Biotech Values

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Boehringer Ingelheim's BI 201335 poster presented at AASLD 2009

Virological Response and Safety of BI 201335 protease inhibitor, Peginterferon alfa 2a and Ribavirin treatment of HCV genotype-1 patients with compensated liver cirrhosis and non-response to previous peginterferon / ribavirin

Background: BI 201335 is a highly potent and specific HCV NS3/4A protease inhibitor. A phase 1 trial in treatment-experienced HCV GT-1 patients demonstrated a mean viral load (VL) reduction of 5.3 LOG10 (IU/mL) for BI 201335 given once daily after 28 days in combination with peginterferon alfa (PegIFN) 2a and ribavirin (RBV). We now describe a phase 1b trial which has assessed safety, short-term efficacy, and pharmacokinetics of BI 201335 in GT-1 patients with compensated liver cirrhosis and non-response to previous PegIFN/RBV, a difficult-to-treat HCV population with a high unmet medical need.
Methods: In this open-label, sequential group comparison, HCV GT-1 patients with compensated liver cirrhosis who have never achieved undetectable VL under previous PegIFN/RBV were treated with 240 mg once (QD; n=6) or twice daily (BID; n=7) in combination with PegIFNa2a (180 mcg/week) and RBV (1000/1200mg/d) for 28 days. All patients received a single loading dose of 480mg of BI 201335 as the first dose. Plasma HCV RNA was measured by Roche COBAS TaqMan assay.
Results: Mean age was 54 years, BMI 26 kg/m2. Mean VL at baseline was 6.1 and 6.3 LOG10 (IU/mL) in both groups. All patients showed a rapid and continuous decline in VL. Mean VL declines on day 28 in the 240mg QD and BID groups were -4.9 and -5.0 LOG10, respectively. No breakthrough (>0.8 log rebound from VL nadir) was observed during treatment. At day 28, 5/6 and 5/7 patients achieved VL below level of quantification (< 25 IU/ml) in the QD and BID group. Furthermore, 4/6 and 1/7 patients had VL below level of detection (<10 IU/ml) in the 240mg QD and BID groups. There were no SAE in the 240mg QD group and 2 SAE in the 240mg BID group. Both were cases of mild to moderate hepatic decompensation attributed to PegIFN/RBV by the investigators. Two patients in the BID group discontinued treatment early, one due to nausea, one due to hepatic decompensation (SAE). Jaundice due to isolated unconjugated hyperbilirubinemia was reported in 2/6 and 1/7 patients at 240mg QD and BID, respectively. Other AE were mainly mild to moderate and typical of PegIFN/RBV. Lab analyses showed decreases of ALT / AST as well as blood cell counts typical of PegIFN/RBV.
Conclusions: BI 201335 once or twice daily combined with PegIFN/RBV exhibited potent antiviral activity in non-responder patients with liver cirrhosis. BI 201335 also exhibited a good safety and tolerability profile in these patients, allowing for their inclusion into the ongoing phase 2 program. These data also confirm that IFN non-responsiveness in previous non-responders can be overcome by rapid and profound inhibition of viral replication by BI 201335.