Objective:
To characterize the effects of ecopipam on growth and development and determine the potential toxicity of ecopipam when administered via oral (gavage) from Postnatal Day (PND) 28-84 to juvenile Crl:CD(SD) Sprague Dawley rats, with a recovery period of ~ 4 weeks.
Background:
Ecopipam is a first-in-class selective dopamine-1 receptor antagonist in Phase 3 clinical development for children and adolescents with Tourette Syndrome (TS) (ages 6 to <18). In a 12-week phase 2b, randomized, double-blind, placebo-controlled trial (D1AMOND), ecopipam-HCl at a dose of 2 mg/kg/day improved the Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS) by 30% (p=0.01).
Design/Methods:
Juvenile rats (N=40/sex/group) were administered 0, 6, 36, or 216 mg/kg/day ecopipam HCl from PND 28 - 84 with a ~4-week recovery period. Endpoints included clinical observations, body weight, food consumption, sexual maturation, ophthalmic examinations, behavioral assessments (Functional Observation Battery (FOB), acoustic startle response, motor activity, Morris Water Maze), clinical pathology (hematology, clinical chemistry, urinalysis), estrous cycle, ovarian, and uterine examinations, sperm motility/concentration, reproductive capacity, organ weights, femur lengths, gross necropsy, and histopathology. A satellite group was dosed to provide toxicokinetic exposures to ecopipam and EBS-101-40853 (metabolite).
Results:
Dose-dependent, ecopipam-related effects included clinical signs, decreased body weight/body weight gain, food consumption, and increased latency times in the Morris Maze (high dose). There were no adverse effects on other behavioral assessments, sexual maturation, mating/fertility, ophthalmic examinations, clinical pathology, macroscopic or microscopic pathology. Systemic exposures increased with dose levels. At the end of the recovery period, ecopipam-related effects demonstrated partial or complete recovery (clinical signs, body weight/body weight gain, food consumption).
Conclusions:
Ecopipam dose-related effects of decreased body weight gain and food consumption in juvenile rats were consistent with its primary pharmacology and demonstrated signs of recovery upon cessation of dosing. Ecopipam did not demonstrate adverse effects on maturation or growth and development.