SCH 503034, an Experimental HCV Protease Inhibitor from Schering Plough, Shows Potent Anti-HCV Activity in Patients Previously Failing on Peginterferon Alfa

By Ronald Baker, PhD

There is a pressing need for more effective and less toxic therapies for chronic hepatitis C Virus (HCV) infection. About 50 percent of individuals with HCV infection fail on therapy with the current standard of care, peginterferon alfa plus ribavirin.

SCH 503034 is a new, orally administered HCV protease inhibitor that has shown potent activity against HCV in earlier laboratory testing. In the current clinical study, a dose-ranging trial, adult patients with HCV infection who had failed peginterferon alfa therapy (defined as those experiencing less than a 2 log decrease in HCV viral load following 12 weeks on treatment) were randomly assigned 3:1 to receive SCH 503034 oral capsules of placebo according to the following doses and dosing schedule for 14 days:

• 100 mg twice daily
• 200 mg twice daily
• 400 mg twice daily
• 400 mg 3-times daily

The pharmacokinetics of the drug were evaluated on the first day of dosing and again on day 14.

HCV RNA levels were measured on a daily basis using quantitative RT-PCR (Taq-Man), which has a 29 IU/milliliter level of quantification.

Results

• 61 patients (45 active, 16 placebo) have completed the study.
• SCH 503034 was rapidly absorbed following oral administration of capsules (mean Tmax = 1 to 2h across doses), and exhibited dose-related increases in Cmax and AUC.
• SCH 503034 trough plasma concentration in the 400 mg TID group approximated the IC90 derived from HCV replicon assays.
• SCH 503034 exhibited potent dose-related antiviral activity that was first detectable 24 hours post-dose. Reductions in mean VL positively correlated with SCH 503034 exposure.
• Mean max VL reduction in the 400 mg TID group was 2.06 log10 from baseline (1.1 to 2.7 log10, n=10).
• A dose-related decline in AST/ALT occurred during treatment and correlated with VL reductions.
• SCH 503034 was well tolerated at all dose levels.
• The adverse event  profiles were similar in patients receiving SCH 503034 and placebo.

Based on these results, the study authors conclude, “SCH 503034 exhibited dose-dependent HCV antiviral activity in patients with HCV-1 who previously failed peg-IFN- α therapy.”

Discussion

The results of this study of 61 patients, though preliminary, are quite promising for a patient population that has failed on prior interferon alfa therapy.

The mean HCV RNA in the 400 mg TID group was >2 log₁₀ from baseline, and the adverse event profile at all doses was favorable and similar to patients in the placebo arm.

The fact that this new compound is dosed orally offers dramatically increased convenience to patients and suggests the potential of significantly improving patient quality of life, assuming studies continue to show potent anti-HCV activity and safety.

Results of a clinical study of combination therapy with SCH 503034 plus peginterferon alfa-2b (PegIntron) will be presented at the AASLD conference on Tuesday, November 15. A review of the study results will appear Wednesday, November 16 on HIV andHepatitis.com.

11/14/05

Reference
S Zeuzem and others. Anti-viral Activity of SCH 503034, a HCV Protease Inhibitor, Administered as Monotherapy in Hepatitis C Genotype-1 (HCV-1) Patients Refractory to Pegylated Interferon (Peg-IFN-a). Abstract 67484. 56^th annual meeting of the American Association for the Study of Liver Diseases    (56^th AASLD). November 11-15, 2005. San Francisco, CA.