Safety, tolerability, and pharmacokinetics of SMT C1100, a 2‐arylbenzoxazole utrophin modulator, following single‐ and multiple‐dose administration to healthy male adult volunteers

Abstract

SMT C1100 is a small molecule utrophin modulator in development to treat Duchenne muscular dystrophy. This study evaluated the safety, tolerability, and pharmacokinetics of SMT C1100 in healthy volunteers. This double‐blind, placebo‐controlled Phase 1 study comprised: Part 1, an escalating, single‐dose with/without fasting involving 50 mg/kg, 100 mg/kg, 200 mg/kg, and 400 mg/kg doses; and Part 2, a multiple 10 day dose evaluation involving 100 mg/kg bid and 200 mg/kg bid doses. Adverse events were recorded. SMT C1100 was absorbed rapidly following single and multiple oral doses, with median tmax attained within 2–3.5 hour across all doses. Considerable variability of pharmacokinetic parameters was noted among subjects. Following single doses, systemic exposure increased in a sub‐proportional manner, with the 8.0‐fold dose increment resulting in 2.7‐ and 2.4‐fold increases in AUC0‐∞ and Cmax, respectively. AUC0‐∞ and Cmax were estimated as 4.2‐ and 4.8‐fold greater, respectively, following food. Systemic exposure reduced upon repeat dosing with steady‐state concentrations achieved within 3–5 days of multiple bid dosing. No serious or severe adverse events were reported. SMT C1100 was safe and well tolerated with plasma concentrations achieved sufficient to cause a 50% increase in concentrations of utrophin in cells in vitro.