Hepatitis C: New Therapies in 2016-2017 Mark Sulkowski, MD Professor of Medicine Johns Hopkins University School of Medicine Medical Director, Viral Hepatitis Center Divisions of Infectious Diseases and Gastroenterology/Hepatology Baltimore, Maryland Current HCV direct acting antiviral regimens cure the majority of persons treated in phase 3 trials Highly efficacious DAAs target New England Journal of Medicine trials in GT 1 1 Receptor binding different points in the HCV lifecycle published in 20142 and endocytosis Transport 96% and release Fusion and uncoating Virion assembly (+) RNA ER lumen Translation and LD polyprotein LD processing NS5A inhibitors LD 3680/ Membranous 3826 web RNA replication ER lumen Sustained Virologic NS3 protease inhibitors Nucleos(t)ide and Non- Response nucleoside NS5B inhibitors [SVR] 1. Lindenbach BD, Rice CM. Nature 2005;436(Suppl):933–8; 2. Liang J, Ghany MG. N Engl J Med 2014;370:2043–7; 3. Burki T. Lancet Infect Dis 2014;14:452–3 Globally, 150 million people are infected with hepatitis C and 350,000 to 500,000 people die each year Messina JP et al, Hepatology, 2015; 61: 77-87. WHO Global Health Sector HCV Strategy Global targets for 2030 Reduce Expand and Decrease new Decrease global enhance services infections deaths suffering and costs • 90% diagnosed • 70% reduction in • 60% reduction in • 90% of eligible HCV incidence HCV-related deaths people treated • 50% reduction by • 90% of those treated 2020 are cured • Zero new infections • 50% of PWID due to unsafe blood covered by harm transfusions reduction services • 75% reduction in by 2020 new infections due to unsafe medical practices by 2020 WHO. Draft global health sector strategy on viral hepatitis, 2016–2021. Available at: www.who.int/hepatitis/news-events/strategy2016- 2021/Draft_global_health_sector_strategy_viral_hepatitis_13nov.pdf?ua=1 (accessed January 2016) New HCV DAAs – where is the unmet medical need? • Access to effective HCV treatment – Regional registration of novel DAAs • HCV treatment without the need for baseline assessment of genotype and/or RAVs – Pangenotypic – High barrier to emergence of resistant variants • Shorter therapy – Reduce cost – Increase treatment capacity • Curative treatments for persons who fail first course regimens HCV treatment regimens available in 2016 – 2017 Antiviral Non- Nuc NS3 NS5A Nuc RBV IFN NS5B NS5B Narlaprevir (2016) 1a Paritaprevir/ritonavir/Ombitasvir + only Dasabuvir Asunaprevir/Daclatasvir/Beclabuvir Grazoprevir/Elbasvir FDC (2016) ABT493/ABT530 (2017) Sofosbuvir/Ledipasvir FDC Sofosbuvir/Velpatasvir FDC (2016) Sofosbuvir + Daclatasvir Sofosbuvir + Simeprevir MK3682/MK8408/Grazoprevir FDC (2018) Sofosbuvir/Ledipasvir/GS9857 FDC (2017) Novel DAAs [Registration pathway outside of the Food and Drug Administration and European Medicines Agency] PYRAMID 1 STUDY: Ravidasvir (PPI-668) + Sofosbuvir for HCV genotype 4 infection in Egypt • Ravidasvir 200 mg QD + SOF 400 QD with or without RBV for 12 weeks and 16 weeks (treatment-experienced patients with cirrhosis) Esmat G et al. EASL 2016 Phase III PIONEER Study: Narlaprevir + PegIFN/RBV • International multicenter randomized placebo-controlled double- blind study • 420 non-cirrhotic naïve and treatment-experienced patients with GT1 • 12 weeks of Narlaprevir 200 mg QD + Ritonavir 100 mg QD + PR + 12 weeks of PR • Randomization 2:1 to Narlaprevir/Ritonavir and placebo (280 patients on Narlaprevir) Narlaprevir/r PegIFN/RBV Follow-up + PegIFN/RBV 270 Naives PegIFN/RBV + PegIFN/RBV Follow-up Placebo Narlaprevir/r PegIFN/RBV Follow-up 150 PegIFN/RBV + PegIFN/RBV failurers PegIFN/RBV + PegIFN/RBV Follow-up Placebo Weeks 0 4 12 24 36 48 60 72 Unblinding SVR 24 SVR 24 Interim analysis In active-treatment In placebo group group 9 Phase III PIONEER Study SVR24 by Fibrosis Stage Narlaprevir/r + PegIFN/RBV All Treatment-naive Previously treated 100% 95,0% 91,9% 88,2% 90% 85,6% 87,2% 82,5% 78,8% 80% 75,0% 71,6% 70% 65,7% 66,7% 60% 53,3% 50% Patients 40% 30% 20% 10% 77/90 82/93 52/63 23/35 57/62 57/60 34/39 15/20 20/28 26/33 16/24 8/15 0% F0 F1 F2 F3 F0 F1 F2 F3 F0 F1 F2 F3 LOD = LLOQ <15 IU/mL 10 NS5A Inhibitor + NS3 Protease Inhibitor [“nuke sparing”] Grazoprevir–Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized Trial Ann Intern Med. 2015;163(1):1-13. doi:10.7326/M15-0785 Grazoprevir/Elbasvir: Impact of baseline NS5A RAVs in patients with HCV 1a and 1b infection GT1a-infected EBR/GZR 12 Weeks (No RBV): Lower SVR with key RAVS Population sequencing is adequate for clinical interpretation [no need for “deep” sequencing] SVR12 Patients with RAVs SVR12 Patients with RAVs RAV Position (NGS 1% ST) (PopSeq) 28 61/68 (89.7%) 29/33 (87.9%) 30 14/23 (60.9%) 4/10 (40.0%) 31 15/23 (65.2%) 5/13 (38.5%) 93 9/14 (64.3%) 5/8 (62.5%) GT1b-infected EBR/GZR 12 Weeks (No RBV): No impact of RAVS RAV Position SVR12 Patients with RAVs (PopSeq) 28 4/4 (100.0%) 30 16/16 (100.0%) 31 17/19 (89.5%)† 93 21/22 (95.5%)‡ Jacobson I, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-22. GZV/EBR: longer treatment (16 weeks) and addition of RBV lead to high SVR rate in patients with baseline NS5A RAVs (positions 28, 30, 31 and 93) Efficacy of EBR/GZR 16/18 Weeks (+ RBV) in GT1a PR Non-responders with Baseline NS5A RAVs† Population Sequencing Next-Generation Sequencing at 1% ST‡ EBR RAVs NS5A Class RAVs EBR RAVs NS5A Class RAVs No RAVs: No RAVs: No RAVs: No RAVs: 51/52 (98%) 44/52 48/52 38/52 (85%) (92%) (73%) Prevalence 51 1 44 8 48 4 38 14 — — — — — — — — 51 1 44 8 48 4 38 14 Jacobson I, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-22. C-SURFER: Grazoprevir/Elbasvir in patients with Stage 4 or 5 Chronic Kidney Disease Treatment Follow-up Follow-up Wk 12 Wk 4 Wk 16 Randomized period SVR12* Grazoprevir/Elbasvir GT1 HCV-infected (n = 111) 99% pts with Open-label period stage 4/5 CKD (n = 224) Placebo Grazoprevir/Elbasvir 98% (n = 113) (n = 113) Grazoprevir/elbasvir dosed orally 100 mg/50 mg once daily • 76% on dialysis • 55% with diabetes • 52% GT1a, 48% GT1b • 6% cirrhosis *Modified full analysis set population (mFAS). Roth D, et al. Lancet. 2015;386:1537-1545. SURVEYOR-I and -II: High SVR in non-cirrhotic patients with ABT-493 + ABT-530 for 8 weeks in G1/2 and 12 weeks in G4/5/6 SVR12 following ABT-493 + ABT-530 Study design for 8 weeks (G1/2) or 12 weeks (G4/5/6) SVR12 SURVEYOR-I ABT-493 (300 mg) + 98 100 100 100 G1 non-cirrhotic 97 ABT-530 (120 mg) 100 • TN or P/R exp 80 SURVEYOR-II ABT-493 (300 mg) + G2 non-cirrhotic ABT-530 (120 mg) • TN or P/R exp 60 SVR12 SURVEYOR-I (part 2) ABT-493 (300 mg) + 40 G4/5/6 non-cirrhotic ABT-530 (120 mg) SVR12 (%) • TN or P/R exp 20 33/34 53/54 22/22 1/1 11/11 Week 0 8 12 20 24 0 G1 G2 G4 G5 G6 8 weeks (ITT) 12 weeks Gane E, et al. EASL 2016, Barcelona. #SAT-137; Poordad F, et al. EASL 2016, Barcelona. #SAT-157 High SVR rates with ABT-493 + ABT-530 for 8 weeks (non-cirrhotic) and 12 weeks (cirrhotic) in patients with GT3 infection Muir et al: SVR12 • Muir et al. 29 patients without 100 97 100 cirrhosis treated with ABT493 + 1 patient withdrew ABT530 for 8 weeks (no RBV) consent after TW6: UND HCV RNA at time of d/c – No virologic failure 50 Patients (%) Patients 28/29 28/28 – No SAE or DC due to AE • 0 Kwo et al. 48 patients with cirrhosis SVR12 mITT SVR12 and no prior treatment – 12 weeks Kwo et al: SVR12 ABT 493 + 530 ± RBV – No virologic failure – No impact of baseline RAVs including Y93H/N – No benefit observed with RBV Muir A, et al. EASL 2016, Barcelona. PS098 MAGELLAN-1 Study: ABT-493 and ABT-530 in non-cirrhotic, GT1 infected patients who have failed DAA-containing regimens 100 100 95 95 SVR12 100 91 n=6 ABT-493 200 mg 90 86 ABT-530 80 mg Arm stopped early, inadequate results of 80 ABT-493 300 mg dose-finding studies in pts across all genotypes n=22 ABT-530 120 mg 70 RBV 800 mg 60 n=22 ABT-493 300 mg ABT-530 120 mg 50 SVR12 (% pts) (% SVR12 40 Day 0 Wk 12 Wk 24 Wk 36 30 20 SVR12 6/6 (100%) 20/ 19/ 20/ 19/ 10 SVR12 15/16 6/6 22 22 6/6 21 20 No RAVs 0 (94%) Both NS3 n=6 SVR12 15/15 (100%) & NS5A ITT mITT 1a; 3D+RBV failure RAVs BT 0 0 1 0 0 1 . 100% SVR12 in 10 pts with Relapse 0 1 0 0 1 0 Breakthrough n=16 NS3 RAVs Y93 NS5A RAVs NS3:Y 56H, D168A/T LTFU 0 1 2 -- -- -- only . 100% SVR12 in 26 pts w/ NS5A:M28V, Q30L/R NS5A n=15 Q80 or R155 NS3 RAVs RAVs only . 100% SVR12 in 17 pts w/ n=10 prior failure of a SOF- containing regimen SVR12 9/10 (90%) 1a; DCV, TVR, PR failure Relapse; NS5A: L31M, H58D Poordad F, et al. EASL 2016, Barcelona. #GS11 NS5A inhibitor + NS5B Nucleotide Analogue Polymerase inhibitor HCV suppression by nucleos(t)ide analogue NS5B polymerase inhibitors Sofosbuvir, β-d-2'-deoxy-2'-α-fluoro-2'-β-C- Potent HCV suppression with sofosbuvir alone, methyluridine nucleotide prodrug (2010) with ribavirin or with both interferon/ribavirin (2010) Sofia J Med Chem 2010 Gane NEJM 2013 HCV Drug Development Advisory Group ASTRAL-1, 2, and 3: Sofosbuvir/Velpatasvir (SOF/VEL) FDC for 12 weeks SVR12 by Genotype 98 98 99 100 97 100 100 95 80 60 2 relapse 11 relapse SVR12 SVR12 (%) 40 1 death 2 LTFU 1 LTFU 2 others 1 WC 20 1015 323 237 264 116 34 41 1035 328 238 277 116 35 41 0 Total GT1 GT2 GT3 GT4 GT5 GT6 Jacobson IM.