Safety and efficacy of TAK-925 in adults with obstructive sleep apnea who experience excessive daytime sleepiness despite adequate use of CPAP (4278)

Objective: To determine the safety of a single 9-hour intravenous infusion of TAK 925 (44 mg or 112 mg) compared with placebo in adults with obstructive sleep apnea and residual excessive daytime sleepiness (EDS) despite compliant continuous positive airway pressure therapy (NCT04091425). Background: Previous preclinical and clinical studies suggest that orexin 2 receptor-selective agonists, such as TAK-925, may be efficacious for the treatment of EDS in patients with hypersomnia who have normal orexin levels. Design/Methods: 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), respectively. Results: Twenty-five participants were enrolled and randomized; most were male (76.0%) and white (80.0%). The mean age was 52.4 years (standard deviation, 9.33). Proportions of participants reporting ≥1 TEAE were 21.7% (placebo), 32.0% (44 mg TAK-925) and 41.7% (112 mg TAK-925); all were mild or moderate in severity. No serious TEAEs or discontinuations due to TEAEs occurred. Urinary-related TEAEs occurred with TAK-925 44 mg (12.0%) and TAK-925 112 mg (29.2%) but not with placebo. Two participants had TEAEs of blood pressure increased. Average LS mean sleep latencies on the MWT for placebo, TAK-925 44 mg and TAK-925 112 mg were 11.45, 33.57 and 39.62 min, respectively (LS mean differences p Conclusions: Overall, a 9-hour infusion of TAK-925 44 mg or 112 mg was generally well tolerated, and significantly improved objective and subjective measurements of wakefulness versus placebo in this study population. Disclosure: Dr. Rubens has received personal compensation for serving as an employee of Takeda Pharmaceuticals. Dr. Rubens has received stock or an ownership interest from Takeda Pharmaceuticals. Dr. Olsson has received personal compensation for serving as an employee of Takeda. Rachel Neuwirth has received personal compensation for serving as an employee of Takeda. Sandy Bialek has received personal compensation for serving as an employee of Takeda Pharmaceuticals. Richard K. Bogan, MD has nothing to disclose. Dr. Maynard has nothing to disclose. HOWARD SCHWARTZ has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Icon. Dr. Alexander has received personal compensation for serving as an employee of Takeda.