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Tibotec HCV Protease TMC435 I Treatment-Naives Genotype 1, Monotherapy & Combination with Peg/RBV
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Jules Levin
EASL Copenhagen, Denmark, April 23-26 2009
In the same late afternoon session this was also presented, again with promising results. Tibotec reported results from OPERA Study of TMC435, the protease inhibitor, in treatment-naives. This protease is a once-daily drug. Previous monotherapy study showed about 4 log reduction in viral load and thats what they say here approximately. With peg/RBV reduction was about 5.5 logs on average but you have to rember in this study as well as in others the level of baseline viral load limits how far of a reduction you can see. For example, if baseline viral load is 6 logs you can't see more than a 6 log reduction. Some reversible elevated bilirubin was seen at the highest dose of 200mg.
OPERA-1 TRIAL: INTERIM ANALYSIS OF SAFETY AND ANTIVIRAL ACTIVITY OF TMC435 IN TREATMENT-NAÏVE GENOTYPE 1 HCV PATIENTS
M. Manns1, H. Reesink2, C. Moreno3, T. Berg4, Y. Benhamou5, Y. Horsmans6, G. Dusheiko7, R. Flisiak8, P. Meyvisch9, O. Lenz9, V. Sekar10, G. van't Klooster9, K. Simmen9, R. Verloes9
1Medizinische Hochschule Hannover, Hannover, Germany, 2Amsterdam Medical Center, Amsterdam, The Netherlands, 3Erasme Hospital, Universite Libre de Bruxelles, Brussel, Belgium, 4Charite-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany, 5Centre Hospitalier Universitaire Pitie-Salpêtrière Paris, Paris, France,6Saint-Luc Universite Catholique de Louvain, Brussel, Belgium, 7Royal Free Hospital, London, UK, 8Medical University of Bialystok, Bialystok, Poland, 9Tibotec BVBA, Mechelen, Belgium, 10Tibotec Pharmaceuticals, Yardley, PA, USA
Background: TMC435 is an NS3/NS4A protease inhibitor in development for treatment of HCV infection.
Methods: OPERA-1 is an ongoing double blind, placebo-controlled Phase IIa trial to assess the antiviral activity, safety and pharmacokinetics of once-daily (QD) regimens of TMC435 in HCV genotype 1 treatment-naÏve and treatment-experienced patients. Interim 4-week results of three dose cohorts (25, 75 or 200mg QD) in treatment-naÏve patients are reported here. Patients were randomized to receive either 7 days of monotherapy of TMC435 or placebo followed by 21 days triple therapy with TMC435 or placebo, PegIFNα-2a and ribavirin (RBV) (Panel A); or 28 days of triple therapy with TMC435 or placebo, and PegIFNα-2a/RBV (Panel B). Thereafter, patients continued on PegIFNα-2a/RBV (Standard Of Care). Stopping rules were included.
Results: There were no TMC435-related treatment discontinuations, Grade 3 or 4 adverse events (AEs) or serious AEs. AEs were generally mild to moderate. Hepatic AST and ALT values improved during therapy. There were no clinically relevant changes in other laboratory parameters, ECGs, QTc, and vital signs. All three TMC435 doses in combination with PegIFN/RBV showed antiviral activity superior to PegIFN/RBV alone. During 7-day monotherapy, an antiviral dose-relationship was observed for TMC435. On triple therapy, a similar antiviral activity was noted between the 75mg and 200mg doses. In the 25, 75, 200mg 4-week triple therapy arms, 6/9, 9/9 and 10/10 patients had HCV RNA concentrations below the lower limit of quantification (< 25 IU/mL) and 3/9, 8/9 and 7/10 had undetectable HCV RNA (< 10 IU/mL) at day 28, respectively. At week 12, 6/9 patients of the 25mg and all patients of the 75mg triple arm had undetectable HCV RNA. Viral breakthroughs during TMC435 treatment were only observed in Panel A and were associated with mutations conferring reduced susceptibility to TMC435 in vitro.
Conclusion: TMC435 at doses of 25, 75 or 200mg QD administered for 4 weeks was well tolerated and demonstrated potent antiviral activity. The trial is ongoing for treatment-experienced patients.
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