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Safety and Pharmacokinetics of PPI-461,
a Potent New HCV NS5A Inhibitor with Pan-Genotype Activity
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Reported by Jules Levin
AASLD Nov 2 2010 Boston, Late Breaker Poster
Nathaniel Brown1, Pamela Vig1, Eric Ruby1, Anna Muchnik1, Elana Pottorff1, Steven Knox2, Salvatore Febbraro3, Bill Wargin4, Tine Molvadgaard5, Andrew Jones3, Leping Li1 & Richard Colonno11Presidio Pharmaceuticals, San Francisco, CA, USA, 2Smerud Medical Research International, Oslo, Norway, 3Simbec Research Ltd, Merthyr Tydfil, UK, 4PK-PM Associates, Chapel Hill, NC, USA, 5Smerud Medical Research Denmark, Brondby, Denmark.
ABSTRACT
Purpose: HCV-related mortality is increasing. Most new direct-acting HCV antivirals are optimized for activity vs. HCV genotype-1, comprising <50% of infections globally. PPI-461 is a novel HCV NS5A inhibitor with potent activity vs. all 7 HCV genotypes, g1-7 (R Colonno, EASL 2010). The 50% inhibitory concentrations (EC50s) for PPI-461 are 0.21 nM and 0.01 nM for HCV g1a and g1b, and 0.1 to 9.3 nM for g2a-7a. Here we report the first human trial of PPI-461.
Methods: This Phase 1 trial was a randomized, double-blind study of safety and pharmacokinetics (PK) for 5 PPI-461 dosing regimens in healthy volunteers: single doses of 20,50,100 and 200 mg; and a multi-dose regimen, 200 mg QD x 5 days. The dose regimens were tested in sequential groups of 8 subjects (total = 40). In each group subjects were randomized in a 6:2 ratio to blinded treatment with PPI-461 or matching placebo, with 7 day follow-up. The PPI-461 bioanalytic assay had a plasma limit of detection of 10 ng/mL.
Results: All PPI-461 dosing regimens were well-tolerated. There were no adverse events (AEs) attributed by the investigator to PPI-461. Non-attributed AEs in the 30 PPI-461 recipients were mild headache (2), moderate backache (1), mild nausea (1), and 2 common colds. AEs in 10 placebo recipients were headache (2) and transient hearing impairment (1). There were no patterns of change or significant abnormalities for any of the safety-related laboratory parameters (hematologic values, serum chemistries, urinalyses and ECGs). PK analyses indicate that systemic uptake of PPI-461 was rapid, with maximal plasma levels (Cmax) reached in 1-4 hr. With single doses of PPI-461 measures of systemic exposure, e.g. Cmaxand plasma concentration areas-under-the-curve (AUCs), were dose-proportional. For each group mean Cmaxlevels far exceeded viral EC50s for HCV g1-7. For the 50 mg or higher dose groups, mean Cmaxlevels exceeded EC50s for HCV g1-7 by 108 to 368,820-fold, depending on HCV genotype and dose, with potentially effective levels in all subjects. A long half-life (ca 8-10 hr across groups) resulted in substantial PPI-461 plasma concentrations 24 hr post-dose (C24 hr). For 50 mg and higher doses, mean C24 hr levels exceeded EC50s for HCV g1-7 by 12 to 65,220-fold, depending on dose and genotype. With the 5-day regimen (200 mg QD)steady-state PK was achieved in 2 days.
Conclusions: In this first trial PPI-461 was well-tolerated with all dose regimens. The PK of PPI-461 and its anti-HCV activity in vitro predict a potential for potent pan-genotypic HCV inhibition with low once-daily doses (50-200 mg), facilitating co-formulation with other HCV antivirals in future combination therapies for hepatitis C.
INTRODUCTION
HCV-related severe morbidity and mortality projected to increase 2 to 4-fold
Potential treatment advances offered by current HCV PIs focused on HCV genotype-1 infection, comprising less than half of patients globally
PPI-461 is a highly potent & selective NS5A inhibitor with pan-genotypic HCV activity in replicon assays (EC50s of 0.2 nM [1a], 0.01 nM [1b], 0.1 -9.3 nM [2a-7a])
Combination studies in HCV replicon cell assays showed additive to synergistic activity with other classes of HCV inhibitors, with no evidence for antagonism
No cross-resistance between PPI-461 and other classes of HCV inhibitors
PPI-461 was well-tolerated in a battery of preclinical toxicology studies
OBJECTIVES
Safety and tolerability of four single oral doses (20, 50, 100, and 200 mg) of PPI-461 taken after an overnight fast
Pharmacokinetics (PK) of PPI-461 after each single dose
Preliminary food effect sub-study: Compare PK profile for fasted vs. fed doses
Safety/tolerability and PK for highest well-tolerated dose administered once daily for 5 days
ASSESSMENTS
Safety-related observations included vital signs, physical exams, clinical adverse events (AEs), serial ECGs, and safety-related laboratory assessments: complete blood counts with leukocyte differentials, full clinical chemistry panels, coagulation (PT & aPTT) and urinalyses
Intensive plasma sampling for PK after each single-dose exposure (cohorts A-D)
Intensive plasma sampling for PK after 1stand last (5th) doses, for cohort E; pre-dose 'trough' PK sampling prior to 2nd, 3rd, 4th, and 5thdoses
Study conducted with applicable approvals from the U.K. MHRA and the local Ethics Committee
STUDY DESIGN & POPULATION
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