Andrews Jinsy, Paganoni Sabrina, Macklin Eric A, Chibnik Lori B, Quintana Melanie, Saville Benjamin R, Detry Michelle A, Vestrucci Matteo, Marion Joseph, McGlothlin Anna, Young Eufrosina, Chase Marianne, Pothier Lindsay, Harkey Brittney, Yu Hong, Sherman Alex, Shefner Jeremy, Hall Meghan, Kittle Gale, Connolly Mariah R, Berry James D, D'Agostino Derek, Tustison Eric, Giacomelli Elisa, Scirocco Erica, Alameda Gustavo, Locatelli Eduardo, Ho Doreen, Quick Adam, Heitzman Daragh, Ajroud-Driss Senda, Appel Stanley H, Shroff Sheetal, Katz Jonathan, Felice Kevin, Maragakis Nicholas J, Simmons Zachary, Goutman Stephen A, Olney Nicholas, Miller Timothy, Fernandes Joseph Americo, Ilieva Hristelina, Jawdat Omar, Weiss Michael D, Foster Laura, Vu Tuan, Ladha Shafeeq, Owegi Margaret Ayo, Newman Daniel S, Arcila-Londono Ximena, Jackson Carlayne E, Swenson Andrea, Heiman-Patterson Terry, Caress James, Fee Dominic, Peltier Amanda, Lewis Richard, Rosenfeld Jeffrey, Walk David, Johnson Kristin, Elliott Matthew, Kasarskis Edward J, Rutkove Seward, McIlduff Courtney E, Bedlack Richard, Elman Lauren, Goyal Namita A, Rezania Kourosh, Twydell Paul, Benatar Michael, Glass Jonathan, Cohen Jeffrey A, Jones Vovanti, Zilliox Lindsay, Wymer James P, Beydoun Said R, Shah Jaimin, Pattee Gary L, Martinez-Thompson Jennifer, Nayar Shakti, Granit Volkan, Donohue Mary, Grossman Katheryn, Campbell Daniel J, Qureshi Irfan A, Cudkowicz Merit E, Babu Suma
Columbia University, New York, New York.
Sean M. Healey and AMG Center for ALS & the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
JAMA Neurol. 2025 Apr;82(4):333-343. doi: 10.1001/jamaneurol.2024.5249. Epub 2025 Feb 17.
Myeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.
To determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.
Verdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.
Eligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.
The primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale-Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.
A total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR <1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, -23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.
Results demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.
Clinical Trial Identifiers: NCT04297683 and NCT04436510.
髓过氧化物酶是活化髓样细胞中最丰富的过氧化物酶之一。髓过氧化物酶抑制剂可能通过减轻神经炎症和氧化应激来减缓神经退行性变，从而对肌萎缩侧索硬化症（ALS）产生临床益处。
确定选择性髓过氧化物酶抑制剂verdiperstat治疗ALS的安全性、耐受性和疗效。
设计、设置和参与者：verdiperstat作为HEALEY ALS平台试验的一个方案进行测试，这是一项多中心、双盲、永久性平台设计的随机临床试验，多个方案共享试验基础设施和安慰剂数据。该研究于2020年7月至2022年4月在美国的54个ALS转诊中心进行。根据修订的埃尔埃斯科里亚尔标准诊断为临床可能、很可能、实验室支持很可能或确诊ALS的成年参与者被随机分配接受verdiperstat或特定方案的安慰剂。分析中纳入了另一组同时从其他方案随机分配到安慰剂的参与者。
符合条件的参与者按3:1的比例随机分组，接受口服verdiperstat，600毫克，每日两次，或匹配的安慰剂，计划进行24周的安慰剂对照试验。
主要疗效结局是从基线到第24周疾病严重程度的变化，通过ALS功能评定量表修订版和生存的联合模型进行测量，治疗效果通过疾病率比（DRR）进行量化，DRR小于1表明verdiperstat相对于安慰剂的疾病进展减缓。
共有167名参与者（平均[标准差]年龄，58.5[11.4]岁；59名[35.3%]女性；108名[64.6%]男性）被随机分配到verdiperstat组（126名[75.4%]）或安慰剂组（41名[25.6%]）。在随机分配到verdiperstat方案的参与者中，130名（78%）完成了试验。估计的DRR为0.98（95%可信区间，0.77 - 1.24；疾病进展减缓[DRR <1]的后验概率 = 0.57）。估计verdiperstat与安慰剂相比疾病进展减缓2%（95%可信区间，-23%至24%；后验概率0.57）。verdiperstat总体上安全且耐受性良好。verdiperstat组常见的不良事件为恶心、失眠和促甲状腺素水平升高。
结果表明，verdiperstat治疗不太可能改变ALS的疾病进展。
临床试验标识符：NCT04297683和NCT04436510。
