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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02977-w

摘要内容如下：

p75神经营养因子受体（p75NTR）信号通路与阿尔茨海默病（AD）中活跃的变性网络基本重叠。在临床前模型中，第一类小分子LM11A-31对p75NTR的调节减轻了淀粉样蛋白诱导和病理性Tau诱导的突触丢失。在此，我们对242名轻度至中度AD患者进行了一项为期26周的随机、安慰剂对照、双盲的2a期安全性和探索性终点试验，试验分为三组：安慰剂、200mg LM11A-31和400mg LM11A-31，每日两次口服胶囊给药。该试验达到了安全性和耐受性的主要终点。在预先指定的次要和探索性结果领域（结构磁共振成像、氟脱氧葡萄糖正电子发射断层扫描和脑脊液生物标记物）中，发现了显著的药物-安慰剂差异，这与LM11A-31减缓AD病理生理特征进展的假设一致。在认知测试中未观察到积极治疗的显著效果。总之，这些结果表明，用LM11A-31靶向p75NTR值得在更长时间的更大规模临床试验中进一步研究。欧盟临床试验注册:2015-005263-16；ClinicalTrials.gov注册：NCT03069014。

英文原文如下：

Abstracts

p75 neurotrophin receptor (p75NTR) signaling pathways substantially overlap with degenerative networks active in Alzheimer disease (AD). Modulation of p75NTR with the first-in-class small molecule LM11A-31 mitigates amyloid-induced and pathological tau-induced synaptic loss in preclinical models. Here we conducted a 26-week randomized, placebo-controlled, double-blinded phase 2a safety and exploratory endpoint trial of LM11A-31 in 242 participants with mild to moderate AD with three arms: placebo, 200 mg LM11A-31 and 400 mg LM11A-31, administered twice daily by oral capsules. This trial met its primary endpoint of safety and tolerability. Within the prespecified secondary and exploratory outcome domains (structural magnetic resonance imaging, fluorodeoxyglucose positron-emission tomography and cerebrospinal fluid biomarkers), significant drug-placebo differences were found, consistent with the hypothesis that LM11A-31 slows progression of pathophysiological features of AD; no significant effect of active treatment was observed on cognitive tests. Together, these results suggest that targeting p75NTR with LM11A-31 warrants further investigation in larger-scale clinical trials of longer duration. EU Clinical Trials registration: 2015-005263-16 ; ClinicalTrials.gov registration: NCT03069014 .

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