HCV Protease Inhibitor BI 201335 Exhibits Promising Antiviral Activity|
Given the limited efficacy and side effects of interferon-based
therapy for chronic hepatitis C virus (HCV)
infection -- especially among patients with hard-to-treat HCV
genotype 1 -- investigators have explored several small molecule agents (dubbed
that directly target various steps of the viral lifecycle.
such candidate, BI201335, is an HCV NS3 protease inhibitor being developed by
Boehringer-Ingelheim. Two posters with results from a Phase 1b study of BI201335
were presented last week at the 59th Annual Meeting of
the American Association for the Study of Liver Diseases (AASLD 2008) in San
1220.2 is a multinational clinical trial evaluating the pharmacokinetics, safety,
and antiviral activity of multiple ascending doses of BI201335 monotherapy for
14 days, followed by triple therapy with BI201335 + pegylated
interferon + ribavirin for an additional 14 days.
The first analysis
looked at 34 treatment-naive patients with genotype 1 chronic hepatitis C in the
U.S., France, Germany, and Spain. Most participants (27) were men, all but 1 were
white, the mean age was about 49 years, and Metavir fibrosis scores were 0-3.
were randomly assigned to receive placebo or 1 of 4 doses of once-daily BI201335:
20 mg (n=8), 48 mg (n=9), 120 mg (n=9), or 240 mg (n=8). BI201335 was given as
monotherapy for 14 days. Patients with less than a 1 log10 decrease in HCV RNA
at day 10 had BI201335 discontinued after day 14. Those with at least a 1 log10
decrease at day 10 continued on BI201335, adding 180 mcg/week pegylated interferon
alfa-2a (Pegasys) + weight-adjusted ribavirin from day 15 through Day 28.
A rapid decline in HCV viral load was
observed in all patients, with maximal decline 2-4 days after starting BI201335.
With the exception of 1 patient in the
20 mg group, all participants receiving BI201335 (96.2%) achieved > 2 log10
decline in HCV RNA during the monotherapy period.
100% of patients in the 48 mg, 120 mg,
and 240 mg BI201335 dose groups achieved > 2.8 log10 drop in HCV viral load
during the first few days of monotherapy.
Median maximal reductions in viral load
during the 14-day monotherapy period were 3.0 log10 in the 20 mg arm, 3.6 log10
in the 48 mg arm, 3.7 log10 in the 120 mg arm, and 4.2 log10 in the 240 mg arm,
versus no significant change in the placebo group.
A majority of patients in all dose groups
experienced viral load rebound during the first 14 days of monotherapy.
Population sequencing of the NS3/NS4A
protease at baseline and after viral rebound revealed selection of HCV variants
previously shown to confer resistance to BI201335 in vitro.
BI201335 was generally well-tolerated,
with no observed dose-dependent increases in adverse events (AEs).
No patients discontinued treatment during
the monotherapy period due to AEs.
AEs observed while on combination therapy
were typical for pegylated interferon + ribavirin.
Changes in bilirubin were observed with
increasing doses of BI 201335.
One serious AE (asthenia, or muscle weakness)
occurred in an individual in the 20 mg dose arm 6 days after starting pegylated
interferon + ribavirin.
conclusion, the investigators stated, "BI 201335 as monotherapy for 14 days
followed by combination with [pegylated interferon + ribavirin] for [an] additional
14 days was well tolerated, and induced a strong and rapid antiviral response."
results support further study of BI201335 as a once-daily potent antiviral for
treatment-naive HCV patients," they added.
Hannover Zentrum Innere Medizin, Hannover, Germany; Hopital Saint Joseph, Marseille,
France; Hopital Pitie Salpetriere, Paris, France; California Pacific Medical Center
Research Institute, San Francisco, CA; Charité Berlin Campus Virchow-Klinikum,
Berlin, Germany; Hopital Hotel Dieu, Lyon, France; Central Texas Clinical Research,
Austin, TX; Hopital Cochin, Paris, France; Boehringer Ingelheim Pharma, Ridgefield,
CT; Hospital Universitario Puerta de Hierro, Madrid, Spain.
1220.2 also included a cohort of 19 treatment-experienced patients with genotype
1 chronic hepatitis C who experienced confirmed virological failure (< 2 log
reduction in HCV RNA from baseline) during or after previous combination therapy
with approved doses of pegylated interferon + ribavirin. Here, too, a majority
of participants were men, all were white, and the mean age was 49 years.
part of the study was open-label, and all patients received BI201335 at doses
of 48, 120, or 480 mg once-daily in combination with standard doses of Pegasys
+ ribavirin for 28 days (none received monotherapy or 20 mg BI201335).
Here again, a rapid dose-related decline
in HCV RNA was observed in all patients.
All participants treated with BI201335
+ pegylated interferon + ribavirin achieved > 2 log10 decline in HCV viral
Median maximal declines in HCV RNA during
28-day combination therapy were 4.8 log10 in the 48 mg arm, 5.2 log10 in the 120
mg arm, and 5.3 log10 in the 240 mg arm.
2 of 6 patients (33%) in the 48 mg group
and 1 of 7 (14%) in the 120 mg group experienced virological rebound during the
first 28 days of triple combination therapy.
In these patients, sequencing of the NS3/4A
protease revealed variants with known BI201335 resistance mutations.
No viral rebound during treatment was
seen in the 240 mg dose arm, and 5 of 6 patients (83%) in this group had HCV RNA
< 25 IU/mL at day 28.
Again, BI201335 was well-tolerated and
no serious drug-related AEs were observed.
AEs were typical for pegylated interferon
1 participant discontinued treatment due
given once-daily in combination therapy with [pegylated interferon + ribavirin]
for 28 days was well tolerated, and induced a strong and rapid antiviral response,"
the researchers concluded. "The results support further study of BI201335
as a potent protease inhibitor for [pegylated interferon + ribavirin] treatment-experienced
Medizinische Hochschule Hannover Zentrum Innere
Medizin, Hannover, Germany; Hopital Saint Joseph, Marseille, France; Hopital Pitie
Salpetriere, Paris, France; I. Med. Klinik und Poliklinik, Mainz, Germany; Universitätsklinikum
Düsseldorf, Düsseldorf, Germany; Hopital Cochin, Paris, France; California
Pacific Medical Center Research Institute, San Francisco, CA; Boehringer Ingelheim
Pharmaceuticals, Inc, Ridgefield, CT.
MP Manns, M Bourliere, Y Benhamou, and others. Safety and antiviral activity
of BI201335, a new HCV NS3 protease inhibitor, in treatment-naive patients with
chronic hepatitis C genotype-1 infection given as monotherapy and in combination
with Peginterferon alfa 2a (P) and Ribavirin (R). 59th Annual Meeting of the American
Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October
31-November 4, 2008. Abstract 1849.
MP Manns, M Bourliere, Y Benhamou,
and others. Safety and antiviral activity of BI201335, a new HCV NS3 protease
inhibitor, in combination therapy with Peginterferon alfa 2a (P) and Ribavirin
(R) for 28 days in P+R treatment-experienced patients with chronic hepatitis C
genotype-1 infection. 59th Annual Meeting of the American Association for the
Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008.