford, NS Shulman, PF Smith Auckland Clinical Studies, Auckland, New Zealand; The Alfred, Melbourne, Australia: Christchurch Clinical Studies, Christchurch, New Zealand; Austin Hospital, Heidelberg, Australia; Royal Adelaide Hospital, Adelaide, Australia; Roche Palo Alto LLC, Palo Alto, CA; Pharmasset, Inc., Princeton, NJ; Intermune, Inc., Brisbane, CA, USA Gane E, et al. Lancet 2010; 376:

4 Will adding Polymerase Inhibitor to the Protease Inhibitor prevent resistance? Different mechanisms of action:» RG7128 is a Nucleoside Polymerase inhibitor» Danoprevir is an NS3/4A protease inhibitor No cross-resistance resistance in vitro Replicon Model»No resistance Tan. AASLD 2008; A 1885 In the INFORM-1 Study 74 pts treated for 14 days Noviral breakthrough No resistance mutations in NS3 or NS5B regions Gane E, et al. Lancet 2010; 376:

5 Will combining protease inhibitor with polymerase inhibitor better than either alone? log 10 HC CV RNA chang ge (IU/m ml) Mean Placebo Start polymerase D0 Add protease D3 Start protease D0-2 Add polymerase ` D Day Start both protease p y 0.5 log 1.8 log 2.3 Antiviral Synergism? AND polymerase D0 2.9 log Gane E, et al. Lancet 2010; 376:

6 Will adding a combination DAA be as effective in previous nonresponders? 7 g 10 HCV RNA (IU U/mL) Me edian Lo 6 Nuc Polymerase inhibitor RG g bid plus Protease inhibitor RG mg bid 5 4 Treatment Naïve patients (n=32) 3 Null Responders to Peg-IFN/ribavirin (n=16) 2 1 Limit of Detection Days Gane E, et al. Lancet 2010; 376:

7 Will Protease plus Polymerase inhibitor be better than Protease plus Peg-IFN/RBV IFN/RBV? 7 Me edian log 10 HCV RNA (IU/ /ml) Danoprevir 900mg bid+ RG mg bid Limit of Detection Danoprevir 900mg bid + Peg-IGN + ribavirin Day 16% <LLOD 65% <LLOD Gane E, et al. Lancet 2010; 376: Forestier et al. J Hepatol 2009;50: A1847

8 Will Combination Direct Acting Antiviral agents cure HCV without IFN? Host cell HBV HIV HCV Viral RNA cccdna Proviral DNA Host DNA Nucleus TREATMENT TREATMENT Lifelong suppression Lifelong suppression of HBV replication 1 of HIV replication 2 TREATMENT No reservoir of infection HCV clearance CURE 1. Pawlotsky JM. J Hepatol 2006;44:S10-S13; 2. Siliciano JD, Siliciano RF. J Antimicrob Chemother 2004;54:6-9;

9 Will Combo DAAs cure HCV without IFN? Human hepatocyte chimeric mice infected with Gt1b Telaprevir plus low-dose Nuc polymerase inhibitor MK-0608 prevents rebound in 4/4 mice HCV RNA (copies/ml) 10 9 Telaprevir (200 mg/kg) MK-0608 (3 mg/kg) (weeks) Ohara E, et al J Hepatol 2010; online 28 Oct

10 Will Combo DAAs cure HCV without IFN? 28 days Telaprevir plus high-dose MK-0608 eradicates HCV infection in 5/5 mice HCV RNA (log copy/ml) Telaprevir (200 mg/kg) MK-0608 (50 mg/kg) <3 Ohara E, et al J Hepatol 2010; online 28 Oct 0W 2W 4W After 4W After 12W After 18W (weeks)

11 Will Combo DAAs cure HCV without IFN? 35 days MK-7009 (protease inhibitor) plus MK-0608 (Nuc polymerase) eradicates HCV in 1/3 chimps 6 5 MK-7009 PLUS MK-0608 MK-7009 monotherapy IU/mL log Chimp A Chimp B Chimp C 1 LOQ Day Merck On File

12 What duration of combination DAA will be needed to eradicate HCV in patients? Typical HCV patient:»baseline VL = 10 6 virions/ml»total Body Water = 15 litres»total viral burden = virions Eradication (<1 virus) =11 log reduction Combination R7128/R7227:»1st Phase: ~3.5 Logs in 1.5 days» 2nd Phase: ~1 1l log per week Duration of Therapy 8-10 wks

13 Will Combo DAAs cure HCV without IFN? HCV impairs immune response»ns3/4a inhibits TLR-3 signaling g and IRF-3 translocation restored by protease inhibitors»ns5a inhibits PKR activation and induces IL8 production IP-10 (ng/ml l) Sklan Gastro & Hepatol 2009;6: HCV increases IP-10 levels exhausts h t endogenous IFN»rapidly normalise with DAA Gane Lancet 2010; 376: D0 D3 D3 D14 D14 D0 D3 D14 D0 D3 D14 D0 D3 D14 Will profound viral suppression reconstitute host immunity? IFN relapsers IFN null responders treatment naïve placebo

14 Will IL28B influence response to DAA? HC CV RNA (log1 10 IU/m ml) IU/mL) HCV RNA (log 10 Phase 2a study of PSI mg OD »28 days triple therapy followed by SOC No impact of IL28B on early viral kinetics during PSI-7977 therapy CC CT TT PSI mg OD Peg-IFN 2a 180 g/wk plus RBV 1-1.2g/day Study weeks Week McHutchison, J et al. Hepatology 2010; 52: 815A

15 Planned Combination DAA trials in HCV GT1 Infection DAA (1) NS3/4a Protease NS3 protease inhibitor (Telaprevir ) DAA (2) NS5B Polymerase Nonnucleoside NS5B inhibitor (VX-222) NS3 protease inhibitor (GS9256) Nonnucleoside NS5B inhibitor (GS9190) NS3 protease inhibitor (BI201335) Nonnucleoside NS5B inhibitor(bi297127) NS3 protease inhibitor (ABT-450) Nonnucleoside NS5B inhibitor (ABT-072) NS3 protease inhibitor (ABT-450) Nonnucleoside NS5a inhibitor NS3 protease inhibitor (MK-7009) Nonnuc polymerase inhibitor (MK-3281) NS3 protease inhibitor (BMS650032) NS5a inhibitor (BMS ) 1. Most include arms ± Ribavirin 2. All shorten duration from 48 wks 12 wks

16 NS3 protease inhibitor GS-9256 plus Non-Nuc Nuc NS5B inhibitor Tegobuvir Open-label, randomized, placebo-controlled phase IIa trial in treatment-naive HCV GT 1 Wk 4 Wk patients with GT1 HCV GS mg BID + Tegobuvir 40 mg BID (n = 15) GS mg BID + Tegobuvir 40 mg BID + RBV (n = 13) GS mg BID + Tegobuvir 40 mg BID + Peg-IFN/RBV (n = 14) Peg-IFN/RBV (n = 16) Peg-IFN/RBV (n = 15) Peg-IFN/RBV (n = 15) Zeuzem S, et al. Hepatology 2010; 52: LB-1.

17 HC CV RN NA IU/ /ml (L Log 10 ) Antiviral Response se GS tegobuvir (Arm 1) Day of fdosing 1/15 (<25 IU/mL) Zeuzem S, et al. Hepatology 2010; 52: LB-1.

18 Antiviral Response se GS tegobuvir + RBV (Arm 2) HC CV RN NA IU/ /ml (L Log 10 ) Day of fdosing 5/13 (<25 IU/mL) Zeuzem S, et al. Hepatology 2010; 52: LB-1.

19 Antiviral Response se GS tegobuvir + PegIFN/RBV (Arm 3) ml (L Log 10 ) HC CV RN NA IU/ Day of fdosing 14/14 <25 IU/mL 14/14 < 25 IU/mL 13/14 < 10 IU/mL Zeuzem S, et al. Hepatology 2010; 52: LB-1.

20 Tegobuvir + GS-9256 Week 4 Interim Analysis with RN NA <25 IU/mL Prop ortion L100% 75% 50% 25% 0% 100% 71% 54% 31% 15% 14% 7% 7% 7% D0 D7 D14 D28 D0 D7 D14 D28 D0 D7 D14 D28 TEG/9256 TEG/9256/RBV TEG/9256/PEG/RBV Zeuzem S, et al. Hepatology 2010; 52: LB-1.

21 Tegobuvir + GS-9256 in HCV GT1 Resistant mutations Population sequencing for NS3 and NS5b Tegobuvir+GS9256 Tegobuvir+GS9256 +Ribavirin Tegobuvir+GS9256 +Ribavirin+Peg-IFN No mutation Single mutant NS3 Dual mutants NS3 and NS5 Multiple Zeuzem S, et al. Hepatology 2010; 52: LB-1.

22 NS3 protease inhibitor BMS plus NS5A inhibitor BMS Open-label, randomized, placebo-controlled phase IIa trial in HCV GT 1 prior null-responders Wk 24 Wk null responders with GT1 HCV BMS mg QD + BMS mg BID (n = 11) BMS mg QD + BMS mg BID + PR* (n = 10) Follow-up Follow-up Lok A, et al. Hepatology 2010; 52: 877A. Abstract LB-8.

23 NS3 protease inhibitor BMS plus NS5A inhibitor BMS Group A BMS /BMS Group B: Peg-IFN+RBV+ BMS /BMS HCV RNA (log10 IU U/mL) Breakthrough in 55% dual vs 0% quad Rx 6» developed as early 5 as 3 weeks» both NS3 and NS5a 4 mutations» all were HCV GT1a3 HCV RNA (log10 IU U/mL) Weeks Weeks Lok A, et al. Hepatology 2010; 52: 877A. Abstract LB-8.

24 Potential Pitfalls for DAA Combinations Overlapping toxicities Drug-drug interactions (esp PIs, ritonivir) High pill burden non-adherence Reduced activity across target population»genotype 1a vs. 1b»Genotypes 2 vs. 3 Low barrier to resistance»low antiviral potency»low binding affinity for target»pre-existing existing single and double mutants

25 in vivo Resistance to DAAs Prevalence in untreated population NS3 and NS5b sequences from 405 treatment-naïve naïve pts, sequenced for known drug resistance mutations frequency of mutations ranged from 0.5-5% 5% Genotype 1a Genotype 1b Genotype 3 11% 16% 21% 7% 77% 55% 58% 35% 21% 0% <1% <1% NS3 Protease Non-nuc NS5B Nuc NS5B Nil Gaudieri S, et al. Hepatology 2009; 49:

26 in vitro Resistance to DAAs 14 Days Monotherapy (Replicon) Protease Inhibitor Nonnucleoside Polymerase inhibitor Nucleoside Polymerase inhibitor McCown et al. Antimicrob Agents Chemother 2008;52:

27 Purine Nucleoside analog (PSI-7977) plus NS5a inhibitor (BMS BMS ) Collaboration between Pharmasset and BMS Includes HCV Genotypes 1, 2, and 3 24 weeks duration SVR Endpoint Commence Q2 2011

28 Combining 2 Nucleoside NS5B inhibitors in vitro Resistance to DAAs Protease inhibitor + Non-nuc NS5B Protease inhibitor + Purine nuc NS5B Pyrimidine nuc NS5B + Purine nuc NS5B Zennou V, et al. J Hepato 2010; 52: S401: Abstract 1034.

29 PSI-7977 plus PSI-938 in HCV GT1 First combination of pyrimidine + purine Nucs»14 days in 40 HCV GT1»Safety, PK, & viral kinetics Nuc combo N=10 Day 0 Day 7 Day 14 PSI mg QD Status COMPLETED N=10 N=10 N=10 PSI mg QD PSI PSI-938 PSI mg QD PSI PSI-938 PSI PSI-938 ENROLLING

30 Current/Future Combination DAA trials in HCV GT1 Infection DAA (1) DAA (2) NS3 protease inhibitor (Telaprevir ) Nonnucleoside NS5B inhibitor (VX-222) NS3 protease inhibitor (GS9256) Nonnucleoside NS5B inhibitor (GS9190) NS3 protease inhibitor (BI201335) Nonnucleoside NS5B inhibitor(bi297127) NS3 protease inhibitor (ABT-450) Nonnucleoside NS5B inhibitor (ABT-072) NS3 protease inhibitor (ABT-450) Nonnucleoside NS5a inhibitor NS3 protease inhibitor (MK-7009) Nonnuc polymerase inhibitor (MK-3281) NS3 protease inhibitor (BMS650032) NS5a inhibitor (BMS ) Pyrimidine Nuc NS5B inhibitor (RG7128) NS3 protease inhibitor (Danoprevir) Pyrimidine idi Nuc NS5B inhibitor (IDX184 NS3 protease inhibitor (IDX320) Pyrimidine Nuc NS5B inhibitor (PSI-7977) NS5a inhibitor (BMS ) Pyrimidine idi Nuc NS5B inhibitor (PSI-7977) Purine Nuc NS5B inhibitor (PSI-938)

31 Potential Combination DAA trials in HCV GT2/3 infection DAA (1) DAA (2) Nuc Polymerase NS5B Other Pyrimidine idi nucleoside NS5B Ribavirini i Pyrimidine nucleoside NS5B Pyrimidine nucleoside NS5B Pyrimidine nucleoside NS5B NS5A inhibitor Cyclophillin Inhibitor Purine nucleotide NS5B

32 P : IFN-sparing study in GT2/3 40 IFN-naïve GT2/3 pts (stratified HCV and IL28B)» 12 weeks PSI RBV ± PEG» SVR Primary Endpoint A N=10 B N=10 Wk PEG-IFN PSI-7977 RBV PSI-7977 RBV follow-up fll follow-up C N=10 PSI-7977 RBV PEG-IFN follow-up PSI-7977 D RBV N=10 PEG-IFN follow-up Viral breakthrough SOC rescue

33 Combination Direct Acting Antivirals in HCV Summary Combinations of potent DAAs with low barriers to resistance will fail without IFN/RBV because of rapid emergence of dual resistance IFN-free combination DAA regimen will require at least one with high barrier to resistance such as Nuc NS5B and Cyclophyllin B inhibitors Roles of both Ribavirin and IL-28B genotype in determining early response and relapse after IFN-free DAA therapy are still to be determined Further studies should include effects of rapid viral decline on innate and adaptive immunity

34 Combination Direct Acting Antivirals in HCV Conclusion Combination DAAs should provide a short duration, IFN-free, oral regimen for all HCV+ patients including those unsuitable for, or nonresponders to current and future SOC Better tolerated, more effective Rx treatment uptake global health global health burden

35 Thanks to INFORM study team: Catherine Stedman, Stuart Roberts, Peter Angus, and Nancy Shulman and Patrick Smith (Roche PA) Michelle Berrey, Bill Symonds, Pharmasset John McHutchison, Gilead Pharmaceuticals Greg Dore, NCHECR, Sydney y Kazuaki Chayama, Hiroshima