Abstract CT137: Safety, pharmacokinetics, and pharmacodynamics of AS-1763, a highly selective, orally bioavailable, non-covalent BTK inhibitor, in healthy volunteers
Authors: Arimura Akinori , Miyamoto Kyoko , Velinova Maria , van den Dobbelsteen Marieke , Mihara Katsuhiro , Miller Robert M. , Sawa Masaaki 
Published: June 2022

Abstract
Background: Covalent Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib are approved for treating patients with B-cell malignancies, but their long-term efficacy is limited due to their toxicity (i.e., on-target and off-target inhibition of kinases) and acquired resistance (i.e., BTK C481 mutation). AS-1763 is a potent, highly selective, orally active, non-covalent inhibitor of both wild-type and C481S-mutant BTK. AS-1763 strongly inhibits the proliferation of B cell lymphoma cell line OCI-LY10 carrying wild-type and C481S-mutatant BTK in vitro and in vivo. AS-1763, therefore, is expected to be a promising BTK inhibitor for patients who have failed or are intolerant to a covalent BTK inhibitor. This study reports the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy volunteers who received single, ascending doses of AS-1763 in an alternating cohort design.
Methods: This is a first-in-human, double-blind, placebo-controlled, randomized, single-center, single-ascending dose Phase I study of AS-1763. Two cohorts of 8 healthy male and female subjects were alternately dosed with AS-1763 (5, 25, 100, 300, 500, and 600 mg) or placebo orally under fasted condition. Intensive blood sampling for PK (up to 72 h) and PD (up to 24 h) was conducted before and post-dosing to allow a successful PK/PD correlation. For the PD assessment, whole blood was stimulated ex vivo with an anti-IgD antibody, and CD69 upregulation on B cells was assessed by flow cytometry.
Results: Single doses of up to 600 mg AS-1763 were well-tolerated. No serious adverse events (AE) were reported during the trial. All treatment-emerged AEs reported were of mild intensity and showed no apparent dose-relationship in frequency. No clinically relevant changes from baseline were observed in all other safety parameters assessed (clinical laboratory, ECGs, vital signs, or physical examinations). AS-1763 was rapidly absorbed with a median time to maximum plasma concentrations (tmax) of 0.5-2.0 h post-dose and thereafter gradually decreased with mean elimination half-time (t1/2) of 8.5-12 h. Overall, mean plasma concentrations of AS-1763 increased with dose up to 500 mg. AS-1763 at 100 mg or higher induced &gt;80% inhibition of B cell activation (%CD69 upregulation in naïve B cells normalized to baseline) at 1-2 h post-dose and the duration of inhibitory effect increased with dose. PK/PD analysis demonstrated that the IC50 and IC90 (90% CI) values for inhibition of CD69 upregulation in naïve B cells were 10.5 ng/mL (9.7-11.2 ng/mL) and 34.6 ng/mL (28.8-40.4 ng/mL), respectively.
Conclusions: Single doses of AS-1763 up to 600 mg were well-tolerated and showed encouraging pharmacodynamics (inhibition of CD69 upregulation) with a favorable safety profile. The data support continued development of AS-1763 for patients with B-cell malignancies.
Citation Format: Akinori Arimura, Kyoko Miyamoto, Maria Velinova, Marieke van den Dobbelsteen, Katsuhiro Mihara, Robert M. Miller, Masaaki Sawa. Safety, pharmacokinetics, and pharmacodynamics of AS-1763, a highly selective, orally bioavailable, non-covalent BTK inhibitor, in healthy volunteers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT137.