Late Breaking Original Research
Monday, November 13, 2023
01:00 PM–02:30 PM
Abstract
Introduction: ATI-2138 is an investigational inhibitor of interleukin 2-inducible T cell kinase (ITK) and Janus kinase (JAK) 3 in development for the treatment of T cell–mediated autoimmune diseases.
Research Question or Hypothesis: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ATI-2138 in healthy subjects.
Study Design: Phase 1 double-blind, placebo-controlled single (SAD) and multiple ascending dose (MAD) studies.
Methods: Eligible subjects between 18 and 55 years were randomized to receive a single oral dose of 1, 3, 5, 15, 25, 50, or 80 mg of ATI-2138 or placebo (SAD) or 5, 15, 25, or 40 mg ATI-2138 twice daily, 30 mg once daily, or 10 mg 3 times daily or placebo for 14 days (MAD). Blood samples for PK and PD measurements were collected predose and at multiple time points through 48 hours postdose (SAD) and predose and at multiple time points through 24 hours postdose on days 1, 7, and 15 (MAD). The PD effects of ATI-2138 were evaluated using ex vivo stimulation assays to assess the inhibition of the ITK and JAK3 pathways. Safety and tolerability were assessed by adverse events (AEs), clinical laboratory values, vital signs, and electrocardiograms.
Results: Sixty-three subjects completed the SAD study and 57 completed the MAD study. There were no deaths, serious AEs, or discontinuations due to AEs. Plasma concentrations of ATI-2138 increased in a dose-dependent manner. Peak concentrations were reached within 2 hours after dosing. ATI-2138 caused dose- and time-dependent modulation of all PD biomarker readouts (aCD3/aCD28 stimulated interleukin [IL]-2 and interferon [IFN]? mRNA levels, IL-15 stimulated and aCD3/IL-15 stimulated IFN? protein production). Near-complete inhibition of biomarker readouts was observed 2 hours post–ATI-2138 treatment at doses of 15 mg to 80 mg.
Conclusion: ATI-2138 was well tolerated and resulted in dose-dependent increases in plasma ATI-2138 and PD effects consistent with the inhibition of ITK and JAK3.
Presenting Author
Heidi Hope PhDAclaris Therapeutics, Inc.
Authors
David Anderson PhD
Aclaris Therapeutics, Inc.
Rakesh Basavalingappa DVM, PhD
Aclaris Therapeutics, Inc.
David Burt PhD
Aclaris Therapeutics, Inc.
Aparna Kaul PhD
Aclaris Therapeutics, Inc.
Melissa Lawrence Pharm.D., M.S.
Aclaris Therapeutics, Inc.
Jessea Lu PhD
Aclaris Therapeutics, Inc.
Nancy McGraw MS
Aclaris Therapeutics, Inc.
Rob Ortmann MD
Aclaris Therapeutics, Inc.