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.