By Liz Highleyman

Given that only about half of all chronic hepatitis C patients treated with pegylated interferon plus ribavirin achieve a "cure," or sustained virological response, researchers have investigated several small-molecule agents that directly target various steps of the HCV lifecycle.

At the 43rd annual meeting of the European Association for the Study of the Liver last month in Milan, researchers presented results from the first study of Tibotec's novel HCV NS3/4a protease inhibitor, TMC435350, in patients with hepatitis C.

In laboratory studies, TMC435350 was found to have an antiviral EC50 (50% effective concentration) of 8nM in an HCV replicon model. The drug was first tested in a placebo-controlled, double-blind study of healthy volunteers without HCV, and results were previously reported [Hepatology 46(4), Suppl. 1, 2007].

At EASL, researchers reported further results from the HCV negative subjects, as well as safety, tolerability, pharmacokinetic, and antiviral activity data from an open-label study of 6 chronic hepatitis C patients.

TMC435350 was administered as an oral solution with food. Healthy volunteers received the drug for 5 days at doses of 100, 200, or 400 mg once daily or 200 mg twice daily. The 6 patients had HCV genotype 1 (4 with 1a; 2 with 1b) and did not achieve sustained response to prior interferon-based therapy. All received open-label TMC435350 at a dose of 200 mg once daily for 5 days.

Results

• No serious or Grade 3 or higher adverse events were observed in healthy volunteers or HCV-infected patients.

• Pharmacokinetic analysis revealed almost 3-fold higher mean TMC435350 plasma levels at day 5 in the HCV-infected patients compared with the uninfected volunteers.

• A rapid decline in HCV RNA was observed in all infected individuals.

• The median declines at days 3, 5, and 6 were 3.5, 3.7, and 3.9 log10 IU/mL, respectively, highlighting the continuing decline beyond the last dose.

• ALT/AST levels decreased in all patients during dosing.

• No HCV virological breakthrough was observed during dosing or in the following 3 days.

• Population sequencing of patient serum samples revealed variants in the HCV NS3 sequence which had previously been shown in vitro to be less sensitive to TMC435350.

• At week 4 of follow-up, plasma HCV RNA levels had returned to baseline levels in all patients.

Conclusion

Based on these findings the investigators concluded, "TMC435350 was well tolerated during 5 days of dosing, and provoked a strong and rapid antiviral activity in genotype 1 infected individuals."

They added that, "The results support further study of TMC435350 as a once-daily protease inhibitor for chronic HCV patients."

5/13/08

Reference
H Reesink, R Verloes, K Abou Farha, and others. Safety of the HCV protease inhibitor TMC435350 in healthy volunteers and safety and activity in chronic hepatitis C infected individuals: a phase I study. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.

Additional Source
Tibotec. Data on Investigational Compounds Being Co-Developed by Tibotec for the Treatment of Chronic Hepatitis C. Press release. April 24, 2008.