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Triple Therapy Today: Phase III Results in G1 Naïve Patients: BOCEPREVIR, Michael Manns 5th Paris Hepatitis Conference, 30 January 2012.

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Presentation on theme: "Triple Therapy Today: Phase III Results in G1 Naïve Patients: BOCEPREVIR, Michael Manns 5th Paris Hepatitis Conference, 30 January 2012."— Presentation transcript:

1 Triple Therapy Today: Phase III Results in G1 Naïve Patients: BOCEPREVIR, Michael Manns 5th Paris Hepatitis Conference, 30 January 2012

2 Original Article Boceprevir for Untreated Chronic HCV Genotype 1 Infection Fred Poordad, M.D., Jonathan McCone, Jr., M.D., Bruce R. Bacon, M.D., Savino Bruno, M.D., Michael P. Manns, M.D., Mark S. Sulkowski, M.D., Ira M. Jacobson, M.D., K. Rajender Reddy, M.D., Zachary D. Goodman, M.D., Ph.D., Navdeep Boparai, M.S., Mark J. DiNubile, M.D., Vilma Sniukiene, M.D., Clifford A. Brass, M.D., Ph.D., Janice K. Albrecht, Ph.D., Jean-Pierre Bronowicki, M.D., Ph.D., for the SPRINT-2 Investigators N Engl J Med Volume 364(13): March 31, 2011

3 Acknowledgements The authors would like to thank the patients, study staff and investigators in the following countries: Argentina: L. Colombato, J. Curciarello, M. Silva, H. Tanno, R. Terg; Belgium: M. Adler, P. Langlet, L. Lasser, F. Nevens; Canada: F. Anderson, R. Bailey, M. Bilodeau, C. Cooper, S.V. Feinman, J. Heathcote, M. Levstik, A. Ramji, M. Sherman, S. Shafran, E. Yoshida; France: A. Achim, S. Ben Ali, M-A. Bigard, C. Bonny, M. Bourliere, N. Boyer-Darrigrand, J-P. Bronowicki, V. Canva, P. Couzigou, V. De Ledinghen, D. Guyader, C. Hezode, D. Larrey, M. Latournerie, P. Marcellin, P. Mathurin, M. Maynard–Muet, J. Moussalli, R. Poupon, T. Poynard, L. Serfaty, A. Tran, C. Trepo, R. Truchi, J-P. Zarski; Germany: T. Berg, N. Dikopoulos, C. Eisenbach, P. R. Galle, G. Gerken, T. Goeser, M. Gregor, D. Klass, M. R. Kraus, C. Niederau, J. F. Schlaak, R. Schmid, P. Thies, K. Schmidt, R. Thimme, H. Weidenbach, S. Zeuzem; Italy: M. Angelico, S. Bruno, G. Carosi, A. Craxì, A. Mangia, M. Pirisi, M. Rizzetto, G. Taliani, A.L. Zignego; Netherlands: H.W. Reesink, ; Portugal: F. Serejo; Puerto Rico: A. Reymunde¸ B. Rosado, E. Torres; Spain: R. Barcena Marugan, M. De La Mata, J.L. Calleja, G. Castellano, M. Diago, R. Esteban, C. Fernandez, J. Sanchez Tapias, M.A. Serra Desfilis; United States: N. Afdhal, A. Al- Osaimi, B. Bacon, L. Balart, M. Bennett, D. Bernstein, M. Black, C. Bowlus, T. Boyer, D. Dalke, C. Davis, G. Davis, M. Davis, G. Everson, F. Felizarta, S. Flamm, B. Freilich, J. Galati, G. Galler, R. Ghalib, A. Gibas, E. Godofsky, F. Gordon, S. Gordon, J. Gross, S. Harrison, J. Herrera, S. Herrine, K-Q. Hu, J. Imperial, I. Jacobson, D. Jones, A. Kilby, J. King, A. Koch, K. Kowdley, E. Krawitt, P. Kwo, L. Lambiase, E. Lawitz, W. Lee, J. Levin, R. Levine, X. Li, A. Lok, V. Luketic, M. Mailliard, J. McCone, J. McHutchison, D. Mikolich, T. Morgan, A. Muir, Don Nelson, F. Nunes, A. Nyberg, L. Nyberg, P. Pandya, M.P. Pauly, C. Peine, G. Poleynard, F. Poordad, D. Pound, J. Poulos, M. Rabinovitz, N. Ravendhran, J. Ready, K. Reddy, R. Reindollar, A. Reuben, T. Riley, L. Rossaro, R. Rubin, M. Ryan, J. Santoro, E. Schiff, T. Sepe, K. Sherman, M. Shiffman, M. Sjogren, R. Sjogren, C. Smith, L. Stein, R. Strauss, M. Sulkowski, R. Szyjkowski, H. Vargas, J. Vierling, D. Witt, R. Yapp, Z. Younes

4 Boceprevir (BOC) is a linear peptidomimetic ketoamide serine NS3 protease inhibitor Effective against Genotype 1 Demonstrated activity in treatment naïve and experienced populations in phase 2 clinical trials

5 Study Objectives Compare safety/efficacy of two treatment strategies with boceprevir added to peginterferon/ribavirin (PR) versus PR alone in previously untreated genotype 1 patients Evaluate safety/efficacy independently in two patient populations, non-black and black Explore response-guided therapy with 24 weeks therapy with a boceprevir regimen (BOC RGT) vs. 44 weeks of therapy with a boceprevir regimen (BOC/PR48) following 4 week lead-in with PR

6 Week 4 Week 48 PR + Placebo Follow-up PR lead-in Week 28 Week 72 SPRINT 2: Study Design Control 48 P/R N = 363 Peginterferon (P) administered subcutaneously at 1.5 μg/kg once weekly, plus ribavirin (R) using weight based dosing of mg/day in a divided daily dose Boceprevir dose of 800 mg thrice daily

7 Week 4 Week 48 PR + Placebo Follow-up PR lead-in Week 28 Week 72 SPRINT 2: Study Design Control 48 P/R N = 363 PR + Boceprevir Follow-up BOC/ PR48 N = 366 PR lead-in Peginterferon (P) administered subcutaneously at 1.5 μg/kg once weekly, plus ribavirin (R) using weight based dosing of mg/day in a divided daily dose Boceprevir dose of 800 mg thrice daily

8 Week 4 Week 48 PR + Placebo Follow-up PR lead-in PR + Boceprevir Week 28 Week 72 TW 8-24 HCV-RNA Undetectable TW 8-24 HCV-RNA Detectable PR + Placebo Follow-up SPRINT 2: Study Design Control 48 P/R N = 363 BOC RGT N = 368 PR + Boceprevir Follow-up BOC/ PR48 N = 366 PR lead-in PR lead-in Peginterferon (P) administered subcutaneously at 1.5 μg/kg once weekly, plus ribavirin (R) using weight based dosing of mg/day in a divided daily dose Boceprevir dose of 800 mg thrice daily

9 SPRINT 2: Study Design Pre-specified endpoints Primary  SVR 24 in ITT population Key Secondary  SVR 24 in mITT population: all patients who received >1 dose of boceprevir/placebo Stopping rule  Detectable HCV RNA at 24 wks Prespecified cohorts  Cohort 1: Non-blacks (N=938)  Cohort 2: Blacks (N=159) Stratification variables  Baseline viral load: > vs. ≤ 400,000 IU/mL  HCV subtype: 1a vs. 1b HCV RNA  TaqMan 2.0 (LLQ=25 IU/mL; LLD=9.3 IU/mL)  LLD used to define undetectable at all decision points LLQ=Lower limit of quantitation; LLD=Lower limit of detection; SVR=Sustained virologic response; ITT=Intent-to-treat; mITT=Modified ITT; IU=International units

10 Baseline Characteristics Cohort 1 (Non-black)Cohort 2 (Black) Arm 1: 48 P/R N = 311 Arm 2: BOC RGT N = 316 Arm 3: BOC/ PR48 N = 311 Arm 1: 48 P/R N = 52 Arm 2: BOC RGT N = 52 Arm 3: BOC/ PR48 N = 55 Mean age (years) Male (%) Region (%) North America Europe BMI – mean (SD)27 (5)28 (5)27 (5)28 (4)29 (5)31 (6) HCV subtype (%)* 1a b HCV RNA level >400,000 IU/mL (%) METAVIR F3/F4 (%) * Subtyping performed by NS5B sequencing (Virco, Mechelen, Belgium)

11 SPRINT-2 Treatment-Naïve Patients SVR and Relapse All Cohorts † † Full Analysis Set. ‡ Relapse is computed on patients who were undetectable at end of treatment and were not missing data at end of follow-up. SVR=sustained virologic response; PR48=peginterferon  -2b + ribavirin 48 weeks; RGT=response-guided therapy; BOC/PR48=boceprevir/PR48 weeks. p< SVRRelapse ‡ % of Patients PR48 (N=363)RGT (N=368)BOC/PR48 (N=366)

12 SPRINT-2 Treatment-Naïve Patients SVR Rates by Non-Black vs. Black n=311n=316n=311n=52 n=55 p=0.044 p=0.004 % of Patients Non-BlackBlack PR48RGTBOC/ PR48 RGTBOC/ PR48 p< Full Analysis Set.

13 SPRINT 2: SVR and Relapse Rates (ITT) p < Non-Black Patients SVR* Relapse Rate /232 18/230 *SVR was defined as undetectable HCV RNA at the end of the follow-up period. The 12-week post-treatment HCV RNA level was used if the 24-week post- treatment level was missing (as specified in the protocol). A sensitivity analysis was performed counting only patients with undetectable HCV RNA documented at 24 weeks post-treatment and the SVR rates for Arms 1, 2 and 3 in Cohort 1 were 39% (122/311), 66% (207/316) and 68% (210/311), respectively and in Cohort 2 were 21% (11/52), 42% (22/52) and 51% (28/55), respectively.

14 SPRINT 2: SVR and Relapse Rates (ITT) p < Non-Black Patients p = p =0.004 Black Patients SVR* Relapse Rate /14 3/ /232 18/230 *SVR was defined as undetectable HCV RNA at the end of the follow-up period. The 12-week post-treatment HCV RNA level was used if the 24-week post- treatment level was missing (as specified in the protocol). A sensitivity analysis was performed counting only patients with undetectable HCV RNA documented at 24 weeks post-treatment and the SVR rates for Arms 1, 2 and 3 in Cohort 1 were 39% (122/311), 66% (207/316) and 68% (210/311), respectively and in Cohort 2 were 21% (11/52), 42% (22/52) and 51% (28/55), respectively.

15 Lead-in Predicts SVR and Resistance SVR (%) BOC RGTBOC/PR48PR BOC RGTBOC/PR48PR Non-Black PatientsBlack Patients ≥1 log 10 HCV RNA decline from baseline<1 log 10 HCV RNA decline from baseline Boceprevir resistance-associated variants: ≥1 log 10 decline: BOC RGT: 4% (10/232) BOC/PR48: 6% (13/231) <1 log 10 decline: BOC RGT: 52% (49/95) BOC/PR48: 40% (38/94) Poordad F. N Engl J Med. 2011; 364:

16 16 Boceprevir 2011 FDA ACM Draft SPRINT 2 SVR Based on Week 4 RNA Decline < – < – < – < – < – <4.0 ≥4.0 Undetectable PR/48 < – < – < – < – < – <4.0 ≥4.0 Undetectable BOC/RGT < – < – < – < – < – <4.0 ≥4.0 Undetectable BOC/PR48 0/253/5812/5613/4025/5621/3633/4229/3013/4714/5033/4720/3144/5547/5342/4717/1911/3725/5829/4818/2542/5748/5445/5018/ Log 10 Viral Load Decrease After 4 Weeks of P/R Lead-in All Patients (Cohort 1 + Cohort 2) % of Patients with SVR Vierling, EASL 2011

17 17 Early Interferon Response (Lead-In) Further Defines Likelihood of Success For Non-CC Patients CCCTTT ≥≥≥ SPRINT-2 and RESPOND-2 combined Poordad, et al. Presented at the European Association for the Study of the Liver Annual Meeting; March 30–April 3, 2011; Berlin, Germany. Abstract 12.

18 SVR (%) SVR in patients with undetectable HCV RNA between Weeks 8-24

19 SVR (%) SVR in patients with undetectable HCV RNA between Weeks % of non-black patients in RGT arm were treated with short duration

20 SVR in patients with undetectable HCV RNA between Weeks 8-24 SVR in patients with detectable HCV RNA at least once between Weeks % of non-black patients in RGT arm were treated with short duration SVR (%)

21 SVR in patients with undetectable HCV RNA between Weeks 8-24 SVR in patients with detectable HCV RNA at least once between Weeks % of non-black patients in RGT arm were treated with short duration 22%* of non-black patients in RGT arm were treated with >28 weeks of therapy SVR (%)

22 22 SPRINT-2 Treatment-Naive Patients Early Responders: TW 8-TW 24 HCV-RNA Undetectable PR Early Responder Boceprevir/PR 48 Weeks TW 0 Boceprevir Response-Guided Therapy PR Early Responder FW 24TW 48TW 4TW 8TW 28 HCV-RNA undetectable at TW8 through TW24, and received at least 28 weeks of therapy. TW=treatment week. TW 24

23 23 SPRINT-2 Treatment-Naïve Patients SVR in Early Responders † Combined Cohorts 57% of patients had undetectable HCV RNA at TW8 156/162155/161 † HCV-RNA undetectable at TW8 through TW24, and received 28 or 48 weeks of therapy. Poordad F, et al. N Engl J Med. 2011; 364:

24 24 Consistent Clinical Trial and Label for Treatment-Naïve Early Responders Early Responder=Undetectable HCV RNA at TW8 European Label –Clinical trial design: 4+24 –Approved label: 4+24

25 25 SPRINT-2 Treatment-Naïve Patients Late Responders: HCV-RNA TW 8 Detectable and TW 24 Undetectable PR Late Responder Boceprevir Response-Guided Therapy Boceprevir/PR 48 Weeks PR Late Responder TW 0FW 24TW 48TW 4TW 8TW 28 HCV-RNA detectable at TW 8, undetectable at TW 24, and received at least 28 weeks of therapy. TW=treatment week. TW 24

26 26 SPRINT-2: SVR in Late Responders † in RGT and Corresponding BOC/PR48 59/8255/7345/6855/73 † HCV-RNA detectable at TW8 - undetectable at TW24, and received at least 28 weeks of therapy. ‡ 14 patients in the RGT arm with false positive HCV-RNA results between TW8 and TW24 were removed from the numerator and denominator. RGT=response-guided therapy; BOC/PR48=boceprevir/peginterfero  -2b + ribavirin 48 weeks; SVR=sustained virologic response; HCV=hepatitis C virus; RNA=ribonucleic acid; TW=treatment week TW8 - TW24FDA / EMEA Analysis % of Patients RGTBOC/PR48 †‡

27 27 Differences Between Clinical Trial and Label for Treatment-Naïve Late Responders Late Responder=Detectable HCV RNA at TW8 European Label –Clinical trial design: –Approved label: Approved regimen ( ) only was tested in subjects who failed previous therapy and were late responders (RESPOND 2) Consistent treatment regimen for late responders regardless of prior treatment history

28 28 SPRINT-2: Overall SVR in RGT & BOC/PR48 by Race and METAVIR Fibrosis Score (F0/1/2/3 vs. F4) 202/ / 268 5/ 12 9/ 22 20/ 40 28/ 52 0/31/2 Modified Intention-to-Treat. SVR=sustained virologic response; FAS=full analysis set; RGT=response-guided therapy; BOC/PR48=boceprevir/peginterferon  -2b + ribavirin 48 weeks. Poordad F, et al. N Engl J Med. 2011; 364:

29 29 Differences Between Clinical Trial and Label for Cirrhotics Protocol –Assigned treatment regimens did not differ based on fibrosis score –All F0-F4 patients were tested with RGT and fixed dose regimens European Label* –48 weeks is the recommended duration regardless of early response –4+44 is the recommended treatment Duration of triple therapy after the lead in should not be less than 32 weeks If patient cannot tolerate triple therapy, consider the final 12 weeks with bi-therapy ( ) *Also driven by RESPOND 2 results in cirrhotics

30 Treatment discontinuations due to stopping rule at Week 24 in Non-Black patients % Discontinuation /31628/311

31 31 Assessment of Stopping Rules for SPRINT-2 Boceprevir Arms Stopping Rule Stopped by Early Rule n=734 Additional Stopped by TW24 Rule Total Stopped 8/24 or 12/24 rule SVR Missed TW8 <3 log drop34 (5%)66100 (13%)1‡1‡ TW12 <2 log drop24 (3%)7195 (13%)0 TW 12 ≥ 100 IU65 (9%)48113 (15%)0 TW16 ≥25 IU73 (10%) TW24 detectableNA 79* (11%)0 ‡ 1/475 treated = 0.2% or 1/34 identified = 3% * 76 discontinued, 3 completed treatment, 2 had SVR. TW24 rule used in study. **Full Data to be presented at AASLD 2011 TW=treatment week; SVR=sustained virological response; BT=breakthrough.

32 32 Differences Between Clinical Trial and Labels for Futility Rule Protocol –No early futility –Detectable HCV RNA (>LLD) at TW24=discontinue all therapy European Label –>100 IU/mL at TW12=discontinue all therapy –Confirmed detectable HCV RNA at TW24=discontinue all therapy –Consistent rule for patients who failed previous treatment

33 Boceprevir – EU labelling for adult patients with chronic HCV G -1 Naive patients Relapsers + partial responders Cirrhotics and Null-Responders Futility rules HCV-RNA testing recommended PegIFN + RBV PegIFN + RBV + Boceprevir STOP when HCV-RNA ≥ 100 IE/ml STOP when HCV-RNA detectable Week HCV-RNA 32 W 24 W 32 W 44 W 4 W 12 W VICTRELIS ® Labelling Germany July 2011 Naive patients

34 SVR Results in Cohort 2 (Blacks) % SVR (n/N) 48 P/RBOC RGTBOC/PR48 ITT Modified ITT 23 (12/52) 26 (12/47) 42 (22/52) 47 (22/47) 53 (29/55) Week 4 Lead-In Response ≥ 1 log 10 decrease < 1 log 10 decrease 46 (12/26) 0 (0/21) 67 (16/24) 25 (6/24) 61 (22/36) 31 (5/16) Week 8 Viral Load Undetectable Detectable 75 (3/4) 21 (8/38) 78 (14/18) 32 (8/25) 82 (18/22) 28 (8/29) Viral Load Week 8 – 24 Undetectable Detectable ≥ 1 time 100 (3/3) 62 (8/13) 87 (13/15) 58 (7/12) 95 (18/19) 88 (7/8) Discontinuations due to Week 24 Stopping Rule 46 (24/52)17 (9/52)15 (8/55)

35 Safety Profile Over Entire Course of Therapy 48 PR n=363 BOC RGT n=368 BOC/PR48 n=366 Median treatment duration, days DeathsN=4N=1 Serious AEs9%11%12% Discontinued due to AEs16%12%16% Dose modification due to AEs26%40%35% Hematologic parameters Neutrophil count (<750 to 500/mm 3 / <500/mm 3 ) 14% / 4%24% / 6%25% / 8% Hemoglobin (<10 to 8.5 g/dL / <8.5 g/dL) Discontinuation due to anemia Dose reductions due to anemia Erythropoietin use Mean (median) days of use 26% / 4% 1% 13% 24% 121 (109) 45% / 5% 2% 20% 43% 94 (85) 41% / 9% 2% 21% 43% 156 (149)

36 Adverse EventArm 1 (PR48); n=363 (%)Arm 2 (RGT); n=368 (%)Arm 3 (BOC/PR48); n=366 (%) Fatigue Headache Nausea Anemia2949 Dysgeusia Chills Pyrexia Insomnia Alopecia Decreased Appetite Pruritis Neutropenia2125 Influenza Like Illness Myalgia Rash Irritability2422 Depression Diarrhea19 23 Dry Skin18 22 Dyspnea Dizziness Most Common Treatment-Related Adverse Events* *Reported in >20% of patients in any treatment arm and listed by decreasing overall frequency

37 SAFETY - SUMMARY Anemia and dysgeusia occurred more often in the boceprevir groups than the control groups (20% and % higher, respectively) Discontinuation due to anemia occurred in ≤2% of patients; EPO was used in 19% more boceprevir recipients compared to controls Anemia can be managed with ribavirin dose reduction alone or with EPO

38 CONCLUSIONS BOCEPREVIR INCREASED SVR IN ALL PATIENT GROUPS COMPARED TO PEGYLATED INTERFERON AND RIBAVIRIN ROUGHLY HALF OF ALL PATIENTS WERE ELIGIBLE FOR SHORTENED COURSE OF THERAPY LEAD IN ALLOWS PREDICTABILITY OF RESPONSE, RESISTANCE, AND INDIVIDUALIZED CARE EITHER PEGYLATED INTERFERON CAN BE USED

39 Triple Therapy Today: Phase III Results in G1 Naïve Patients: BOCEPREVIR, Michael Manns 5th Paris Hepatitis Conference, 30 January 2012

40 SPRINT-2 Final Results Boceprevir Combined with Peginterferon alfa- 2b/Ribavirin for Treatment-Naïve Patients with HCV Genotype 1 SPRINT-2 Final Results Fred Poordad, Jon McCone, Bruce R. Bacon, Savino Bruno, Michael Manns, Mark Sulkowski, Ira Jacobson, Rajender Reddy, Navdeep Boparai, Vilma Sniukiene, Clifford A. Brass, Janice K. Albrecht, and Jean-Pierre Bronowicki For the SPRINT-2 Investigators

41 naive >100 IU/ml Nullresponder Cirrhosis Part. Resp. Relapser VICTRELIS (Boceprevir)+PEG-IFN+RBVINCIVO (Telaprevir)+PEG-IFN+RBV >1000 IU/ml positive but <1000 IU/ml + detectable Naive Relapser Part. Resp. Nullresponder Cirrhosis 1236 detektierbar PEG-IFN / RBV 12


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