Ulotaront Fails to Differentiate From Placebo in Phase 1b Crossover Trial for Narcolepsy-Cataplexy

Steven T. Szabo, MD, PhD

Recently published in Sleep Medicine, findings from a phase 1b crossover trial (NCT05015673) assessing 2 doses of ulotaront (Sunovion) in adult patients with narcolepsy-cataplexy showed that the agent failed to demonstrate significant differences in efficacy from placebo despite increased latency or reduced duration in rapid eye movement (REM) sleep.¹ These findings suggest that the effect of ulotaront on REM sleep parameters, not for symptomatic end points, represents a disconnect from efficacy observed with other medications used for narcolepsy-cataplexy.

Acute treatment with both 25 mg and 50 mg of ulotaront reduced minutes spent in nighttime REM compared with placebo (−29.9 min [SD, 16.7] vs. −38.0 min [SD, 46.7], respectively). Similarly, a sustained 2-week administration of both doses of ulotaront reduced the mean number of sleep-onset REM periods during daytime multiple sleep latency test (MSLT) compared with placebo (25 mg: 1.9 [SD, 2.0]; 50 mg: 2.0 [SD, 2.0]; placebo: 3.5 [SD, 1.8]). Despite a reduction in cataplexy events from baseline during the treatment period, neither dose statistically separated from placebo (25 mg: P = .76; 50 mg: P = .82).

Lead author Steven T. Szabo, MD, PhD, translational medicine (TMED) clinical drug development, Sumitomo Pharma America, and colleagues assessed acute and sustained treatments of ulotaront on REM sleep and symptoms of cataplexy among participants with narcolepsy-cataplexy. In this multicenter, double-blind, placebo-controlled, randomized, 3-way crossover study, 16 adults with narcolepsy-cataplexy received treatment with either 2 oral doses of ulotaront (25 mg and 50 mg) or matching placebo for 2 weeks.

Eligible patients were given diaries to document their sleep-wake patterns and consumption of alcohol, caffeine, and nicotine, as well as for assessment of cataplexy and excessive daytime sleepiness. In the study, the patient median age was 31.0 years (range, 20–52 years) with 75% (n = 12) of patients White, 12.5% (n = 2) Black or African American, 1 patient (6.3%) Asian, and 1 patient (6.3%) identified in more than one category. Most of the patients (81.3%; n = 13) completed the study and 3 (18.8%) withdrew because of either adverse events (AEs) (n = 2) or lack of meeting the study criteria (n = 1).

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Overall, the mean baseline number of cataplexy events was 72.8. During the 2-week treatment period, 49.6 (SD, 21.8) events occurred in the placebo group, 47.8 (SD, 25.6) in the 25-group, and 59.7 (SD, 46.8) in the 50-mg group. At the end of the treatment period, mean duration of REM sleep decreased to 19.7 min (SD, 28.0) in the 25-mg group and 7.9 min (SD, 26.7) in the 50-mg group compared with baseline. In addition, mean total sleep time decreased from baseline by 13.7 min (SD, 32.8) and 31.9 min (SD, 42.9) in the 25-mg and 50-mg ulotaront groups, respectively. Authors noted that larger mean decreases in the number of SOREMPs from MSLT were observed in the ulotaront treatment groups compared with placebo (25 mg: −1.6 [SD, 1.4]; 50 mg: −1.5 [SD, 1.1]; placebo: −0.1 [SD, 1.6]) yet despite this, these differences were not significant.

At least one treatment-emergent adverse event (TEAE) occurred in 43.8% of patients (n = 7), the majority of them occurring after administration of 50 mg ulotaront (40.0%; n = 6), followed by placebo (14.3%; n = 2) and 25 mg ulotaront (7.7%; n = 1). Overall, there were 5 (31.3%) patients who reported TEAEs during the treatment period. The most reported TEAEs were nervous system disorders (31.3%; n = 5) and gastrointestinal disorders (25.0%; n = 4). Overall, the most commonly occurring TEAEs were nausea (25.0%; n = 4), somnolence (12.5%; n = 2), and fatigue (12.5%; n = 2). TEAEs were either mild or moderate in severity in 57.1% (4/7) patients. Only 3 patients (18.8%) reported severe TEAEs (somnolence, n = 2; presyncope, n = 1) and 2 patients discontinued the study because of nausea.

All told, besides the primary end points, the study was limited by the small sample size, and that it was not adequately active to detect changes in the outcome measures for sleepiness.Authors concluded that having an increased sample size would also be recommended to better evaluate the effects of ulotaront for excessive daytime sleepiness in patients with narcolepsy.

REFERENCES
1. Szabo ST, Hopkins SC, Lew R, Loebel A, Roth T, Koblan KS. A multicenter, double-blind, placebo-controlled, randomized, Phase 1b crossover trial comparing two doses of ulotaront with placebo in the treatment of narcolepsy-cataplexy. Sleep Med. 2023;107:202-211. doi:10.1016/j.sleep.2023.04.019