The «second wave» PI Narlaprevir in Russian patients with genotype 1 chronic hepatitis C Professor Igor Bakulin Moscow Clinical Scientific Center June 5, 2015 Key points Background Narlaprevir in clinical trials Interim results of Phase III Russian PIONEER study Conclusions 11.06.2015 2 HCV Epidemiology in Russia Total population size1 143 000 000 Anti-HCV Ab-positive1 5 861 000 CHC diagnosed (viremic)1 1 789 500 New cases2 55 900/year AVT3 5 500*/year AVT – antiviral therapy; CHC – chronic hepatitis C 1 2010 data, Saraswat V, Norris S, et al. J Viral Hepat. 2015 ;22 Suppl 1:6-25; 2 Yuschuk ND, Znoyko OO, et al. Epidemiol Vaccine Prevent. 2013; 3 11.06.2015 Regional registries data, 2011 in Saraswat V, Norris S, et al. J Viral Hepat. 2015 ;22 Suppl3 1:6-25 *8 000/year according to IMS Health data calculated on the basis of PegIFN sales for all genotypes in 2014 Access to Direct Acting Antivirals in 2015 SMV SOF SMV No access to PR federal budget SOF SOF LDV Access to new DAA in DCV Russia and some other European countries is limited 3D/r EASL Monothematic Conference on “Liver Disease in Resource Limited Settings”, 2015 11.06.2015 4 EASL Recommendations 2015 IFN-free regimens Genotype Sofosbuvir + RBV 2, 3 Sofosbuvir/Ledipasvir (+/- RBV) 1, 4, 5, 6 Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir (+/- RBV) 1 Sofosbuvir + Simeprevir (+/- RBV) 1, 4 Sofosbuvir + Daclatasvir (+/- RBV) All Ombitasvir/Paritaprevir/Ritonavir (+/- RBV) 4 For countries with limited resources IFN-containing regimens are still relevant PegIFN-α + RBV + Sofosbuvir All PegIFN-α + RBV + Simeprevir 1, 4 11.06.2015 5 HCV Protease Inhibitors Value in Russia Protease inhibitors - a promising DAA group for the treatment of HCV 1b GT, the most prevalent genotype in Russia HCV Genotypes Protease inhibitors Asunaprevir Boceprevir Narlaprevir/r Paritaprevir/r Simeprevir Saraswat V, Norris S, de Knegt RJ, et al. J Viral Hepat. 2015;22 Suppl 1:6-25. Russian MoH Guidelines on HCV Diagnostics and Treatment in Adults. 2014. 11.06.2015 6 Key points Background Narlaprevir in clinical trials Preliminary results of Phase 3 first Russian PIONEER study Conclusions 11.06.2015 7 Narlaprevir – a new “second wave” PI • Oral HCV NS3 serine protease inhibitor (PI) • Reversible covalent binding with active NS3-protease site with ketoamid functional group • Ki = 7 ± 1 nМ, EC50 = 20 nМ, EC90 = 40 nМ • Mild cross-reactivity exists just with human cathepsin and neutrophyl elastase • No cross-reactivity with HIV-proteases Tong X et al. Antimicrob. Agents Chemother. 2010;54:2365-2370 11.06.2015 8 Extensive Clinical Program was Conducted by Merck/Schering-Plough Nearly 500 healthy volunteers and HCV-infected patients received at least one dose of Narlaprevir in completed clinical trials to date 9 Phase I Studies • 360 healthy volunteers and 32 chronic hepatitis C patients were exposed to at least one dose of Narlaprevir Phase IIa Study (NEXT-1) • 93 chronic hepatitis C patients were on Narlaprevir 11.06.2015 9 Increase in Narlaprevir Exposure after Standard Meal TabletTablet formulationFormulation ) 350 FastedFasted ng/mL FedFed ( 300 250 200 (ng/mL) 150 100 plasma concentration 50 SCH900518Plasma Concentration 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Narlaprevir TimeTime (hours (hr) ) Narlaprevir administration under fed condition leads to increase in mean AUC(I) by 1,8 and Cmax by 2,8 compared to fasted state Reesink H.W., Bergmann J.F., et al., 2009, 50 (Suppl. 1), S35-S36. 11.06.2015 10 Low Doses of Ritonavir Significantly Increased Narlaprevir Exposure after Single Dosing mL) / Narlaprevir 400 mg alone ng ( Narlaprevir 400 mg with Ritonavir plasma concentration plasma concentration Narlaprevir Time (hours) Single Narlaprevir dosing in combination with Ritonavir leads to Narlaprevir AUC(I) and Cmax increase by 10 and 4 times, respectively, compared to single Narlaprevir dosing alone Reesink H.W., Bergmann J.F., et al., 2009, 50 (Suppl. 1), S35-S36. 11.06.2015 11 Phase 2а Study NEXT-1 Design HCV RNA <LOD on Week 4: PegIFN/RBV for 36 weeks PegIFN α2b (PegIFN)+ Ribavirin (RBV) Group 1 Control HCV RNA ≥LOD on Week 12: 200 mg Narlaprevir + 100 mg Ritonavir QD Group 2 Narlaprevir 400 mg + Ritonavir + PegIFN/RBV QD + PegIFN/RBV till 48 weeks 400 mg Narlaprevir + 100 mg Ritonavir QD Group 3 + PegIFN/RBV HCV RNA <LOD after 4 weeks 4 wks 200 mg Narlaprevir + 100 mg Ritonavir QD Group 4 NVR/r/PegIFN/RBV: PegIFN/RBV + PegIFN/RBV PegIFN/RBV for 12 weeks 4wks 400 mg Narlaprevir + 100 mg Ritonavir QD Group 5 HCV RNA ≥LOD after 4 weeks PegIFN/RBV + PegIFN/RBV NVR/r/PegIFN/RBV: 100 mg Narlaprevir + 100 mg Ritonavir BID PegIFN/RBV for 36 weeks Group 6 + PegIFN/RBV NVR/r – Narlaprevir + Ritonavir 12 weeks LOD – Low limit of detection Vierling J., Poordad F., et al. AASLD 2009. Boston. Oct 30-Nov 1, 2009. Abstract LB4. Vierling J., Poordad F., et al. Hepatology, 2011, 54, 1439A. 11.06.2015 12 Phase 2а Study NEXT-1 Baseline Patients Characteristics Most of patients were with genotype 1a and high viral load in all treatment groups Group 2 Group 3 Group 4 Group 5 Group 6 Group 1 NVR 200mg NVR 400mg LI + NVR LI + NVR NVR 100mg Control QD QD 200mg QD 400mg QD BID N=18 N=20 N=19 N=17 N=20 N=17 Male, % (n) 56 (10) 55 (11) 74 (14) 59 (10) 50 (10) 53 (9) White, % (n) 72 (13) 100 (20) 79 (15) 88 (15) 80 (16) 88 (15) Age (SD), years 46 (7) 43 (9) 45 (11) 45 (10) 46 (9) 46 (9) Weight (SD), kg 81 (20) 80 (11) 85 (10) 76 (17) 82 (18) 80 (18) BMI (SD), kg/m2 28 (6) 29 (4) 28 (2) 26 (5) 28 (4) 27 (5) Genotype 1а, % (n) 72 (13) 80 (16) 74 (14) 76 (13) 80 (16) 82 (14) Viral load 83 (15) 65 (13) 84 (16) 82 (14) 85 (17) 94 (16) >600 000 IU/mL, % (n) BMI – body mass index, LI – lead-in, NVR – narlaprevir, SD – standard deviation Vierling J., Poordad F., et al. AASLD 2009. Boston. Oct 30-Nov 1, 2009. Abstract LB4. Vierling J., Poordad F., et al. Hepatology, 2011, 54, 1439A. 11.06.2015 13 Phase 2а Study NEXT-1 High Antiviral Activity Mean HCV RNA decrease after 2 weeks of therapy exceeded 5 log10 IU/mL Narlaprevir was administered with Ritonavir 100 mg in all dosage groups * Including detected and non-detected HCV RNA < 25 IU/mL LLQ – low limit of quantification; NVR – narlaprevir; PegIFN – pegylated interferon alfa, RBV - ribavirin 11.06.2015 Vierling J., Poordad F., et al. AASLD 2009. Boston. Oct 30-Nov 1, 2009. Abstract14 LB4. Vierling J., Poordad F., et al. Hepatology, 2011, 54, 1439A. Phase 2а Study NEXT-1 Pharmacokinetics Narlaprevir* 200 mg QD Narlaprevir 400 mg QD Narlaprevir 100 mg BID Twice daily dosing and increased 400 mg dose didn’t give significant benefits for therapeutic concentration achievement compared to dose 200 mg once daily Time, hours * Narlaprevir was administered with Ritonavir 100 mg in all dosage groups Vierling J., Poordad F., et al. AASLD 2009. Boston. Oct 30-Nov 1, 2009. Abstract LB4. Vierling J., Poordad F., et al. Hepatology, 2011, 54, 1439A. 11.06.2015 15 Phase 2а Study NEXT-1 Sustained Virological Response 200 mg once daily without lead-in period group had the optimal SVR rate , % , % Patients * Narlaprevir was administered with Ritonavir 100 mg in all dosage groups LI – 4-week lead-in period; NVR – narlaprevir; PegIFN – pegylated interferon alfa; RBV – ribavirin; SVR – sustained virological response Vierling J., Poordad F., et al. AASLD 2009. Boston. Oct 30-Nov 1, 2009. Abstract LB4. Vierling J., Poordad F., et al. Hepatology, 2011, 54, 1439A. 11.06.2015 16 Phase 2а Study NEXT-1 Baseline Patients Characteristics Dosage groups with 200 mg Narlaprevir will be present on the next slide Group 2 Group 3 Group 4 Group 5 Group 6 Group 1 NVR NVR LI + NVR LI + NVR NVR Control 200mg QD 400mg QD 200mg QD 400mg QD 100mg BID N=18 N=20 N=19 N=17 N=20 N=17 Men, % (n) 56 (10) 55 (11) 74 (14) 59 (10) 50 (10) 53 (9) White, % (n) 72 (13) 100 (20) 79 (15) 88 (15) 80 (16) 88 (15) Age (SD), years 46 (7) 43 (9) 45 (11) 45 (10) 46 (9) 46 (9) Weight (SD), kg 81 (20) 80 (11) 85 (10) 76 (17) 82 (18) 80 (18) BMI (SD), kg/m2 28 (6) 29 (4) 28 (2) 26 (5) 28 (4) 27 (5) Genotype 1а, % (n) 72 (13) 80 (16) 74 (14) 76 (13) 80 (16) 82 (14) Viral load 83 (15) 65 (13) 84 (16) 82 (14) 85 (17) 94 (16) >600 000 IU/mL, % (n) BMI – body mass index, LI – lead-in, NVR – narlaprevir, SD – standard deviation Vierling J., Poordad F., et al. AASLD 2009. Boston. Oct 30-Nov 1, 2009. Abstract LB4. Vierling J., Poordad F., et al. Hepatology, 2011, 54, 1439A. 11.06.2015 17 Phase 2а Study NEXT-1 Safety Profile All adverse event rates were comparable to control PegIFN/RBV group Control Groups 2 + 4 Adverse events, % (n) PegIFN/RBV NVR 200 mg QD N=18 N=37 Fatigue 56 (10) 32 (12) Nausea 50 (9) 43 (16) Flu-like illness 44 (8) 16 (6) Headache 39 (7) 22 (8) Insomnia 39 (7) 30 (11) Anaemia 6 (1) 27 (10) Arthralgia 28 (5) 16 (6) Diarrhoea 17 (3) 14 (5) Pyrexia 17 (3) 14 (5) Irritability 28 (5) 19 (7) Pruritus 33 (6) 11 (4) Rash 11 (2) 3 (1) NVR – narlaprevir, PegIFN – pegylated interferon alfa; QD – once daily; RBV – ribavirin 11.06.2015 Vierling J., Poordad F., et al.