The Phase 1a dose-ranging assessment of PPI-668 was conducted with 32 healthy volunteers in New Zealand. The trial was a randomized, double-blind, placebo-controlled assessment of the safety and pharmacokinetics of three oral doses of PPI-668, initially assessed as single doses and subsequently as a multi-day regimen, in which the highest PPI-668 dose was given once daily for five successive days. The trial results indicated that all dose regimens of PPI-668 were well-tolerated. There were no serious or severe clinical adverse events, no patterns of treatment-related adverse events or laboratory abnormalities, and all subjects completed the trial successfully.
Pharmacokinetic (PK) analyses of subjects' plasma samples in the Phase 1a trial indicated that substantial blood levels of PPI-668 were rapidly and consistently achieved and dose proportional. PPI-668 plasma concentrations were orders of magnitude above those shown to inhibit HCV replication in vitro and were maintained at predicted effective concentrations for more than 24 hours. These PK results support once-daily dosing for PPI-668 in future studies. Also important was the observation that in the 5-day multi-dose regimen, steady-state PK was achieved rapidly (by Day 2), with no evidence of subsequent accumulation or changes in the clearance profile of PPI-668.
"These first clinical data for PPI-668 indicate excellent tolerance in healthy subjects for up to five days," said Nathaniel A. Brown, M.D., Presidio's Chief Medical Officer. "Equally important, the pharmacokinetic profile of PPI-668 is very encouraging, suggesting that effective plasma concentrations can be obtained with relatively low, once-daily doses of PPI-668 - which will facilitate co-formulation of PPI-668 with other HCV antivirals in future combination therapies for hepatitis C."
Patient screening for the Phase 1b evaluation of PPI-668 in hepatitis C patients has begun in New Zealand and the United States and will soon include Australia. Dosing of the first cohort of hepatitis C patients will begin this week. Presidio expects to have results regarding the antiviral efficacy of PPI-668 in HCV patients in the second quarter of 2012.
In a second HCV research program focused on inhibitors of the HCV NS5B polymerase, Presidio has discovered a lead chemical series of non-nucleosidic NS5B inhibitors with potent activity against all major HCV genotypes. Preclinical profiling is ongoing with a goal of nominating a candidate for clinical development in the coming months.
With its novel NS5A and NS5B inhibitors, Presidio's objective is to provide two complementary HCV antivirals that will be appropriate for broad use in optimized future combination therapies for patients with HCV infection. Presidio anticipates that such therapies will have a convenient oral dosing regimen (once or twice daily), will exhibit rapid pan-genotypic efficacy and will be well-tolerated.