Safety, tolerability, and efficacy of RIPK1 inhibitor, SAR443820, in amyotrophic lateral sclerosis (HIMALAYA): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

SAR443820 is a selective, oral, CNS-penetrant, reversible RIPK1 inhibitor.

SAR443820是一种选择性的口服中枢神经系统渗透性RIPK1抑制剂，具有可逆性。

We aimed to evaluate the safety, tolerability, and efficacy of SAR443820 in participants with ALS.

我们旨在评估SAR443820在肌萎缩侧索硬化症（ALS）患者中的安全性和耐受性。

Methods

This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at 63 clinical sites in 13 countries (Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Poland, Spain, Sweden, the UK, and the USA).

这项多中心、随机、双盲、安慰剂对照的2期试验在13个国家的63个临床站点进行（比利时、加拿大、中国、法国、德国、意大利、日本、荷兰、波兰、西班牙、瑞典、英国和美国）。

Adults (aged 18-80 years) with a diagnosis of possible ALS, clinically probable ALS, clinically probable laboratory-supported ALS, or clinically definite ALS, in accordance with the revised El Escorial World Federation of Neurology criteria, were randomly assigned (2:1) by use of a stratified block design (blocks of three) to receive either 20 mg SAR443820 orally twice per day or matching placebo in the 24-week double-blindperiod.

根据修订的El Escorial世界神经病学联盟标准，18-80岁的成年人，被诊断为可能的ALS、临床可能的ALS、临床可能的实验室支持的ALS或临床确定的ALS，按照2:1的比例，使用分层阻塞设计（阻塞大小为3），随机分配接受每天两次口服20mg的SAR443820或匹配安慰剂，为期24周的双盲期。

Randomisation was done centrally using interactive response technology and stratified by geographical region of trial site, region of ALS onset, use of riluzole, use of edaravone, and use of the combination of sodium phenylbutyrate and taurursodiol.

随机化是通过交互式响应技术在中心进行的，并根据试验地点的地理区域、ALS发病区域、使用利鲁唑、使用依达拉奉以及使用苯丁酸钠和牛磺酸的组合进行分层。

Participants, care providers, investigators, and outcomes assessors were masked to trial intervention.

参与者、护理提供者、研究人员和结果评估者对试验干预措施是盲目的。

The primary outcome was a change in ALS Functional Rating Scale Revised (ALSFRS-R) total score from baseline to week 24 and was calculated for all participants who had an ALSFRS-R total score available at baseline and at week 24.

主要结果是ALS功能评级量表修订版（ALSFRS-R）总分从基线到第24周的变化，并计算了所有在基线和第24周都有ALSFRS-R总分的参与者。

Safety analyses included all randomly assigned participants receiving one dose or more of trial intervention.

安全性分析包括所有随机分配的参与者，他们接受了一次或多次试验干预。

This trial is registered with ClinicalTrials.gov (NCT05237284) and was terminated early.

该试验已在ClinicalTrials.gov注册（NCT05237284），并已提前终止。

Results

Between April 13, 2022, and July 17, 2023, 397 participants were screened and 305 randomly assigned to SAR443820 (n=203) or placebo (n=102); six were excluded from the primary analysis due to missing baseline ALSFRS-R values.

从2022年4月13日到2023年7月17日，共有397名参与者接受了筛查，其中305名随机分配到SAR443820（n=203）或安慰剂（n=102）；由于缺少基线ALSFRS-R值，六名被排除在主要分析之外。

Mean age was 56·9 years (SD 11·5); 183 (60%) participants were male and 122 (40%) were female.

平均年龄为56.9岁（标准差11.5）；183名（60%）参与者为男性，122名（40%）为女性。

Least squares mean change in ALSFRS-R from baseline to week 24 was -6·73 (95% CI -7·48 to -5·98) for SAR443820 group (n=169) and -6·32 (-7·36 to -5·27) for placebo group (n=87).

从基线到第24周，SAR443820组（n=169）的ALSFRS-R的最小二乘平均变化为-6.73（95% CI -7.48至-5.98），安慰剂组（n=87）为-6.32（-7.36至-5.27）。

There was no statistically significant difference between the study groups (least squares mean difference -0·41 [95% CI -1·71 to 0·88]).

两个研究组之间没有统计学上的显著差异（最小二乘平均差异-0.41 [95% CI -1.71至0.88]）。

Participants in the SAR443820 group had higher incidenceof adverse events (171 [85%] of 202 vs placebo 80 [78%] of 102) and treatment discontinuations (28 [14%] of 202 vs placebo five [5%] of 102), with elevated hepatic enzymes being the most common cause.

SAR443820组的不良事件发生率较高（202名中的171名[85%]对比安慰剂102名中的80名[78%]），以及治疗中断（202名中的28名[14%]对比安慰剂102名中的五名[5%]），其中肝酶升高是最常见的原因。

Nine deaths occurred in the double-blindperiod (seven [3%] of 202 in the SAR443820 group and two [2%] of 102 in the placebo group); none was attributed to SAR443820.

在双盲期间发生了九起死亡事件（SAR443820组的202名中的七名[3%]和安慰剂组的102名中的两名[2%]）；没有一起被归因于SAR443820。

interpretation

SAR443820 did not show clinical benefit and was associated with higher hepatic enzyme increase, indicating that further clinical development of SAR443820 in ALS is not warranted.

SAR443820未显示出临床益处，并且与更高的肝酶增加相关，表明在肌萎缩侧索硬化症（ALS）中进一步开发SAR443820并不合理。

funding

Sanofi.

赛诺菲。