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Dose-Ranging Trial of PPI-461, a Potent New Pan-Genotypic HCV NS5A Inhibitor, in Patients with HCV Genotype-1 Infection
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Reported by Jules Levin AASLD Nov 5-9 2011 SF
J. Lalezari1, K. Agarwal2, G. Dusheiko3,
A. Brown4, N. Weis5, P. Christensen6, A. Laursen7,
D. Asmuth8, P. Vig9, E. Ruby9, N. Huang9, Q. Huang9,
R. Colonno9, G. Harding10and N. Brown9
1Quest Clinical Research (San Francisco, CA, U.S.A.), 2Kings College Hospital (London, U.K.), 3Royal Free Hospital (London, U.K.), 4Imperial College Healthcare (London, U.K.), 5Hvidovre Hospital (Copenhagen, Denmark), 6Odense University Hospital (Odense, Denmark), 7U. Hospital of Arhus (Arhus, Denmark), 8University of California-Davis Medical Center (Sacramento, CA, U.S.A.), 9Presidio Pharmaceuticals (San Francisco, CA, U.S.A.), 10Smerud Medical Research International (Oslo, Norway)
PPI-461 Phase 1b Conclusions
PPI-461 well-tolerated at all dose levels (50-200 mg/d x 3 days)
PK results support once-daily dosing
--Rapid and consistent efficacy (maximal response at ≥ 100 mg QD)Mean maximal HCV RNA reductions 3.6 log for 100 and 200 mg QD
-- Similar efficacy in HCV g1a and g1b patients
Marked HCV RNA responses in 17/18 active-dosed patients
-- 1 patient in 50 mg group had pre-existing, high-level resistance
-- Occasional non-responding patients also reported in monotherapytrials for other NS5As (BMS-790052, GS-5885), and for other DAAs (telaprevir, etc)
-- 4 patients with low-level Baseline resistance had multi-log responses
Rapid enrichment of pre-existing resistant variants, similar to data reported for BMS-790052 and HCV protease inhibitors
-- NS5A inhibitors need to be used in combination with SOC or other DAAs
Pan-genotypic potency, rapid efficacy, good tolerance, and QD dosing
support PPI-461 as a good candidate for future HCV combination therapies
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