TAK-861, a potent, orally available orexin receptor 2-selective agonist, produces wakefulness in monkeys and improves narcolepsy-like phenotypes in mouse models

• Published in: Scientific reports 2024-09, Vol.14 (1), p.20838-15, Article 20838
• Main Authors: Mitsukawa, Kayo, Terada, Michiko, Yamada, Ryuji, Monjo, Taku, Hiyoshi, Tetsuaki, Nakakariya, Masanori, Kajita, Yuichi, Ando, Tatsuya, Koike, Tatsuki, Kimura, Haruhide
• Format: Article
• Language: English
• Subjects: 631/154; 631/378; Administration, Oral; Agonists; Animal models; Animals; Ataxin; Cataplexy; Danavorexton; Disease Models, Animal; Humanities and Social Sciences; Humans; Male; Mice; Modafinil; multidisciplinary; Narcolepsy; Narcolepsy - drug therapy; Narcolepsy type 1; Neurotrophin 1; Orexin; Orexin receptor 2 agonist; Orexin Receptors - agonists; Orexin Receptors - metabolism; Orexins; Phenotype; Phenotypes; Science; Science (multidisciplinary); Sleep and wakefulness; Sleep disorders; TAK-861; TAK-994; Toxicity; Wakefulness - drug effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-70594-1

Narcolepsy type 1 (NT1) is associated with severe loss of orexin neurons and characterized by symptoms including excessive daytime sleepiness and cataplexy. Current medications indicated for NT1 often show limited efficacy, not addressing the full spectrum of symptoms, demonstrating a need for novel drugs. We discovered a parenteral orexin receptor 2 (OX2R) agonist, danavorexton, and an orally available OX2R agonist, TAK-994; both improving NT1 phenotypes in mouse models and individuals with NT1. However, danavorexton has limited oral availability and TAK-994 has a risk of off-target liver toxicity. To avoid off-target-based adverse events, a highly potent molecule with low effective dose is preferred. Here, we show that a novel OX2R-selective agonist, TAK-861 [ N -{(2 S ,3 R )-4,4-Difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3′,5′-trifluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide], activates OX2R with a half-maximal effective concentration of 2.5 nM and promotes wakefulness at 1 mg/kg in mice and monkeys, suggesting ~ tenfold higher potency and lower effective dosage than TAK-994. Similar to TAK-994, TAK-861 substantially ameliorates wakefulness fragmentation and cataplexy-like episodes in orexin/ataxin-3 and orexin-tTA;TetO DTA mice (NT1 mouse models). Compared with modafinil, TAK-861 induces highly correlated brain-wide neuronal activation in orexin-tTA;TetO DTA mice, suggesting efficient wake-promoting effects. Thus, TAK-861 has potential as an effective treatment for individuals with hypersomnia disorders including narcolepsy, potentially with a favorable safety profile.