The Safety and Antiviral Activity of BZF961 with or without Ritonavir in Patients Infected with Hepatitis C Virus: A Randomized, Multicenter Trial

Eric Lawitz, Mohamed Bidair, Thomas Marbury, Christopher T. Jones, Avantika Barve, Baldur Magnusson, David T. Barkan, Ursula Bodendorf, Kathryn Bracken, Erica Canino, Darlene Chen, Kristina Dabovic, Tycho Heimbach, Marjorie Ison, Catherine L. Jones, Steven J. Kovacs, Jay P. Lakshman, Bin Li, Prakash Raman, Rachael Steiner-SwiatSanjeev Thohan, Kelly A. Wong, Weidong Zhong, Richard A. Colvin

Research output: Contribution to journalArticle

Abstract

Purpose: Infection with hepatitis C virus is the leading cause of infectious disease mortality in the United States. BZF961 is a novel small molecule inhibitor of the hepatitis C virus NS3-4A protease. Here we present the results of a randomized, double-blinded, placebo-controlled, multicentered study in treatment-naïve patients with chronic hepatitis C virus genotype-1 infection. Methods: Patients were enrolled sequentially in 2 parts and treated for 3 days. BZF961 was administered as monotherapy (500 mg BID for 3 days) or in combination with the cytochrome P450 3A4 inhibitor ritonavir to boost its exposure (BZF961 10, 20, or 50 mg QD or BID). Findings: BZF961 was safe and well tolerated in the patients studied with no serious adverse events. There were no appreciable differences in adverse events among patients who received BZF961, BZF961 with ritonavir, or placebo. There was a significant, clinically meaningful reduction in viral load from baseline in patients treated either with BZF961 500 mg every 12 hours alone or BZF961 50 mg every 12 hours in combination with ritonavir. Activity against the hepatitis C virus of the lower-dose regimens was apparent but more modest. There were no relevant changes from baseline viral loads in placebo-treated patients. Implications: Coadministration of ritonavir with BZF961 boosted BZF961 exposure (including Cmin, which is the clinically relevant parameter associated with antiviral activity) in a therapeutic range with less variability compared with BZF961 alone. For strategic reasons, BZF961 is no longer under development.

Original languageEnglish (US)
Pages (from-to)1567-1581.e4
JournalClinical Therapeutics
Volume40
Issue number9
DOIs
StatePublished - Sep 2018

Keywords

  • clinical trial
  • hepatitis C
  • protease inhibitor

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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    Lawitz, E., Bidair, M., Marbury, T., Jones, C. T., Barve, A., Magnusson, B., Barkan, D. T., Bodendorf, U., Bracken, K., Canino, E., Chen, D., Dabovic, K., Heimbach, T., Ison, M., Jones, C. L., Kovacs, S. J., Lakshman, J. P., Li, B., Raman, P., ... Colvin, R. A. (2018). The Safety and Antiviral Activity of BZF961 with or without Ritonavir in Patients Infected with Hepatitis C Virus: A Randomized, Multicenter Trial. Clinical Therapeutics, 40(9), 1567-1581.e4. https://doi.org/10.1016/j.clinthera.2018.07.019