Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Food Effect of Bexicaserin in Healthy Participants: A First‐in‐Human Randomized, Double‐Blind, Placebo‐Controlled Single Ascending Dose Escalation Phase 1 Study

Bexicaserin (LP352) is a selective 5-hydroxytryptamine 2C (5-HT_2C) superagonist in development for the treatment of seizures in developmental and epileptic encephalopathies (DEEs). This double-blind, placebo-controlled, single ascending dose (SAD) Phase 1 study aimed to assess the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles of single oral doses of bexicaserin and determine any relevant food effects. Forty healthy adult females were randomized to six treatment groups (1, 3, 6, 12, and 24 mg fasted; 6 mg fed) or placebo. Bexicaserin was generally safe and well tolerated: treatment-related adverse events were mild to moderate. Bexicaserin was rapidly absorbed into circulation (median T_max 1.02-1.54 h), with a mean terminal elimination half-life ranging from 4.67-6.66 h. Mean C_max and AUC_last of bexicaserin increased by at least >55-fold for a 24-fold dose increase. Three pharmacologically inactive circulatory metabolites (M9, M12, and M20) were further characterized. M20 was the major metabolite, with levels ranging from 3.47 to 10.8 times higher than bexicaserin. In comparison, M12 ranged from 0.35 to 0.98 times, and M9 from 0.037 to 0.53 times, relative to bexicaserin. Metabolism was the major route of clearance, as <5% of parent bexicaserin was eliminated in the urine. A high-fat meal did not alter the exposure of bexicaserin, supporting administration without regard to food. Increases in prolactin concentrations, a potential PD marker, were dose-dependent, suggesting central 5-HT_2C receptor engagement. In summary, this Phase 1 SAD study demonstrated safety, tolerability, and adequate characterization of PK/PD of bexicaserin, which is currently in Phase 3 clinical development.