Investigational Med for Tourette Syndrome Promising

PHILADELPHIA — The investigational agent ecopipam reduces tic severity in children and adolescents with Tourette syndrome (TS) without exacerbating common psychiatric comorbidities, results of a new analysis suggest.

As previously reported, the first-in-class dopamine-1 (D1) receptor antagonist reduced the primary endpoint of tic severity scores by 30% compared with placebo among 149 patients in the 12-week, phase 2b D1AMOND trial. 

What was unknown, however, is whether ecopipam would affect the comorbidities of attention-deficit/hyperactivity disorder (ADHD), anxiety, obsessive-compulsive disorder (OCD), and depression that were present in two thirds of participants.

The two key findings in this post hoc analysis were “first, that patients with a nonmotor diagnosis like depression or ADHD did not do any worse in terms of tic efficacy; and second, we didn’t find any evidence that any of the nonmotor symptoms of Tourette’s got worse with ecopipam,” study investigators Donald Gilbert, MD, professor of pediatrics and neurology at University of Cincinnati Children’s Hospital Medical Center, told Medscape Medical News.

Gilbert presented the results at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024. 

No Worsening of ADHD Symptoms

TS affects approximately 1 in 160 children between 5 and 17 years of age in the United States, data from the Tourette Association of America show. Research has shown that 85% of patients with TS will have a co-occurring psychiatric condition. 

Guidelines recommend Comprehensive Behavioral Intervention for Tics (CBIT) as first-line treatment for TS, but cost and access are barriers. The only currently approved medications to treat TS are antipsychotics that act on the D2 receptor, but their use is limited by the potential for weight gain, metabolic changes, drug-induced movement disorders, and risk for suicidality, said Gilbert. 

The D1AMOND study randomly assigned patients aged 6-17 years with TS and a Yale Global Tic Severity Total Tic Scale score of at least 20 to receive a target steady-state dose of 2 mg/kg/d of oral ecopipam or placebo for a 4-week titration period, followed by an 8-week treatment phase before being tapered off the study drug. 

Patients were allowed to remain on medications without D2-receptor blocking activity for anxiety, OCD, and ADHD if the dosage was stable for 4 weeks before screening and not specifically prescribed for tics. 

A mixed model for repeated measures was used to assess changes in several scales administered at baseline and at weeks 4, 6, 8, and 12: the Swanson, Nolan, and Pelham Teacher and Parent Rating Scale (SNAP-IV); Pediatric Anxiety Rating Scale; Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), and Children’s Depression Rating Scale–Revised (CDRS-R). 

In patients with a co-occurring psychiatric condition, no significant differences were found over time between ecopipam and placebo in terms of SNAP-IV (-4.4; P = .45), Pediatric Anxiety Rating Scale (1.0; P = .62), CDRS-R (-3.2; P = .65), or CY-BOCS (-0.7; P = .76) scores.

For ADHD, the most frequent comorbidity, scores trended lower in the ecopipam group but were not significantly different from those in the placebo group. “We found no evidence that ecopipam worsened ADHD symptoms,” Gilbert said.

No Weight Gain

Suicidal ideation was reported during the dosing period in eight patients in the placebo group and none in the ecopipam group. One patient treated with ecopipam had multiple depressive episodes and dropped out of the study on day 79. Ecopipam was discontinued in another patient because of anxiety. 

Notably, there was more weight gain in the placebo group than in the ecopipam group (2.4 kg vs 1.8 kg) by 12 weeks. No shifts from baseline were seen in blood glucose, A1c, total cholesterol, or triglycerides in either group. 

The lack of weight gain with ecopipam is important, Gilbert stressed. “Medicines that block D2 so often cause weight gain, and a lot of our patients, unfortunately, can be heavier already,” he explained. “We don’t want to make that worse or put them at a long-term risk of type 2 diabetes.” 

For patients with more severe disease, we really “do need something else besides D2-blockers in our tool kit,” he added. 

Commenting on the study for Medscape Medical News, Tanya Simuni, MD, co-moderator of the session and director of the Parkinson’s Disease and Movement Disorders Center, Northwestern Feinberg School of Medicine, Chicago, said the aim of assessing D1-directed medications is to reduce the negative impact of traditional antipsychotics with a theoretical benefit on hyperkinetic movement.

But the most important thing that they’ve shown is that “there was no negative effect, no liability for the nonmotor manifestations of Tourette’s. That is important because Tourette’s is not a pure motor syndrome, and psychiatric manifestations in a lot of cases are associated with more disease-related quality of life impairment compared to the motor manifestations,” said Simuni.

That said, she noted, the “ideal drug would be the one that would have benefit for both motor and nonmotor domains.” 

Multiple Agents in the Pipeline 

“The neuropharmacology of TS has long remained stagnant, and most existing treatments often fail to balance efficacy with tolerability, underscoring the urgent need for newer therapeutics,” Christos Ganos, MD, professor of neurology, University of Toronto, commented in a press release.

He noted that three studies have been published on ecopipam since 2014: an 8-week, open-label trial in adults with TS, a 4-week, placebo-controlled crossover trial in 38 children with TS, and the 12-week D1AMOND trial.

“These studies demonstrated clinically meaningful reductions in tics, without relevant safety concerns or changes in TS-typical neuropsychiatric measures, as also shown by the abstract highlighted here,” Ganos said. 

“This emerging body of research provides a solid foundation for introducing ecopipam as a novel pharmacological agent to treat tics and may motivate further work, both on the pathophysiology and pharmacotherapy of tic disorders and their associations.”

A single-arm, phase 3 trial is currently underway at 58 centers in North America and Europe investigating the long-term safety and tolerability of ecopipam over 24 months in 150 children, adolescents, and adults with TS. The study is expected to be completed in 2027.

Several other new medications are also under investigation including the vesicular monoamine transporter (VMAT2) inhibitors tetrabenazine, deutrabenazine, and valbenazine; the PEDE10A inhibitor gemlapodect; the allopregnanolone antagonist sepranolone; and SCI-110, which combines dronabinol (the synthetic form of tetrahydrocannabinol) and the endocannabinoid palmitoylethanolamide.

The study was funded by Emalex Biosciences. Gilbert’s institution received research support from Emalex Biosciences and PTC Therapeutics. Gilbert has received publishing royalties from a healthcare-related publication; compensation for serving as a medical expert with Teldoc; Advanced Medical; and the National Vaccine Injury Compensation Program, US Department of Health and Human Services. Simuni reports no relevant conflicts of interest. Ganos has received honoraria for educational activities from the Movement Disorder Society and academic research support from VolkswagenStiftung.