To evaluate the safety and tolerability of a single 9-hour intravenous infusion of TAK-925 112 mg compared with placebo in adults with idiopathic hypersomnia (NCT04091438).

Previous preclinical and clinical studies suggest that orexin 2 receptor-selective agonists, such as TAK-925, may be efficacious for the treatment of excessive daytime sleepiness in individuals with hypersomnia who have normal orexin levels.

In this phase 1b, randomized, double-blind, placebo-controlled, crossover study, primary endpoints included the occurrence of treatment-emergent adverse events (TEAEs). Exploratory outcomes included assessments of objective and subjective wakefulness, using the Maintenance of Wakefulness Test (MWT) and Karolinska Sleepiness Score (KSS).

Twenty-seven participants were randomized and administered treatment; most were female (77.8%) and approximately two thirds were white (66.7%). The mean age was 31.7 years (standard deviation, 8.79). The proportion of participants reporting ≥1 TEAE during any treatment was 44.4%; apart from one severe event of insomnia, all TEAEs were mild (44.4%) or moderate (7.4%) in severity. No serious TEAEs or discontinuations due to TEAEs occurred. The most common TEAEs were pollakiuria (n=3), dizziness (n=2) and rhinorrhoea (n=2) with TAK-925, and headache (n=2) with placebo. Urinary-related TEAEs occurred with TAK-925 (16.0%) but not with placebo. The least-squares (LS) mean sleep latencies on the MWT (across four sessions) for TAK-925 and placebo were 39.89 and 10.49 minutes, respectively (LS mean difference: 29.41 minutes [95% confidence interval (CI): 25.64, 33.17]; p<0.0001). The mean KSS score was statistically significantly lower (indicating decreased sleepiness) for TAK-925 (3.63) versus placebo (6.95) (LS mean difference: −3.31 [95% CI: −4.15, −2.48]; p<0.0001). Objective and subjective pharmacodynamic effects persisted and remained relatively stable over the infusion period.

Overall, TAK-925 was generally well tolerated, and significantly improved objective and subjective measurements of wakefulness versus placebo in adults with idiopathic hypersomnia.