Pharmacokinetics, pharmacodynamics, and safety of HE009, a novel selective S1P1 receptor modulator, in healthy Chinese subjects

HE009,a novel selective sphingosine-1-phosphate receptor-1(S1P1) modulator, was evaluated in healthy Chinese subjects to assess itspharmacokinetics, pharmacodynamics, and safety profile. This randomized, placebo-controlled phase I studycomprised single ascending dose (SAD, 0.05-4.0 mg), multiple ascending dose(MAD, 0.5-3.0 mg), dose titration, and food effect components. HE009 exhibited dose-proportional exposure, with T_maxof 4-6 hours and t_1/2 of 16-24 hours, supporting once-daily dosing.Steady-state was achieved by day 7 with minimal accumulation (1.7-2.0 fold). Aclear concentration-effect relationship was observed, with maximum lymphocytecount reductions of 58% (SAD) and 70-80% (MAD). Notably, HE009 demonstrated afavorable cardiac safety profile, with transient, asymptomatic bradycardiamitigated by dose titration. No events related to hypertension were observedduring the study period. Thesefindings suggest HE009 offers potential advantages in efficacy, safety, anddosing flexibility compared to existing S1P receptor modulators for treatingautoimmune disorders like systemic lupus erythematosus. The trial was registered on the ChineseClinical Trial Registry, (Identifier No. ChiCTR2200066345), Registered December1, 2022.