46th EASL Congress, Berlin, Germany March 30 April 3, 2011 Abstract 66

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1 SILEN-C2: Sustained Virologic Response (SVR) and Safety of BI21335 Combined with Peginterferon Alfa-2a and Ribavirin (P/R) in Chronic HCV Genotype-1 Patients with Non-response To P/R M.S. Sulkowski, M. Bourliere, J.-P. Bronowicki, A. Streinu-Cercel, L. Preotescu, T. Asselah, J.-M. Pawlotsky, S. Shafran, S. Pol, F.A. Caruntu, S. Mauss, D. Larrey, C. Häfner, Y. Datsenko, J.O. Stern, R. Kubiak, W. Böcher, G. Steinmann 46th EASL Congress, Berlin, Germany March 3 April 3, 211 Abstract 66 SILEN-C2 trial Double-blind, placebo-controlled, phase IIb study in HCV genotype-1 (GT-1) patients with nonresponse to previous n = 142 * n = 76 n = 7 * 24 mg QD LI BI mg QD BI mg BID LI BI D1 D4 24 *3-day lead-in period (LI) of PegIFN alfa 2a (18 μg/week) plus ribavirin (1, mg or 1,2 mg/day); Re-randomisation 1:1 of patients with ervr (extended rapid virological response) to 24 versus 48 weeks of QD, once daily; BID, twice daily 48

2 Main Inclusion Criteria Age 18 to 65 years Chronic hepatitis C GT-1 infection Confirmed nonresponse during previous treatment 12 weeks of an approved dose of Null response: <1 log1 maximum HCV RNA reduction any time during treatment Partial response: >1 log1 maximum HCV RNA reduction, but never undetectable (with a sensitive assay) Relapsers were excluded HCV RNA 1, IU/mL at screening Liver biopsy within 2 years without evidence of cirrhosis Baseline characteristics 24 mg QD LI n= mg QD n=76 24 mg BID LI n=7 Mean age (years) Male gender Ethnicity White Black Asian Mean HCV RNA (log 1 ) Genotype a 1a 1b 1, other subtypes b Prior response to Null response Partial response Nonresponse Others a Based on NS3/4A sequencing; b Other genotypes were 1C (n=1), 1D (n=1) and 1G (n=1). 1 patient was GT-1 but subgenotype could not be determined

3 Virological response mg QD LI 24 mg QD 24 mg BID LI 45 ervr 47 61/142 34/76 33/7 39/142 31/76 22/ SVR 31 ervr: HCV RNA < 25 IU/mL at 4 and undetected at s 8 to 2 SVR in partial- and null-responders Partial-responders mg QD LI 24 mg QD 24 mg BID LI 16/54 13/26 1/24 12/57 14/4 11/ Null-responders 29 Null response, <1 log1 maximum HCV RNA reduction any time during treatment; Partial response, > 1 log1 maximum HCV RNA reduction, but never undetectable (with a sensitive assay)

4 SVR and relapse in ervr patients by duration of 24 mg QD LI 24 weeks 24 mg QD LI 48 weeks P= /3 21/29 18/3 6/29 SVR Relapse Relapse: rebound from undetectable at end of all treatment Virological failures Breakthrough on BI mg QD LI 24 mg QD 24 mg BID LI Breakthrough on 25 Relapse a a b 9 19 A 1 log 1 rebound from nadir, or rebound to 1 IU/mL if nadir < lower limit of detection (LLOD) on treatment, confirmed in a second sample B Rebound after end of all treatment from nadir < LLOD after end of treatment

5 Adverse events a Mild Moderate Severe Jaundice Severe 24 mg QD LI 24 mg QD 24 mg BID LI All patients (n b ) Rash c Nausea Diarrhea Vomiting a Adverse events > 1% compared with b Number quoted is according to given treatment c No cases of Stevens-Johnson syndrome, erythema multiforme or drug rash with eosinophilia and systemic symptoms Adverse events: overall summary 24 mg QD LI 24 mg QD 24 mg BID LI All patients (n a ) With severe adverse events Fatalities Discontinuations for adverse events Discontinuations for Rash Photosensitivity Jaundice Others b a Number quoted is according to given treatment b Other discontinuations mainly due to general disorders and administration site conditions, gastrointestinal and others

6 Effect of BI on bilirubin and haemoglobin 24 mg QD LI 24 mg QD 24 mg BID LI Total bilirubin mg/dl (normal range.1-1) Mean total bilirubin (mg/dl) BL Day Mean haemoglobin (g/dl) Mean haemoglobin (g/dl) BL Day BL, baseline Discussion and conclusion Virological response robust SVR rates up to 41% at 24 mg QD dose selected for phase III response-guided therapy was not effective for nonresponsive patients achieving ervr 3-day lead-in did not increase SVR Safety and tolerability most adverse events were those commonly related to therapy no excess effect on haemoglobin mild-to-moderate jaundice and rash are the main BI related adverse events and are dose-dependent jaundice is due to isolated indirect hyperbilirubinaemia In treatment-experienced patients, BI mg QD appears to offer the best safety/efficacy balance phase III trial in preparation