Safety and pharmacodynamics of a single infusion of TAK-925 in adults with idiopathic hypersomnia (S1.009)

Objective: 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).

Background: 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.

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).

Results: 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.

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

Disclosure: Dr. Mignot has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Takeda. Dr. Mignot has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Jazz Pharmaceutical. Dr. Mignot has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai Pharmaceuticals, Inc. . Dr. Mignot has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Takeda. Dr. Mignot has received stock or an ownership interest from Dreem. Dr. Mignot has received stock or an ownership interest from Centessa. Dr. Bogan has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Harmony. Dr. Bogan has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Jazz. Dr. Bogan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Takeda. Dr. Bogan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Avadel. Dr. Bogan has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Merck. Dr. Bogan has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Harmony. Dr. Bogan has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Jazz. The institution of Dr. Bogan has received research support from Jazz Pharmaceuticals. The institution of Dr. Bogan has received research support from Harmony . The institution of Dr. Bogan has received research support from Philips. The institution of Dr. Bogan has received research support from Eisai. The institution of Dr. Bogan has received research support from Fresca. The institution of Dr. Bogan has received research support from Avadel. The institution of Dr. Bogan has received research support from Takeda. The institution of Dr. Bogan has received research support from Suven. The institution of Dr. Bogan has received research support from Axsome. Dr. Bogan has received intellectual property interests from a discovery or technology relating to health care. Dr. Bogan has a non-compensated relationship as a Chair with National Sleep Foundation that is relevant to AAN interests or activities. The institution of Dr. Emsellem has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GuidePoint Consulting. The institution of Dr. Emsellem has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Takeda Pharmaceuticals. The institution of Dr. Emsellem has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Harmony Bioscience. The institution of Dr. Emsellem has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Avadel . The institution of Dr. Emsellem has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Philips Respironics. The institution of Dr. Emsellem has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for NLS Pharma. The institution of Dr. Emsellem has received research support from ApniMed. The institution of Dr. Emsellem has received research support from Axsome. The institution of Dr. Emsellem has received research support from Balance. The institution of Dr. Emsellem has received research support from Expansion. The institution of Dr. Emsellem has received research support from Avadel (Flamel). The institution of Dr. Emsellem has received research support from Harmony. The institution of Dr. Emsellem has received research support from Idorsia. The institution of Dr. Emsellem has received research support from Imbrium. The institution of Dr. Emsellem has received research support from Jazz. The institution of Dr. Emsellem has received research support from Merck. The institution of Dr. Emsellem has received research support from NLS. The institution of Dr. Emsellem has received research support from Philips. The institution of Dr. Emsellem has received research support from Suven. The institution of Dr. Emsellem has received research support from Takeda. The institution of Dr. Emsellem has received research support from Vanda. Dr. Foldvary-Schaefer has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Jazz. The institution of Dr. Foldvary-Schaefer has received research support from Jazz. The institution of Dr. Foldvary-Schaefer has received research support from Suven. The institution of Dr. Foldvary-Schaefer has received research support from Takeda. Dr. Foldvary-Schaefer has received publishing royalties from a publication relating to health care. Dr. Foldvary-Schaefer has received publishing royalties from a publication relating to health care. Ms. Naylor has received personal compensation for serving as an employee of Takeda. Ms. Naylor has received stock or an ownership interest from Takeda. Rachel Neuwirth has received personal compensation for serving as an employee of Takeda. Dr. Swick has received personal compensation for serving as an employee of Takeda Pharmaceuticals. Dr. Swick has received stock or an ownership interest from Takeda Pharmaceuticals. Dr. Olsson has received personal compensation for serving as an employee of Takeda.