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Investigational HCV Inhibitor TMC435 Demonstrates Promising Safety and Efficacy in Phase 1 Study

SUMMARY: Tibotec's investigational hepatitis C virus (HCV) NS3/4A protease inhibitor TMC435 demonstrated good antiviral activity and appeared to be safe and generally well-tolerated in a Phase 1 placebo-controlled clinical trial, according to a report in the March 2010 Gastroenterology.

By Liz Highleyman

As the first of the directly-targeted oral anti-HCV drugs near the end of the drug development pipeline, researchers continue to test a variety of novel agents.
Henk Reesink from the Academic Medical Center in Amsterdam and colleagues recently published data from the first-in-humans Phase 1 clinical trial (dubbed TMC435350-C101) to evaluate the safety, tolerability, and pharmacokinetics of TMC435.

In the first part of the study, 49 healthy HCV negative volunteers were randomly assigned to receive TMC435 as single ascending doses (up to 600 mg) or multiple ascending doses (100, 200, or 400 mg once-daily or 200 mg twice-daily) over 5 days, or else placebo.

Then, in the open-label second part of the study, 6 patients with hard-to-treat HCV genotype 1 received 200 mg TMC435 once-daily for 5 days to assess antiviral activity.


There were no serious adverse events, grade 3 reactions, or treatment-related discontinuations reported during either part of the study.
The pharmacokinetic profile of TMC435 was suitable for a once-daily dosing regimen.
Among the participants with hepatitis C, plasma HCV viral load levels decreased rapidly in all patients.
An initial steep decline in HCV RNA (median 3.5 log10 IU/mL at day 3) was followed by a more gradual decline that was maintained over the dosing period.
The median maximal HCV RNA reduction was 3.9 log10 IU/mL, occurring after a median 6 days.
No instances of viral breakthrough (>1 log10 IU/mL HCV RNA increase from the nadir or lowest level) were observed during treatment or the first 3 days post-treatment.
After completing treatment, HCV viral load levels returned to pre-treatment levels by week 4 of follow-up.

Based on these findings, the investigators concluded, "Once-daily TMC435 given orally was generally safe and well tolerated, and demonstrated potent antiviral activity."

Academic Medical Center, Amsterdam, Netherlands; Tibotec Pharmaceuticals Ltd, Eastgate Village, Little Island, Cork, Ireland; PRA International EDS, Zuidlaren, Netherlands.


HW Reesink, GC Fanning, K Abou Farha, and others. Rapid HCV-RNA decline with once-daily TMC435: A Phase I study in healthy volunteers and hepatitis C patients. Gastroenterology 138(3): 913-921 (Abstract). March 2010.






















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