Safety and efficacy of TAK-925 in adults with obstructive sleep apnea who experience excessive daytime sleepiness despite adequate use of CPAP
Robert Rubens1, Tina Olsson1, Rachel Neuwirth1, Sandy Bialek1, Richard Bogan2, James Maynard3, Howard Schwartz4, Robert Alexander1
1Takeda Pharmaceutical Company Limited, 2Bogan Sleep Consultants, 3CTI Clinical Research Center, 4Research Centers of America
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<0.0001 for both TAK‑925 doses vs placebo). Mean KSS scores were statistically significantly lower (indicating decreased sleepiness) for TAK-925 44 mg and 112 mg versus placebo (both p<0.0001). Objective and subjective pharmacodynamic effects persisted and remained relatively stable over the infusion period.

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.