Reported by Jules Levin
EASL Apr 14-18 2010 Vienna Austria
ANA59 is a potent non-nucleoside inhibitor of HCV genotype 1 NS5B polymerase.
ANA59 200 mg bid plus Peg/Rbv resulted in a 73% cEVR (week 12). At 8 weeks, ANA598 400 mg bid plus Peg/Rbv resulted in 72% of patients achieving undetectable levels of virus. No patient receiving ANA598 has experienced viral breakthrough in this ongoing study. 1 patient on ANA598 discontinued all study drugs at week 8 due to grade 3 rash, resumed Peg/Rbv alone and is included in the 12-week data.
Patients who achieved undetectable virus at weeks 4 & 12 were randomized to Peg/Rbv alone for 12 or 36 additional weeks remaining patients were to receive Peg/Rbv for additional 36 weeks.
Phase 1 in treatment-naïve G1
The median viral load reduction was 2.4 log (range 0.4 - 3.4 log) at 200 mg bid, 2.3 log (range 1.6 to 3.5 log) at 400 mg bid and 2.9 log (range 2.2 - 3.4 log) at 800 mg bid on day 4 (EOT, abstract LB 1055 EASL 2009).
Based on antiviral acivity/kinetics in the 3 day monotherapy study, a loading dose was selected (Feg 1b). Simulations predicted that a loading dose of 800 mg q12h would rapidly achieve ANA598 trough concentrations exceeding the minimum needed to prevent replication of wild-type virus and sustain Cmin above the EC95 (24 ug/ml).
We now describe the preliminary results of an ongoing phase 2 trial which evaluates safety and antiviral activity of ANA598 and Peg/Rbv for 12 weeks.
No patient receiving ANA597 experienced viral breakthrough. 6 patients receiving placebo +Peg/Rbv failed to achieve at least a 1 log decline by week 4; in contrast, only one patient receiving 200 mg bid ANA597 plus Peg/Rbv and no patient on 400 mg bid ANA597 + Peg/Rbv failed to meet this protocol-defined benchmark.
PHARMACOKINETICS
In the 200 mg cohort ANA597 plasma concentratins achieved steady state by week 1 (1st time point measured;
The observed mean concentrations of ANA597 were consistent with predicted trough values. There was no unexpected drug accumulation in the 200 mg bid cohort over time.
Data not yet available for 400 mg bid and placebo groups at weeks 10 and 12 (in progress).
