法国Montpellier大学Yves Dauvilliers团队近日研究了口服食欲素受体2选择性激动剂Oveporexton在1型嗜睡症中的作用。该研究于2025年5月15日发表在《新英格兰医学杂志》上。

1型嗜睡症是一种由食欲素神经元缺失引起的嗜睡症。在这项2期随机安慰剂对照试验中，1型发作性睡病患者每天接受1次或2次overporexton (TAK-861)，一种口服食欲素受体2选择性激动剂或安慰剂。主要终点是维持清醒测试（MWT）的平均睡眠潜伏期（入睡所需的时间）从基线到第8周的平均变化（范围，0至40分钟；正常≥20）。次要终点包括从基线到第8周Epworth嗜睡量表（ESS）总分的变化（范围，0至24；正常，≤10），第8周的周发作率，不良事件发生情况。

共有90名参与者接受了oveporexton治疗（23名参与者每天两次服用0.5mg；21名参与者每天二次服用2mg；23名参与者服用2mg后每天服用5mg；23名参与者服用7mg每日一次），22名参与者服用了安慰剂。从基线到第8周，MWT平均睡眠潜伏期的平均变化分别为12.5、23.5、25.4、15.0和1.2分钟（与安慰剂相比，所有比较调整后P≤0.001）。 

第8周ESS总分的平均变化分别为8.9、13.8、12.8、11.3和2.5（与安慰剂相比，所有比较的调整后P≤0.004）。第8周的每周猝倒发生率分别为4.24、3.14、2.48、5.89和8.76（与安慰剂相比，每天两次服用2 mg和2 mg后每天服用5 mg的调整后P<0.05）。与oveporexton相关的最常见不良事件是失眠（48%的参与者；大多数病例在1周内解决）、尿急（33%）和尿频（32%），没有任何肝毒性作用。

研究结果表明，在这项涉及1型嗜睡症患者的2期试验中，在8周的时间里，overporexton显著改善了清醒、嗜睡和猝倒的测量。

附：英文原文

Title: Oveporexton, an Oral Orexin Receptor 2–Selective Agonist, in Narcolepsy Type 1

Author: Yves Dauvilliers, Giuseppe Plazzi, Emmanuel Mignot, Gert Jan Lammers, Rafael del Río Villegas, Ramin Khatami, Mitsutaka Taniguchi, Anson Abraham, Yaming Hang, Harisha Kadali, Marta Lamberton, Sarah Sheikh, Ellie Stukalin, Rachel Neuwirth, Todd J. Swick, Shinichiro Tanaka, Christian von Hehn, Philipp von Rosenstiel, Hao Wang, Alice Cai, Melissa Naylor, Tina Olsson

Issue&Volume: 2025-05-15

Abstract:

BACKGROUND

Narcolepsy type 1 is a disorder of hypersomnolence caused by a loss of orexin neurons, which results in low orexin levels in the brain.

METHODS

In this phase 2, randomized, placebo-controlled trial, participants with narcolepsy type 1 received once- or twice-daily oveporexton (TAK-861), an oral orexin receptor 2–selective agonist, or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (MWT) (range, 0 to 40 minutes; normal, ≥20). Secondary end points included the change from baseline to week 8 in the Epworth Sleepiness Scale (ESS) total score (range, 0 to 24; normal, ≤10), the weekly cataplexy rate at week 8, and the occurrence of adverse events.

RESULTS

A total of 90 participants received oveporexton (0.5 mg twice daily, 23 participants; 2 mg twice daily, 21 participants; 2 mg followed by 5 mg daily, 23 participants; and 7 mg once daily, 23 participants), and 22 received placebo. The mean changes from baseline to week 8 in average sleep latency on the MWT were 12.5, 23.5, 25.4, 15.0, and 1.2 minutes, respectively (adjusted P≤0.001 for all comparisons vs. placebo). The mean changes in the ESS total score at week 8 were 8.9, 13.8, 12.8, 11.3, and 2.5, respectively (adjusted P≤0.004 for all comparisons vs. placebo). The weekly incidence of cataplexy at week 8 was 4.24, 3.14, 2.48, 5.89, and 8.76, respectively (adjusted P<0.05 for 2 mg twice daily and 2 mg followed by 5 mg daily vs. placebo). The most common adverse events associated with oveporexton were insomnia (in 48% of the participants; most cases resolved within 1 week), urinary urgency (in 33%), and urinary frequency (in 32%), without any hepatotoxic effects.

CONCLUSIONS

In this phase 2 trial involving participants with narcolepsy type 1, oveporexton significantly improved measures of wakefulness, sleepiness, and cataplexy over a period of 8 weeks.

DOI: NJ202505153921908

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2405847