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Antiviral Activity and Pharmacokinetics of a Novel HCV Protease Inhibitor Narlaprevir

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Antiviral Activity and Pharmacokinetics of a Novel HCV Protease Inhibitor Narlaprevir Antiviral Activity and Pharmacokinetics of a Novel HCV Protease Inhibitor Narlaprevir Professor Vasily Isakov Department of Gastroenterology & Hepatology, Institute of Nutrition, Moscow, Russia June 3, 2016 Narlaprevir – a new “second generation” protease inhibitor • 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 2 Extensive Early Development 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 II Study (NEXT-1) • 93 chronic hepatitis C patients were on Narlaprevir 3 NEXT-1 Study 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 Vierling J., Poordad F., et al. AASLD 2009. Boston. Oct 30-Nov 1, 2009. Abstract4 LB4. Vierling J., Poordad F., et al. Hepatology, 2011, 54, 1439A. Resistance Profile of Approved and Investigational Protease Inhibitors V36 F43L T54A V55A Y56H Q80 S122R R155 A156 D168 V170A A/M K/R G/K/T/ G/S/T/ A/E/F/G/ Q/W V H/I/K/L/ N/T/V/Y Narlaprevir1 Simeprevir2,3 Paritaprevir4 Grazoprevir5 Resistance mutations of NS3 PIs with a ≥ and < 4-fold increase in EC50 shown in red and white respectively. 1. Halfon P. et al. J Hepatol. 2011;55:192-206 2. GALEXOS. Product Monograph, 2015 3. Lenz O. et al. Antimicrob Agents Chemother 2010; 54, 1878-1887 4. HOLKIRA PAK. Product Monograph, 2016 5 5. ZEPATIER. Product Monograph, 2016 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. 6 Low Doses of Ritonavir Significantly Increased Narlaprevir Exposure after Single Dosing mL) / Narlaprevir 400 mg alone ng Narlaprevir 400 mg with Ritonavir ( 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. 7 NEXT-1 Study 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. et al. AASLD 2009, abstract LB4. Vierling J. et al. Hepatology, 2011, 54, 1439A. 8 Pharmacokinetics in Compensated Cirrhosis: Study Design • Open-label parallel-group phase I study • Pharmacokinetics assessment in patients with compensated cirrhosis (Child-Pugh class A) and matched healthy volunteers • Single Narlaprevir dose alone and in combination with Ritonavir 8 healthy volunteers 8 healthy volunteers Interim Part 1 Part 2 8 Child-Pugh class A analysis 8 Child-Pugh class A cirrhotic patients cirrhotic patients Single dose Single dose Narlaprevir 200 mg Narlaprevir 100 mg + Ritonavir 100 mg Koloda D. et al., AASLD-2015, poster 721 9 Pharmacokinetics in Compensated Cirrhosis: Steady State Modelling AUCtau, area under narlaprevir concentration – time curve at steady state; Cmax ss, max narlaprevir concentration at steady state; H, healthy volunteers; P, cirrhotic patients Koloda D. et al., AASLD-2015, poster 721 10 Pharmacokinetics in Compensated Cirrhosis: Key conclusions − NVR exposure after a single dose 200 mg was higher in cirrhotic patients than in healthy subjects. − No significant effect on NVR exposure in cirrhotic patients compared to healthy subjects was found when NVR 100 mg was co-administered with RTV 100 mg. − NVR Ctrough at steady-state was at least 8 times higher than IC90 values both in cirrhotic patients and in healthy volunteers. − Single NVR dose as monotherapy and in combination with RTV was well tolerated both by cirrhotic patients and healthy volunteers. Koloda D. et al., AASLD-2015, poster 721 11 Narlaprevir Development Program by R-Pharm Phase I PK study in Compensated Cirrhosis – completed Phase III PIONEER double-blind study – completed Phase III PIONEER open-label extension study – ongoing Drug interaction study – start-up All-oral IFN-free combo study – start-up 12 Possible DAA combinations with narlaprevir • NRL + SOF • NRL + DCV • NRL + future NS5A or NNUC Polymerase inhibitors 13 Thank you for your attention! 14 .
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