By Liz Highleyman

Given the suboptimal efficacy and side effects of interferon-based therapy for chronic hepatitis C virus (HCV) infection, investigators have explored several small molecule agents -- collectively designated "STAT-C" -- that directly target various steps of the viral lifecycle.

One such candidate is TMC435350 (or simply TMC435), an HCV NS3/4A protease inhibitor being developed by Tibotec and Medivir. Data from a Phase 2a clinical trial of TMC435 were presented last week at the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) in San Francisco.

In the ongoing double-blind, proof-of-concept OPERA-1 trial, investigators from 5 European countries are assessing the pharmacokinetics (PK), antiviral activity, and safety of TMC435 in genotype 1 treatment-naive chronic hepatitis C patients.

Study participants were randomly assigned to receive either:

• TMC435 or placebo once-daily for 7 days, followed by TMC435 or placebo + standard of care treatment with 180 mcg/week pegylated interferon alpha-2a (Pegasys) + 1000-12000 mg/day ribavirin for 21 days;

• TMC435 or placebo + Pegasys + ribavirin for 28 days.

Thereafter, all participants continued on Pegasys + ribavirin for an additional 20 or 44 weeks (24 or 48 weeks total). Results from 50 patients in Cohort 1, who received 25 or 75 mg TMC435 versus placebo, were reported at AASLD. About two-thirds were men and almost all were white.

Results

• At doses of 25 mg and 75 mg once-daily, TMC435 demonstrated dose-dependent antiviral activity, both alone and in combination with Pegasys/ribavirin.

• Using the 25 mg dose, mean reductions in HCV RNA at day 7 were 2.63 log10 IU/mL with TMC435 monotherapy and 3.47 log10 IU/mL with triple therapy.

• Using the 75 mg dose, the corresponding reductions were 3.43 and 4.55 log10 IU/mL, respectively.

• In the 25 mg 4-week triple therapy arm, 3 of 9 patients achieved undetectable HCV RNA (< 10 IU/mL) at day 28 -- for a rapid virological response (RVR) rate of 33% -- while 3 more achieved HCV RNA < 25 IU/mL.

• In the 75 mg 4-week triple therapy arm, 8 of 9 participants achieved HCV RNA < 10 IU/mL at day 28 -- for a RVR rate of 89% -- while the remaining patient achieved HCV RNA < 25 IU/mL.

• No serious or severe adverse events related to TMC435 were observed.

• No patients discontinued treatment for safety-related reasons, and there were no dose-related adverse safety findings.

• The most common adverse events considered to be associated with TMC435 were nausea, diarrhea, and headache.

• There were no clinically relevant mean changes in laboratory parameters, ECGs, or vital signs.

Based on these findings, the researchers concluded that "In Cohort 1 of the OPERA-1 study, 25 mg and 75 mg TMC435 administered once-daily in combination with standard of care ([Pegasys/ribavirin]) demonstrated dose-dependent potent antiviral activity and a favorable safety and tolerability profile up to 28 days of dosing in treatment-naive, chronic hepatitis C patients with genotype 1."

"These data demonstrate the potent antiviral activity of TMC435350 against genotype-1 HCV," stated Medivir CEO and President Lars Adlersson in a press release issued by the company. "Based on these clinical and non-clinical studies, we are confident that TMC435350 has the potential to become a valuable addition to available therapy, providing an efficacious treatment with once-daily dosing."

In related presentations, investigators reported that TMC435 had favorable pharmacokinetic parameters (abstract 1895) and was a potent inhibitor of NS3/4A proteins from HCV genotypes 1 through 6 (abstract 1912).

The OPERA-1 study is ongoing, and is currently assessing a higher dose of TMC435 (200 mg once-daily) in Cohort 2. The trial is also recruiting treatment-experienced patients who have not responded to or have relapsed after a previous course of pegylated interferon + ribavirin.

Medizinische Hochschule , Hannover, Germany; Amsterdam Medical Center, Amsterdam, Netherlands; Erasme Hospital, Université Libre de Bruxelles, Bruxelles, Belgium; Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany; Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France; Saint-Luc Université Catholique de Louvain, Leuven, Belgium; Royal Free Hospital, London, UK; Medical University of Bialystok, Bialystok, Poland; Tibotec BVBA, Mechelen, Belgium.

11/11/08

References

MP Manns, HW Reesink, C Moreno, and others. Safety and antiviral activity of TMC435350 in treatment-naïve genotype 1 HCV-infected patients. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract LB8.

GA van 't Klooster, I Vanwelkenhuysen, R Verloes, and others. Pharmacokinetics of once-daily regimens of the novel HCV NS3/4A-protease inhibitor TMC435350, with and without pegIFN and ribavirin, in HCV-infected individuals. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1895.

T Lin, B Devogelaere, O Lenz, and others. Inhibitory activity of TMC435350 on HCV NS3/4A proteases from genotypes 1 to 6. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1912.

Other source
Tibotec. Tibotec Presents Interim Findings for TMC435, an Investigational Genotype 1 Hepatitis C Treatment, at the AASLD Liver Meeting 2008. Press release. November 3, 2008.