Evaluation of , a novel thromboxane receptor antagonist, in a first-in-human phase I clinical trial.

The thromboxane receptor (TP) antagonist is in clinical development for treatment of cardiopulmonary diseases, such as pulmonary arterial hypertension. In this randomized, placebo-controlled Phase I clinical trial, , administered as the oral formulation , was evaluated for safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy males. The first-in-human trial had three Parts: A, single ascending dose (SAD) study with seven groups given 0.25-243 mg or placebo; B, food effect study where one SAD group (9 mg) was also given or placebo after a high-fat breakfast; C, multiple ascending dose study with three groups given 15-135 mg or placebo once-daily for 7 days. Seventy-nine volunteers participated. No serious adverse events occurred, where any drug- or placebo-related adverse events were mild to moderate, with no correlation to dose. was rapidly absorbed, yielding dose proportional increases in exposure after single and repeat dosing. PK confirmed that, with a clearance (T) of 18.7 h, is suited to once-daily dosing, can be taken with or without food, and does not accumulate on repeat dosing. At doses ≥1 mg, led to complete and sustained inhibition of thromboxane-, but not ADP-, induced platelet aggregation , with direct correlation between exposure and duration of PD effects. Orally administered was well tolerated, with favorable PK/PD profiles and evidence of specific TP target engagement. These findings support continued clinical development of for cardiopulmonary or other relevant diseases with unmet needs. clinicaltrials.gov, identifier NCT04919863.