First-in-human study to assess the safety, pharmacokinetics, and pharmacodynamics of BMS-986141, a novel, reversible, small-molecule, PAR4 agonist in non-Japanese and Japanese healthy participants
Creators: name: Merali, Samira
name: Wang, Zhaoqing
name: Frost, Charles
name: Meadows-Shropshire, Stephanie
name: Hawthorne, Dara
name: Yang, Jing
name: Seiffert, Dietmar
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biochemistry
subject: Medicine
subject: Microbiology
subject: FOS: Biological sciences
subject: Cell Biology
subject: Pharmacology
subject: Biotechnology
subject: Chemical Sciences not elsewhere classified
subject: Ecology
subject: Immunology
subject: FOS: Clinical medicine
subject: Cancer
subject: Mental Health
subject: Virology

description: BMS-986141 is a novel, oral, protease-activated, receptor 4 (PAR4)-antagonist that exhibited robust antithrombotic activity and low bleeding risk in preclinical studies. The pharmacokinetic, pharmacodynamic, and tolerability profiles of BMS-986141 in healthy participants were assessed in a randomized, double-blind, placebo-controlled, single-ascending-dose (SAD; <i>N</i> = 60) study; a multiple-ascending-dose (MAD; <i>N</i> = 32) study; and a Japanese MAD (JMAD; <i>N</i> = 32) study. Exposure was dose-proportional for BMS-986141 2.5 mg and 150 mg; maximum concentrations were 17.6 ng/mL and 958 ng/mL; and areas under the curve (AUC) to infinity were 183 h* × ng/mL and 9207 h* × ng/mL, respectively. Mean half-life ranged from 33.7 to 44.7 hours across dose panels. The accumulation index following once-daily administration for 7 days suggested a 1.3- to 2-fold AUC increase at steady state. In the SAD study, BMS-986141 75 and 150 mg produced ≥80% inhibition of 25–100 µM PAR4 agonist peptide (AP)-induced platelet aggregation, without affecting PAR1-AP-induced platelet aggregation, through ≥24 hours postdose. In the MAD and JMAD studies, BMS-986141 doses ≥10 mg completely inhibited 12.5 μM and 25 μM PAR4-AP-induced platelet aggregation through 24 hours. This study found BMS-986141 was safe and well tolerated, with dose-proportional pharmacokinetics and concentration-dependent pharmacodynamics in healthy participants over a wide dose range. ClinicalTrials.gov ID: NCT02341638. <b>Why was the study done?</b>Antiplatelet therapies have shortcomings that limit their clinical utility, and there is an unmet need for a new, safe, and effective antiplatelet agent with reduced bleeding risk.PAR4 antagonists are a promising novel class of antiplatelet drugs due to late-stage inhibition of thrombus growth with minimal effects on platelet-driven hemostasis.BMS-986141 is a novel, potent, orally bioavailable, small-molecule antagonist specific for PAR4. Antiplatelet therapies have shortcomings that limit their clinical utility, and there is an unmet need for a new, safe, and effective antiplatelet agent with reduced bleeding risk. PAR4 antagonists are a promising novel class of antiplatelet drugs due to late-stage inhibition of thrombus growth with minimal effects on platelet-driven hemostasis. BMS-986141 is a novel, potent, orally bioavailable, small-molecule antagonist specific for PAR4. <b>What is new?</b>BMS-986141 is safe and well tolerated, with dose-proportional pharmacokinetics and concentration-dependent pharmacodynamics in healthy participants over a wide dose range.BMS-986141 has robust antithrombotic activity and low bleeding risk. BMS-986141 is safe and well tolerated, with dose-proportional pharmacokinetics and concentration-dependent pharmacodynamics in healthy participants over a wide dose range. BMS-986141 has robust antithrombotic activity and low bleeding risk. <b>What is the impact?</b>BMS-986141 has the potential to improve the benefit–risk of antiplatelet therapy in patients with atherothrombosis. BMS-986141 has the potential to improve the benefit–risk of antiplatelet therapy in patients with atherothrombosis.