HEPATITIS WEB STUDY HEPATITIS C ONLINE Ribavirin Copegus

HEPATITIS WEB STUDY HEPATITIS C ONLINE Ribavirin (Copegus, Rebetol, Ribasphere) Prepared by: David Spach, MD and H. Nina Kim, MD Last Updated: February 14, 2014 Hepatitis web study

RIBAVIRIN (COPEGUS, REBETOL, RIBASPHERE) Background Hepatitis web study

Ribavirin: Mechanism of Action Th 2 Defective HCV Particle Th 1 X X CTL RBV IFN-γ TNF-α 1: Immune Clearance Hepatocyte RBV IMP RBV – P IMPDH GMP 2: Inhibition of IMPDH GTP HCV RNA Rd. Rp RBV P 3: Inhibition of HCV Rd. Rp P – RNA Mutagen RBV P P 4: RNA Mutagenesis P X Modified from: Feld JJ, Hoofnagle JH. Nature. 2005; 436: 967 -72. X X X Hepatitis web study

Ribavirin (Copegus, Rebetol, Ribasphere) • Mechanism: purine nucleoside analog • Approval Status: - First approved by FDA in 1998 - Multiple preparations subsequently FDA approved • Indications - In combination with other agents for all HCV genotypes • Dosing (brand dependent): - Fixed dose (800 mg PO per day in two divided doses) - Weight based (1000 -1200 mg per day in two divided doses) - Weight based (800 -1400 mg per day in two divided doses) • Drug Interactions - Use of ribavirin and didanosine can cause life-threatening toxicity - Use of ribavirin and azathioprine can cause azathioprine-related toxicity • Adverse Effects (AE) - Hemolytic anemia - Birth defects (pregnancy category X) Hepatitis web study

Ribavirin: Key Studies • Interferon alfa-2 b +/- Ribavirin for 24 or 48 weeks • Peginterferon alfa-2 a +/- Ribavirin for Chronic HCV • Duration and Dose Finding Peginterferon alfa-2 a + Ribavirin • Flat versus Weight-Based Ribavirin Dosing: WINR Study Hepatitis web study

Phase 3 Treatment Naïve, Chronic HCV Interferon alfa-2 b +/- Ribavirin for 24 or 48 weeks Mc. Hutchison JG, et al. N Engl J Med. 1998; 339: 1485 -92. Hepatitis web study

Interferon alfa-2 b +/- Ribavirin for Chronic HCV Study Outline • Study - Randomized, double-blinded, placebo controlled, phase 3 trial - Conducted in 44 centers in United States • Subjects - N = 912 with chronic hepatitis C - Treatment naïve; 72% genotype 1 • Regimens - Interferon alfa-2 b + Placebo x 24 or 48 weeks - Interferon alfa-2 b + Ribavirin (weight based) x 24 or 48 weeks • Primary Endpoint - Undetectable serum HCV RNA 24 weeks after stopping treatment *Ribavirin weight based dosing: <75 kg = 1000 mg/day; >75 kg = 1200 mg/day Source: Mc. Hutchison JG, et al. N Engl J Med. 1998; 339: 1485 -92. Hepatitis web study

Interferon alfa-2 b +/- Ribavirin for Chronic HCV Study Design Week 0 24 Interferon 48 72 SVR 24 (n = 231) Interferon SVR 24 (n = 225) Interferon + Ribavirin (n = 228) SVR 24 Drug Dosing Interferon alfa-2 b 3 million U 3 x/week Weight-based Ribavirin (divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg Source: Mc. Hutchison JG, et al. N Engl J Med. 1998; 339: 1485 -92. Hepatitis web study

Interferon alfa-2 b +/- Ribavirin for Chronic HCV Study Results SVR 24, by Treatment Regimen Patients with SVR 24 (%) 50 38 40 31 30 20 13 10 0 6 13/231 29/225 70/228 Interferon (24 weeks) Interferon (48 weeks) Interferon + Ribavirin (24 weeks) Source: Mc. Hutchison JG, et al. N Engl J Med. 1998; 339: 1485 -92. 87/228 Interferon + Ribavirin (48 weeks) Hepatitis web study

Interferon alfa-2 b +/- Ribavirin for Chronic HCV Study Conclusions: “In patients with chronic hepatitis C, initial therapy with interferon and ribavirin was more effective than treatment with interferon alone. ” Source: Mc. Hutchison JG, et al. N Engl J Med. 1998; 339: 1485 -92. Hepatitis web study

Phase 3 Treatment Naïve, Chronic HCV Peginterferon alfa-2 a +/- Ribavirin for Chronic HCV Fried MW, et. al. N Engl J Med. 2002; 347: 975 -82. Hepatitis web study

Peginterferon alfa-2 a +/- Ribavirin for Chronic HCV Study Design • Study - Open-label randomized controlled trial • Subjects - N = 1149 with chronic hepatitis C randomized - Treatment naïve; 62% genotype 1 - Serum ALT above upper limit of normal x prior 6 months • Regimens (48 Week Treatment) - Peginterferon alfa-2 a 180 µg 1 x/week + Ribavirin 1000 -1200 mg/day Hepatitis web study

Peginterferon alfa-2 a +/- Ribavirin for Chronic HCV Study Design Week 0 48 72 N = 453 Peginterferon alfa-2 a + Ribavirin SVR 24 N = 224 Peginterferon alfa-2 a + Placebo SVR 24 N = 444 Standard interferon + Ribavirin SVR 24 Drug Dosing Peginterferon alfa-2 a 180 µg 1 x/week Weight-based Ribavirin (divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg Interferon alfa-2 b 3 million U 3 x/week Source: Fried MW, et. al. N Engl J Med. 2002; 347: 975 -82. Hepatitis web study

Peginterferon alfa-2 a + Ribavirin for Chronic HCV Results Response after 48 Weeks of Treatment 100 Patients (%) 80 60 Peginterferon alfa-2 a 180 µg + Ribavirin Peginterferon alfa-2 a 180 µg + Placebo Interferon alfa-2 b + Ribavirin 69 59 52 56 44 40 29 20 0 313/453 132/224 231/444 End of Treatment Response Source: Fried MW, et. al. N Engl J Med. 2002; 347: 975 -82. 255/453 66/224 197/444 Sustained Virologic Response Hepatitis web study

Peginterferon alfa-2 a + Ribavirin for Chronic HCV Predictive Value of Early Virologic Response Yes Week 12 HCV RNA (N = 453) N = 390 (86%) SVR N = 253 (65%) No SVR N = 137 (35%) SVR N=2 (3%) No SVR N = 61 (97%) 2 -log drop or undetectable HCV RNA No N = 63 (14%) Source: Fried MW, et. al. N Engl J Med. 2002; 347: 975 -82. Hepatitis web study

Peginterferon (with and without Ribavirin) versus Interferon and Ribavirin Conclusions: “In patients with chronic hepatitis C, once-weekly peginterferon alfa-2 a plus ribavirin was tolerated as well as interferon alfa -2 b plus ribavirin and produced significant improvements in the rate of sustained virologic response, as compared with interferon alfa-2 b plus ribavirin or peginterferon alfa-2 a alone. ” Source: Fried MW, et. al. N Engl J Med. 2002; 347: 975 -82. Hepatitis web study

Phase 3 Treatment Naïve, Chronic HCV Duration and Dose Finding Peginterferon alfa-2 a + Ribavirin Randomized study of low-dose versus weight based ribavirin and 24 versus 48 weeks of therapy Hadziyannis SJ, et. al. Ann Intern Med. 2004; 140: 346 -55. Hepatitis web study

Peginterferon alfa-2 a + Ribavirin for Chronic HCV Treatment Duration and Ribavirin Dose • Study - Randomized, double-blind trial • Subjects - N = 1311 with chronic hepatitis C (1284 treated) - Treatment naïve adult patients; 58% genotype 1 - Serum ALT above upper limit of normal x prior 6 months • Regimens - Peginterferon alfa-2 a: 180 µg/wk + Ribavirin: 800 mg/day x 24 wks - Peginterferon alfa-2 a: 180 µg/wk + *Ribavirin: 1000 -1200 mg/day x 24 wks - Peginterferon alfa-2 a: 180 µg/wk + Ribavirin: 800 mg/d x 48 weeks - Peginterferon alfa-2 a: 180 µg/wk + *Ribavirin: 1000 -1200 mg/day x 48 wks • Primary Endpoint - Undetectable serum HCV RNA at end of treatment (ETR) - Undetectable serum HCV RNA 24 wks after cessation of treatment (SV *Ribavirin dose: 1000 mg/day for Wt <75 kg, 1200 mg/day for Wt ≥ 75 kg Source: Hadziyannis SJ, et. al. Ann Intern Med. 2004; 140: 346 -55. Hepatitis web study

Peginterferon alfa-2 a + Ribavirin for Chronic HCV Treatment Duration and Ribavirin Dose Week 0 12 24 48 72 Randomize Peginterferon alfa-2 a + Ribavirin (low dose) (n = 214) SVR 24 Peginterferon alfa-2 a + Ribavirin (weight-based dose) (n = 288) SVR 24 Peginterferon alfa-2 a + Ribavirin (low dose) (n = 365) SVR 24 Peginterferon alfa-2 a + Ribavirin (weight-based dose) (n = 158) SVR 24 Source: Hadziyannis SJ, et. al. Ann Intern Med. 2004; 140: 346 -55. Hepatitis web study

Peginterferon alfa-2 a + Ribavirin for Chronic HCV Treatment Duration and Ribavirin Dose SVR 24 Rates, by Regimen PEG + RBV (low dose) x 24 weeks PEG + RBV (weight-based dose) x 24 weeks PEG + RBV (low dose) x 48 weeks PEG + RBV (weight-based dose) x 48 weeks 100 Patients with SVR (%) 84 80 60 40 81 79 80 n = 144 n = 99 n = 153 52 42 41 n = 118 n = 250 29 20 0 n = 101 n = 271 n = 96 Genotype 1 Genotypes 2 or 3 Genotype Source: Hadziyannis SJ, et. al. Ann Intern Med. 2004; 140: 346 -55. Hepatitis web study

Peginterferon alfa-2 a + Ribavirin for Chronic HCV Treatment Duration and Ribavirin Dose Rates of SVR with Different Peginterferon + Ribavirin Regimens Peginterferon + Ribavirin (low dose) x 24 weeks Peginterferon + Ribavirin (weight-based dose) x 24 weeks Patients with SVR (%) Peginterferon + Ribavirin (low dose) x 48 weeks Peginterferon + Ribavirin (weight-based dose) x 48 weeks 100 80 84 81 79 80 85 83 88 77 84 80 74 82 60 40 20 0 All Patients Low Viral Load Source: Hadziyannis SJ, et. al. Ann Intern Med. 2004; 140: 346 -55. High Viral Load Hepatitis web study

Peginterferon alfa-2 a + Ribavirin for Chronic HCV Treatment Duration and Ribavirin Dose Conclusion: “Treatment with peginterferon-alpha 2 a and ribavirin may be individualized by genotype. Patients with HCV genotype 1 require treatment for 48 weeks and a standard dose of ribavirin; those with HCV genotypes 2 or 3 seem to be adequately treated with a low dose of ribavirin for 24 weeks. ” Source: Hadziyannis SJ, et. al. Ann Intern Med. 2004; 140: 346 -55. Hepatitis web study

Phase 3 Treatment Naïve, Chronic HCV WINR Study Flat versus Weight-Based Ribavirin Dosing Jacobson IM, et. al. Hepatology. 2007; 46: 971 -81. Hepatitis web study

Peginterferon alfa-2 b + Ribavirin (weight-based or flat-dose) WIN-R Study: Design • Study - Prospective, randomized, open-label trial • Subjects - N = 5027 with chronic hepatitis C (4913 analyzed) - Treatment naïve adult patients (Age 18 -70) • Treatment Regimens - Peginterferon alfa-2 b: 1. 5 µg/kg/wk + Wt-based* Ribavirin: 800 -1400 mg/d - Peginterferon alfa-2 b: 1. 5 µg/kg/wk + Flat-dose Ribavirin: 800 mg/d • Treatment Duration - Genotypes 1, 4, 5, 6: duration of 48 weeks - Genotypes 2, 3: duration of 24 or 48 weeks • Primary Endpoint - Undetectable serum HCV RNA at end of treatment (ETR) - Undetectable serum HCV RNA 24 weeks after cessation of treatment (SVR) *Weight-based ribavirin dosing: < 65 kg: 800 mg/d; 65 -85 kg: 1000 mg/d; >85 -105 kg: 1200 mg/d; >105 kg: 1400 mg/d Source: Jacobson IM, et. al. Hepatology. 2007; 46: 971 -81. Hepatitis web study

Peginterferon alfa-2 b + Ribavirin (weight-based or flat-dose) WIN-R Study: Design Week 0 24 48 PEG + Ribavirin (weight-based) GT 1 -6 GT 2, 3 SVR 24 (n = 2111) PEG + Ribavirin (flat dose) (n = 2144) PEG + RBV (weight-based) SVR 24 (n = 333) SVR 24 PEG + Ribavirin (flat dose) SVR 24 (n = 335) 72 Drug Dosing Peginterferon alfa-2 b: 180 µg once weekly Weight-based Ribavirin (in 2 divided doses): - 800 mg/d if < 65 kg; 1000 mg/d if 65 -85 kg; 1200 mg/d if >85 -105 kg; 1400 mg/d if >105 kg Flat-dose Ribavirin (in 2 divided doses): 800 mg/day Source: Jacobson IM, et. al. Hepatology. 2007; 46: 971 -81. Hepatitis web study

Peginterferon alfa-2 b + Ribavirin (weight-based or flat-dose) WIN-R Study: Results SVR 24, by Genotype and Treatment Regimen Weight-Based Ribavirin Patients with SVR 24 (%) 80 Flat Dose Ribavirin P =. 252 62 60 60 P =. 008 P =. 005 44 41 40 34 29 20 0 938/2121 852/2121 All 447/1313 377/1305 GT-1 Source: Jacobson IM, et. al. Hepatology. 2007; 46: 971 -81. 479/775 462/777 GT-2, 3 Hepatitis web study

Peginterferon alfa-2 b + Ribavirin (weight-based or flat-dose) WIN-R Study: Results All Treated: SVR 24 by Weight Distribution 100 65 -85 kg >85 -105 kg Patients with SVR (%) 80 >105 kg 60 P =. 973 45, 2 42. 0 47, 3 40 P =. 001 43, 8 38, 8 33, 5 20 0 Weight-Based Ribavirin Source: Jacobson IM, et. al. Hepatology. 2007; 46: 971 -81. Flat-Dose Ribavirin Hepatitis web study

Peginterferon alfa-2 b + Ribavirin (weight-based or flat-dose) WIN-R Study: Results Genotype 1: SVR 24 by Weight Distribution 80 65 -85 kg >85 -105 kg >105 kg Patients with SVR (%) 60 P =. 569 40 33, 8 33, 3 P =. 019 37, 3 31, 1 28, 8 21, 3 20 0 Weight-Based Ribavirin Source: Jacobson IM, et. al. Hepatology. 2007; 46: 971 -81. Flat-Dose Ribavirin Hepatitis web study

Peginterferon alfa-2 b & Weight-based or Flat-dose Ribavirin WIN-R Study: Results Genotypes 2, 3: SVR 24 by Weight Distribution 100 65 -85 kg >85 -105 kg Patients with SVR (%) 80 >105 kg 64 60 P =. 356 59 61 64 P =. 034 55 55 40 20 0 Weight-Based Ribavirin Source: Jacobson IM, et. al. Hepatology. 2007; 46: 971 -81. Flat-Dose Ribavirin Hepatitis web study

Peginterferon alfa-2 b + Ribavirin (weight-based or flat-dose) WIN-R Study: Results Sustained Virologic Response (SVR) by Weight Distribution African American Genotype 1 100 Patients with SVR (%) 65 -85 kg >85 -105 kg 80 >105 kg 60 P =. 036 40 P =. 446 31, 3 22, 2 20 0 13, 1 Weight-Based Ribavirin Source: Jacobson IM, et. al. Hepatology. 2007; 46: 971 -81. 11, 7 9, 9 6, 7 Flat-Dose Ribavirin Hepatitis web study

Peginterferon alfa-2 b & Weight-based or Flat-dose Ribavirin WIN-R Study: Results Relapse Rates among Patients who Achieved End-of-Treatment Responses 35 Weight-Based Ribavirin 29, 6 Relapse Rates (%) 30 25 23, 0 19, 0 20 15 Flat-Dose Ribavirin 15, 3 10 7, 0 8, 3 5 0 All Treated Genotype 1 Source: Jacobson IM, et. al. Hepatology. 2007; 46: 971 -81. Genotypes 2 & 3 Hepatitis web study

Peginterferon alfa-2 b & Weight-based or Flat-dose Ribavirin WIN-R Study: Conclusions Conclusion: “Peginterferon alfa-2 b plus weight-based ribavirin is more effective than flat-dose ribavirin, particularly in genotype 1 patients, providing equivalent efficacy across all weight groups. Ribavirin 1400 mg/day is appropriate for patients 105 to 125 kg. For genotype 2/3 patients, 24 weeks of treatment with flat-dose ribavirin is adequate; no evidence of additional benefit of extending treatment to 48 weeks was demonstrated. ” Source: Jacobson IM, et. al. Hepatology. 2007; 46: 971 -81. Hepatitis web study

This slide deck is from the University of Washington’s Hepatitis C Online and Hepatitis Web Study projects. Hepatitis C Online www. hepatitisc. uw. edu Hepatitis Web Study http: //depts. washington. edu/hepstudy/ Funded by a grant from the Centers for Disease Control and Prevention. Hepatitis web study