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).
