By Liz Highleyman

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 "STAT-C") that directly target various steps of the viral lifecycle.

One 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 Francisco.

Treatment-naive Patients

Study 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.

Participants 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.

Results

• 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.

In 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."

"The results support further study of BI201335 as a once-daily potent antiviral for treatment-naive HCV patients," they added.

Medizinische Hochschule 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.

Treatment-experienced Patients

Study 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.

This 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).

Results

• 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 load.

• 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 + ribavirin.

• 1 participant discontinued treatment due to anxiety.

"BI201335 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 HCV patients."

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.

11/11/08

References
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. Abstract 1882.