Talks：

Human research and hypocretin agonist: Where are we and what can we expect?

Name：

Deborah S. Hartman

Position：

Doctor Vice President and Global Program Leader

Affiliation：

Neuroscience Takeda Pharmaceuticals Neuroscience Therapy Area at Takeda Pharmaceuticals in Cambridge, MA

Email：

Photo：

Research Interests：

Narcolepsy、Hypersomnolence、Sleep Medicine

Selected Publications：

Abstract：

The hypocretin/orexin system is a critical regulator of sleep/wake states, and Narcolepsy Type 1 (NT1) is caused by loss of the neurons producing the hypocretin/orexin neuropeptides in the lateral hypothalamus. The orexin neuropeptides regulate sleep/wakefulness, energy homeostasis, mood, stress, and reward through activation of two G-protein coupled receptors, Orexin Receptor 1 (OX1R) and Orexin Receptor 2 (OX2R). In mouse models, destruction of the orexin-producing neurons results in narcolepsy-like symptoms including fragmented sleep/wake states and cataplexy-like events. In mice, OX2R activation strongly promotes wakefulness and reduces cataplexy-like events, whereas OX1R activation may enhance rewarding behaviors and risk of addiction in mice. We recently developed TAK-925, an orexin 2 receptor-selective agonist, which significantly increased wakefulness time, reduced wakefulness fragmentation and decreased cataplexy-like episodes in orexin/ataxin-3 transgenic mice during their active phase. We are evaluating TAK-925 in Phase 1 studies to investigate its safety, tolerability, and pharmacokinetics in healthy subjects, and its pharmacodynamic effects using the Maintenance of Wakefulness Test (MWT) in individuals with Type 1 narcolepsy (clinicaltrial.gov identifier NCT03748979). We anticipate that an OX2R agonist has the potential to substantially improve orexin neurotransmission in NT1, and may reduce disease specific symptoms such as sleepiness and cataplexy.