Clinical Pharmacokinetics and Pharmacodynamics of Pwt-143, an Oral, Potent and Selective Inhibitor of Phosphatidylinositol 3-Kinase P110delta, Following Single Oral Administration to Healthy Volunteers
Authors: Moreno Ofir M , Zann Vanessa , Leung Pui 
Published: October 2019

Abstract
Background: The Phosphatidylinositol 3-Kinases p110δ isoform (P110δ PI3K) is hyperactive in B cell malignancies and is central to multiple signaling pathways that drive proliferation, survival, homing and retention of malignant cells in lymphoid tissue and bone marrow. PI3Kd inhibitors have demonstrated important clinical activity in various lymphoid malignancies, albeit with certain toxicities and PK limitations. PWT-143, comprised of a novel molecular scaffold that is distinctive from other known PI3Kd-selective inhibitors, is a potent and selective inhibitor of P110δ PI3K enzymatic activity. PWT-143 exhibits low nanomolar potency in cellular assays, as well as in a pre-clinical whole blood functional assay of basophil activity (poster presented at 54th ASH Annual Meeting, 2012). PWT-143 also demonstrated highly favorable pharmacokinetics from oral administration in preclinical experiments. Preclinical toxicology and safety pharmacology data supported initial clinical assessment of oral PWT-143 in healthy volunteers, consistent with its target selectivity profile. Here we report the initial PK and PD results of a single dose of oral PWT-143 in healthy volunteers.
Methods: A flexible, adaptive first-in-human study was conducted using a Translational Pharmaceutics® platform which enables rapid real-time PK/PD analysis and GMP manufacture of drug products between dosing periods. Based on the NOAEL in rats and dogs, with a standard safety margin for a first-in-human study, the starting dose level was 10 mg, with higher doses and/or formulation adjustments to be selected, based on review of emerging safety, tolerability and pharmacokinetic data. Blood samples were collected at regular time intervals, and plasma concentrations of PWT-143 were measured using a validated liquid chromatography tandem mass spectrometry method. Blood samples were also collected for testing with a PD assay; specifically, basophil activation assessed via CD63 expression by flow cytometry following ex-vivo stimulation with an anti-FCeR1 monoclonal antibody.
Results: To date, subjects (n=3/cohort) have been orally administered 10 mg and 30 mg of PWT-143, and escalation is continuing (n=6/cohort). The 10 mg and 30 mg doses resulted in up to 55 % and 80 % inhibition of basophil activation, respectively, within 4 hours of dosing. Both doses resulted in no reported Adverse Events nor clinically significant changes in vital signs, ECGs or safety laboratory assessments. The geometric mean Cmax and half-life were 3.9 ng/ml (range; 2.0-6.6 ng/ml) and 29 hours (range; 20-42 hours), respectively, following oral administration of 30 mg.
Conclusions: Measurable plasma levels of PWT-143, as well as significant inhibition of basophil activation have been observed at the lowest planned dose levels. These findings suggest that PWT-143 is orally bioavailable and exhibits potent on-target activity in humans. PK results suggest daily dosing is achievable. Results from the completed study with all dose levels will be presented.

Disclosures
No relevant conflicts of interest to declare.