Superior SVR24 rates with alisporivir (ALV) plus peg-interferon/ribavirin (P/R) in chronic HCV hepatitis (CHC) genotype 1 (G1) prior P/R treatment failures: Final results of the fundamental study.

Background/aims: ALV suppresses HCV replication by inhibiting cyclophilin A, a host protein essential for HCV replication, with pangenotypic activity and high barrier to resistance. The FUNDAMENTAL study investigated viral response to combinations of oral ALV plus P/R in CHC G1 failing prior P/R treatment, including hardest-totreat populations: prior non-responders, cirrhotic at baseline, and IL28B CT/TT genotypes. Method(s): Prospective, double-blind, multinational, randomized, placebo controlled trial evaluating P/R alone or in combination with ALV 600 mg QD, 800 mg QD, or 400 mg BID in patients who previously failed P/R. Following a partial clinical hold imposed by FDA, ALV/placebo was discontinued in all patients; at that time, all active patients had received at least 31 weeks of triple therapy out of a total of 48 weeks. Patients randomized to ALV containing groups were allowed to complete the scheduled 48 weeks on P/R only. Nondetectable HCV RNA (<25 IU/mL) at Week 72 (SVR24) was evaluated according to pre-specified categories and a logistic regression (multivariate analysis) was conducted. Result(s): A total of 459 patients were randomized; 77 % were Caucasian, mean HCV RNA of 6.3 log10 IU/mL, 30 % G1a, 25 % had compensated cirrhosis/transition to cirrhosis, 57 % were P/R prior non-responders and 79 % had IL28B CT/TT genotype. All ALV dosing added to P/R significantly improved treatment responses in a dose-dependent fashion, with 400 mg BID achieving the best responses vs P/R: null non-response (67.6 vs 2.8 %); cirrhosis/transition to cirrhosis (52.2 vs 0 %), and IL28B CT/TT genotypes (65.2 vs 11.5 %). Most frequently reported AEs with ALV/PR were hematologic abnormalities, GI symptoms, hypertension, hyperbilirubinemia and hypertriglyceridemia; frequency was higher in the 400 mg BID arm. Conclusion(s): The addition of ALV to P/R significantly improved SVR24 in CHC G1 patients who previously failed P/R therapy. All doses of ALV were superior to P/R alone; 400