Endocannabinoid Modulation Using Monoacylglycerol Lipase Inhibition in Tourette Syndrome: A Phase 1 Randomized, Placebo-Controlled Study

Introduction: Tourette syndrome (TS) is a complex neurodevelopmental disorder characterized by chronic motor and vocal tics. While consistently effective treatment is lacking, evidence indicates that the modulation of endocannabinoid system is potentially beneficial. Lu AG06466 (previously ABX-1431) is a highly selective inhibitor of monoacylglycerol lipase, the primary enzyme responsible for the degradation of the endocannabinoid ligand 2-arachidonoylglycerol. This exploratory study aimed to determine the effect of Lu AG06466 versus placebo on tics and other symptoms in patients with TS.

Methods: In this phase 1b cross-over study, 20 adult patients with TS on standard-of-care medications were randomized to a single fasted dose of Lu AG06466 (40 mg) or placebo in period 1, followed by the other treatment in period 2. The effects on tics, premonitory urges, and psychiatric comorbidities were evaluated using a variety of scaled approaches at different time points before and after treatment.

Results: All scales showed an overall trend of tic reduction, with two out of three tic scales (including the Total Tic Score of the Yale Global Tic Severity Score) showing a significant effect of a single dose of Lu AG06466 versus placebo at various timepoints. Treatment with Lu AG06466 resulted in a significant reduction in premonitory urges versus placebo. Single doses of Lu AG06466 were generally well-tolerated, and the most common adverse events were headache, somnolence, and fatigue.

Conclusion: In this exploratory trial, a single dose of Lu AG06466 showed statistically significant positive effects on key measures of TS symptoms.