Safety, tolerability, and efficacy of alixorexton, a selective orexin 2 receptor agonist for narcolepsy type 1 (Vibrance-1): a randomised, double-blind, placebo-controlled, phase 2 trial.

Here, we aimed to evaluate the safety, tolerability, and efficacy of alixorexton, another oral OX2R agonist, in narcolepsy type 1.

在这里，我们的目标是评估另一种口服OX2R激动剂alixorexton在1型嗜睡症中的安全性和耐受性。

Methods

In this randomised, double-blind, placebo-controlled, phase 2 trial, adult participants (aged 18-70 years) with narcolepsy type 1 were recruited from 46 hospitals and private research centres across the USA, Europe, and Australia.

在这项随机、双盲、安慰剂对照的2期试验中，招募了来自美国、欧洲和澳大利亚46家医院和私人研究中心的成年参与者（年龄在18-70岁之间），他们被诊断为1型嗜睡症。

Participants were centrally randomly assigned (1:1:1:1) in blocks of four via an interactive response technology system stratified by region and baseline weekly cataplexy rate (WCR) to receive 4 mg, 6 mg, or 8 mg tablets of alixorexton or placebo once daily for 6 weeks, followed by an optional 7-week open-label extension.

参与者通过交互式响应技术系统以1:1:1:1的比例随机分配（每四人一组），根据地区和基线每周猝倒率（WCR）进行分层，接受alixorexton 4 mg、6 mg或8 mg片剂或安慰剂，每天一次，为期6周，随后是一个可选的7周开放标签扩展期。

Participants had narcolepsy type 1, diagnosed per the International Classification of Sleep Disorders, Third Edition, and confirmed by overnight polysomnography and the Multiple Sleep Latency Test or cerebrospinal hypocretin-1 concentrations.

参与者被诊断为1型嗜睡症，根据国际睡眠障碍分类第三版，并通过夜间多导睡眠图和多次睡眠潜伏期测试或脑脊液下丘脑素-1浓度进行确认。

The sponsor, assessors, investigators, and participants were masked during the randomised double-blindtreatment period.

在随机双盲治疗期间，赞助商、评估者、调查员和参与者均被蒙蔽。

Efficacy and safety assessments were conducted in participants who received at least one dose of study drug.

在至少接受了一次研究药物的参与者中进行了疗效和安全性评估。

The primary endpoint was change from baseline to week 6 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT).

主要终点是从基线到第6周在维持清醒测试（MWT）上平均睡眠潜伏期（MSL）的变化。

Safety endpoints included treatment-emergent adverse events.

安全性终点包括治疗后出现的不良事件。

This trial was registered with ClinicalTrials.gov (NCT06358950) and is completed.

该试验已在ClinicalTrials.gov上注册（NCT06358950），并已完成。

Results

Between May 24, 2024, and May 5, 2025, 153 individuals were screened and 92 participants were randomly assigned to receive alixorexton 4 mg (n=23), 6 mg (n=22), 8 mg (n=24), or placebo (n=23).

在2024年5月24日至2025年5月5日期间，共有153名个体接受了筛选，92名参与者被随机分配接受alixorexton 4 mg（n=23），6 mg（n=22），8 mg（n=24）或安慰剂（n=23）。

Mean age was 33·5 years (SD 12·1), 57 (62%) were women, and 35 (38%) were men.

平均年龄为33.5岁（标准差12.1），57名（62%）为女性，35名（38%）为男性。

At week 6, the observed MSL on the MWT was 2·3 min (SD 2·7) for placebo, 24·0 min (8·7) for alixorexton 4 mg, 25·9 min (9·4) for 6 mg, and 28·2 min (11·4) for 8 mg.

在第6周，安慰剂组在多次睡眠潜伏期试验（MSLT）上的平均睡眠潜伏期（MSL）为2.3分钟（标准差2.7），alixorexton 4 mg组为24.0分钟（标准差8.7），6 mg组为25.9分钟（标准差9.4），8 mg组为28.2分钟（标准差11.4）。

Alixorexton improved MSL on the MWT, with a least-squares mean placebo-corrected change from baseline of 22·2 min (95% CI 17·2-27·2) for alixorexton 4 mg, 24·1 min (19·0-29·1) for 6 mg, and 26·0 min (21·0-31·0) for 8 mg (adjusted p=0·0099 for 4 mg, adjusted p<0·0001 for 6 mg and 8 mg).

Alixorexton改善了MSLT上的MSL，与基线相比，alixorexton 4 mg的最小二乘平均安慰剂校正变化为22.2分钟（95%置信区间17.2-27.2），6 mg为24.1分钟（19.0-29.1），8 mg为26.0分钟（21.0-31.0）（调整后的p=0.0099对于4 mg，调整后的p<0.0001对于6 mg和8 mg）。

Treatment-emergent adverse events occurring in at least 5% of participants given alixorexton and more frequently than those given placebo up to week 6 were pollakiuria (38 [55%]), insomnia (19 [28%]), salivary hypersecretion (17 [25%]), micturition urgency (ten [14%]), blurred vision (ten [14%]), and hyperhidrosis (five [7%]).

在至少5%的给予alixorexton的参与者中，并且比给予安慰剂的参与者更频繁地出现的治疗后出现的不良事件，直到第6周，包括多尿（38 [55%]），失眠（19 [28%]），唾液分泌过多（17 [25%]），排尿急迫感（十 [14%]），视力模糊（十 [14%]），和多汗症（五 [7%]）。

interpretation

In this phase 2 trial, once-daily oral alixorexton provided clinically meaningful improvements at 6 weeks for participants with narcolepsy type 1, including in wakefulness, excessive daytime sleepiness, and cataplexy.

在这项2期试验中，每日一次口服alixorexton在6周时为1型嗜睡症患者提供了临床意义上的改善，包括清醒度，白天过度嗜睡和猝倒。

The treatment was generally well tolerated, with adverse events consistent with the known on-target effects of OX2R agonists.

治疗通常耐受性良好，不良事件与OX2R激动剂已知的靶向效应一致。

Together, these findings support the further phase 3 evaluation of alixorexton as a potential therapeutic option for people with narcolepsy type 1.

这些发现共同支持进一步进行第三阶段评估，以将alixorexton作为治疗1型嗜睡症的潜在治疗选择。

funding

Alkermes.

Alkermes。