期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：35
DOI：10.1073/pnas.2207531119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Despite the discovery of the orexin (hypocretin) neuropeptides in 1998 and their role in narcolepsy type 1 (NT1), current pharmacotherapy addresses only the associated symptoms and not the underlying loss of orexin. Danavorexton (TAK-925) is an orexin 2 receptor (OX2R)–selective agonist that was developed to address the loss of orexin signaling in NT1. Here, we present promising results from preclinical mouse studies through to human clinical studies, which support the therapeutic potential of OX2R-selective agonists for the treatment of NT1. Improvements in excessive daytime sleepiness were also observed in individuals with narcolepsy type 2, indicating that OX2R-selective agonists could also provide therapy for sleep disorders that involve partial or no impairment of the orexin system.
Narcolepsy type 1 (NT1) is a sleep disorder caused by a loss of orexinergic neurons. Narcolepsy type 2 (NT2) is heterogeneous; affected individuals typically have normal orexin levels. Following evaluation in mice, the effects of the orexin 2 receptor (OX2R)-selective agonist danavorexton were evaluated in single- and multiple-rising-dose studies in healthy adults, and in individuals with NT1 and NT2. In orexin/ataxin-3 narcolepsy mice, danavorexton reduced sleep/wakefulness fragmentation and cataplexy-like episodes during the active phase. In humans, danavorexton administered intravenously was well tolerated and was associated with marked improvements in sleep latency in both NT1 and NT2. In individuals with NT1, danavorexton dose-dependently increased sleep latency in the Maintenance of Wakefulness Test, up to the ceiling effect of 40 min, in both the single- and multiple-rising-dose studies. These findings indicate that OX2Rs remain functional despite long-term orexin loss in NT1. OX2R-selective agonists are a promising treatment for both NT1 and NT2.
