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BI 207127 is a potent HCV RNA polymerase inhibitor during 5 days monotherapy in patients with chronic hepatitis C
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Reported by Jules Levin
AASLD Nov 3 2009, Boston, MA
Dominique Larrey,1 Yves Benhamou,2 Ansgar W Lohse,3 Christian Trepo,4 Christian Mölleken,5 Jean-Pierre Bronowicki,6 Markus Heim,7 Keikawus Arasteh,8 Jean-Pierre Zarski,9 Marc Bourliere,10 Reiner Wiest,11 Jose Luis Calleja,12 Jaime Enriquez,13Andreas Erhardt,14 Heiner Wedemeyer,15 Tilman Gerlach,16 Thomas Berg,17 Jerry Stern,18 Katherine Wu,18 Nasri Abdallah,19 Gerhard Nehmiz,20 Wulf Boecher,20 Frank Berger,21 Jürgen Steffgen20 for the BI 207127 study group
1INSERM 632-CIC Hopital Saint Eloi Montpellier, 2Hopital La Pitie Salpetriere Paris, 3Universitatsklinikum Hamburg-Eppendorf Hamburg, 4Hopital Hotel Dieu Lyon, 5Universitatsklinik Bochum, 6Hopital de Brabois Nancy, 7Universitatsspital Basel, 8Epimed GmbH Berlin, 9Hopital Michalon Grenoble, 10Hopital Saint Joseph Marseille, 11Klinikum der Universitat Regensburg,12Clinica Puerta de Hierro Madrid, 13Hospital de la Santa Creu I Sant Pau Barcelona, 14Universitatsklinikum Düsseldorf, 15Medizinische Hochschule Hannover, 16Kantonsspital St Gallen, 17Charite Berlin Campus Virchow-Klinikum Berlin, 18Boehringer Ingelheim (BI) Ridgefield CT, 19BI Reims, 20BI Biberach, and 21BI Ingelheim
ABSTRACT
Background: BI 207127 is a potent and specific non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase in vitro.
Methods: In a double blinded, sequential group comparison, 60 male and female HCV genotype-1 patients with liver fibrosis stage 1 and 2 were randomized in 3:1 ratio to active or placebo per group and treated with 100, 200, 400, 800 or 1200 mg BI 207127 Q8H over 5 days, given p.o. as experimental tablet. All patients were followed for 10-14 days. Plasma HCV RNA virus load (VL) was measured by Roche COBAS TaqMan assay.
Results: Mean age was 49.1 + 9.8 years, BMI 25.1 + 3.0 kg/m2. 15/60 patients were naive for anti-HCV therapy. Mean LOG10 VL(IU/mL) at baseline was 6.4.
VL decreased by ≥1 LOG10 in 2/9, 6/9, 8/9, 8/9 and 10/10 patients treated with 100, 200, 400, 800 and 1200 mg, respectively. No response was seen with placebo. No breakthrough was observed during treatment.
Median VL declines on day 5 were 0.4, 0.8, 1.3, 3.8 and 3.2 LOG10, respectively. A ≥3 LOG10 drop in VL was observed in 2, 3, 6 and 6 patients in the 200, 400, 800 and 1200 mg group. Two patients in the 800 mg group achieved HCV RNA BLQ (25 IU/ml) at day 5.
BI 207127 showed supra-dose proportional plasma exposure on day 5 at doses of400 mg Q8H and above. One drug-related SAE was reported in the 800 mg dose group (a moderate generalized erythema with facial involvement, which resolved within 2 days after discontinuation of BI 207127). Two more cases of mild localized rash were reported, one at 800 mg and the other at 1200 mg which disappeared during BI 207127 treatment without additional therapy. In the 1200 mg dose group, 6 patients showed signs of mild photosensitization and 7 patients reported mild to moderate diarrhea. All other AEs were not considered dose-related. The investigators' assessment of tolerability was "good" in 41/46 active-treated patients. Laboratory parameters did not indicate any relevant changes from baseline. The first phase of VL decline correlated with early BI 207127 plasma exposure.
Conclusions: BI 207127, given as monotherapy p.o., demonstrated reliable antiviral activity against HCV genotype 1 that correlated with BI 207127 plasma exposure, and reached a maximal effect at 800 mg Q8H dose. A 4 week investigational study with doses of BI 207127 up to 800 mg tid in combination with Peg-IFN and RBV has been initiated.
INTRODUCTION
Hepatitis C virus (HCV) genotype 1 (GT-1) infection, prevalent in many parts of the world, is associated with less than a 50% sustained virologic response to standard treatment with pegylated interferon (PegIFN) and ribavirin (RBV). This limited response stresses the need for more potent and tolerable antiviral treatment options
BI 207127 is an orally bioavailable, reversible, thumb pocket 1 non-nucleoside inhibitor of the HCV RNA-dependent polymerase in vitro
BI 207127 exhibits potent and specific inhibition of the HCV RNA-dependent RNA polymerase with cell-based HCV sub-genomic replicon EC50 values of 23 nM and 11 nM for GT-1a and GT-1b, respectively
The objective of this study was to assess safety, pharmacokinetics and antiviral potency of BI 207127 in patients with chronic HCV infection of GT-1
METHODS
Study design and BI 207127 dosages
· Design: double-blinded, sequential, dose-escalating group comparison
· Doses: 100 mg, 200 mg, 400 mg, 800 mg and 1,200 mg every8 hours (Q8H), given for 5 days orally (experimental tablet). The last dose was administered on the morning of Day 5
· At each dose level, patients were randomized either to BI 207127 (n=9) or a matching placebo (n=3)
· All patients were followed for 10-14 days
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