Suppr
超能文献

1 型发作性睡病中的口服食欲素受体 2 激动剂。

Oral Orexin Receptor 2 Agonist in Narcolepsy Type 1.

机构信息

From the Sleep and Wake Disorders Center, Department of Neurology, Gui de Chauliac Hospital, and the University of Montpellier, INSERM Institute for Neurosciences of Montpellier - both in Montpellier, France (Y. Dauvilliers); the Stanford Department of Psychiatry and Behavioral Sciences, Center for Sleep Sciences and Medicine, Stanford University Medical School, Palo Alto, CA (E.M.); the Neurophysiology and Sleep Disorders Unit, Vithas Hospitals, and Universidad CEU San Pablo, CEU Universities - both in Madrid (R.R.V.); Takeda Development Center Americas, Lexington (Y. Du, E.H., H.K., E.K., S.M., R.R., S.I.S., T.S., P.R., J.W., H.Z., N.V.M., C.H.), and the Department of Neurology, Division of Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston (T.E.S.) - both in Massachusetts; Japan Somnology Center, Institute of Neuropsychiatry, and the Department of Somnology, Tokyo Medical University - both in Tokyo (Y.I.); the State Health Center, Budapest, Hungary (Z.S.); and IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, and the Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, Modena - both in Italy (G.P.).

出版信息

N Engl J Med. 2023 Jul 27;389(4):309-321. doi: 10.1056/NEJMoa2301940.

DOI:10.1056/NEJMoa2301940

PMID:37494485

Abstract

BACKGROUND

Narcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides.

METHODS

We conducted a phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2-selective agonist, in patients with narcolepsy type 1. Patients with confirmed narcolepsy type 1 according to clinical criteria were randomly assigned to receive twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) 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 (range, 0 to 40 minutes; normal ability to stay awake, ≥20 minutes). Secondary end points included the change in the Epworth Sleepiness Scale (ESS) score (range, 0 to 24, with higher scores indicating greater daytime sleepiness; normal, <10) and the weekly cataplexy rate.

RESULTS

Of the 73 patients, 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo. The phase 2 trial and an extension trial were terminated early owing to hepatic adverse events. Primary end-point data were available for 41 patients (56%); the main reason for missing data was early trial termination. Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes in the 30-mg group, 27.4 minutes in the 90-mg group, 32.6 minutes in the 180-mg group, and -2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30-mg group, 29.9 minutes in the 90-mg group, and 35.0 minutes the 180-mg group; P<0.001 for all comparisons). Least-squares mean changes to week 8 in the ESS score were -12.2 in the 30-mg group, -13.5 in the 90-mg group, -15.1 in the 180-mg group, and -2.1 in the placebo group (difference vs. placebo, -10.1 in the 30-mg group, -11.4 in the 90-mg group, and -13.0 in the 180-mg group). Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group). A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urinary urgency or frequency. Clinically important elevations in liver-enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy's law criteria occurred in 3 patients.

CONCLUSIONS

In a phase 2 trial involving patients with narcolepsy type 1, an orexin receptor 2 agonist resulted in greater improvements on measures of sleepiness and cataplexy than placebo over a period of 8 weeks but was associated with hepatotoxic effects. (Funded by Takeda Development Center Americas; TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov numbers, NCT04096560 and NCT04820842.).

摘要

背景

1 型发作性睡病是由严重缺乏或丧失脑源性食欲素神经肽引起的。

方法

我们进行了一项为期 2 期、随机、安慰剂对照的 TAK-994 试验，TAK-994 是一种口服食欲素受体 2 选择性激动剂，用于 1 型发作性睡病患者。根据临床标准确诊为 1 型发作性睡病的患者被随机分配接受每日两次口服 TAK-994（30mg、90mg 或 180mg）或安慰剂。主要终点是从基线到第 8 周维持觉醒试验（范围为 0 至 40 分钟；正常保持清醒的能力，≥20 分钟）上平均睡眠潜伏期的平均变化。次要终点包括 Epworth 嗜睡量表（ESS）评分的变化（范围为 0 至 24，分数越高表示白天嗜睡越严重；正常，<10）和每周猝倒的发生率。

结果

在 73 名患者中，17 名患者接受了每日两次 30mg 的 TAK-994 治疗，20 名患者接受了每日两次 90mg 的 TAK-994 治疗，19 名患者接受了每日两次 180mg 的 TAK-994 治疗，17 名患者接受了安慰剂治疗。由于肝不良事件，2 期试验和扩展试验提前终止。主要终点数据可用于 41 名患者（56%）；数据缺失的主要原因是试验提前终止。在 MWT 上，8 周时平均睡眠潜伏期的最小二乘均数变化在 30mg 组为 23.9 分钟，90mg 组为 27.4 分钟，180mg 组为 32.6 分钟，安慰剂组为-2.5 分钟（与安慰剂相比的差异，30mg 组为 26.4 分钟，90mg 组为 29.9 分钟，180mg 组为 35.0 分钟；所有比较均 P<0.001）。8 周时 ESS 评分的最小二乘均数变化在 30mg 组为-12.2，90mg 组为-13.5，180mg 组为-15.1，安慰剂组为-2.1（与安慰剂相比的差异，30mg 组为-10.1，90mg 组为-11.4，180mg 组为-13.0）。第 8 周时每周猝倒的发生率在 30mg 组为 0.27，90mg 组为 1.14，180mg 组为 0.88，安慰剂组为 5.83（与安慰剂相比的发生率，30mg 组为 0.05，90mg 组为 0.20，180mg 组为 0.15）。56 名接受 TAK-994 治疗的患者中有 44 名（79%）发生了不良事件，最常见的是尿急或尿频。5 名患者出现了肝酶水平的临床显著升高，3 名患者出现了符合 Hy's 法则的药物性肝损伤。

结论

在一项涉及 1 型发作性睡病患者的 2 期试验中，与安慰剂相比，食欲素受体 2 激动剂在 8 周的时间内使睡眠和猝倒的测量指标有了更大的改善，但与肝毒性作用有关。（由武田开发中心美洲公司资助；TAK-994-1501 和 TAK-994-1504 临床试验.gov 编号，NCT04096560 和 NCT04820842）。