Single- and multiple-dose safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ASP0367, or bocidelpar sulfate, a novel modulator of peroxisome proliferator-activated receptor delta in healthy adults: Results from a phase 1 study

Introduction/aims: ASP0367, or bocidelpar sulfate, is an orally administered small molecule that potently and selectively modulates Peroxisome Proliferator-activated Receptor δ (PPARδ) to address mitochondrial dysfunction occurring in diseases including primary mitochondrial myopathy and Duchenne muscular dystrophy. The objectives of this first-in-human trial were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of ASP0367 in healthy participants.

Methods: In this double-blind phase 1 study, adult participants were randomized to single or multiple ascending oral doses of ASP0367 or placebo. The study duration was 1 and 14 days, respectively. Pharmacokinetic parameters under fed conditions were also evaluated.

Results: A total of 64 (single-dose cohort) and 37 (multiple-dose cohort) participants were included in the study. After single doses of 1 to 120 mg, ASP0367 was rapidly absorbed, with median time to maximum plasma concentration (t_max ) of 1.50 to 2.24 hours under fasting conditions; ASP0367 concentrations declined in a multiphasic manner after reaching maximum plasma concentration. Under fed conditions, t_max was delayed 1.7 hours. After multiple once-daily doses, mean half-life of ASP0367 10 to 75 mg ranged from 14.1 to 17.5 hours; steady state was reached after 4 days. Negligible accumulation was observed after repeated dosing. No participants receiving ASP0367 discontinued treatment, and all treatment-emergent adverse events were mild to moderate in severity; none were considered drug-related. No clinically significant changes were observed on laboratory or electrocardiographic evaluation. Treatment- and dose-dependent upregulation of six PPARδ target genes was observed with single and multiple doses of ASP0367.

Discussion: ASP0367, or bocidelpar sulfate, was well tolerated; rapid absorption, roughly dose-proportional bioavailability, and effects on PPARδ target genes were demonstrated in healthy adult participants.

Duchenne muscular dystrophy; PPARδ agonist; mitochondrial disease; mitochondrial myopathy; peroxisome proliferator-activated receptors.