Experimental HCV Protease Inhibitor BI 201335 Demonstrates Promising Results in Combination with Pegylated Interferon and Ribavirin

		SUMMARY: The experimental hepatitis C virus (HCV) protease inhibitor BI 201335, in combination with pegylated interferon plus ribavirin, demonstrated rapid, potent antiviral activity with a majority of patients achieving virological responses at weeks 4 and 12, according to a study presented at the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009) this past weekend in Boston. Virological rebound rates were low and tolerability was good, with rash (1.7%) and jaundice (15.9%) being the most common adverse effects associated with BI 201335.

By Ronald Baker, PhD

BI 201335 is a potent experimental HCV NS3/4A protease inhibitor from Boehringer Ingelheim that is administered orally once daily. The drug is being studied in phase 2 trials of chronic hepatitis C patients with HCV genotype 1, in combination with a standard of care regimen.

The double-blind international SILEN-C1 trial included 427 treatment-naive genotype 1 HCV patients. Approximately half (55%) were men, more than 80% were white, the mean age was 46 years, the mean body mass index (BMI) was 26.0, and the mean HCV viral load was 6.4 log10 IU/mL at baseline.

All participants received a standard-of care regimen consisting of 180 mcg/week pegylated interferon alfa-2a (Pegasys) + 1000-1200 mg/day weight adjusted ribavirin for 48 weeks. In addition, they were randomly allocated in a 1:2:2:1 manner to received either placebo, 240 mg BI 201335 once-daily (QD) for 24 weeks started concurrently with pegylated interferon/ribavirin, 240 mg BI 201335 for 24 weeks started after a 3-day pegylated interferon/ribavirin lead-in phase, or 120 mg BI 201335 started after a 3-day lead-in.

HCV viral load was measured using the Roche TaqMan assay, with a lower limit of detection of 10 IU/mL and a lower limit of quantification of 25IU/mL. Viral load rebound was defined as > 1 log increase from nadir (lowest-ever level) or confirmed increase > 100 IU/mL if previously undetectable.

The researchers presented interim results after 12 weeks of therapy at AASLD 2009 meeting.

Results

	BI 201335 + pegylated interferon/ribavirin demonstrated rapid, potent antiviral activity.
	Virological response rates at weeks 4 and 12 were significantly higher in the BI 201335 arms compared with the placebo arm (see table).
	BI 201335 120 mg/day appears to be as effective as 240 mg/day
	Mean ALT/AST levels improved with treatment in all groups.
	Flu-like symptoms and fatigue were the most commonly reported adverse events.
	16 patients reported drug-related serious adverse events.
	18 patients (5%) discontinued BI 201335 due to adverse events, of which 1.7% were due to rash.
	Rash occurred more frequently in BI 201335 recipients.
	Severe rashes occurred in 2.5% of BI 201335 recipients versus 1.4% of placebo recipients.
	16% of patients in the BI 201335 groups developed jaundice versus 1.4% receiving placebo.
	BI 201335 led to dose-dependent unconjugated hyperbilirubinemia elevation, reaching a plateau in 2-4 weeks.
	Other adverse events were mostly mild to moderate and typical of pegylated interferon/ribavirin.
	Changes in hematology (blood cell) parameters were similar across groups and typical of pegylated interferon/ribavirin use.

Table

Treatment	Virological Response (wk 4)*		Virological Response (wk 12)*		Viral Rebound (%)*
	< 25 IU/ml (%)	< 10 IU/ml (%)	< 25 IU/ml (%)	< 10 IU/ml ( %)
(1) Placebo (N=71)	16	4	58	42	2.8
(2) 240 mg QD (N=143)	94	77	91	90	4.9
(3) 240 mg QD / LI (N=146)	84	62	82	80	4.1
(4) 120 mg QD / LI (N=69)	90	70	87	84	2.9

*Some data not available for all patients at week 4 and 12; ITT: missing=failure
LI = lead-in period; QD = once-daily

In conclusion, the study investigators wrote, "SILEN-C1 confirmed robust antiviral activity with good tolerability and safety of BI 201335 given once daily in combination with [pegylated interferon/ribavirin] in treatment-naive patients with chronic HCV genotype 1 infection."

Johns Hopkins University, Baltimore, MD; Medical University, Vienna, Austria; Hospital for Infectious and Tropical Diseases, Bucharest, Romania; Hôpital Beaujon, Clichy Cedex, France; Institute of Infectious Diseases 1, Bucharest, Romania; Quest Clinical Research, San Francisco, CA; Hôpital Saint Joseph, Marseille, France; Center for HIV and Hepatogastroenterology, Düsseldorf, Germany; Hôpital TENON, Paris, France; Charité, Campus Virchow-Klinikum, Berlin, Germany; J.W. Goethe University Hospital, Frankfurt am Main, Germany; Central Texas Clinical Research, Austin, TX; University of Chicago Hospitals, Chicago, IL; Boehringer Ingelheim Pharma, Biberach, Germany and Ridgefield, CT.

11/06/09

Reference
MS Sulkowski, P Ferenci, C Emanoil, and others. SILEN-C1: Early antiviral activity and safety of BI 201335 combined with peginterferon alfa-2a and ribavirin in treatment-naive patients with chronic genotype 1 HCV infection. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract LB3.