Single ascending dose escalation study of the specific Syk inhibitor P505-15 investigating pharmacokinetics, pharmacodynamics, and safety in healthy male volunteers.

Abstract

8574 Background: The spleen tyrosine kinase (Syk) regulates immune cell activation in response to ligation of a variety of receptors, making it an intriguing target for inflammatory and autoimmune disorders, as well as certain B cell malignancies. Here we present data from our first human study aimed at characterizing the pharmacokinetics (PK), pharmacodynamics (PD), and safety of P505-15, a selective Syk inhibitor in male volunteers following single oral administration. Methods: This study was a single center, blinded, randomized, placebo-controlled, ascending, single dose study of oral P505-15 suspension or its matching placebo, administered to healthy male volunteers. Dosing was initiated at 3mg and escalated to 400mg over seven cohorts. Serial blood samples for PK and PD evaluations were analyzed. The PD assays were designed to determine the potency and specificity of Syk inhibition. Potency for Syk inhibition was determined by measuring B cell receptor- (BCR) mediated ERK Y204 phosphorylation and cellular activation (CD69), as well as FcεRI-mediated basophil degranulation. Results: PK data indicate that P505-15 has a long terminal half life (~50-60 hrs), a Tmax of about 2 hrs, and oral exposure more than dose proportional up to the 200mg dose. Complete inhibition of all three Syk-dependent assays was observed in the 200mg and greater dose levels. PD effect in the basotest approximated IC50 at 24 hours post-dose, and returned to pre-dose levels by 72 hours. At all dose levels, no inhibition of PMA or fMLP induced signaling and leukocyte activation was observed, consistent with a high degree of selectivity for Syk. Analysis of the PK/PD relationship indicated an IC50of 208nM (95% confidence interval of 190-225) for inhibition of BCR-mediated B cell activation, and 124nM (95% confidence interval of 117-131) for inhibition of FcεRI-mediated basophil degranulation. Conclusions: P505-15 was safe and well tolerated across the entire range of doses. These data show that P505-15 has a favorable PK profile, and demonstrate its utility to safely and potently suppress Syk kinase function in humans.