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BI201335 Shows Potent Activity against HCV

HCV protease inhibitor BI201335 plus pegylated interferon/ribavirin was well-tolerated and demonstrated good activity in treatment-naive and -experienced genotype 1 chronic hepatitis C patients.

By Liz Highleyman

The advent of direct-acting antiviral agents active against different steps of the hepatitis C virus (HCV) lifecycle will dramatically change therapy, especially for difficult-to-treat patients. Current drugs, however, still must be used in combination with pegylated interferon alfa (Pegasys or PegIntron) plus ribavirin.

The first 2 HCV protease inhibitors -- boceprevir (Victrelis) and telaprevir (Incivek) -- were approved in May; next-generation agents are currently moving through the development pipeline.

As described in the June 2011 Journal of Hepatology, Michael Manns from Hannover Medical School and colleagues evaluated the safety and efficacy of Boehringer-Ingelheim's candidate, BI201335, in a dose-escalation trial of treatment-naive and experienced participants.

A total of 34 previously untreated genotype 1 chronic hepatitis C patients were randomly assigned to receive BI201335 at doses of 20 mg to 240 mg once-daily, or else placebo, for 14 days, followed by pegylated interferon/ribavirin through day 28. In addition, 19 treatment-experienced people received 48 mg to 240 mg BI201335 once-daily in combination with pegylated interferon/ribavirin for 28 days.


Treatment-naive patients experienced good viral load reductions at all doses:
3.0 log median maximal reduction in 20 mg group;
3.6 log reduction in 48 mg group;
3.7 log reduction in 120 mg group;
4.2 log reduction in 240 mg group.
Most people receiving monotherapy experienced HCV viral load breakthrough (at least 1 log increase from the nadir or lowest level).
Viral breakthrough was associated with NS3/4A mutations including R155K and D168V that conferred resistance to BI201335 in vitro.
Adding pegylated interferon/ribavirin during days 15-28 led to continuous HCV viral load reductions in most patients.
Among treatment-experienced participants, treatment with BI201335 plus pegyalted interferon/ribavirin produced undetectable viral load (< 25 IU/mL) at day 28 in a majority of patients:
50% (3 of 6) in the 48 mg group;
57% (4 of 7) in the 120 mg group;
83% (5 of 6) in the 240 mg groups.
16% of previously treated patients experienced viral breakthrough during triple combination therapy.
Prior relapsers achieved 28-day rapid virological response (RVR) rates similar to those of treatment-naive individuals.
Previous partial responders and null responders had similar response and breakthrough rates across all dose groups.
BI201335 was generally well-tolerated in both treatment-naive and treatment-experienced patients.
The majority of adverse events were mild-to-moderate, not dose-dependent, and judged to be unrelated to BI201335.
4 patients experienced mild skin rash or photosensitivity.
Mild elevation of unconjugated bilirubin was the only dose-dependent laboratory abnormality.
No hemolysis (blood cell destruction leading to anemia) or liver-related "events of concern" were reported.
Pharmacokinetic analysis showed that BI201335 had an elimination half-life supporting once-daily dosing.

"BI201335 combined with [pegylated interferon/ribavirin] was well-tolerated and induced strong antiviral responses," the study authors concluded. "These results support further development of BI201335 in HCV genotype 1 patients."

BI201335 "induced a rapid, dose-dependent decrease in plasma HCV RNA" by more than 2 log in all patients," they elaborated in their discussion. "Maximal viral load declines from baseline occurred within 2-3 days of first administration."

"The magnitude of viral load declines was similar to those recorded for other highly potent protease inhibitors in development," they added, but this was achieved with once-daily dosing compared with 3 times daily for boceprevir and telaprevir.

The high rate of rapid viral breakthrough during the monotherapy phase, however, underlines the importance of combination therapy with either pegylated interferon/ribavirin or all-oral regimens with other direct-acting agents that inhibit HCV polymerase or other viral targets.

The researchers noted that these variants have also been seen with other HCV protease inhibitors including boceprevir, telaprevir, RG7227 (a.k.a. ITMN-191), and TMC-435, and therefore are "likely to confer cross-resistance and to eventually cause virologic breakthrough in case of combination or sequential treatment with different compounds of this class."

Researchers reported data from later, larger trials of BI201335 plus pegylated interferon/ribavirin in treatment-naive and treatment-experienced participants (SILEN-C1 and SILENC-2) at the European Association for the Study of the Liver's International Liver Congress (EASL 2011) this spring in Berlin.

Investigator affiliations: Hannover Medical School, Department of Gastroenterology, Hepatology, and Endocrinology, Center for Internal Medicine, Hannover, Germany; Hopital Saint Joseph, Marseille, France; Hopital Pitie Salpetriere, Paris, France; Hopital Cochin, Paris, France; California Pacific Medical Center Research Institute, San Francisco, CA; Hopital Hotel Dieu, Lyon, France; Central Texas Clinical Research, Austin, TX; Charité Berlin Campus Virchow-Klinikum, Berlin, Germany; Hospital Universitano Puerta de Hierro, Madrid, Spain; Boehringer Ingelheim (Canada) Ltd., Laval, Canada; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT; Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.


MP Manns, M Bourliere, Y Benhamou, et al. Potency, safety, and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection. Journal of Hepatology 54(6):1114-1122 (abstract).
























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