title: A Diacylglycerol Transferase 1 Inhibitor Is a Potent Hepatitis C Antiviral in Vitro but Not in Patients in a Randomized Clinical Trial.
abstract: 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.
authors: Auckland Clinical Sciences , Grafton, Auckland 1010, New Zealand.
authors: Edward
authors: E
authors: Gane
authors: Christchurch Hospital and University of Otago , Christchurch 4710, New Zealand.
authors: Catherine
authors: C
authors: Stedman
authors: Novartis Institutes for BioMedical Research , Cambridge, Massachusetts 02139, United States.
authors: Kiran
authors: K
authors: Dole
authors: Novartis Institutes for BioMedical Research , Cambridge, Massachusetts 02139, United States.
authors: Jin
authors: J
authors: Chen
authors: Novartis Institutes for BioMedical Research , Cambridge, Massachusetts 02139, United States.
authors: Charles Daniel
authors: CD
authors: Meyers
authors: Novartis Institutes for BioMedical Research , Cambridge, Massachusetts 02139, United States.
authors: Brigitte
authors: B
authors: Wiedmann
authors: Novartis Institutes for BioMedical Research , Cambridge, Massachusetts 02139, United States.
authors: Jin
authors: J
authors: Zhang
authors: Novartis Institutes for BioMedical Research , Cambridge, Massachusetts 02139, United States.
authors: Prakash
authors: P
authors: Raman
authors: Novartis Institutes for BioMedical Research , Cambridge, Massachusetts 02139, United States.
authors: Richard A
authors: RA
authors: Colvin
mesh_terms: D000085:Acetates / Q000008:administration & dosage* / Q000494:pharmacology; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000631:Aminopyridines / Q000008:administration & dosage* / Q000494:pharmacology; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000494:pharmacology; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors*; D005260:Female; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D016896:Treatment Outcome; D014779:Virus Replication / Q000187:drug effects; D055815:Young Adult
chemical_list: D000085:Acetates; D000631:Aminopyridines; D000998:Antiviral Agents; D012367:RNA, Viral; C000594809:pradigastat; C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase; D000410:Alanine Transaminase
keywords: HCV; clinical trial; diacylglycerol transferase 1; pradigastat