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NS5B HCV Inhibitor Strong in 7-Day Monotherapy Trial
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17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, June 8-10, 2016, Washington DC
Mark Mascolini
MK-3682, an investigational NS5B inhibitor, suppressed HCV RNA by an average 4.3 log10 IU/mL in genotype 1, 2, and 3 patients without cirrhosis and by an average 3.1 log in genotype 1 patients with mild hepatic impairment [1]. Results of the studies by Merck investigators and colleagues led Merck to select a dose of 450 mg once daily for further development.
This phase 1b placebo-controlled trial enrolled noncirrhotic adults with genotype 1, 2, or 3 HCV and genotype 1 patients with mild hepatic impairment (Child-Pugh score A) [2]. In the noncirrhotic group, genotype 1 patents received placebo or 50 to 450 mg of MK-3682 daily for 7 days. Genotype 2 and 3 patients received 50 to 300 mg daily. Genotype 1 participants with mild hepatic impairment got 300 or 450 mg once daily for 7 days.
Among 73 people without cirrhosis, MK-3682 yielded an average 4.3 log10 IU/mL maximum decline from baseline viral load. With 450 mg once daily, maximum viral load drops averaged 4.9 log in 2 patients with genotype 1a and 4.1 log in 5 patients with genotype 1b. With the 300-mg dose, maximum viral load drops averaged 4.7 log in 2 patients with genotype 2 and 4.1 log in 7 patients with genotype 3. Among 7 people with genotype 1 HCV and mild hepatic impairment, maximum viral load decline with 450 mg once daily averaged 3.1 log.
Median time to maximum concentration ranged from 0.5 to 2 hours for MK-3682 and from 2 to 4 hours for M6, its major circulating metabolite. Respective terminal half-lives were less than 3 hours and less than 30 hours. Exposure of MK-3682 was approximately dose-proportional, while exposure of M6 proved slightly less than dose-proportional. Viral load declines were dose-proportional.
Exposure-response analyses suggested to the Merck team that the 450-mg once-daily dose largely maintains antiviral activity at the plateau level, and they will test that dose in further trials.
All adverse events in this 7-day study were mild and transient. No clinically significant lab abnormalities or changes in vital signs or ECG readings emerged.
References
1. Kim N, Gao W, Glasgow XS, et al. MK-3682, a HCV NS5B inhibitor with a broad spectrum of HCV genotypic activity, demonstrates potent antiviral activity in genotypes-1, -2, and -3 HCV-infected patients. 17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, June 8-10, 2016, Washington DC. Abstract O15.
2. ClinicalTrials.gov. Single and multiple dose study of MK-3682 (IDX21437) in healthy and hepatitis C virus (HCV)-infected participants (MK-3682-001). ClinicalTrials.gov Identifier NCT01974687. https://clinicaltrials.gov/ct2/show/NCT01974687
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