Objective:

To characterize the E-R relationship of ecopipam in TS patients, to identify any differences between adult and pediatric patients, and to perform clinical trial simulations to add to the weight of efficacy in adults with TS.

Background:

Ecopipam is a first-in-class selective dopamine-1 receptor (D1R) antagonist being investigated for treatment of TS. Ecopipam is primarily metabolized to ecopipam glucuronide (E-G), with a minor metabolite, EBS-101-40853 (EBS) and its glucuronide conjugate (EBS-G). EBS and E-G are also active but much less potent at the D1R than ecopipam. 

Design/Methods:

A pre-specified population pharmacokinetics (PopPK), exposure-response (E-R), and clinical trial simulation plan was utilized throughout the clinical development of ecopipam. An E-R model for efficacy was developed using data from Phase 2b study EBS-101-CL-001 (RCT) and Phase 3 study EBS-101-TD-301 (RWD). Exposure was defined as the combined active exposure (ecopipam, EBS, and E-G), corrected for differences in potency, protein binding, and brain penetration predicted using PopPK. Response was defined as a ≥25% improvement from baseline in the Yale Global Tic Severity Scale – Total Tic Score (YGTSS-TTS) at Week 8. Clinical trial simulations (n=500) were conducted assuming a RCT study (50 adults/50 pediatrics on ecopipam, 50 adults/ 50 pediatrics on placebo. Success was defined as a p <0.017 AND a probability of response active-placebo of ≥15%, ≥20%, or ≥25%.

Results:

Combined active exposure, study type (whether RCT or RWD) and age group (<18, ≥18 years) were important covariates describing the probability of being a responder. Clinical trial simulations showed that the probability of successfully demonstrating efficacy (active-placebo ≥ 20%) and clinically meaningful benefit for ecopipam is ≥ 90% if an RCT was conducted in adult and pediatric patients with TS. 

Conclusions:

PopPK, E-R, and clinical trial simulations add to the weight of evidence for the efficacy of ecopipam in pediatrics and adults with TS.