Safety and efficacy of the anti-α-synuclein monoclonal antibody amlenetug for the treatment of patients with multiple system atrophy (AMULET): a phase 2, randomised, double-blind, multicentre trial.

We assessed the efficacy and safety of amlenetug, a monoclonal antibody targeting aggregated α‑synuclein, versus placebo in slowing clinical disease progression in people with MSA.

我们评估了靶向聚集的α-突触核蛋白的单克隆抗体amlenetug与安慰剂相比，在减缓MSA患者临床疾病进展方面的有效性和安全性。

Methods

We did a randomised, controlled, parallel-group trial (AMULET) at 18 movement disorder and autonomic dysfunction specialist sites across the USA and Japan.

我们在美国和日本的18个运动障碍和自主神经功能障碍专科中心进行了一项随机对照的平行组试验（AMULET）。

Patients aged 40-75 years with MSA who had motor symptom onset in the past 5 years were randomly assigned (2:1) to intravenous amlenetug or placebo every 4 weeks for 48-72 weeks in a common close design.

年龄在40-75岁之间，过去5年内出现运动症状的多系统萎缩（MSA）患者，按照2:1的比例随机分配接受静脉注射amlenetug或安慰剂治疗，每4周一次，持续48-72周，采用共同的封闭设计。

Randomisation was performed via an interactive response system, stratified by region and blood neurofilament light chain concentration, using a block size of three.

随机化是通过交互式响应系统进行的，按地区和血液神经丝蛋白轻链浓度进行分层，使用大小为三的块状随机化。

The double-blindtreatment period ended when the last randomised participant had concluded the week 48 visit.

双盲治疗期在最后一名随机参与者完成第48周访问时结束。

Participants, study partners, treating investigators, study site personnel, and the sponsor were masked to treatment allocation.

参与者、研究伙伴、治疗研究人员、研究现场人员以及赞助商对治疗分配情况均不知情。

The primary endpoint was disease progression, assessed using a Bayesian progression model of the longitudinal changes from baseline in the Unified Multiple System Atrophy Rating Scale (UMSARS) total (parts I and II) score up to week 72, in all participants who had a valid baseline assessment and at least one valid post-baseline assessment of UMSARS total score.

主要终点是疾病进展，使用贝叶斯进展模型评估从基线开始的纵向变化，以统一多系统萎缩评分量表（UMSARS）总分（包括第一部分和第二部分）的变化，直至第72周，所有有有效基线评估且至少有一次有效随访UMSARS总分评估的参与者均纳入评估。

Safety was assessed in all treated participants.

所有接受治疗的参与者均进行了安全性评估。

This trial is registered at ClinicalTrials.gov (NCT05104476); the open-label phase of the trial is ongoing.

该试验已在ClinicalTrials.gov注册（NCT05104476）；试验的开放标签阶段正在进行中。

Results

Between Nov 16, 2021, and Oct 6, 2022, 91 unique participants were screened, of whom 64 were randomly assigned and 61 received treatment (amlenetug n=40; placebo n=21).

在2021年11月16日至2022年10月6日期间，共有91名独特参与者接受了筛查，其中64人被随机分配，61人接受了治疗（amlenetug组40人；安慰剂组21人）。

Among treated participants, mean age was 60·8 years (SD 7·7); 32 (52%) were male and 29 (48%) female. 48 (79%) of 61 participants completed double-blindtreatment (mean 56 weeks [SD 13] treatment).

在接受治疗的参与者中，平均年龄为60.8岁（标准差7.7）；32人（52%）为男性，29人（48%）为女性。61名参与者中有48人（79%）完成了双盲治疗（平均治疗时间为56周，标准差为13周）。

The Bayesian probability of 89·4% for a true slowing of clinical disease progression did not reach the predefined threshold of 97·5%, and accordingly, the primary endpoint was not met.

贝叶斯概率为89.4%的真实疾病进展减缓，并未达到预设的97.5%阈值，因此，主要终点未达成。

The effect parameter of 0·81 (2·5th to 97·5th percentile 0·56 to 1·13) equates to a non-significant slowing of clinical progression by 19% (2·5th to 97·5th percentile -13 to 44) for amlenetug versus placebo.

与安慰剂相比，amlenetug的效果参数为0.81（2.5至97.5百分位数为0.56至1.13），相当于临床进展的非显著性减缓19%（2.5至97.5百分位数为-13至44）。

Amlenetug was generally well tolerated, with comparable rates of treatment‑emergent adverse events (n=40 [100%] with amlenetug vs n=20 [95%] with placebo) and serious treatment‑emergent adverse events (n=12 [30%] vs n=7 [33%]).

Amlenetug通常耐受性良好，治疗相关不良事件的发生率（amlenetug组40例[100%]对比安慰剂组20例[95%]）和严重治疗相关不良事件的发生率（amlenetug组12例[30%]对比安慰剂组7例[33%]）相当。

The most common treatment-emergent adverse events were COVID‑19 infection (n=11 [28%] vs n=5 [24%]), back pain (n=6 [15%] vs n=2 [10%]), headache (n=5 [13%] vs n=1 [5%]), urinary tract infection (n=4 [10%] vs n=3 [14%]), peripheral oedema ([n=4] 10% vs n=1 [5%]), flushing (n=4 [10%] vs 0), and hypertension (n=4 [10%] vs 0).

最常见的治疗相关不良事件是COVID‑19感染（amlenetug组11例[28%]对比安慰剂组5例[24%]）、背痛（amlenetug组6例[15%]对比安慰剂组2例[10%]）、头痛（amlenetug组5例[13%]对比安慰剂组1例[5%]）、尿路感染（amlenetug组4例[10%]对比安慰剂组3例[14%]）、周围水肿（amlenetug组4例[10%]对比安慰剂组1例[5%]）、潮红（amlenetug组4例[10%]对比0例），以及高血压（amlenetug组4例[10%]对比0例）。

Two deaths occurred in each group, with only one death, in the placebo group, considered possibly treatment related.

每个组中发生了两例死亡，其中安慰剂组中只有一例死亡被认为可能与治疗有关。

interpretation

Although the trial did not meet its primary endpoint, the statistically non-significant finding of potentially slowed clinical progression, together with an acceptable safety profile, supported further evaluation in a phase 3 trial.

尽管该试验未达到其主要终点，但潜在减缓临床进展的统计学上非显著性发现，加上可接受的安全性档案，支持在第三阶段试验中进一步评估。

funding

H Lundbeck.

H Lundbeck 公司。