Emerging Direct-Acting Antivirals for Treatment of Chronic Hepatitis C Debra Birnkrant, MD Director, DAVP DILI Conference March 20, 2013 1
HCV in the United States 3 to 4 million people have chronic HCV Most unaware of their infection HCV Genotype 1 most common (~75%), followed by Genotypes 2 and 3 (~20%) Most common reason for liver transplant 15,000 deaths/year More annual deaths than related to HIV 2
HCV in the United States Decompensated cirrhosis Projected Peak incidence: 2020 with >145,000 cases/year Hepatocellular carcinoma Projected Peak incidence: 2019 with 14,000 cases/year CDC issued recent recommendation to screen all baby boomers Gastroenterology. 2010;138(2):513-521. 3
Sustained Virologic Response (SVR) Lack of detection of HCV RNA in blood several weeks after complete treatment (e.g., SVR12) Florian, Jeffry, Chen, Jianmeng, Jadhav, Pravin, Carter, Wendy, Murray, Jeff, Birnkrant, Debra. Consideration of new endpoints for regulatory approval and dose selection of hepatitis C therapies. In: 62nd AASLD, San Francisco, CA, 4 8 November 2011. Abstract LB- 28. (accepted for publication in Gastroenterology, 2013) Used as determination of treatment success; primary endpoint in clinical trials Correlated with improvements in development of hepatocellular carcinoma, hepatic events, fibrosis, allcause mortality Adriann van der Meer, et al., JAMA, 2012;308:2584-2593 Considered equal to virologic cure of chronic HCV 4
HCV Treatment Evolution Standard Interferon Ribavirin Pegylated Interferon 1991 1995 1998 2001 2002 Boceprevir Telaprevir 2011 100% Percent Sustained Response 80% 60% 40% 20% 6% 16% 34% 42% 39% 54% 70 + % 0% IFN 6 m IFN 12 m IFN/R 6 m IFN/R 12 m PegIFN 12m Peg/R 12m Peg/R/PI 5
May 2011 New era of direct acting antiviral- (DAA) based treatment Two HCV protease inhibitors approved for use in HCV genotype 1-infected patients Boceprevir and Telaprevir represents a new direction in the treatment of hepatitis C and a significant improvement over the current standard of care Dr. Margaret A. Hamburg, Commissioner of the FDA 6
Direct-Acting Antivirals (DAAs) 7
Boceprevir: Treatment-Naïve SVR 38% 63% 66% Response Guided Therapy (RGT) ~60% eligible to receive a shortened 28 week duration -> ~90% SVR 8
Telaprevir: Treatment-Experienced SVR significantly higher in pooled T12/PR48 groups compared with PR48 % SVR 100 90 80 70 60 50 40 30 20 10 0 86 22 Relapsers 59 15 Partial Responders 32 Nulls 5 T12/PR48 PR48 9
Boceprevir: Safety 4 pills 3x/day Plus PEG/RBV Anemia, neutropenia Dysgeusia Drug-drug interactions CYP3A4/5 inhibitor 10
Telaprevir: Safety 2 pills 3x/day with high fat food Plus PEG/RBV Anemia Rash, pruritus, anorectal disorders Drug-drug interactions CYP3A inhibitor/substrate Pgp inhibitor/substrate 11
Approved DAA-based HCV Treatment Boceprevir and Telaprevir approvals are major advance in HCV treatment options Improved SVR rates compared to PEG/RBV alone Potential for shorter duration through RGT Limitations Still need PEG/RBV (bone marrow suppression, neuropsychiatric effects, hemolytic anemia, teratogenicity, etc.) Only for HCV GT1 Drug-drug interactions High pill burden Serious side effects, i.e. rash, anemia Intensive clinical management 12
Challenges for Future DAA Therapy Simple regimens Short duration, simple futility rules Easy dosing Low pill burden, limited drug interactions All oral Pan-genotypic Highly effective In challenging populations Safe and tolerable Manageable side effect profile 13
Future DAA-based HCV Treatment boceprevir telaprevir NS3/4A PIs simeprevir faldaprevir Vaniprevir ABT-450 MK-5172 and others sovaprevir GS-9451 asunaprevir danoprevir GS-9256 NS5B Polymerase inhibitors Nuc. Analogues NS5B Polymerase inhibitors Non-Nuc. sofosbuvir mericitabine and others BI 207127 ABT-333 tegobuvir ABT-072 VX-222 filibuvir setrobuvir BMS-791325 and others NS5A inhibitors daclatasvir ABT-267 GS-5885 and others 14 Assembled based on information included in HCV Drug ResisSS 2012 v1.2 (HCV DrAG)
DAA Classes NS3/4A PIs NS5B Polymerase Inhibitors NS5A Inhibitors Nucleoside /tide Non-nuc (multiple subclasses) Genotypic Coverage Limited* Pangenotypic Limited Variable Potency High Variable Intermediate High Barrier to Resistance Low* High Low Low* *Varies with the generation of the drug within the class 15 Adapted/Updated from Vachon M. and Dieterich D., Semin Liver Dis. 2011;31(4):399-409
SVR Rates With 24 Wks of Daclatasvir + Sofosbuvir ± RBV: Treatment Naïve, non-cirrhotic, GT 1-3 Very high SVR24 rates with 24-wk regimens across genotypes GT1 GT2/3 HCV RNA < LLOQ (%) 100 80 60 40 20 100 100 100 100 100 100 100 100 93 94 88 93 100 80 60 40 20 100 100 98 95 0 EOT* SVR24 EOT* Sulkowski MS, et al. AASLD 2012. Abstract LB-2. SVR24 EOT* SVR4 SOF LI + DCV SOF + DCV SOF + DCV (12 wk) SOF + DCV + RBV SOF + DCV + RBV (12 wk) *EOT includes pts who discontinued early, with last visit considered EOT. 0 16
AVIATOR: SVR12 Rates With ABT-450/RTV, ABT-267, ABT-333, and RBV SVR12 rates higher in pts with GT1b HCV but also high in pts with GT1a HCV 12-wk regimen with all 3 DAAs + RBV produced highest SVR12 rates Treatment-Naive Patients Null Responders SVR12 (%) 100 80 60 40 20 0 n = 86 100 100 100 96 98 100 100 88 88 82 100 100 96 96 96 100 81 100 84 79 85 83 81 56 24 29 12 52 27 52 25 54 25 26 18 89 89 100 100 28 17 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b Observed data (above bar) ITT (within bar) ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 RBV 8 wks 12 wks 12 wks Kowdley KV, et al. AASLD 2012. Abstract LB-1. 17
Daclatasvir/Asunaprevir Dual Regimen in GT1b Null Responders Group A1: DCV+ASV 200 mg BID SVR12 = 78% (14/18) Group A2: DCV+ASV 200 mg QD SVR12 = 65% (13/20) Bristol-Myers Squibb. Investigational Hepatitis C Dual DAA Regimen of Daclatasvir and Asunaprevir Achieved SVR12 in 78% of Difficult-to-Treat Genotype 1b Prior Null Responders In Expanded Phase II Study. Press release. November 11, 2012. 18
Fission GT2/3 Naïve Sofosbuvir NS5B nucleotide polymerase inhibitor + RBV x 12 weeks vs PEG/RBV x 24 weeks SOF+RBV N=207 SVR12 67% PEG+RBV N=243 SVR12 67% 0 12 24 Weeks Gilead Sciences: Press release February 4, 2013 36 19 19
FDA Guidance (DILI) Intended to assist in the evaluation of the potential for a drug to cause severe liver injury during new drug development Does not address the issue of DILI in patients with preexisting liver disease such as chronic hepatitis C who often have elevated liver enzymes at baseline 20
Challenges in the Evaluation of Potential DILI in HCV Drug Development Should trials have standardized entry and monitoring criteria? Concern that clinical trial inclusion or exclusion criteria are too stringent do not reflect the wide range of patients who will receive treatment in real-world setting. Which criteria should be used for suspicion of DILI in patients with elevated liver enzymes at baseline? During a clinical trial, change in ALT from a patient s own baseline or nadir value on treatment may be more informative 21
Future DAA-based HCV Treatment IFN-free regimens Pan-genotypic Shorter durations Once daily dosing Improved efficacy All patient subgroups Oral regimen with low pill burden Improved safety 22
Conclusions Chronic HCV may lead to cirrhosis, hepatocellular carcinoma, and/or hepatic decompensation if left untreated Growing at-risk population in the US PI approvals in 2011 marked a significant improvement in HCV treatment options, but many limitations remain Future IFN-free DAA options are rapidly advancing 23