Final Results of a Phase 1B, Multiple-dose Study of VX-950, a Hepatitis C Virus Protease Inhibitor

In development by Vertex Pharmaceuticals, VX-950 is an orally administered, highly selective peptidomimetic inhibitor of the Hepatitis C virus (HCV) NS3·4A protease that is designed to block HCV replication.

The preliminary safety and anti-viral results from the interim analysis of a

Phase 1b clinical study, in healthy subjects and patients with HCV, were presented in May 2005. The final results of the clinical study were presented at the 56^th AASLD meeting in San Francisco (November 11-15, 2005).

The VX04-950-101 clinical study included three panels of eight healthy

subjects (Part A) and three panels of twelve patients with genotype-1 HCV (Part B).

In Part A, subjects were dosed for 5 days at doses of 450 mg, 750 mg, or 1250 mg every 8 hours, or placebo. In Part B, patients were dosed for 14 days at doses of 450 mg or 750 mg every 8 hours, or 1250 mg every 12 hours, or placebo.

The major objectives of the study were to assess safety and tolerability, and antiviral activity in patients with HCV.

Results

• VX-950 was well tolerated in both healthy subjects and patients with HCV, with no serious adverse events and no discontinuations.
• All adverse events considered possibly related to study drug were mild in severity.
• The most commonly reported study drug-related adverse events in patients were headache and diarrhea; each event was reported in the placebo group at a similar frequency as in the VX-950 groups.
• VX-950 had substantial antiviral effects, with every patient demonstrating at least a 2-log drop in viral load.
• In the 750 mg q8h dose group, in which the highest trough plasma concentrations of VX-950 were observed, there was a reduction in median HCV RNA of 4.4 log10 at the end of 14 days of dosing.
• VX-950 also demonstrated antiviral effects in the two dose groups with lower trough blood concentrations, with reductions in median HCV RNA of greater than 2 log10.
• Maximal effect was seen in these latter two groups between 3 and 7 days of dosing and there was an increase in viral load between days 7 and 14.
• Median ALT levels, which were elevated at baseline, normalized during 14 days of dosing in all VX-950 dose groups, with a median change from baseline of 25-30 U/L.

In conclusion, the study authors write, “VX-950 was well tolerated for 5-14 days in healthy subjects and patients with HCV.”

“Median ALT levels normalized in all three VX-950 dose groups.

“Exploration of the reasons for the increase in HCV RNA between days 7 and 14 in the two sub-optimal dose groups, including pharmacokinetic/ pharmacodynamic analysis and viral sequencing, is in progress.”

11/14/05

Reference
H W Reesink and others. Final Results of a Phase 1B, Multiple-dose Study of VX-950, a Hepatitis C Virus Protease Inhibitor. Abstract 62580. 56^th annual meeting of the American Association for the Study of Liver Diseases (56^th AASLD). November 11-15, 2005. San Francisco, CA.