65 CLONAL ANALYSIS OF MUTATIONS SELECTED IN THE HCV NS3 PROTEASE DOMAIN OF GENOTYPE 1 NON-RESPONDERS TREATED WITH BOCEPREVIR (SCH503034)

Methods: TMC435350 as an oral solution in PEG400 was taken with food. Healthy volunteers were divided in 4 panels of maximum 9 subjects (6 TMC435350 and 3 placebo) for 5 days at doses of 100mg QD, 200mg QD, 200mg BID and 400mg QD. Six patients with genotype 1 (four 1a, two 1b) HCV infection, who had failed prior interferon treatment received open label 200mg TMC435350 QD for 5 days. All subjects were monitored for safety, tolerability and pharmacokinetics. Plasma HCV-RNA levels were measured using the Roche COBAS TaqMan assay (LLOQ 30 IU/mL). Results: The healthy volunteer data from this trial have been reported in Verloes et al; Hepatology (2007) Vol 46, No 4, Suppl 1. No serious or Grade 3 or higher adverse events were observed in healthy or HCVinfected individuals. Pharmacokinetic analysis revealed almost three-fold higher mean TMC435350 plasma levels at Day 5 in the HCV infected compared to non-infected subjects. A rapid decline of HCV-RNA was observed in all individuals. The median declines at Days 3, 5 and 6 were 3.5, 3.7 and 3.9 log10 viral IU/mL respectively, highlighting the continuing decline beyond the last dosing. ALT/AST levels decreased in all subjects during dosing. No virologic breakthrough was observed during dosing or in the following three days. Population sequencing of the serum samples revealed variants in the NS3 sequence which were shown in vitro to be less sensitive to TMC435350, but remained sensitive to interferon. At a 4 week follow-up, plasma levels of HCV-RNA had returned to baseline levels in all individuals. Conclusions: TMC435350 was well tolerated during 5 days of dosing, and provoked a strong and rapid antiviral activity in genotype 1 infected individuals. The results support further study of TMC435350 as a oncedaily protease inhibitor for chronic HCV patients.