HCV Protease Inhibitor TMC435350 Demonstrates Favorable Safety and Efficacy in
Phase 2a Trial|
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.
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
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
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.
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.
At doses of 25 mg and 75 mg once-daily,
TMC435 demonstrated dose-dependent antiviral activity, both alone and in combination
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.
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."
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.
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.
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.
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.