A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis.
A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis.
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肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，有很大的未满足的患者需求。我们的目的是评估诱导间充质干细胞分泌高水平的神经营养因子（MSC-NTF），一种能够靶向多种途径的新型自体细胞疗法，是否可以安全地减缓ALS疾病的进展。这项随机化、双盲、安慰剂对照研究入组了符合修订后的埃尔埃斯科里亚标准、修订后的ALS功能评定量表（ALSFRS-R）≥25（筛选）和随机化前ALSFRS-R评分下降≥3分的ALS受试者。参与者鞘内接受了三次MSC-NTF或安慰剂治疗。主要终点通过应答者分析和安全性评价了MSC-NTF的疗效。治疗后疾病进展变化≥1.25分/月定义为临床应答。预先指定的分析利用基线ALSFRS-R 35作为亚组阈值。总体而言，MSC-NTF治疗耐受性良好;没有安全性问题。33%的MSC-NTF和28%的安慰剂参与者在28周时符合临床应答标准（比值比[OR] = 1.33，P = .45）;因此，未达到主要终点。对基线ALSFRS-R ≥ 35的受试者（n = 58）进行的预先规定的分析显示，MSC-NTF和安慰剂在28周时的临床应答率分别为35%和16%（OR = 2.6，P = 0.29）。使用MSC-NTF观察到神经炎症、神经变性和神经营养因子支持的脑脊液生物标志物的显著改善，而安慰剂不变。该研究的主要终点未达到统计学显著性。然而，一个预先指定的亚组表明，与安慰剂相比，病情较轻的MSC-NTF参与者可能保留了更多的功能。鉴于未满足的患者需求，本试验的结果需要进一步研究。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC‐NTF), a novel autologous cell‐therapy capable of targeting multiple pathways, could safely slow ALS disease progression. This randomized, double‐blind, placebo‐controlled study enrolled ALS participants meeting revised El Escorial criteria, revised ALS Functional Rating Scale (ALSFRS‐R) ≥25 (screening) and ≥3 ALSFRS‐R points decline prior to randomization. Participants received three treatments of MSC‐NTF or placebo intrathecally. The primary endpoint evaluated efficacy of MSC‐NTF through a responder analysis and safety. A change in disease progression post‐treatment of ≥1.25 points/mo defines a clinical response. A pre‐specified analysis leveraged baseline ALSFRS‐R of 35 as a subgroup threshold. Overall, MSC‐NTF treatment was well tolerated; there were no safety concerns. Thirty‐three percent of MSC‐NTF and 28% of placebo participants met clinical response criteria at 28 wk (odds ratio [OR] = 1.33, P = .45); thus, the primary endpoint was not met. A pre‐specified analysis of participants with baseline ALSFRS‐R ≥ 35 (n = 58) showed a clinical response rate at 28 wk of 35% MSC‐NTF and 16% placebo (OR = 2.6, P = .29). Significant improvements in cerebrospinal biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support were observed with MSC‐NTF, with placebo unchanged. The study did not reach statistical significance on the primary endpoint. However, a pre‐specified subgroup suggests that MSC‐NTF participants with less severe disease may have retained more function compared to placebo. Given the unmet patient need, the results of this trial warrant further investigation.
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