Treatment with the novel TAAR1 agonist ulotaront is associated with reductions in quantitative polysomnographic REM sleep without atonia in healthy human subjects: Results of a post-hoc analysis

• Published in: Sleep medicine Vol. 101; pp. 578 - 586
• Main Authors: Feemster, John C., Westerland, Sarah M., Gossard, Thomas R., Steele, Tyler A., Timm, Paul C., Jagielski, Jack T., Strainis, Emma, McCarter, Stuart J., Hopkins, Seth C., Koblan, Kenneth S., St. Louis, Erik K.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2023
• Subjects: Adult; Healthy Volunteers; Humans; Male; Muscle Hypotonia; Polysomnography; REM sleep Behavior disorder; REM Sleep Behavior Disorder - complications; REM sleep without atonia; SEP-363856; Sleep, REM; Trace amine-associated receptor 1 (TAAR1); Ulotaront; Young Adult; Ulotaront; REM sleep without atonia; RBD; SEP-363856; REM sleep Behavior disorder; RAI; Polysomnography; TAAR1; RSWA; Trace amine-associated receptor 1 (TAAR1); BMI
• ISSN: 1389-9457; 1878-5506
• DOI: 10.1016/j.sleep.2022.11.022

Isolated REM sleep behavior disorder (RBD) is a potentially injurious parasomnia lacking an established treatment. Ulotaront is a trace amine-associated receptor 1 (TAAR1) agonist with 5-HT1A receptor agonist activity that has demonstrated efficacy in patients with schizophrenia. In a single dose challenge study in humans, ulotaront 50 mg demonstrated significant REM suppressant effects. We now report post-hoc exploratory analyses designed to evaluate the effect of ulotaront on quantitative REM sleep without atonia (RSWA). Young healthy adult men (ages 19–35) were randomized to double-blind, cross-over treatment (after 7-day wash-out) with single doses of ulotaront (50 mg or 10 mg) versus placebo followed by polysomnography (PSG) on each of the nights following treatment. Quantitative RSWA was analyzed in a blinded fashion using established visual and automated methods. Subjects received 50 mg (n = 11) or 10 mg (n = 9) of ulotaront. Treatment with ulotaront 50 mg was associated with lower RSWA (p < 0.05), with greatest RSWA reduction (vs. placebo) observed in subjects with RSWA levels above the mean on the baseline night. RSWA levels were similar between treatment with ulotaront 10 mg and placebo. Treatment with ulotaront 50 mg (but not 10 mg) was associated with reductions in RSWA levels in healthy subjects, especially in subjects with higher baseline RSWA levels, providing proof-of-concept for ulotaront efficacy in reducing RSWA levels. However, whether ulotaront might have efficacy as a treatment for human RBD awaits double-blind trials with ulotaront in clinical RBD populations. •We report here the results of a post-hoc analysis of a study in which a single dose of ulotaront 50 mg (but not 10 mg) demonstrated significant REM suppressant effects.•The current post-hoc analyses were specifically designed to evaluate the effect of ulotaront on quantitative REM sleep without atonia (RSWA).•Treatment with ulotaront 50 mg (but not 10 mg) was associated with a significant reduction in RSWA levels, especially notable in subjects with higher baseline RSWA levels, providing proof-of-concept for ulotaront efficacy in reducing RSWA levels.•Ulotaront may hold promise as a symptomatic treatment for RBD. Further double-blind trials with ulotaront should be considered.