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Pegasys ® Copegus ® Hoffmann-La Roche BLA 125061

Pegasys ® Copegus ® Hoffmann-La Roche BLA 125061. Antiviral Drugs Advisory Committee Bethesda, Maryland November 14, 2002. Center for Biologics Evaluation and Research. Indications and Usage.

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Pegasys ® Copegus ® Hoffmann-La Roche BLA 125061

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  1. Pegasys® Copegus ®Hoffmann-La RocheBLA 125061 Antiviral Drugs Advisory Committee Bethesda, Maryland November 14, 2002 Center for Biologics Evaluation and Research

  2. Indications and Usage Pegasys® Copegus® in Combination Are Indicated for the Treatment of Previously Untreated Patients With Chronic Hepatitis C Infection Center for Biologics Evaluation and Research

  3. Chronic Hepatitis C: SustainedTreatment Response (SVR) • Interferon alfa-2a monotherapy ~ 15% • Peg-Interferon alfa-2a monotherapy ~ 30% • Interferon alfa-2b with ribavirin ~ 45% • Peg-Interferon alfa-2b with ribavirin ~ 50% • Response rate adversely affected by: • HCV genotype and viral load • Cirrhosis • Age, race Center for Biologics Evaluation and Research

  4. Study Drugs • Hoffmann-La Roche • Interferon alfa-2a (Roferon A) IFN alfa-2a • Pegylated interferon alfa-2a (Pegasys) PEG-IFN • Ribavirin (Copegus) R • Schering Plough • Interferon alfa-2b (Intron A) IFN • Ribavirin (Rebetol) R • IFN alfa-2b/R combination (Rebetron) Center for Biologics Evaluation and Research

  5. Clinical Development Phase 1 Pegasys (n=1393) Healthy subjects Copegus(n=305) Patients with CHC PK of PEG-IFN alfa-2a Comparability of Copegus and Rebetol Phase 2 PK study of Pegasys 180 g and Copegus 1000/1200 mg in 20 patients with CHC Center for Biologics Evaluation and Research

  6. Clinical Development: Phase 3 • NV15801: Randomized, partially blinded study comparing Pegasys/Copegus to IntronA/Rebetol (n=1121) • NV 15942: Randomized, double blinded, study of Pegasys/Copegus (n=1284) • Treatment duration (6 vs. 12 months) • Ribavirin dose (800 vs. 1000/1200 mg) Center for Biologics Evaluation and Research

  7. Rationale for Selection of Peginterferon and Ribavirin Dosages for Phase 3 Studies Center for Biologics Evaluation and Research

  8. % SVR in Pegasys Monotherapy Studies Center for Biologics Evaluation and Research

  9. Rationale for Selection of Ribavirin Dose • Similarity of PK data for Roche’s and Schering’s ribavirin • 1000-1200mg recommended dosage for Schering’s ribavirin and IFN alfa-2b • 800mg recommended dosage for Schering’s ribavirin and PEG-IFN alfa-2b Center for Biologics Evaluation and Research

  10. Analysis of Phase 3 Clinical Trials Center for Biologics Evaluation and Research

  11. Phase 3 Protocols: Study Population Inclusion • Men and women 18 yrs or older • Histologically proven CHC • Elevated ALT, detectable HCV RNA • Interferon-treatment naïve Exclusion • Other forms of hepatitis, HIV co-infection • History of severe psychiatric, cardiac, neurologic, or ocular disorders International participation • North/South America, Europe, Asia. • US patients 37% of total of both studies Center for Biologics Evaluation and Research

  12. Phase 3 Protocol: Assessment of Response • Primary Endpoint at 24 wk Post-therapy • Combined SVR and SBR for study 1 • SVR alone for study 2 • Futility Withdrawal at 24-weeks • Inadequate early viral response (HCV RNA 2 log drop) OR • No biochemical response ( ALT remains elevated) Center for Biologics Evaluation and Research

  13. NV 15801 (Study 1) Center for Biologics Evaluation and Research

  14. NV 15801 Clinical Protocol • Study Design • n=1121 patients randomized 1:2:2 • PEGASYS alone, PEGASYS/COPEGUS, or REBETRON x 48 weeks • Dosing • PEGASYS 180 μg sc qw, INTRON A 3MIU tiw, Ribavirin 1000/1200 mg po qd • Primary efficacy analysis • ITT population (all randomized) • Cochran-Mantel-Haenszel Test with stratification variables of country/genotype • Pegasys/Copegus vs. Rebetron Center for Biologics Evaluation and Research

  15. Population Characteristics Center for Biologics Evaluation and Research

  16. Baseline Disease Characteristics Center for Biologics Evaluation and Research

  17. Principal Efficacy Outcomes Center for Biologics Evaluation and Research

  18. Percent SVR in Subgroups Center for Biologics Evaluation and Research

  19. Histologic Responders in Patients with Paired Biopsies Center for Biologics Evaluation and Research

  20. SVR by Genotype and Region Overlay Chart 80 60 PEG/R US Proportion of responders 40 IFN/R US 20 PEG/R Non-US IFN/R Non-US 0 Geno Non1 All Geno1 High Low Center for Biologics Evaluation and Research

  21. Percent SVR by Genotype 80 PEG/R 60 IFN/R Percent Responders 40 20 0 Geno non1 High titer Low Titer all Geno1 Center for Biologics Evaluation and Research

  22. SVR by Body Weight 75 Weight <85kg Percent Responders 50 Weight  85kg 25 0 PEG/R 1000-1200mg IFN/R 1000-1200mg Center for Biologics Evaluation and Research

  23. Adverse Events Center for Biologics Evaluation and Research

  24. Percent Serious Adverse Events Center for Biologics Evaluation and Research

  25. Number of Serious Infections Center for Biologics Evaluation and Research

  26. Neutropenia during Treatment and Follow-up 60 50 PEG Mono 40 PEG/R IFN/R 30 20 10 0 Normal Grade1 1500-2000 Grade2 1000-1500 Grade3 500-1000 Grade 4 <500 Center for Biologics Evaluation and Research

  27. Lymphopenia During Treatment and Follow-up 75 PEG Mono 50 PEG/Combo IFN/Combo 25 0 Normal Grade1 1500-1000 Grade2 1000-500 Grade 3 <500 Center for Biologics Evaluation and Research

  28. Patient Withdrawal Numbers Center for Biologics Evaluation and Research

  29. Dose Modification Center for Biologics Evaluation and Research

  30. Serum Triglycerides 75 PEG Mono 50 PEG/R IFN/R 25 0 <200 200-400 400-1000 >1000 Center for Biologics Evaluation and Research

  31. Laboratory Abnormalities by Weight 75 PEG mono <65kg 50 PEG mono  65kg PEG/R <65kg PEG/R  65kg 25 IFN/R <65 kg IFN/R  65kg 0 Neutropenia Grade >3 Hemoglobin <10g/dl Center for Biologics Evaluation and Research

  32. Lab Abnormalities by BMI 75 PEG/M <25BMI 50 PEG/M25BMI PEG/R <25BMI 25 Percent involved PEG/R25BMI IFN/R <25BMI 0 IFN/R 25BMI Neutropenia Grade 3 Hemoglobin <10g/dl Center for Biologics Evaluation and Research

  33. Summary: Efficacy • Peg-IFN alfa-2a 180g /Ribavirin 1000-1200mg higher SVR than IFN alfa-2b/Ribavirin 1000-1200mg • Treatment difference 8% • Prognostic factors associated with lower response • HCV genotype 1/High viral titer (>2 million copies/ml) • Cirrhosis • Older age • Higher body weight • Response rates lower in US compared to Non-US

  34. Summary: Safety • Peg-IFN/R: higher observed incidence of certain adverse events compared to IFN/R • Serious adverse events (12% vs 9%) • Serious infections (3.4% vs 1.7%) • Grade 4 neutropenia (5% vs 1%) • Grade 3 thrombocytopenia (5% vs 0.2%) • Dose modifications (32% vs 18%) • Similar premature withdrawals (10% vs 11%) • Greater toxicity with lower body weight Center for Biologics Evaluation and Research

  35. NV 15942 (Study 2) Center for Biologics Evaluation and Research

  36. NV 15942 Clinical Protocol • Design: 1311 patients randomized by genotype and viral load to 4 arms receiving Pegasys (180µg) • Two treatment duration arms (24 vs. 48 weeks) • Two ribavirin dose arms (800 and1000-1200 mg) • Primary Efficacy Analysis • Sustained viral response in ITT population (all randomized receiving > 1dose) • Cochran-Mantel-Haenszel Test with stratification variables of region, HCV genotype and titer, ribavirin dose Center for Biologics Evaluation and Research

  37. Randomization/Allocation Center for Biologics Evaluation and Research

  38. Population Characteristics Center for Biologics Evaluation and Research

  39. Baseline Disease Characteristics Center for Biologics Evaluation and Research

  40. Pooled Sustained Virologic Response Center for Biologics Evaluation and Research

  41. %SVR by Strata, Treatment Duration and Ribavirin Dose Center for Biologics Evaluation and Research

  42. SVR by Strata and Treatment Arm Center for Biologics Evaluation and Research

  43. SVR by Body Weight 75 Weight <85kg 50 Weight  85kg Percent Responders 25 0 PEG/R 1000/48 PEG/R 800/24 PEG/R 1000/24 PEG/R 800/48 Center for Biologics Evaluation and Research

  44. Treatment Duration x24 wks x48 wks Ribavirin Dose 800mg 1000-1200mg Gen1 High 4/29(13) 36/115(31) 19/72(26) 21/72(29) Low 9/21(43) 15/30 (50) 6/18(33) 18/33(54) Non1 High 34/48(71) 27/41(66) 19/31(62) 44/58(76) Low 13/37(35) 16/20(80) 10/14(71) 19/43(44) Pooled SVR in Patients with Cirrhosis Center for Biologics Evaluation and Research

  45. Pooled SVR in Genotype 4 Center for Biologics Evaluation and Research

  46. Histologic Responders: Patients with Paired Biopsies Center for Biologics Evaluation and Research

  47. Percent with Adverse Events Center for Biologics Evaluation and Research

  48. Serious Adverse Events Center for Biologics Evaluation and Research

  49. Number of Serious Infections Center for Biologics Evaluation and Research

  50. Case Report: Infection/Neutropenia 68 yo man with difficulty swallowing and fever on study day 33 Day 47: Severe Neutropenia (ANC 400) Study treatment PEG-IFN/ 1200mg R discontinued Day 59: Hospital admission with severe throat pain, anemia, neutropenia and thrombocytopenia S. aureus epiglottitis diagnosed by laryngoscopy by smear S. aureus grown by urine culture Day 60: Improvement Response to multiple antibiotics and RBC transfusion WBC reported to be near normal at time of discharge on this day.

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