Abstract CT157: Clinical pharmacokinetics and pharmacodynamics of ME-401, an oral, potent and selective inhibitor of phosphatidylinositol 3-kinase P110δ, following single ascending dose administration to healthy volunteers
Authors: Moreno Ofir , Imani Robert , Zann Vanessa , Leung Pui 
Published: July 2016

Abstract
Background: ME-401 is a potent and selective inhibitor of the Phosphatidylinositol 3-Kinase p110δ isoform, which demonstrated highly favorable PK from oral administration in preclinical experiments. Preclinical toxicology and safety pharmacology data supported initial clinical assessment of oral ME-401 in healthy volunteers, consistent with its target selectivity profile.
Methods: A first-in-human study was conducted using the Translational Pharmaceutics® platform which enables rapid real-time PK/PD analysis and GMP manufacture of drug products between dosing periods, under a flexible protocol. This was an open-label, single dose design, where it was planned to enroll up to 3 sequential groups, comprising 3, 6 and 6 subjects. The planned dose levels were 10, 30, 60 90 and 150 mg. Blood samples were collected to measure plasma concentrations of ME-401, and for testing with a PD assay: basophil activation assessed via CD63 expression by flow cytometry following ex-vivo stimulation with an anti-FCϵR1 monoclonal antibody.
Results: A total of 15 healthy volunteers were enrolled in the clinical study. ME-401 was orally administered at the planned dose levels. Plasma concentration vs time profiles were consistent with extravascular dosing. There was a linear relationship between both Cmax and AUC as a function of dose (mg). At the 60 mg dose, geometric mean Cmax, AUCinf and half-life were 9.4 ng/ml, 230 ng*h/ml and 28 h, respectively. Half-life appeared dose-independent.
Significant inhibition of basophil activation was observed at all dose levels. The individual concentrations and percent inhibition data were fitted to a simple Emax model: E = (Emax*C)/(C+EC50). EC50 and EC90 were 0.6 and 5 ng/mL (1 and 9 nM), respectively.
A PK model was fitted to the individual data observed from the 60 mg dose level, and was used to generate steady state trough plasma concentrations from daily dosing of a simulated population of 250 individuals. Statistical analysis indicated a 95% confidence interval of 5.7-6.4 ng/ml for the geometric mean trough plasma levels, which is above the EC90.
All doses were generally well tolerated. There were no serious adverse events, severe TEAEs, TEAEs leading to death or TEAEs leading to discontinuation reported.
Conclusions: ME-401 is orally bioavailable, exhibiting linear increase in exposure, over the 10-150 mg dose range. Daily dosing of 60 mg, or higher, is expected to afford trough plasma levels that lie above the EC90, on the plateau of the effectiveness dose-response curve. ME-401 was well tolerated when administered to healthy volunteers as a single oral dose up to 150 mg. This highly selective, oral PI3K delta inhibitor is expected to enter a Phase Ib study for the treatment of B-cell malignancies in the first half of 2016.
Citation Format: Ofir Moreno, Robert Imani, Vanessa Zann, Pui Leung. Clinical pharmacokinetics and pharmacodynamics of ME-401, an oral, potent and selective inhibitor of phosphatidylinositol 3-kinase P110δ, following single ascending dose administration to healthy volunteers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT157.