Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Ascending Doses and Dose Titration of Bexicaserin in Healthy Participants in a Randomized, Double‐Blind, Placebo‐Controlled Study

Bexicaserin (LP352) is a selective superagonist of the 5-hydroxytryptamine 2C (5-HT_2C) receptor currently in development for the treatment of seizures that arise from developmental and epileptic encephalopathies. This phase 1, double-blind, placebo-controlled multiple ascending dose (MAD) study assessed the safety, tolerability, and pharmacokinetic profile of bexicaserin in healthy participants. Doses ranging from 3 to 24 mg three times daily (TID) were administered for up to 14 days. Serial blood and urine samples were collected to assess pharmacokinetics, and prolactin was assessed as a pharmacodynamic biomarker. Bexicaserin was generally safe and well-tolerated, rapidly absorbed, metabolized to three circulatory pharmacologically inactive metabolites, and had a median T_max of about 1-2 h. C_max accumulation ranged from 1.5 to 5.1-fold for all analytes after multiple doses. M20 was the major metabolite, with exposures ranging from 9 to 33-fold versus bexicaserin. Overall clearance of bexicaserin ranged from 45.9 to 125 L/h, with renal clearance between 5.04 to 6.58 L/h, suggesting that hepatic metabolism and/or excretion is the main elimination pathway. There was a weak dose-dependent positive correlation between bexicaserin C_max and prolactin mean percentage change from baseline, suggesting successful engagement of central 5-HT_2C receptors. Overall, this Phase 1 MAD study demonstrated bexicaserin to be safe and well-tolerated, with rapid absorption, presence of one major metabolite, accumulation upon multiple dosing TID, and a greater than dose-proportional increase in exposures. These findings support the continued development of bexicaserin, which is currently in Phase 3 clinical trials.