Muscle & nerve | 2021
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.
Abstract
INTRODUCTION/AIMS\nASP0367, or bocidelpar sulfate, is an orally administered small molecule that potently and selectively modulates PPARδ to address mitochondrial dysfunction occurring in diseases including primary mitochondrial myopathy and Duchenne muscular dystrophy. Objectives of this first-in-human trial were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of ASP0367 in healthy participants.\n\n\nMETHODS\nIn this double-blind phase 1 study, adult participants were randomized to single or multiple ascending oral doses of ASP0367 or placebo; study duration was 1 and 14\u2009days, respectively. Pharmacokinetic parameters under fed conditions were also evaluated.\n\n\nRESULTS\nA total of 64 (single dose cohort) and 37 (multiple dose cohort) participants were included. Following single doses of 1-120 mg, ASP0367 was rapidly absorbed with median time to maximum plasma concentration (tmax ) of 1.50-2.24 hours under fasting conditions; ASP0367 concentrations declined in a multiphasic manner after reaching maximum plasma concentration. Under fed conditions, tmax was delayed 1.7 hours. Following multiple once-daily doses, mean half-life of ASP0367 10-75 mg ranged from 14.1-17.5 hours; steady state was reached after 4\u2009days. Negligible accumulation was observed following repeated dosing. No participants receiving ASP0367 discontinued treatment, and all treatment-emergent adverse events were mild-to-moderate in severity; none were deemed drug-related. No clinically significant changes were observed on laboratory or electrocardiography evaluations. Treatment- and dose-dependent upregulation of six PPARδ target genes were observed with single and multiple doses of ASP0367.\n\n\nDISCUSSION\nASP0367, or bocidelpar sulfate, was well tolerated; rapid absorption, roughly dose-proportional bioavailability, and effects on PPARδ target genes were demonstrated in healthy adult participants.