A Diacylglycerol Transferase 1 Inhibitor Is a Potent Hepatitis C Antiviral in Vitro but Not in Patients in a Randomized Clinical Trial

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• 作者：Edward Gane ; Catherine Stedman ; Kiran Dole ; Jin Chen ; Charles Daniel Meyers ; Brigitte Wiedmann ; Jin Zhang ; Prakash Raman ; Richard A. Colvin
• 刊名：ACS Infectious Diseases
• 出版年：2017
• 出版时间：February 10, 2017
• 年：2017
• 卷：3
• 期：2
• 页码：144-151
• 全文大小：451K
• ISSN：2373-8227

文摘

Hepatitis C virus (HCV) infection is a significant cause of liver disease affecting 80–150 million people globally. Diacylglycerol transferase 1 (DGAT-1), a triglyceride synthesis enzyme, is important for the HCV life cycle in vitro. Pradigastat, a potent DGAT-1 inhibitor found to lower triglycerides and HgbA1c in patients, was investigated for safety and efficacy in patients with HCV. This was a two-part study. In the in vitro study, the effect of pradigastat on virus production was evaluated in infected cells in culture. In the clinical study (https://clinicaltrials.gov/ct2/show/NCT01387958), 32 patients with HCV infection were randomized to receive pradigastat or placebo (26:6) once daily for 14 days. Primary efficacy outcomes were serum viral RNA and alanine aminotransferase levels. In vitro, pradigastat significantly reduced virus production, consistent with inhibition of viral assembly and release. However, the clinical study was prematurely terminated for lack of efficacy. There was no significant change in serum viral RNA levels after dosing with pradigastat or placebo for 14 days. Pradigastat was safe and well-tolerated in this population. Most treatment-emergent adverse events were gastrointestinal; there were no hepatic adverse events. Although pradigastat had a potent antiviral effect in vitro, no significant antiviral effect was observed in patients at predicted efficacious exposures.