Hepatitis C: Non-responders Nikunj Shah, MD Associate Professor of medicine University of Illinois Medical center 1 Current Standard of Care for Naïve HCV Patients (SVR) 1 8 8 6 53 45 4 6 52 46 4 2 2 Peg IFN 2a 18 mcg + 1-12/RBV Pegasys Package Insert 1 Current Standard of Care for Naïve HCV 1 Genotype 1 Patients 1 (SVR) 8 8 6 44 4 36 6 41 4 33 2 Peg IFN 2b 1.5 mcg + 8/RBV Peg-Intron Package Insert 2 Peg IFN 2a 18 mcg + 1-12/RBV Peg IFN 2b 1.5 mcg + 8/RBV Pegasys Package Insert Peg-Intron Package Insert IFN 24 Wk 8% - 12% HCV Antiviral Therapy: Increasing Rates of Sustained Viral Remission Over the Past 15 Years IFN 48 Wk 15% - 22% PEG IFN-alfa 2a/2b 48 Wk 25% - 39% IFN alfa-2b/ RBV 48 Wk 41% PEG IFN-alfa 2a/ 2b RBV Overall 54% - 56% PEG IFN alfa-2b/rbv Weight-Based Dosing 61%
Genotype 2 or 3 Genotype 1 Minimal Fibrosis Advanced Fibrosis Low High Age 4 Age > 4 Female Male Weight 75 kg Weight > 75 kg HCV Genotype is the Most Important Predictor of SVR 2 4 6 8 Factors Predicting a Response to Therapy Fixed Variable Genotype Level of virus in the blood Usually expressed in millions/iu Histology at liver biopsy Rapidity of viral clearance Type of therapy Dose and duration Adherence to therapy Quality of life Treating physician Genotype Frequency and Viral Load in US Patients 4% (Others) 22% Genotype 2,3 Genotype 1 High Viral Load Genotype 1 (> 85, IU/mL) 5% Low Viral Load 24% Blatt LM, et al. J Viral Hepat. 2;7:196-22. Treatment of IFN α-2 Nonresponders with PEG-IFN α-2a + Ribavirin CATEGORY ETR SVR IFN monotherapy 44% 3% IFN + R therapy 3% 11% Genotype I 29% 14% Genotypes 2/3 72% 52% Caucasians 37% 2% African Americans 14% 6% Shiffman M, et al. AASLD 22. 2
Patterns of Response Baseline Treatment Relapser Nonresponder Negative Sustained Responder Time Growing Number of Non-responders to Alpha 2 Interferons 6 5 Actively treated Nonresponder pool 4 3 2 1 Patterns of Response Baseline Treatment Follow-up Nonresponder Partial Nonresponder Negative Sustained Responder Time 3 23 24 25 26 27 28 29 21 211 212 213 214 Warburg Pincus, 23. What Do We Do Now? Patients (thousands)
Retreatment Options for Nonresponders to IFN α-2 Therapy Re-treat with more aggressive/effective treatment? Place on maintenance therapy? Wait for future agents to be developed? Goals of Therapy Primary Goal Eradicate HCV infection Treatment options: nonresponders No FDA-approved treatments. Combination therapy Maintainence Interferon Treatment May decrease late complications of hepatitis Several ongoing studies Discontinuation of therapy Treatment Options for Alpha 2 Interferon Nonresponders Primary Goal Secondary Goal Antiviral Strategy Alpha 2 high-dose retreatment More effective interferons Future therapies Hepatitis Histology Strategy Maintenance therapy Future therapies 4
Change in Fibrosis Stage 3 Years After Study Entry.6.59.3.15 -.3 -.6 -.6 Untreated patients No SVR SVR IFN-treated Shiratori Y, et al. Ann Int Med. 2;132:517-524. SVR in Alpha 2 IFN Monotherapy Relapsers and Nonresponders 6 58% 4 2 13% 12 months (n=33) 12 months (n=69) Retreatment of Alpha 2 IFN Monotherapy Relapsers and Nonresponders 5 Change in fibrosis stage Heathcote, et al. Hepatology. 1998;27:1136-1143. SVR in Alpha 2 IFN Relapsers 58% 6 * 49% 4 28% 2 5% * P=.24. P<.1. 6 months (n=32) 12 months (n=33) IFN-α 2b 6 months (n=173) IFN-α 2b + Ribavirin 6 months (n=172) Heathcote, et al. Hepatology. 1998;27:1136-1143. Davis, et al. N Engl J Med. 1998;339:1493-1499. negative (%)
Studies of Retreatment in Alpha 2 IFN Monotherapy Nonresponders IFN-α 2b (Intron-A ) %-3% Previously failed 3 MU x 6 months Puoti 1996 (6-3 MU x 12 months) % Giudici 1996 (3-6 MU x 12-24 months) 3% Chemello 1997 (6 MU x 12 months) % Chow 1998 (5 MU x 12 months) % Consensus Interferon 13% Heathcote 1998 (15 mcg x 12 months) 13% Future Disease Burden: 28 6 Estimated Increase by the Year 28 528% 5 4 279% 3 223% 2 1 61% 68% 6 Cirrhosis HCC Liver-related deaths Decompensation Need for OLT Growing Number of Nonresponders to Alpha 2 Interferons 6 5 Actively treated Nonresponder pool 4 3 2 1 % HCC=hepatocellular carcinoma. Davis GL, Hepatology. 1998;28:39a. 23 24 25 26 27 28 29 21 211 212 213 214 Warburg Pincus, 23. Patients (thousands)
Protein Targets for Specific HCV Antiviral Therapy HCV polyprotein NS 2/3 metalloprotease Binds PKR C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B NS3 protease domain NS3 helicase domain NS3/NS4 bifunctional protease/helicase NS5B RNA-dependent RNA polymerase Company Product Status Description Anadys ANA245 Ph. I Nucleoside Boehringer BILN 261 stop Protease inhibitor Chiron/CSL HCV vaccine Ph. I Vaccine Human Genome Albuferon Ph III Fusion albumin + IFN IDEA Transfersome IFN Ph. I Transferome + IFN Roche/Ribapharm Levovirin Ph. I L-isomer of ribavirin Idenix NM283 Ph. I/II Polymerase inhibitor Amarillo IFN alpha Ph. II Oral formulation BioMedicines Omega IFN Ph. II IFN omega Innogenetics HCV E1 vaccine Ph. II HCV E1 protein InterMune Actimmune Ph. II Antifibrotic Peg-alfacon-1 Ph. II Pegylated consensus IFN Isis ISIS 1483 Ph. II Antisense targeting IRES Maxim Ceplene Ph. II Histamine immune modulator Ribapharm Viramidine Ph. III Ribavirin prodrug Viragen Multiferon Ph. II Multisubtype human IFN 1% Timelines for FDA New Drug Approval 1% 8% 6% 71% 4% 2% 32% 21% 21% % Pre- Clinical Phase I-II Phase II-III Phase III- Market FDA Approval 1 Year 3 Years 3 Years 1 Year DiMasi, et al. J Health Econ 23;22(2):151-185. 7