Antiviral activity of narlaprevir combined with ritonavir and peginterferon in chronic hepatitis C patients

J. de Bruijne 1,†, J.F. Bergmann 2,†, H.W. Reesink 1,*,‡, C.J. Weegink 1, R. Molenkamp 3, J. Schinkel 3, X. Tong 4, J. Li 4, M.A. Treitel 4, E.A. Hughes 4, J.J. van Lier 5, A.A. van Vliet 5, H.L.A. Janssen 2, R.J. de Knegt 2

Hepatology
DOI: 10.1002/hep.23899
Accepted Article (Accepted, unedited articles published online for future issues)
Copyright © 2010 American Association for the Study of Liver Diseases

Author Information
1 Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, Department of Gastroenterology and Hepatology, The Netherlands
2 Erasmus MC University Hospital, 's-Gravendijkwal 230, 3015 CE Rotterdam, Department of Gastroenterology and Hepatology, The Netherlandz
3 Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, Department of Medical Microbiology, The Netherlands
4 Schering-Plough Research Institute, Kenilworth, NJ, USA
5 PRA International EDS, Stationsweg 163, 9471 GP Zuidlaren, The Netherlands

Email: H.W. Reesink (H.W.Reesink@amc.nl)
*Correspondence: H.W. Reesink, Department of Hepatology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

† These authors contributed equally to this study
‡ Ph: +31205667863; Fax: +31205669582

Publication History
Accepted manuscript online: 19 AUG 2010 08:52AM EST
Manuscript Accepted: 30 JUL 2010
Manuscript Revised: 29 JUN 2010
Manuscript Received: 19 APR 2010

Funded by
Schering-Plough and designed by Schering-Plough employees and H.W. Reesink

Abstract
Narlaprevir (SCH 900518) is a potent inhibitor of the HCV NS3 serine protease that is primarily metabolized by the cytochrome P450-3A4 system (CYP3A4). In order to explore the use of ritonavir-based pharmacokinetic enhancement of an HCV protease inhibitor, this study investigated the safety, tolerability, pharmacokinetics and antiviral activity of narlaprevir (with or without ritonavir) administered as monotherapy and combination therapy with pegylated interferon-α-2b to HCV genotype 1 infected patients. This was a randomized, placebo-controlled, two period, blinded study in 40 HCV genotype 1 infected patients (naïve and treatment-experienced). In Period 1, narlaprevir was administered for 7 days as 800 mg TID without ritonavir or 400 mg BID with 200 mg ritonavir BID. In Period 2, after a 4 week washout, the same dose and regimen of narlaprevir was administered in combination with pegylated interferon-α-2b for 14 days. Upon completion of Period 2, all patients initiated pegylated interferon-α-2b and ribavirin treatment. A rapid and persistent decline in plasma HCV RNA was observed in both treatment-experienced and -naive patients during Period 1, with a mean viral load decline of at least 4 log10 in all treatment groups. A high percentage of both treatment-experienced (50% and 50%) and naïve (75% and 63%) patients had undetectable HCV RNA (<25 IU/mL) after Period 2. Standard of care resulted in SVR rates of 38% and 81% in treatment-experienced and treatment–naïve patients, respectively. Narlaprevir (with or without ritonavir) alone or in combination with pegylated interferon-α-2b was safe and well tolerated.

Conclusion:
Narlaprevir administration resulted in a robust HCV RNA decline and high SVR rates when followed by standard of care in both treatment-experienced and treatment-naïve HCV genotype 1-infected patients. (HEPATOLOGY 2010.)

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