Human safety, pharmacokinetics and antiviral activity of TMC647055, a novel HCV nonnucleoside polymerase inhibitor

Abstract

Background TMC647055 is a macrocyclic indole non-nucleoside inhibitor of the hepatitis C virus (HCV) NS5B polymerase, binding in the thumb-1 region. It has demonstrated potent in vitro activity against HCV genotype 1a and 1b and has a broad genotypic coverage. We report data of the TMC647055 HPC1001 trial, investigating the safety and pharmacokinetics in healthy volunteers and patients, and the antiviral activity in genotype 1 HCV patients. Method Two panels of 9 healthy volunteers (6 active, 3 placebo) were given single doses of 100, 250, 500, 1000 and 1500mg, as an oral solution with standard meals. A washout period of 10 days was respected between consecutive dosing within panels. Multiple oral doses of 300mg, 1000mg and 1250mg bid were given to 3 panels of 9 healthy volunteers (6 active, 3 placebo) for 5 days with a morning dose on Day 6. Finally, multiple doses of 500mg bid and 1000mg bid were similarly administered in genotype 1 HCV patients (naives, relapsers, non-responders to previous treatment regimens (IFN/RBV or pegylated IFN/RBV)), in 2 cohorts of 10 patients (8 active, 2 placebo). Plasma concentrations, tolerability and short term antiviral effect on plasma HCV RNA were monitored. Patients had minimal or no fibrosis (biopsy, elastography) and a compensated liver function. Results TMC647055 was well tolerated in this study in healthy volunteers and patients. The PK exposure of subjects receiving the 1000mg single dose under fasted conditions was comparable to the fed condition. The most common reported adverse events were gastrointestinal (nausea, vomiting, loose stools, diarrhea and abdominal cramps/discomfort), probably related to the hydroxypropyl-beta-cyclodextrin vehicle. There were no SAEs, no grade 3 or 4 AEs, no clinically significant effects on laboratory parameters, vital signs, food consumption, appetite or ECG profile. TMC647055 plasma concentrations were about 2-fold higher in patients than in healthy volunteers. The antiviral response showed a dose-dependent median maximum decrease in HCV RNA from baseline of 1.4 log10 and 2.4 log10 in GT1a patients with HCV RNA data available up to Day 6 at 500 and 1000 mg bid, respectively. In GT1b patients, the median maximum decrease in HCV RNA was similar at the two dose levels i.e. 3.3 log10 at 500mg bid and 3.4 log10 at 1000mg bid. Mean trough concentrations in patients exceeded the replicon genotype 1a/1b EC50 values. Conclusion TMC647055 was well tolerated and had good antiviral activity in HCV genotype 1 patients. These results encourage further assessments of TMC647055 in combination with Peg-IFN/RBV and/or other direct antiviral agents.