Friday, November 2, 2018

Ecopipam for Tourette syndrome


Gilbert DL, Murphy TK, Jankovic J, Budman CL, Black KJ, Kurlan RM, Coffman KA, McCracken JT, Juncos J, Grant JE, Chipkin RE. Ecopipam, a D1 receptor antagonist, for treatment of tourette syndrome in children: A randomized, placebo-controlled crossover study. Mov Disord. 2018 Aug;33(8):1272-1280.

Abstract

BACKGROUND:
Dopamine D2 receptor antagonists used to treat Tourette syndrome may have inadequate responses or intolerable side effects. We present results of a 4-week randomized, double-blind, placebo-controlled crossover study evaluating the safety, tolerability, and efficacy of the D1 receptor antagonist ecopipam in children and adolescents with Tourette syndrome.

METHODS:
Forty youth aged 7 to 17 years with Tourette syndrome and a Yale Global Tic Severity Scale - total tic score of ≥20 were enrolled and randomized to either ecopipam (50 mg/day for weight of <34 kg, 100 mg/day for weight of >34 kg) or placebo for 30 days, followed by a 2-week washout and then crossed to the alternative treatment for 30 days. Stimulants and tic-suppressing medications were excluded. The primary outcome measure was the total tic score. Secondary outcomes included obsessive compulsive and attention deficit/hyperactivity disorder scales.

RESULTS:
Relative to changes in placebo, reduction in total tic score was greater for ecopipam at 16 days (mean difference, -3.7; 95% CI, -6.5 to -0.9; P = 0.011) and 30 days (mean difference, -3.2; 95% CI, -6.1 to -0.3; P = 0.033). There were no weight gain, drug-induced dyskinesias, or changes in laboratory tests, electrocardiograms, vital signs, or comorbid symptoms. Dropout rate was 5% (2 of 40). Adverse events reported for both treatments were rated predominantly mild to moderate, with only 5 rated severe (2 for ecopipam and 3 for placebo).

CONCLUSIONS:
Ecopipam reduced tics and was well tolerated. This placebo-controlled study of ecopipam supports further clinical trials in children and adolescents with Tourette syndrome
_________________________________________________________________________ 

Shaw, Gina.  In the Pipeline-Tourette Syndrome: Novel D1 Receptor Antagonist Reduces Tics in Tourette Syndrome. Neurology Today: November 1, 2018 - Volume 18 - Issue 21 - p 20–21. https://journals.lww.com/neurotodayonline/Fulltext/2018/11010/In_the_Pipeline_Tourette_Syndrome__Novel_D1.8.aspx/?cid=eTOC%20Issues.2018-neurotodayonline 

Study results demonstrated the efficacy of the first in class D1 receptor antagonist for Tourette syndrome. The drug was well tolerated with no weight gain, sedation, or heart problems.

A new D1 receptor antagonist, ecopipam, reduced tics and was well tolerated in a group of 40 young people aged 7-17 years with Tourette syndrome (TS), according to the results of a phase 2b randomized, placebo-controlled crossover study published in Movement Disorders in August.

The multicenter study randomized participants to either a weight-based dose of ecopipam or placebo for 30 days. After a two-week washout, participants were crossed to the alternative treatment for 30 days. A total tic score on the Yale Global Tic Severity Scale (YGTSS) of ≥20 was required for enrollment, and all stimulants and tic-suppressing medications were excluded.

Relative to changes in placebo, reduction in total tic score was greater for ecopipam at 16 days (p = 0.011) and 30 days (p = 0.033). On the Clinical Global Impression-Severity (CGI-S) scale, the proportion of children with moderate, marked, or severe symptoms decreased from 97.5 percent at baseline to 55 percent by day 30 on ecopipam but remained at 80 percent by day 30 on placebo. On the CGI-Improvement (CGI-I) scale, 47.5 percent of those treated with ecopipam were very much or much improved by day 30 compared with 25 percent in the placebo arm, but this difference in proportions failed to reach significance.

Adverse events for both arms of the study were rated as predominantly mild to moderate; most notably, participants did not report the weight gain or drug-induced movement disorders that have been reported with the D2 receptor antagonists that have been the mainstay of TS therapy for decades.

“Tourette syndrome is one of many neurological conditions with a significant unmet need,” lead author Donald Gilbert, MD, MS, FAAN, director of the Movement Disorder Clinic and Tourette's Syndrome Clinic at Cincinnati Children's Hospital, told Neurology Today. “Despite all the treatments we have, people still have symptoms that interfere with their lives — with school, with work, with social and family relationships. We have been eager to look for treatments that differ from those currently on the market, all of which act on the D2 receptor. This new dopamine-blocking drug acts on D1, which is in the same neighborhood but probably functions differently in terms of controlling movement, and this is the first placebo-controlled study of this class of medication in children and teens with Tourette.”

Current D2 receptor inhibitors for TS, which include haloperidol (Haldol), pimozide (Orap), and aripiprazole (Abilify) target faulty inhibition in the basal ganglia, and all have significant side effects.

“It's very exciting to have medications that are not ‘copycat’ drugs with totally different mechanisms of action that might be available for us to help our patients,” said Dr. Gilbert…

 “When aripiprazole was approved in 2014, it was the first new drug for Tourette to come to market since 1984,” said Irene Malaty, MD, FAAN, associate professor of neurology, director of the Tourette Association of America Southeast Regional Center of Excellence, and director of the Parkinson Foundation Center of Excellence at the University of Florida. “But all three of these therapies are fraught with metabolic side effects, such as weight gain, and often give only partial improvement in tics.”

The new D1 receptor agonist is thought to work instead by modifying the excitatory direct pathway, Dr. Malaty explained. “Having a new mechanism for this condition is very exciting, and it's encouraging to see that it is so well tolerated, with no weight gain or new onset of depression. Patients who have been unsuccessful with the current options could potentially have something else to try.”

Harvey S. Singer, MD, FAAN, professor of neurology and pediatrics and director of the Tourette Association of America's Center of Excellence at the Johns Hopkins Hospital, also emphasized the importance of developing new therapies for tic suppression and noted prior published studies with fluphenazine, a combined D1 and D2 antagonist.

But he suggested that the study's findings should be interpreted cautiously, as the authors themselves noted in the paper. “I have several concerns, including the fact that this was a small study with a total of 40 subjects evaluated at ten different centers, the total maximum duration of therapeutic dosing was only three weeks, since the first week was tapering up, and the timing of the placebo arm affected the ecopipam effect,” he said.

He also pointed to the small effect size seen in the study's raw data and the lack of statistical improvement on the YGTSS Impairment and CGI-I scales. And while many side effects commonly seen in current therapies for TS were not observed, there were some side effects, including insomnia and GI issues.

“Some questions on the YGTSS, the tic ranking scale, can be vague and in multicenter studies, it is essential that all investigators are consistent in their evaluations. There needs to be confirmed inter-rater reliability,” he said. “This is particularly important given that the raw-data effect size for improvement at 30 days in motor tics was only 1.6, maximum motor tic score being 25, and only 1.8 for phonic tics, maximum phonic tic score being 25. It was also disappointing to note that while the report claims statistical improvement for tics, on the 50-point YGTSS Impairment scale — the component that quantifies the extent to which tics are interfering with daily activities — there was no statistical improvement.”

But the authors suggested that this difference in the raw data might be attributable to limitations of crossover studies, primarily the confounding factors of treatment and carryover or order effects. “In this study, the statistical estimate of effects used a standard method to account for this, generating an estimate of the difference in ecopipam and placebo in the total tic score that exceeded the prespecified difference,” they wrote. “The difference using the raw data, which does not account for order or carry-over effects, is lower than the prespecified difference.”

Current therapies in use for TS also frequently have variable findings regarding their efficacy, noted Dr. Malaty. “Sometimes studies are contradictory and have variable outcomes. Even a partial tic reduction is very exciting, because of the potential role for combination therapy as well as monotherapy. I'm very interested to see what this agent will show in a larger population, with longer duration follow-up.”

“Additional trials are required to confirm ecopipam efficacy and for comparison with other tic-suppressing medications,” Dr. Singer agreed.

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