HEALEY肌萎缩侧索硬化症平台试验写作委员会Jasdeep Kaur研究小组探讨了金纳米晶体悬浮液CNM-Au8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》。

生物能量衰竭被认为是肌萎缩侧索硬化症（ALS）的驱动因素。CNM-Au8是一种金纳米晶体悬浮液，催化烟酰胺腺嘌呤二核苷酸氢化物转化为NAD⁺，导致细胞三磷酸腺苷产量增加。

为了探讨CNM-Au8对ALS疾病进展的影响，2020年7月至2022年3月，研究组在美国54个地点进行了一项2/3期、多中心、随机、双盲平台试验（最终随访时间为2022年3月17日）。共有161名ALS患者被随机分配接受CNM-Au8 （n = 120）或方案特异性安慰剂（n = 41）。来自123名同时随机分配的其他方案安慰剂参与者的数据被合并分析。

将符合条件的参与者以3:3:2的比例随机分配，接受CNM-Au8每天60毫克（n = 61），CNM-Au8每天30毫克（n = 59），或匹配安慰剂（n = 41），持续24周。主要疗效指标是通过贝叶斯共享参数模型（基于修订的肌萎缩侧索硬化症功能评定量表）和生存率测量的ALS疾病严重程度从基线到第24周的变化，该模型提供了通过疾病发病率比（DRR）测量的疾病进展率的估计，DRR小于1表明治疗获益。次要终点包括使用联合秩检验的功能和生存综合评估、慢肺活量下降率（预测百分比）和无永久性辅助通气的生存。

在随机分配到CNM-Au8方案的161名参与者中（平均年龄58.4岁；61例（37.9%）女性），145例（90%）完成试验。在比较CNM-Au8联合剂量组与联合安慰剂组的初步分析中，主要终点（DRR， 0.97[95%可信区间，0.783-1.175]；DRR的后验概率（1,0.65））和3个次要终点提示CNM-Au8无益处或危害。在积极组（n = 120）和安慰剂组（n = 163）中，最常见的不良事件是腹泻（23[19%]对12[7%]）、恶心（17[14.2%]对14[8.6%]）、疲劳（12[10.8%]对30[18.4%]）和肌肉无力（24[20%]对45[27.6%]）。

研究结果表明，24周时未观察到CNM-Au8对ALS疾病进展的益处。

Title: CNM-Au8 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, 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  Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD+, resulting in an increase of cellular adenosine triphosphate production.

Objective  To determine the effects of CNM-Au8 on ALS disease progression.

Design, Setting, and Participants  CNM-Au8 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 July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n=120) or regimen-specific placebo (n=41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses.

Interventions  Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n=61), CNM-Au8 30 mg daily (n=59), or matching placebo (n=41) for 24 weeks.

Main Outcomes and Measures  The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation.

Results  Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR <1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n=120) vs placebo (n=163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]).

Conclusions and Relevance  No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks.

DOI: 10.1001/jama.2024.27643

Source: https://jamanetwork.com/journals/jama/fullarticle/2830508