1 / 106

Pegasys + Copegus Combination Therapy

Pegasys + Copegus Combination Therapy. BLA 125061/NDA 21-511 Antiviral Drugs Advisory Committee Meeting November 14, 2002. Pegasys Monotherapy Indication. Indication:

carlynda
Download Presentation

Pegasys + Copegus Combination Therapy

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Pegasys + Copegus Combination Therapy BLA 125061/NDA 21-511 Antiviral Drugs Advisory Committee Meeting November 14, 2002

  2. Pegasys Monotherapy Indication • Indication: Pegasys, Peginterferon alfa-2a, is indicated for the treatment of adults with chronic hepatitis C who have compensated liver disease and have not been previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated cirrhosis. • Dosage and Administration 180 g once weekly for 48 weeks

  3. Pegasys + Copegus Proposed Label Additions • Pegasys, Peginterferon alfa-2a, in combination with Copegus, ribavirin, is indicated for the treatment of adults with chronic hepatitis C who have compensated liver disease and have not been previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated cirrhosis. • Dosage and administration accordingto genotype: • Treatment duration • Ribavirin dose

  4. Regulatory History of Application July 16, 1998US IND submitted October 6, 1998End of phase II meeting August 9, 2000Fast-Track designation May 7, 2002Pre-BLA/NDA meeting June 3, 2002BLA/NDA Filed to FDA October 16, 2002Pegasys monotherapy approved November 14, 2002Advisory Committee

  5. Roche Presentation Agenda IntroductionCandice Teuber, Pharm.D. Overview of Pegasys-CopegusJoseph Hoffman, M.D. Development Program EfficacyFrank Duff, M.D. SafetyJonathan Solsky, M.D. ConclusionsJoseph Hoffman, M.D.

  6. Experts Available for Q & A Donald M. Jensen, M.D. Director, Section of Hepatology Rush-Presbyterian-St. Luke’s Medical CenterChicago, IL Mitchell Shiffman, M.D. Chief, Hepatology Section,Virginia Commonwealth University Health System Medical College of Virginia Richmond, VA

  7. Roche Experts Available for Q & A Clinical ScienceMichael Brunda, Ph.D. ToxicologyCeline Eliahou, M.S. StatisticsAmy Lin, M.S. Clinical PharmacologyMatthew Lamb, Pharm.D. Clinical PharmacologyKarin Jorga, Ph.D.

  8. Pegasys + Copegus Combination Therapy Overview Dr. Joseph Hoffman VP & Group Leader,Virology and Transplantation

  9. Background • Rationale for development of Pegasys • Overview of clinical program • Dose selection in combination therapy program

  10. SVR: Difficult-to-Treat Disease IFN alfa 3 or 6/3 MIU tiw x 48 wks SVR 11% -19% 7% 5% 1% - 2% <1% Overall Geno 1 Cirrhosis Geno 1,HVL Geno 1,Cirrhosis Zeuzem et al. N Engl J Med. 2000;343:1666-1672 Heathcote et al. N Engl J Med. 2000;343:1673-1680 Pockros et al. 41st ICAAC Meeting. 2001:285(Abstract H-457) Roche data on file

  11. Mon Tue Wed Thu Fri Sat Sun 14 12 10 8 Periods of time when IFN is not detectable in circulation 6 4 2 0 0 24 48 72 96 120 144 168 192 Pharmacokinetics of Standard Alpha Interferons Interferon (U/mL) Time (hours) First dose measured; others simulated Roche data on file

  12. O CH3OCH2CH2(OCH2CH2)n O  C  NH a CH2 Lysine (CH2)3 mPEG e CH Interferon O CH3OCH2CH2(OCH2CH2)n O  C  NH CNH O Peginterferon Alfa-2a (40KD)

  13. Pegasys • Soluble formulation • Retains immunomodulatory and antiproliferative properties • Sustained action • Decreased clearance • Extended absorptive phase • Limited volume of distribution • Allows unit dosing

  14. After first dose 15 10 Mean Concentration (ng/mL) 5 0 Weekly Dose Given Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Weekly Dose Given NV15496Pegasys Systemic Concentrations – 180 g sc Once Weekly

  15. Change in Pegasys Total Apparent Body Clearance vs Total Body Weight

  16. Comprehensive Pegasys Clinical Program • Dose-finding study • Study in patients with cirrhosis • Study vs standard IFN • Study vs induction regimen IFN Monotherapy 2/97 12/99 • 1600 patients were enrolled in 4 separate Phase II and III trials in cirrhotic and noncirrhotic patients • 1001 patients were randomized to Pegasysand 599 patientswere randomized to Roferon-A

  17. NV15489Phase II Dose-finding Study SVR N = 33 N = 20 N = 20 N = 45 N = 41 Roferon-A 3 MIU Pegasys 45 µg Pegasys 90 µg Pegasys 180 µg Pegasys 270 µg Reddy et al. Hepatology. 2001;33:433-438

  18. NV15489Dose-finding Study: SVR in Genotype 1 31% Genotype 1 SVR 14% N = 14 N = 35 Pegasys 90 µg Pegasys 180 µg Reddy et al. Hepatology. 2001;33:433-438

  19. NV15495Sustained Virological Response in Patients with Cirrhosis SVR N = 88 N = 96 N = 87 *P= 0.001 vs Roferon-A; **NS vs Roferon-A Heathcote et al. N Engl J Med. 2000;343:1673-1680

  20. NV15496Virological Response at Weeks 24 and 72 Pegasys 135 g vs 180 g Virological Response N = 214 N = 215 N = 210 N = 214 N = 215 N = 210 HCV RNA undetectable (<100 copies/mL) *P = 0.01 vs Roferon-A at week 72 Pockros et al. 41st ICAAC Meeting. 2001:285 (Abstract H-457) and Roche data on file

  21. NV15496Histological Response: Pegasys 135 g vs 180 g in Patients with Paired Biopsies Histological Response† N = 147 N = 171 N = 160 †Histological response defined as 2 point decrease in HAI score *NS vs Roferon-A **P = 0.017 vs Roferon-A Pockros et al. 41st ICAAC Meeting. 2001:285 (Abstract H-457) and Roche data on file

  22. Overview of Adverse Events in Integrated Summary of Safety for Pegasys Monotherapy Pegasys Pegasys 135 g 180 g Adverse Event (N = 215) (N = 604) Severe AEs 30% 32% Serious AEs 10% 9% Treatment-related serious AEs* 3% 5% AEs and laboratory abnormalities leading to withdrawal 10% 10% AEs and laboratory abnormalities requiring dose modification 21% 27% *Events judged by investigator to be possibly or probably related to treatment

  23. SVR: Difficult-to-Treat Disease IFN alfa 3 or 6/3 MIU tiw x 48 wks SVR 11% -19% 7% 5% 1% - 2% <1% Overall Geno 1 Cirrhosis Geno 1,HVL Geno 1,Cirrhosis Zeuzem et al. N Engl J Med. 2000;343:1666-1672 Heathcote et al. N Engl J Med. 2000;343:1673-1680 Pockros et al. 41st ICAAC Meeting. 2001;285 (Abstract H-457) Roche data on file

  24. SVR: Difficult-to-Treat Disease Pegasys 180 g qw x 48 wks 28% -39% SVR 30% 22% - 28% 14% 13% Overall Geno 1 Cirrhosis Geno 1,HVL Geno 1,Cirrhosis Zeuzem et al. N Engl J Med. 2000;343:1666-1672 Heathcote et al. N Engl J Med. 2000;343:1673-1680 Pockros et al. 41st ICAAC Meeting. 2001;285 (Abstract H-457) Roche data on file

  25. Comprehensive Pegasys Clinical Program Monotherapy 2/97 12/99 Combination Therapy 10/98 1/02 • Pilot safety study • Comparative trial vs Rebetron • Duration and dosing by genotype trial

  26. Ribavirin • Better efficacy seen with combination than IFN alone • Teratogenic and mutagenic; induces hemolysis • Dose of 1000 or 1200 mg is safe and efficacious with standard IFN • Pegasys 180 g and 1000 or 1200 mg of ribavirin tolerated in pilot safety study (NV15800) • No PK interaction between ribavirin and IFN

  27. 0-24h AUC Predicted Copegus Exposure1000 or 1200 mg Body-Weight-Adjusted Dose 70 1000 mg 1200 mg 60 50 40 <75 kg 75 kg 30 20 10 0 40 50 60 70 80 90 100 110 120 130 140 Body Weight (kg)

  28. PegasysCombination Development Program • Pegasys (180 g) + Placebo • Intron A (3 MIU) + Rebetol (1000 or 1200 mg) • Pegasys (180 g) + Copegus (1000 or 1200 mg) Phase II: NV15800 10/98 3/00 Phase III: NV15801 2/99 4/01 48 Weeks

  29. SVR: Rebetron Registration Trials SVR N = 505 N = 504 McHutchison et al. Seminars in Liver Disease. 1999;19(suppl 1):57-65

  30. PegasysCombination Development Program Phase II: NV15800 10/98 3/00 Phase III: NV15801 2/99 4/01 • Comparative Trial vs Rebetron Phase III: NV15942 11/99 1/02 • Duration and Dosing by Genotype Trial

  31. Pegasys + Copegus Optimization of Therapy • Duration of combination therapy • Pegasys weekly dose • Copegus daily dose

  32. Copegus Dose Selection • Chose Copegus 1000 or 1200 mg in control arm to bridge to comparative trial • No powered dose-finding trials with ribavirin were available • Literature and anecdotal experience suggested ribavirin dose of 800 mg might be adequate but 600 mg too low

  33. Pegasys + Copegus Optimization of Therapy • Duration of combination therapy 24 vs 48 weeks • Pegasys weekly dose 180 g • Copegus daily dose 800 vs 1000 or 1200 mg

  34. Pegasys Combination Program Designed to Evaluate: • Efficacy and safety of Pegasys + Copegus across genotypes • vs Rebetron • vs Pegasys monotherapy • Impact of shorter treatment duration on response for genotype 1 and genotype non-1 • Impact of lower Copegus dose on response for genotype 1 and genotype non-1

  35. Pegasys + Copegus Combination Therapy Efficacy Results Dr. Frank Duff Clinical Leader

  36. Study NV15801 Comparative Trial vs Rebetron

  37. NV15801Efficacy Objectives Primary • Compare efficacy of Pegasys + Copegusvs Rebetron Secondary • Compare efficacy of Pegasys + Copegusvs Pegasys monotherapy • Compare efficacy across treatment armsby HCV genotype

  38. NV15801Study Design • Randomized • Open label for Pegasys and Rebetron • Blinded for Copegus vs placebo (Pegasys arms) • Stratified by • Country • HCV genotype

  39. NV15801Study Design: Treatment Pegasys 180 g sc qw + Copegus 1000 or 1200 mg po daily Follow-up Rebetron (Intron A 3 MIU sc tiw +Rebetol 1000 or 1200 mg po daily) Follow-up Screen Pegasys 180 g sc qw + Placebo Follow-up 0 48 72 Weeks

  40. NV15801Study Design • Primary endpoint • Combined sustained virological response (SVR) and sustained biochemical response (SBR) at end of follow-up • Secondary endpoints • SVR • SBR • End-of-follow-up histological response (20% of patients) • Analysis population • All patients randomized

  41. NV15801Major Inclusion Criteria • Serological evidence of HCV infection • HCV RNA >2000 copies/mL • Elevated serum ALT • Liver biopsy consistent with CHC • Compensated liver disease • Child-Pugh grade A • Age 18 years • Naïve to interferon and ribavirin

  42. NV15801Major Exclusion Criteria • Decompensated liver disease • Child-Pugh grades B and C • Coinfection with HIV or HBV • Anemia or inability to tolerate anemia • Hb <12 g/dL (F) or 13 g/dL (M) • Significant co-morbid medical conditions

  43. NV15801Patient Characteristics Pegasys + Pegasys Copegus Rebetron (N = 227) (N = 465) (N = 457) Genotype 1 (%) 64 66 64 HCV RNA titer(mean, x 106 copies/mL) 5.8 6.0 6.0 Cirrhosis/Bridging Fibrosis (%) 15 12 12 Age (mean, y) 42 43 42 Weight (mean, kg) 79 80 78 Male (%) 67 71 73 All patients randomized

  44. NV15801Summary of Reasons for Premature Withdrawal from Treatment Pegasys + Pegasys Copegus Rebetron (N = 224) (N = 453) (N = 444) Safety 7% 10% 11% Nonsafety Insufficient therapeutic response 22% 8% 13% Refused treatment/failed to return 4%4% 7% Protocol violation0% <1% <1% Administrative 0% 0% <1% Total 25% 12% 21% Total prematurely withdrawn 32% 22% 32%

  45. NV15801Protocol Defined Analyses Pegasys Pegasys + +Copegus Rebetron Copegus Pegasys (N = 465) (N = 457) P-value (N = 465) (N = 227) P-value SVR 50% 42% 0.004 50% 27% 0.001 SBR 50% 43% 0.022 50% 32% 0.001 SVR +SBR 45% 39% 0.057 45% 24% 0.001 All patients randomized

  46. NV15801Virological Analyses • Validated HCV RNA assays now available • Virological response preferred as efficacy endpoint • SVR defined as 2 negative HCV RNA assessments (<100 copies/mL) at least 21 days apart after week 60 • All treated population

  47. NV15801 SVR – All Genotypes P = 0.001 P = 0.005 SVR N = 224 N = 453 N = 444 All treated, SVR = 2 HCV RNA <100 copies/mL

  48. NV15801 SVR by Genotype P = 0.002 P = 0.044 P = 0.001 P = 0.046 SVR N = 145 N = 298 N = 285 N = 79 N = 155 N = 159 All treated, SVR = 2 HCV RNA <100 copies/mL

  49. NV15801 SVR Genotype 1 by Viral Load SVR N = 44 N = 115 N = 94 N = 101 N = 182 N = 189 All treated, SVR = 2 HCV RNA <100 copies/mL

  50. NV15801Efficacy Findings • Pegasys and Copegus SVR superior to Rebetron and to Pegasys monotherapy • Overall • Genotype 1 • Contributed to by HVL and LVL responses • Genotype non-1

More Related