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HIV and Hepatitis.com Coverage of the
45th Annual Meeting of the European
Association for the Study of the Liver (EASL 2010)

April 14 - 18, 2010, Vienna, Austria
Experimental HCV Protease Inhibitor BI 201335 Shows Robust Antiviral Activity in Genotype 1 Non-responders

SUMMARY: Boehringer Ingelheim's investigational NS3/4A hepatitis C virus (HCV) protease inhibitor BI 201355, in combination with pegylated interferon plus ribavirin, produced rapid and early virological response in patients with HCV genotype 1 who did not achieve sustained response with a prior course of therapy, according to a late-breaker oral presentation at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010) last week in Vienna. Skin rash was a common side effect, however, affecting 30%-60% of patients.

By Liz Highleyman

Mark Sulkowski and fellow investigators with the SILEN-C2 study evaluated the safety and efficacy of BI 201335 in an international double-blind Phase 2 clinical trial.

The study included 280 genotype 1 chronic hepatitis C patients who were non-responders to previous treatment with pegylated interferon/ribavirin for at least 12 weeks. People who relapsed after achieving undetectable HCV viral load during prior treatment were excluded. About 60% were men, about 90% were white, and the average age was 49 years. At baseline, the average baseline HCV viral load was 6.6 log IU/mL

Participants were randomly allocated (1:2:1) to receive the following regimens in combination with 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day weight-adjusted ribavirin for 24 weeks:

240 mg BI 201335 once-daily;
240 mg BI 201335 once-daily after a 3 day lead-in period of pegylated interferon/ribavirin;
240 mg BI 201335 twice-daily after a 3 day lead-in period of pegylated interferon/ribavirin.

After 24 weeks, all participants continued on pegylated interferon/ribavirin without BI 201335 through week 48. The data presented at EASL were from a planned interim analysis at 12 weeks.

Results

BI 201335 plus pegylated interferon/ribavirin demonstrated potent antiviral activity in all dose groups.
Rapid virological response (RVR) rates (HCV RNA < 25 IU/mL) at week 4 were similar in all BI 201335 dose groups:
 
62% in the 240 mg once-daily group;
64% in the 240 mg once-daily with lead-in group;
69% in the 240 mg twice-daily with lead-in group.
Early virological response (EVR) rates at week 12 (HCV RNA < 10 IU/mL) were also comparable:
 
59% in the 240 mg once-daily group;
59% in the 240 mg once-daily with lead-in group;
54% in the 240 mg twice-daily with lead-in group.
Rates of viral breakthrough (defined as an HCV RNA increase of ? 1 log from nadir during therapy or a confirmed increase of ? 100 IU/ml if previously undetectable) were slightly higher in the 2 once-daily groups:
 
22% in the 240 mg once-daily group;
22% in the 240 mg once-daily with lead-in group;
14% in the 240 mg twice-daily with lead-in group.
Mean alanine aminotransferase (ALT) levels also decreased in all BI 201335 dose groups.
BI 201335 plus pegylated interferon/ribavirin was generally well-tolerated.
The most frequently reported adverse events were:
 
Gastrointestinal symptoms;
Jaundice (usually mild) resulting from isolated unconjugated hyperbilirubinemia: 9%, 14%, and 34%, respectively, in the 3 dose groups;
Skin rash or photosensitivity reactions (mostly mild-to-moderate): 33%, 40%, and 59%, respectively;
1.3%, 0.7%, and 6%, respectively, developed severe rash.
4% of patients discontinued treatment prematurely due to adverse events (rash, photosensitivity, or jaundice) in the 2 once-daily groups, compared with 24% in the twice-daily group.

Based on these findings, the researchers concluded, "BI 201335 given in combination with pegylated interferon/ribavirin produced a rapid and early virologic response in HCV genotype 1 patients non-responsive to previous pegylated interferon/ribavirin."

"In treatment-experienced patients, BI 201335 [at] 240 mg once-daily appears to offer the best safety/efficacy balance based on the this interim analysis," they added.

Department of Viral Hepatitis, Johns Hopkins University, Baltimore, MD; Hôpital Saint Joseph, Marseille, France; Hôpital de Brabois, Vandoeuvre Cedex, France; Prof. Dr. Matei Bals Institute of Infectious Diseases 1, Bucharest, Romania; Hôpital Beaujon, Clichy, France; Hôpital Henri Mondor, Créteil, France; University of Alberta, Edmonton, Canada; Hôpital Cochin, Paris, France; Center for HIV and Hepatogastroenterology, Düsseldorf, Germany, 10Hôpital Saint-Eloi, Montpellier Cedex, France; Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/ Riss, Germany; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT.


Reference
M Sulkowski, M Bourliere, JP Bronowicki, and others. SILEN-C2: early antiviral activity and safety of BI 201335 combined with peginterferon alfa-2a and ribavirin (pegIFN/RBV) in chronic HCV genotype-1 patients with non-response to pegIFN/RBV. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract).


 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



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