MOSCOW CLINICAL SCIENTIFIC CENTER Efficacy and safety of Narlaprevir in Russian population of patients with HCV-infection genotype 1: the final results of multicenter randomized placebo-controlled double-blind phase III study PIONEER Prof. Bakulin Igor Department of Hepatology of Moscow Clinical Scientific Center, HealthCare Department of Moscow
Disclosures Professor Igor Bakulin, MD, PhD Head of the Department of Gastroenterology of Moscow Healthcare Department Head of the Department of Hepatology of Moscow Central Scientific Institute of Gastroenterology Grants/Clinical trials: Speaking/Teaching: Advisory board: Bristol-Myers Squibb, GSK, Gilead, Falk, Johnson&Johnson, Roche, Schering-Plough/Merck Bristol-Myers Squibb, Abbvie, GSK, Johnson&Johnson, Roche, Schering-Plough/Merck Bristol-Myers Squibb, Johnson&Johnson, Abbvie, GSK, Roche, Schering-Plough/Merck М
Compound Overview Narlaprevir (SCH 900518) is a novel potent oral DAA that prevents viral replication in infected host cells by inhibiting the HCV NS3 protease Narlaprevir is approximately 10-fold more potent in vitro than other protease inhibitors telaprevir and boceprevir Phase I clinical studies have confirmed that significantly increased plasma exposures of narlaprevir (NVR) in healthy volunteers can be achieved when coadministered with ritonavir (RTV) (data on file at Schering-Plough Research Institute) DAA - Direct-Acting Antiviral Agent Tong X et al. Antimicrob. Agents Chemother. 2010;54:2365-2370 Joep de Bruijne et al., HEPATOLOGY 2010;52:1590-1599
Phase III Study PIONEER Design (1) International multicenter randomized placebo-controlled doubleblind study 20 research centers 420 non-cirrhotic naïve and treatment-experienced patients with HCV GT1 were randomized Randomization 2:1 to Narlaprevir/Ritonavir and placebo (282 patients on Narlaprevir) PegIFN choise: PegIntron/ Pegasys 50 / 50
Key Inclusion criteria: Age 18 and 70 years, Inclusion / Exclusion criteria in PIONEER study Body weight 40 and 125 kg, Documented infection with HCV genotype 1, Minimum HCV-RNA level of 10,000IU at baseline, No evidence of cirrhosis; availability at Baseline of at least one of the following tests negative results: - Liver biopsy showing no cirrhosis (not later than within 3 years prior to Baseline) or - FibroScan elasticity score < 12.5 kpa 12 months prior to baseline or - FibroTest < 0.75 12 months prior to baseline and AST/platelet ratio (APRI) of 1 during screening Key Exclusion criteria: Previous treatment with any HCV NS3-specific protease inhibitor and/ or other direct antiviral agents (e.g. HCV polymerase inhibitors), Findings suspicious for hepatocellular carcinoma (HCC), Serum hemoglobin of <13g/dL for males and <12g/dL for females, Neutrophils <1500/mm 3 (<1,5х10 9 /L) at Screening, Platelets <150000/mm 3 (<150х10 9 /L) at Screening, HBsAg positive, HIV positive
Phase III Study PIONEER Design (2) Narlaprevir/r + PegIFN/RBV PegIFN/ RBV Follow-up Follow-up А PegIFN/RBV + Placebo PegIFN/ RBV Cohort A 272 treatmentnaïve patients В Narlaprevir/r + PegIFN/RBV PegIFN/RBV + Placebo PegIFN/ RBV PegIFN/ RBV Follow-up Cohort B 148 patients, who failed PegIFN/RBV treatment Follow-up Weeks 0 4 12 24 36 48 60 72 Unblinding interim analysis SVR 24 in active- Treatment group SVR 24 in placebo group
Baseline Patient Characteristics in PIONEER study Narlaprevir/r + PegIFN/RBV N (%) Placebo PegIFN/RBV N (%) All N (%) Randomized * 282 (67.1%) 138 (32.9%) 420 IFN, strata Pegasys 141 (50.0%) 69 (50.0%) 210 (50.0%) Peg-Intron 141 (50.0%) 69 (50.0%) 210 (50.0%) Genotype HCV 1a 3 (1.1%) 0 3 (0.7%) 1b 258 (91.5%) 129 (93.5%) 387 (92.1%) 1X (is not defined) 21 (7.4%) 9 (6.5%) 30 (7.1%) Previous treatment status Naives 183 (64.9%) 89 (64.5%) 272 (64.8%) Previously treated 99 (35.1%) 49 (35.5%) 148 (35.2%) Null responders ** 40 (40.4%) 20 (40.8%) 60 (40.5%) Partial responders or relapsers** 56 (56.6%) 28 (57.1%) 84 (56.8%) Other** 3 (3.0%) 1 (2.0%) 4 (2.7%) *% is calculated on the total number of randomized patients, ** % is calculated on the number of patients who previously treated for categories of virologic response to therapy
Baseline Characteristics of naïve patients in PIONEER study (ITT analysis ) Narlaprevir/r + PegIFN/RBV Placebo + PegIFN/RBV All (N=183) (N=89) (N=272) Age Mean value (*) 39.8 (10.8) 37.2 (9.8) 38.9 (10.6) Minimum Мaximum 19-69 18-59 18-69 Median 38.0 37.0 37.5 Male 98 (53.6%) 55 (61.8%) 153 (56.3%) Female 85 (46.4%) 34 (38.2%) 119 (43.8%) Viral load > 800 000 IU/ml 106 (57.9%) 55 (61.8%) 161 (59.2%) Baseline fibrosis score F0 62 (33.9%) 36 (40.4%) 98 (36.0%) F1 60 (32.8%) 33 (37.1%) 93 (34.2%) F2 41 (22.4%) 14 (15.7%) 55 (20.2%) F3 20 (10.9%) 6 (6.7%) 26 (9.6%) * Standard deviation
HCV RNA level (Log10 IU/mL) Viral Load Dynamics in PIONEER study (ITT analysis) 7 HCV RNA level decreased by a mean of 5.3 log10 after 2 weeks of treatment on Narlaprevir and by a mean of 5.9 log10 after 4 weeks 6 5 4 Narlaprevir Placebo 3 >5 lg IU/mL 2 1 0 Baseline Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Week 16 Week 20 Week 24 9
SVR24 by Previous Treatment Status (ITT analysis) 2/6 4/19 p<0.001 Previously treated patients: relapsers, with partial response, with null response LOD = LLOQ <15 IU/mL
Optimal group of patients with 1 GT HCV to triple therapy with narlaprevir based on previous treatment status (ITT analysis ) SVR24 by Previous Treatment Status (ITT analysis) Optimal group p<0.001 SVR24 in placebo group was 59,6% in naïve patients, SVR24 in placebo group was 24,5% in previously treated patients Previously treated patients: relapsers, with partial response, with null response LOD = LLOQ <15 IU/mL
Optimal group of patients with 1 GT HCV to triple therapy with narlaprevir based on previous treatment status (Per Protocol analysis) Optimal group SVR24 in placebo group was 59,7% in naïve patients, SVR24 in placebo group was 30,0% in previously treated patients Previously treated patients: relapsers, with partial response, with null response. LOD = LLOQ <15 IU/mL
SVR24 by Fibrosis Stage (F0-1 / F2-3) based on previous treatment status (ITT analysis) LOD = LLOQ <15 IU/mL LOD = LLOQ <15 IU/mL 13
Patients with SVR 24 (%) SVR24 on Narlaprevir by Fibrosis and Baseline Viral Load in Treatment-Naïve Patients in Narlaprevir group 83/90 35//38 30/32 VL Viral Load
Patients with SVR 24 (%) SVR24 on Narlaprevir by Fibrosis and Baseline Viral Load in Treatment-Experienced Patients in Narlaprevir group 27/36 17/25 18/24 7/14 VL Viral Load
Non-Response Rate in Narlaprevir Group by Previous Treatment Status (ITT analysis) LOD = LLOQ <15 IU/mL
Safety Data in phase III PIONEER study Adverse events, % (n) Narlaprevir/r + PegIFN/RBV N=282 Placebo + PegIFN/RBV N=138 Severe adverse events* 1,8% (5) 0% (0) At least one of any adverse event 92,9% (262) 94,2% (130) Most common adverse events list (>10% of cases) Neutropenia 48,9% (138) 56,5% (78) Leukopenia 35,5% (100) 39,9% (55) Influenza-like illness 29,4% (83) 31,9% (44) Asthenia 27,3% (77) 26,1% (36) Hemoglobin decrease 23,4% (66) 23,2% (32) Pyrexia 23,4% (66) 21,7% (30) Anaemia 24,8% (70) 25,4% (35) Thrombocytopenia 19,5% (55) 22,5% (31) Weight decrease 16,3% (46) 20,3% (28) Alopecia 15,2% (43) 9,4% (13) Road traffic accident (death); vertebrobasilar insufficiency; psychotic disorder; acute psychosis; thyroiditis
Conclusion IFN-containing regimens in Russia are currently relevant and supposed to be important in the near future Protease inhibitors is an essential DAA group for the treatment of HCV 1b GT, the most prevalent genotype in Russia Phase III PIONEER study proved a potent antiviral activity, a high efficacy and a good safety profile of Narlaprevir triple therapy Triple therapy with Narlaprevir ensured SVR above 90% in treatment naïve patients as well as a high efficacy in relapse patients and will be an appropriate regimen among DAA-based treatment options for chronic hepatitis C 18
We thank all the investigators who contributed to the PIONEER study. We also thank the patients who took part in the study for their efforts and contribution! City Moscow Moscow Moscow Moscow Moscow Stavropol Saint-Petersburg Moscow Samara Saint-Petersburg Moscow Saratov Samara Moscow Novosibirsk Stavropol Chelyabinsk Kazan Moscow Saint-Petersburg Principle investigator D. T. Abdurakhmanov I. G. Bakulin P. О. Bogomolov E. Z. Burnevich М. Yu. Galushko N. I. Geivandova K. V. Zhdanov V. Т. Ivashkin D. Yu. Konstantinov S. N. Kizhlo Е. А. Klimova N. I. Mironova V. G. Morozov I. G. Nikitin М. F. Osipenko V. D. Pasechnikov О. I. Sagalova I. М. Khaertynova V. P. Chulanov А. А. Yakovlev
Narlaprevir marketing authorization approval in Russia # LP-003622 dated 12.05.2016 Russian Federation Ministry of Health in accordance with Article 27 of the Federal Law of 12.04.2010 number 61 "On Medicine Circulation made a positive decision on the state registration of the drug for medical use: Narlaprevir, tablets, film-coated, 100 mg, manufactured by JSC "R-Pharm"
Thank you for your attention! 21