Ecopipam cuts Tourette tics

Children and adolescents with Tourette syndrome (TS) may benefit from ecopipam, a first-in-class selective dopamine-1 (D₁) receptor antagonist, as it reduced the number of tics and level of daily interference in a post hoc analysis of the phase IIb D1AMOND trial.

Initial analysis

The current results build on the initial findings demonstrating greater reduction in the YGTSS-TTS* Tic Domain scores from baseline to week 12 with ecopipam vs placebo (least-squares mean difference, –3.4; p=0.01). [Pediatrics 2023;151:e2022059574]

“The primary dependent variable is the YGTSS-TTS – a clinician interview … with five subdomains,” explained Dr Donald Gilbert from the Cincinnati Children’s Hospital Center, Cincinnati, Ohio, US, at AAN 2024.

The subdomains are number (how big a patient’s repertoire is), frequency (how often tics occur during the day), intensity (whether tics are painful or not), complexity (mostly for simple movements such as blinking), and interference (how much it slows down movement or speech), he continued.

When looking at each subdomain under the motor tic scale, all but one improved, with the largest being intensity (p<0.01), followed by number (p=0.04), frequency (p=0.03), and interference (p=0.03). [AAN 2024, abstract S30.009]

For the phonic tic scale, only one of the five subdomains improved (complexity; p=0.02). Reductions in the other dimensions fell short of statistical significance (p>0.05).

However, Gilbert pointed out that the scalar design of the YGTSS-TTS comes with certain issues. “For instance, [a patient going from a score of] 5 to 4 is not the same as going from 2 to 1 … yet both count as 1 point. Also, a 20-percent score reduction is not the same as saying [a patient is] 20 percent better.”

“[Hence, while the findings could be] a good start, there are some shortcomings in terms of communicating to patients … [If a patient] budges by half a point or a point, are they getting better? Will they be … happy with the treatment or did they just have a reduction in their score?” Gilbert said.

Alternative analysis: From ‘bad to good’

As such, instead of just looking at the point change, Gilbert and team conducted an alternate analysis wherein participants were categorized into ‘bad’ (those who had YGTSS-TTS scores of 3–5) or ‘good’ (those with scores of 0–2). They included 149 participants (mean age 12.7 years, 74 percent boys) who were randomized 1:1 to ecopipam 2 mg/kg or placebo for 12 weeks.

In this analysis, ecopipam was found to be associated with a greater probability of switching participants from bad to good as opposed to placebo by week 12.

For motor tics, more ecopipam vs placebo recipients went from bad to good across four subdomains: intensity (48 percent vs 21 percent; p<0.01), number (54 percent vs 23 percent; p=0.04), frequency (31 percent vs 18 percent; p=0.03), and interference (51 percent vs 27 percent; p=0.03).

For phonic tics, the only significant outcome was in the complexity subdomain (57 percent vs 40 percent; p=0.02).

No D₁ receptor blockers yet

In sum, 12-week treatment with ecopipam significantly improved motor tic characteristics in four of five dimensions vs placebo. For phonic tic characteristics, the benefit of ecopipam vs placebo was limited to the complexity subdomain.

“We do not have any D₁ receptor blockers in our [TS] treatment toolkit … Whether features of motor and phonic tics in TS are more or less responsive to D₁ receptor blockers is still unclear, but wouldn’t it be interesting to see how [ecopipam] compares to D₂ blockers and sieve it to see if different domains are … responsive to different interventions?” Gilbert shared.

“These data have increased our understanding of the effects of ecopipam on TS tic characteristics. We look forward to additional data once the phase III study is completed,” he concluded.