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Virological response and safety of 4 weeks' treatment with the protease inhibitor BI 201335combined with 48 weeks of peginterferon alfa 2a and ribavirin for treatment of HCV GT-1 patients who failed peginterferon/ribavirin
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Reported by Jules Levin
AASLD 2010 Nov 1 Boston
Thomas Berg,1 Douglas Dieterich,2 Jacob Lalezari,3 Maurizio Bonacini,4 Rainer Günther,5 Marc Bourliere,6 Michael Manns,7 Yves Benhamou,8 Jose Luis Calleja,9 Marcus Schuchmann,10 Michael Biermer,1 Gerd Steinmann,11 Jerry Stern,12 Joe Scherer,12 Wulf O. Boecher11
1Charite, Campus Virchow-Klinikum, Berlin, Germany; University of Leipzig, Leipzig, Germany; 2Mount Sinai School of Medicine, New York, NY, USA; 3Quest Clinical Research, San Francisco, CA, USA; 4California Pacific Medical Center, San Francisco, CA, USA; 5UK S-H, Campus Kiel, Kiel, Germany; 6Hopital Saint Joseph, Marseille, France;7Medical School of Hannover, Hannover, Germany; 8Hopital Pitie Salpetriere, Paris, France; 9Hospital Puerta de Hierro, Madrid, Spain; 10University of Mainz, Mainz, Germany; 11Boehringer Ingelheim Pharma GmbH, Biberach, Germany; 12Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
ABSTRACT
Background: BI 201335 is a highly potent and specific hepatitis C virus (HCV) NS3/4A protease inhibitor. BI 201335 given at 240 mg once daily (QD) demonstrated a median maximum viral load (VL) reduction by 4.2 log10 (IU/mL) during 14 days of monotherapy in treatment-naïve HCV genotype-1 (GT-1) patients, and by 5.3 log10 in combination with peginterferon (PegIFN) alfa 2a and ribavirin (RBV) for 28 days in treatment-experienced patients. This phase 1 study describes safety and efficacy of BI 201335 in GT-1 patients with virological failure to PegIFN/RBV.
Methods: Patients were randomized to open-label treatment with 240 mg QD (n=15) or twice daily (BID; n=15) in combination with PegIFN (180 mcg/week) and RBV (1,000/1,200 mg/day) for 28 days, followed by PegIFN/RBV until Week 48. Patients with cirrhosis were excluded. All patients received an initial loading dose of 480 mg of BI 201335. Plasma HCV RNA was measured by Roche COBAS TaqMan assay.
Results: Mean age was 50 years, body mass index 26 kg/m2. Mean VL at baseline was 6.6 log10 (IU/mL). Most patients were null- (40%), or partial- (47%) responders to previous treatment, while 3 patients had breakthroughs and 1 relapsed. During 4 weeks of treatment with BI 201335 and standard-of-care (SOC), all patients showed a rapid VL decline. Mean VL reduction on Day 28 was -5.1 log10 in both groups. All 30 patients continued SOC treatment beyond Day 28. Virological responses until Week 48 are displayed in the table. Sustained virological response rates will be available at the meeting. One virologic breakthrough (≥1 log rebound from VL nadir or VL >100 IU/mL after undetectable VL) was observed during BI 201335 treatment. Treatment was generally safe and well tolerated. Adverse events (AEs) were mainly mild to moderate and typical of PegIFN/RBV. There were no serious AEs. Bilirubin elevations of 2.5-6 x upper limit of normal were observed in 8 and 10 patients at 240 mg QD and BID and were exclusively caused by isolated unconjugated hyperbilirubinemia, likely due to UGT1A1 inhibition. Other lab analyses showed decreases of alanine aminotransferase and blood cell counts typical of PegIFN/RBV.
Conclusions: Four weeks of BI 201335 240 mg once or twice daily combined with PegIFN/RBV exhibited similarly potent on-treatment efficacy in PegIFN/RBV non-responder patients. These data support further studies of both doses in these patients.
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