Antiviral effect, safety, and pharmacokinetics of five-day oral administration of Deleobuvir (BI 207127), an investigational hepatitis C virus RNA polymerase inhibitor, in patients with chronic hepatitis C

Abstract

Deleobuvir (BI 207127) is an investigational oral nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B RNA polymerase. Antiviral activity, virology, pharmacokinetics, and safety were assessed in HCV genotype 1-infected patients receiving 5 days' deleobuvir monotherapy. In this double-blind phase 1b study, treatment-naive (TN; n = 15) and treatment-experienced (TE; n = 45) patients without cirrhosis received placebo or deleobuvir at 100, 200, 400, 800, or 1,200 mg every 8 h (q8h) for 5 days. Patients with cirrhosis (n = 13) received deleobuvir at 400 or 600 mg q8h for 5 days. Virologic analyses included NS5B genotyping and phenotyping of individual isolates. At day 5, patients without cirrhosis had dose-dependent median HCV RNA reductions of up to 3.8 log10 (with no placebo response); patients with cirrhosis had median HCV RNA reductions of approximately 3.0 log10. Three patients discontinued due to adverse events (AEs). The most common AEs were gastrointestinal, nervous system, and skin/cutaneous tissue disorders. Plasma exposure of deleobuvir was supraproportional at doses ≥ 400 mg q8h and approximately 2-fold higher in patients with cirrhosis than in patients without cirrhosis. No virologic breakthrough was observed. NS5B substitutions associated with deleobuvir resistance in vitro were detected in 9/59 patients; seven encoded P495 substitutions, including P495L, which conferred 120- to 310-fold-decreased sensitivity to deleobuvir. P495 variants did not persist in follow-up without selective drug pressure. Deleobuvir monotherapy was generally well tolerated and demonstrated dose-dependent antiviral activity against HCV genotype 1 over 5 days.

Fig 1

Median changes in the HCV RNA level for patients without cirrhosis according to deleobuvir dose and HCV genotype.

Fig 2

Clonal sequence analysis at baseline, day 6, and day 14 of samples from a patient in the 400-mg-dose group (A), 1,200-mg-dose group (B), and 200-mg-dose group (C). HCV RNA at the 48-h time point for the patient whose results are presented in panel C could not be confirmed. WT, wild type.

Fig 3

Initial HCV RNA decline at 24 h versus deleobuvir log₁₀ C_min,ss (A) and deleobuvir log₁₀ inhibitory quotient (IQ) (B).