Once-Daily BI201335 Ups Response to Interferon for Hepatitis C

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Once-Daily BI201335 Ups Response to Interferon for Hepatitis C

SUMMARY: Boerhinger Ingelheim's experimental HCV protease inhibitor BI201335 added to pegylated interferon and ribavirin improved sustained response rates for both treatment-naive and treatment-experienced genotype 1 patients, researchers reported at EASL 2011.

Direct-acting antiviral agents that target various steps of the hepatitis C virus (HCV) lifestyle are expected to bring about a new paradigm in treatment for chronic hepatitis C, especially for patients with hard-to-treat HCV genotype 1. To date, most experimental drug candidates have been added to standard therapy consisting of pegylated interferon (Pegasys or PegIntron) plus ribavirin, but investigators have started to look at all-oral regimens.

At the European Association for the Study of the Liver's International Liver Congress (EASL 2011) this month in Berlin, researchers presented results from SILEN-C1 and SILEN-C2, which evaluated the NS3/4A protease inhibitor BI201335 in people starting treatment for the first time and in those who did not respond to prior therapy, respectively.

SILEN-C1: Treatment-naiveThe Phase 2b SILEN-C1 trial included 429 chronic hepatitis C patients with HCV genotype 1 who had not received prior interferon-based therapy. Just over half were men, more than 80% were white, and the average age was about 45 years. Participants were randomly allocated into 4 arms. The first 2 arms added either 120 mg or 240 mg once-daily BI201335 after a 3-day lead-in period taking pegylated interferon alfa-2a (Pegasys) plus weight-adjusted ribavirin. The third group started 240 mg once-daily BI201335 and pegylated interferon/ribavirin at the same time with no lead-in. The final control group received standard therapy consisting of pegylated interferon/ribavirin plus placebo. All groups received BI201335 for 24 weeks. The 120 mg BI201335 and placebo groups then continued pegylated

interferon/ribavirin through week 48. Patients in the 240 mg BI201335 arms who had an extended rapid virological response (eRVR; HCV viral load < 25 IU/mL at week 4 and weeks 8-20) were randomized again to either stop all therapy at week 24 or continue interferon/ribavirin through week 48. Results

All groups receiving BI201335 had significantly better response than those receiving standard therapy plus placebo.

The highest rapid and sustained virological response (SVR) rates were seen in participants who received 240 mg once-daily BI201335 without the lead-in.

Extended RVR:

240 mg BI201335 without lead-in: 87%;

240 mg BI201335 with lead-in: 78%;

120 mg BI201335 with lead-in: 80%;

Standard therapy: 16%.

SVR:

240 mg BI201335 without lead-in: 83%;

240 mg BI201335 with lead-in: 73%;

120 mg BI201335 with lead-in: 71%;

Standard therapy: 56%.

Among participants in the 240 mg BI201335 arms randomized to different treatment durations, response rates were as follows:

240 mg with lead-in: 82% for 24 weeks vs 96% for 48 weeks, a significant difference;

240 mg without lead-in: 93% for 24 weeks vs 90% for 48 weeks, not significant;

Relapse rates were about 8% in the 240 mg BI201335 without lead-in arm vs 14% in the standard therapy arm.

Overall adverse event rates were higher in the BI201335 arms, though most were mild to moderate.

Severe adverse event rates were 12% and 16% in the 120 mg and 240 mg BI201335 with lead-in arms and 13% in the 240 mg BI201335 without lead-in arm, compared with 4% in the standard therapy arm.

Rates of discontinuation due to adverse events were 4%, 12%, 5%, and 1%, respectively.

Patients taking BI201355, especially the 240 mg dose, were more likely to experience nausea and vomiting.

About 20% of patients taking the higher BI201335 dose developed jaundice, compared with about 1% in the control arm; there were no severe cases.

Patients taking the higher BI201335 dose were more likely to experience skin rash, including moderate and severe (about 4%) rash.

Mean ALT levels improved in all BI201335 arms compared with placebo.

The investigators concluded that BI201335 once-daily with pegylated interferon/ribavirin "achieved high efficacy with good tolerability and safety at all dose levels."In the 240 mg BI201335 without lead-in arm, 87% achieved SVR, and continuing pegyalted interferon/ribavirin for an additional 24 weeks did not improve outcomes. The 3-day pegyalted interferon/ribavirin lead-in was associated with reduced response rates and more adverse events.SILEN-C2: Treatment-experiencedThe Phase 2b SILEN-C2 study looked at the efficacy of BI201335 among genotype 1 chronic hepatitis C patients who did not respond to a prior course of at least 12 weeks of pegyalted interferon/ribavirin.This study included 288 participants. About two-thirds were men, about

90% were white, and the mean age was about 50 years. About half were prior null responders -- meaning they never had a substantial (at least 1 log) decrease in HCV RNA during treatment -- and about one-third were prior partial responders (more than 1 log decrease, but never undetectable); prior relapsers were not included.Participants were randomly assigned to receive 240 mg BI201355 either once or twice daily, and if once-daily, with or without a 3-day pegylated interferon/ribavirin lead-in period. Again, everyone stopped BI201335 at week 24. The 240 mg once-daily lead-in group was further randomized to stop pegylated interferon/ribavirin at the same time or continue through week 48.

Results

The arms with and without the lead-in had similar extended RVR rates, but the once-daily arm without lead-in pulled ahead for SVR.

Extended RVR rates were as follows:

240 mg BI201335 twice-daily with lead-in: 47%;

240 mg BI201335 once-daily with lead-in: 43%;

240 mg BI201335 once-daily without lead-in: 45%;

SVR rates were as follows:

240 mg BI201335 twice-daily with lead-in: 31%;

240 mg BI201335 once-daily with lead-in: 27%;

240 mg BI201335 once-daily without lead-in: 41%;

50% of prior partial responders and 35% of null responders achieved SVR in the once-daily without lead-in arm.

Among patients in the once-daily with lead-in group, those treated for 48 weeks had a significantly higher SVR rate than those treated for 24 weeks (72% vs 40%, respectively).

Participants receiving twice-daily BI201335 had about double the rate of severe adverse events compared with once-daily recipients (28% vs 14%, respectively).

About 15% of patients in the twice-daily lead-in arm, but only 1% in the once-daily without lead-in arm, discontinued due to adverse events.

About 6% of patients in the twice-daily lead-in arm experienced severe skin rash vs 1% in the once-daily without lead-in arm.

There were no cases of severe jaundice in any arm.

The investigators concluded that 240 mg BI201335 given once-daily with pegylated interferon/ribavirin "showed high efficacy and good tolerability in this very difficult-to-treat patient population with non-response to previous [pegylated interferon/ribavirin] therapy."Again, the 3-day pegylated interferon/ribavirin lead-in was associated with decreased virological response. In contrast with the treatment-naive patients in SILEN-C1, however, prior non-responders did significantly better with 48 weeks compared with 24 total weeks of treatment.Investigator affiliations:SILEN-C1: s Hopkins University, Baltimore, MD; Dr. Victor Babes Hospital for Infectious and Tropical Diseases, Bucharest, Romania; Hôpital Beaujon, Clichy Cedex, France; Prof. Dr. Matei Bals Institute of Infectious Diseases, Bucharest, Romania; Quest Clinical Research, San Francisco, CA; Medical

University of Vienna, Vienna, Austria; Hospital Francisco J. Muniz, Uspallata, Arhentina; Hospital Provincial Del Centenario, rio, Argentina; Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia; Instituto CAICI, rio, Argentina; Center for HIV and Hepatogastroenterology, Düsseldorf, Germany; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT; Boehringer Ingelheim Pharma, Biberach, Germany.SILEN-C2: s Hopkins University, Baltimore, MD; Hôpital Saint ph, Marseille, France; Hôpital de Brabois, Vandoeuvre Cedex, France; Prof. Dr. Matei Bals Institute of Infectious Diseases, Bucharest, Romania; Hôpital Beaujon, Clichy, France; Hôpital Henri Mondor, Créteil, France; University of Alberta, Edmonton, Alberta, Canada; Hôpital Cochin, Paris, France; Center for HIV and Hepatogastroenterology, Düsseldorf, Germany; Hôpital Saint-Eloi, Montpellier, France; Boehringer Ingelheim Pharma, Biberach, Germany; Boehringer

Ingelheim Pharmaceuticals, Ridgefield, CT.

4/15/11

ReferencesM Sulkowski, E Ceasu, T Asselah, et al. SILEN-C1: Sustained Virologic Response (SVR) and safety of BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in treatment-naive patients with chronic genotype 1 HCV infection. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 60/324. M Sulkowski, M Bourliere, J-P Bronowicki, et al. SILEN-C2: Sustained Virologic Response (SVR) and safety of BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in chronic HCV genotype-1 patients with non-response to P/R. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract

66/330. Other SourceBoehringer-Ingelheim. Positive Phase 2 results reported with Boehringer Ingelheim's investigational HCV protease inhibitor in both previously treated and untreated patients. Press release. April 1, 2011.

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