Safety, pharmacokinetics and pharmacodynamics of NXC736, a novel sphingosine‐1‐phosphate receptor modulator

AIMS: NXC736 is a sphingosine 1-phosphate (S1P) receptor modulator, under development as a novel oral treatment for autoimmune diseases. The goals of this study were to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of NXC736 and its active metabolite (NXC736-P) in healthy male participants. METHODS: A randomized, double-blind, placebo-controlled, single and multiple ascending dose study was conducted. Six doses (1, 3, 10, 20, 40, 80 mg) were administered in a single-dosing study, and four doses (20, 40, 60, 80 mg BID) were administered in a multiple-dosing study. The safety, PK and PD were evaluated throughout the study. RESULTS: NXC736 was well tolerated up to 80 mg, twice daily for 14 days. NXC736 was rapidly absorbed and eliminated in a biphasic manner with mean terminal half-lives ranging from 3.92 to 15.96 h; mean terminal half-lives of NXC736-P ranged from 3.35 to 13.50 h. At the steady state, systemic exposures of both NXC736 and NXC736-P increased dose-proportionally and were accumulated up to ~2 times. First-dose heart rate reduction was transient and attenuated with repeated dosing. In multiple dosing study, means of individual maximum percent reductions in absolute lymphocyte counts were 33.69%, 37.93%, 57.98%, 67.77% and 66.60% in the placebo, 20 mg BID, 40 mg BID, 60 mg BID and 80 mg BID, respectively; reductions were dose-dependent up to 60 mg BID and plateaued at higher doses. CONCLUSIONS: NXC736 demonstrated a favourable safety profile at doses up to 80 mg, and its PK and PD profiles were considered adequate for further clinical development.