Increasing Ecopipam Exposure Improves Yale Global Tic Severity Scale-Total Tic Scores (YGTSS-TTS) in Children and Adolescents with Tourette Syndrome (TS): Results from a Population Pharmacokinetic (popPK) Model-Based Simulation Using D1AMOND Trial Data (P5-9.007)

Abstract

<h3>Objective:</h3> To develop popPK and exposure-response (E-R) models to characterize the relationship between ecopipam concentrations and efficacy as well as safety in children and adolescents (ages 6 to &lt;18 years) with TS. <h3>Background:</h3> Ecopipam is a first-in-class selective dopamine-1 receptor antagonist in development for TS. Results from the 12-week randomized, double-blind placebo-controlled phase 2b D1AMOND trial demonstrated 2 mg/kg/day ecopipam significantly reduced motor and phonic tics (YGTSS-TTS) and was well-tolerated. Understanding the PK of ecopipam and its active metabolite, the intrinsic/extrinsic factors affecting variability, and the relationships between exposure and efficacy/safety in TS are key to perform model-based simulations to ensure the optimal dose in TS. <h3>Design/Methods:</h3> In D1AMOND, a responder was defined as a ≥25% improvement in YGTSS-TTS. Logistic regression modeling was used to determine the relationship between responder status and exposure (area-under-the-curve, AUC) of ecopipam and its active metabolite (E+M) in children and adolescents with TS. <h3>Results:</h3> The steady-state (E+M) AUC exposure predicted clinical YGTSS-TTS responders at week 12. A 2-compartment model with first-order absorption and elimination described plasma concentration-time data for ecopipam and a 1-compartment model with first order elimination described the active metabolite concentration-time data. The final logistic regression model was based on the combined steady-state AUC for E+M as a univariate predictor for a clinical responder. The odds of ≥25% improvement in YGTSS-TTS increased near linearly by 6.8% for each 100 unit increase in E+M steady-state AUC. E-R modeling of safety parameters was not performed as there were not enough adverse events in the study to model. <h3>Conclusions:</h3> These data demonstrate a positive relationship between ecopipam exposure and efficacy in pediatric patients with TS. This study validates the D1AMOND trial ecopipam dosing and informed the posology for a confirmatory Phase 3 trial, currently recruiting patients. <b>Disclosure:</b> Dr. Freidy has received personal compensation for serving as an employee of Allucent. Dr. Pene Dumitrescu has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Allucent. Dr. Pene Dumitrescu has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for TEVA Pharmaceutics. Dr. Pene Dumitrescu has stock in GlaxoSmithkline. Dr. Schmith has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Emalex Biosciences. Dr. Schmith has received research support from Emalex BIosciences. The institution of Dr. Gilbert has received research support from NIMH. The institution of Dr. Gilbert has received research support from Emalex. The institution of Dr. Gilbert has received research support from Erydel. The institution of Dr. Gilbert has received research support from PTC Therapeutics. Dr. Gilbert has received publishing royalties from a publication relating to health care. Dr. Gilbert has received publishing royalties from a publication relating to health care. Dr. Gilbert has received personal compensation in the range of $500-$4,999 for serving as a Medical Second Opinion Expert with Teldoc/Advanced Medical. Dr. Gilbert has received personal compensation in the range of $5,000-$9,999 for serving as a Medical Expert with Department of Health and Human Services/Vaccine Injury Compensation Program. Atul Mahableshwarkar has received personal compensation for serving as an employee of Emalex Biosciences. Atul Mahableshwarkar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ecor1 Capital. Atul Mahableshwarkar has stock in Johnson &amp; Johnson. Dr. Dubow has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Paragon Biosciences. Dr. Dubow has stock in Avadel Pharmaceuticals. Dr. Cunniff has received personal compensation for serving as an employee of Paragon Biosciences. Dr. Cunniff has stock in Harmony Biosciences. Dr. Cunniff has stock in Emalex Biosciences. Mr. Kim has received personal compensation for serving as an employee of Emalex Biosciences. Mrs. Miller has received personal compensation for serving as an employee of Emalex Biosciences. Mrs. Miller has stock in Emalex Biosciences. Dr. Wanaski has received personal compensation for serving as an employee of Paragon Biosciences. Dr. Wanaski has stock in Paragon Biosciences.