近期，HEALEY肌萎缩侧索硬化症平台试验写作委员会Jasdeep Kaur研究组研究了σ1受体激动剂普利多匹定治疗肌萎缩侧索硬化症的疗效与安全性。该项研究成果发表在2025年2月17日出版的《美国医学会杂志》上。

肌萎缩侧索硬化症（ALS）是一种致命的疾病。sigma-1 （σ1）受体成为干预的目标。

为了探讨σ1受体激动剂普利多匹定在ALS中的作用，2021年1月至2022年7月，研究组在美国54个地点进行了一项临床2/3期、多中心、随机、双盲、平台试验（最终随访时间为2022年7月14日）。共有163名ALS患者被随机分为普利多匹定组和安慰剂组。另外122名同时随机分配的参与者在其他方案中接受安慰剂，并纳入分析。

将符合条件的参与者按3：1随机分配，接受口服普利多匹定45 mg，每日两次（n = 121）或相匹配的口服安慰剂（n = 42），计划持续24周。主要疗效终点是从基线到第24周ALS疾病严重程度的变化，使用贝叶斯共享参数模型进行分析，该模型具有功能（修订肌萎缩侧索硬化症功能评定量表[ALSFRS-R]）和生存的组成部分，通过对治疗依赖性疾病减缓的综合估计将这两个组成部分联系起来。这被表示为发病率比（DRR），当DRR小于1时，表明相对于安慰剂，普利多匹定的疾病进展减慢。

有5个关键次要终点：基线时有延髓功能障碍的参与者的ALSFRS-R总分下降2分或以上的时间，基线时有延髓功能障碍的参与者的慢肺活量下降率，基线时ALSFRS-R延髓区域评分没有恶化的参与者的百分比，ALSFRS-R延髓区域评分达到1分或以上变化的时间，以及死亡或永久辅助通气的时间。

研究组共招募162例患者（平均年龄57.5岁）；其中136例（84%）患者完成了试验。在比较普利多匹定与联合安慰剂组的主要分析中，在主要终点，普利多匹定与安慰剂之间的主要终点没有显著差异（DRR， 0.99[95%可信区间，0.80-1.21]；DRR<1，P=0.55），ALSFRS-R的组成部分和生存率没有差异。在次要终点上，普利多匹定没有益处。在安全性数据集中（普利多匹定，n=121；安慰剂组，n=163），最常见的不良事件是跌倒（分别为28.1%对29.3%）和肌肉无力（分别为24.0%对31.7%）。

研究结果表明，在这项为期24周的研究中，普利多匹定不能改善ALS的进展。

Title: Pridopidine in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial

Author: Writing Committee for the HEALEY ALS Platform Trial, Douglas Hayden, Po-Ying Lai, Rachel A. Donahue, Hao-Wun Chen, Jianing Wang, Nithya Mathai, Gabriela Lopes, Alexandra McCaffrey, Jennifer Scalia, Sarah Luppino, Clotilde Lagier-Tourenne, Ghazaleh Sadri-Vakili, Stephen Kolb, Sarah Heintzman, Robert Sufit, April Szymanski, Liberty Jenkins, Alan Martin, Ericka (Simpson) Greene, Jason R. Thonhoff, Bing Liao, Charles Whitaker, Lora L. Clawson, Alpa Uchil, Kristen M. Riley, JinAe Arneklev, James Grogan, Xiaowei Su, Mansoureh Mamarabadi, Amber Malcolm, Tracy Bazan, Nassim Rad, Leo H. Wang, Eva L. Feldman, Ezequiel Piccione, Pariwat Thaisetthawatkul, Constantine Farmakidis, Duaa Jabari, Jeffrey Statland, Mamatha Pasnoor, Mazen Dimachkie, Robert H. Brown, Jr., Mehdi Ghasemi, Hajar Houmani, Catherine Douthwright, Kate Daniello, Niraja Suresh, Jerrica Farias, I-Hweii A. Chen, Piera Pasinelli, Kara Steijlen, Ratna Bhavaraju-Sanka, Bill Jacobsen, Jourdan Milliard, Robert Bowser, Anahita Deboo, Michael S. Cartwright, Christopher Nance, Ludwig Gutmann, Julia Yasek, Matthew Harms, Matthew Burford, Frank Diaz, David Shrilla, Goran Rakocevic, Sarah Jones, Guillermo Solorzano, Xiaoyan Li, Zabeen Mahuwala, Vishakhadatta (Vish) Mathur Kumaraswamy, Colin Quinn, Michael Baer, David Borg, Karthikeyan Bhuvaneswaran, Jasdeep Kaur

Issue&Volume: 2025-02-17

Abstract:

Importance  Amyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.

Objective  To determine the effects of pridopidine, a σ1-receptor agonist, in ALS.

Design, Settings, and Participants  Pridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.

Interventions  Eligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n=121) or matching oral placebo (n=42) for a planned duration of 24 weeks.

Main Outcomes and Measures  The primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.

Results  Among 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR <1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n=121; placebo, n=163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).

Conclusions and Relevance  In this 24-week study, pridopidine did not impact the progression of ALS.

DOI: 10.1001/jama.2024.26429

Source: https://jamanetwork.com/journals/jama/fullarticle/2830509