Hepatitis C Therapy Falk Symposium September 20, 2008

Transcription

1 Hepatitis C Therapy Falk Symposium September 20, 2008 Ira M. Jacobson, MD Vincent Astor Professor of Clinical Medicine Chief, Division of Gastroenterology and Hepatology Medical Director, Center for the Study of Hepatitis C Weill Medical College of Cornell University Attending Physician New York Presbyterian Hospital New York, NY USA

2 The Evolution of HCV Therapy: The Goal is Virologic Cure SVR (%) IFN 6m IFN 12m IFN/RBV 6m IFN/RBV 12m PEG-IFN 12m PEG-IFN /RBV 12m Strader DB, et al. Diagnosis, Management, and Treatment of Hepatitis C. Hepatology 2004;39:

3 The Phases in the Evolution of HCV Therapy The Empiric Phase The Refinement Phase Optimal dosing Viral kinetics Challenging populations Nonresponders The Phase of Specifically Targeted Antiviral Therapy For HCV (STAT-C) The Final Phase: Small Molecule Combinations??? Weisberg IW, Sigal SH, Jacobson IM. Current Hepatitis Reports 2007;6:75-82

4 IDEAL Study: PEG 2a Compared With PEG 2b U.S. Treatment Naïve, Genotype 1 Screening N=1019 PEG-IFN α-2b 1.5 µg/kg/wk + Ribavirin mg/d x 48 Weeks N=1016 PEG-IFN α-2b 1.0 µg/kg/wk + Ribavirin mg/d x 48 Weeks N=1035 PEG-IFN α-2a 180 µg/wk + Ribavirin mg/d x 48 Weeks Follow-up 24 Weeks Follow-up 24 Weeks Follow-up 24 Weeks Stratified by baseline viral load (> or 600,000 IU/mL) and race (African American) Standard response stop criteria applied at weeks 12 (No EVR) and 24 (HCV-RNA +) Sulkowski M et al, EASL 2008

5 Proportion of Subjects With Undetectable HCV-RNA (ITT) PEG IFN 2b R N=1019 PEG IFN 2b R N=1016 PEG IFN 2a R N= % of Patients With Undetectable HCV-RNA TW4 TW12 TW24 EOT SVR Sulkowski M et al, EASL 2008

6 IDEAL Study: Relapse Rates % PEG IFN 2b 1.5+R N=1019 PEG IFN 2b 1.0+R N=1016 PEG IFN 2a 180+R N=1035 PEG-IFN IFN 2b 1.5 vs PEG-IFN IFN 2a 180: 8% difference 95% CI-13.2%, -2.8% PEG-IFN IFN 2b 1.5/RBV vs PEG-IFN IFN 2b 1.0/RBV: 4% difference 95% CI-1.6%, 8.6%

7 Viral Kinetics Negative Predictive Value: 12 Weeks Positive Predictive Value: 4 Weeks

8 The Accordion Effect in Anti-HCV Therapy The Earlier HCV RNA Clears, the Shorter the Treatment Required Start Time to first RNA neg End of Treatment Berg T, et al. Gastroenterology. 2006;130:1086. Mangia, et al. NEJM. 2005;352:2609. Dalgard O, et al. Hepatology Sanchez-Tapias JM, et al. Gastroenterology. 2006;131:451. Von Wagner et al. Gastroenterology Zeuzem, et al. J Hepatology. 2006;44:97.

9 SVR and Viral Kinetics: More Relapse in Slow Responders Virologic Response (%) End of Treatment Sustained Virologic Response n=33 n=93 n=20 n=21 n=30 n=63 HCA RNA Status Week 4 Negative >2 Log 10 <2 Log 10 >2 Log 10 <2 Log 10 Any Week 12 Negative Negative Negative >2 Log 10 >2 Log 10 Positive Week 24 Negative Negative Negative Negative Negative Positive Ferenci P, et al. J Hepatol. 2005;43(3):

10 SVR With Standard Versus Extended Therapy in Patients With Slow Response or Failure of RVR SVR (%) wks 72 wks PEG 2a + PEG 2a+ PEG 2b + RBV RBV RBV PEG 2a + RBV Sanchez-Tapias et al, Gastroenterology 2006;131: Berg et al, Gastroenterology 2006;130: Pearlman et al, Hepatology 2007;46: Mangia et al, Hepatology 2008;47:43

11 Can Treatment Be Shortened for Rapid Response? RVR associated with SVR up to 90% in G1 More data in G1 pts with low viral load than high Few comparisons of 24 wks with 48 wks 77% vs 87% (p=0.12) in one study 1 Debate re: whether 24 wks should be routine Extensive studies in G2,3 patients High rates of SVR, similar with vs 24 wks Largest studies show slight advantage for 24 wks 1. Mangia A et al, Hepatology 2008;47:43-50

12 SVR in Patients With G2,3 With RVR SVR (%) Factors affecting efficacy of shortened treatment duration: Age Fibrosis (platelets) BMI 60 Short (12-16 wk) 40 Standard (24 wk) 20 0 PEG 2a RBV PEG 2b + RBV PEG 2a + RBV PEG 2b + RBV Von Wagner et al, Gastroenterology 2005;129: Mangia et al, N Engl J Med 2004;352: Shiffman et al, N Engl J Med 2007;357:124 4.Dalgard et al, Hepatology 2008;47:35

13 Treatment of Nonresponders to PEG IFN and Ribavirin Retreatment with same or different PEG IFN yields SVR rates of 2-16% Induction therapy does not improve SVR Extended treatment duration to 72 weeks doubles SVR rates CIFN (9-15 ug/d) + RBV yields SVR in 5-10% Better in noncirrhotics with good response to prior therapy Maintenance therapy studies have been negative

14 Maintenance Therapy HALT-C Data at 3.5 Years % Patients No treatment (n = 533) PEG IFN α-2a 90 µg/wk (n = 517) Death 6.6* * Decompensation *P = NS 17% d/c at 1 y and 30% d/c at 3.5 y 3.2 HCC 2.8* * Increase in Fibrosis Di Bisceglie AM, et al. Hepatology. 2007;46:290A.

15 Emerging HCV Therapies Specifically Targeted Antiviral Therapy for HCV (STAT-C) Enzyme Inhibitors Polymerase Genome Sequence-Based RNA interference (substantial challenges) Other IFN and RBV modifications Albumin IFN, omega IFN Taribavirin (viramidine) Protease Antisense Oligonucleotides (halted) Immune approaches Therapeutic vaccines Toll-like receptor agonists Yeast expressing HCV Ag Helicase (no trials yet) Ribozymes (halted) Targeting cellular factors Cyclophilin antagonists Nitazoxanide

16 Key Themes at the Dawn of a New Era Increased SVR Resistance Decreased duration Side effects

17 PROVE1: Phase II Study Design U.S., Genotype 1, Treatment Naive PR48 (control) (n=75) Placebo + Peg-IFN + RBV Peg-IFN + RBV Follow-up T12/PR12 (n=17) TVR + Peg-IFN + RBV Follow-up T12/PR24 (n=79) TVR + Peg-IFN + RBV Peg-IFN + RBV Follow-up T12/PR48 (n=79) TVR + Peg-IFN + RBV Peg-IFN + RBV Follow-up Weeks McHutchison J et al, EASL 2008

18 PROVE 2 Study European Phase 2: G1, Naïve Interim Analysis Arm A PEG IFN alfa-2a 180 ug + RBV mg N=82 Arm B TVR+PEG+RBV PEG+RBV N=81 Arm C TVR+PEG+RBV N=82 Arm D TVR+PEG N= Weeks Dusheiko G et al, EASL 2008

19 Themes From PROVE1 and PROVE2 High rates of rapid virologic response with telaprevir Increased rates of SVR with telaprevir compared with standard treatment Potential to shorten duration of therapy Importance of ribavirin 24 versus 48 weeks of telaprevir-based therapy (TVR for first 12 weeks, as in phase 2 program) being evaluated in phase 3 trials McHutchison et al, EASL 2008; Dusheiko et al, EASL 2008

20 Boceprevir: SPRINT-1 Study Inernational, Genotype 1, Treatment Naive PEG-2b + PEG 1.5 µg/kg + RBV mg Follow-up RBV mg x + boceprevir 800 mg TID for 24 weeks 4 weeks x 44 weeks Lead-in Dosing Strategy PEG-2b + PEG 1.5 µg/kg + RBV mg + RBV Follow-up mg x boceprevir 800 mg TID for 44 weeks 4 weeks x 24 weeks No Lead-in Dosing Strategy PEG 1.5 µg/kg + RBV mg + boceprevir 800 mg TID for 28 weeks PEG 1.5 µg/kg + RBV mg + boceprevir 800 mg TID for 48 weeks Follow-up x 44 weeks Follow-up x 24 weeks Low dose RBV Dosing Strategy PEG 1.5 µg/kg + RBV mg + boceprevir 800 mg TID for 48 weeks Follow-up x 24 weeks Control PEG 1.5 µg/kg +RBV mg for 48 weeks Follow-up x 24 weeks Kwo P et al, EASL 2008

21 SPRINT-1: Boceprevir Genotype 1 Treatment Naïve Study Lead-in SVR % No lead-in Control wks 48 wks (SVR-12) 48 wks (SVR-12) Schering press release, August 4, 2008

22 Treatment Discontinuations x 28 Weeks P/R lead-in P/R/boceprevir, N=103 (%) P/R/boceprevir, N=107 (%) P/R Control, N=104 (%) Total Discontinued 27 (26) 30 (28) 15 (14) Adverse Events 15 (15) 12 (11) 8 (8) Viral Breakthrough 4 (4) 7 (7) 0 Other* 8 (8) 11 (10) 7 (7) Kwo P et al., EASL 2008

23 Telaprevir + PEG-2a +RBV in Null Responders From Phase 2 Studies * Null responders defined as Non-Response Week 4 (<1log) and Week 12 (<2log) Percentage HCV RNA neg ( %) Week 4 Week 8 Week < 10 IU/mL (% ) <25 IU/mL (%) 0 n=34 n=20 n=12 Poordad F et al. EASL 2008

24 Interim Results From PROVE3: Nonresponders, Relapsers, and Breakthroughs Vertex press release, June 9, 2008 TVR/PEG IFN alfa-2a/rbv x 12 weeks, PEG 2a + RBV 12 weeks Interim results in 115 patients (total n=453) (No data yet for 2 other active arms) Week 12 Week 24 F/U wk Control group (n=114) Wk 12-8% HCV RNA neg Wk 36-30% HCV RNA neg 0 All n=115 Nonresponders n=66 Relapsers N=40 Breakthroughs n=9

25 HCV RNA Polymerase Nucleoside and Non-nucleoside Inhibition Fingers Allosteric GTP-binding sites Flap Thumb NNI Thumb inhibitors Catalytic site Nucleoside analogs NNI Palm Adapted from Butcher. Nature. 2001;410:235. Reprinted with permission.

26 R1626 (Nucleoside Inhibitor) + PEG IFN 2a + RBV Rapid Virologic Response HCV RNA neg week 4 (%) PEG-2a + RBV Pockros PJ, et al. Hepatology. August 2008 PEG-2a + R bid PEG-2a + R bid PEG-2a+ RBV+ R bid

27 PEG IFN 2a + RBV + R7128 (Nucleoside Polymerase Inhibitor) 28 Day Data % PCR Neg (RVR) % 40 30% % P+R P+R+R mg bid P+R+R mg bid McHutchison J et al, EASL 2008

28 The Promise of Combination Therapy In Vitro Combinations Resistance Studies Drug 1 Drug 2 Enhanced Suppression Decreased Emergence of de Novo Resistance Suppression of Preexisting Resistant Variants Boceprevir 1 Valopicitabine Yes Yes Yes Boceprevir 2 HCV-796 Yes Yes Yes ITMN R1479 Yes NA Yes NM107 4 ACH-806 Yes NA NA Telaprevir 4 ACH-806 Yes NA NA Telaprevir 5 R1479 NA Yes NA Valopicitabine 6 Various NA NA Yes NA=not applicable 1. Ralston. J. Hepatol. 2007;46:S Howe. J. Hepatol. 2007;46:S Seiwert. J. Hepatol. 2007;46:S Huang. J. Hepatol. 2007;46:S8. 5. McCowen. 14th International Symposium on Hepatitis C Virus and Related Viruses. September 9-13, Abstract P Bichko. J. Hepatol. 2007;46:S163. Slide by Ira M. Jacobson, MD

29 How Should the Prospect of Novel Treatments Factor Into Your Decision-Making? Treatment naïve G1 Stage 0-1: Watch and wait is acceptable in many patents Stage 3-4: Should treat now Stage 2: Considerable lattitude Where in stage 2 is patient? Mindset of patient; age; duration of infection Contraindications Treatment naïve G2,3 Need good reason not to treat Nonresponders Watch and wait is appropriate for most; when retreat, consider 72 wks Relapsers Consider longer course of retreatment (especially if advanced fibrosis is present)