A Diacylglycerol Transferase 1 Inhibitor Is a Potent Hepatitis C Antiviral in Vitro but Not in Patients in a Randomized Clinical Trial
| Autor: | Kiran Dole, Brigitte Wiedmann, Jin Chen, Edward Gane, Charles D. Meyers, Prakash Raman, Richard Colvin, Jin Zhang, Catherine A.M. Stedman |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male 0301 basic medicine Hepatitis C virus Aminopyridines Hepacivirus Acetates Biology Virus Replication medicine.disease_cause Placebo Antiviral Agents Virus law.invention Young Adult 03 medical and health sciences Liver disease 0302 clinical medicine Randomized controlled trial law medicine Humans Diacylglycerol O-Acyltransferase Alanine Transaminase Hepatitis C Hepatitis C Chronic Middle Aged medicine.disease Virology In vitro Clinical trial Treatment Outcome 030104 developmental biology Infectious Diseases RNA Viral Female 030211 gastroenterology & hepatology |
| Zdroj: | ACS Infectious Diseases. 3:144-151 |
| ISSN: | 2373-8227 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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