Intermediate-sized Expanded Access Protocol for CNM-Au8 in Amyotrophic Lateral Sclerosis (ALS).

摘要 哥伦比亚大学、Clene和Synapticure正在合作并采取创新的方法 为所有50个州的肌萎缩侧索硬化症患者提供- 包括偏远/农村地区的人-获得CNM-Au8®，一种耐受性良好的神经保护 治疗肌萎缩侧索硬化症的药物正在研究中。肌萎缩侧索硬化症是一种进行性神经退行性疾病 影响大脑和脊髓的运动神经元。对其形成机制的探讨 疾病揭示了ALS患者运动神经元的能量受损。精力充沛的迹象 运动神经元损伤先于临床表现，能量损伤是 影响线粒体功能、谷氨酸能信号、钙稳态、RNA的事件 加工/功能和蛋白平衡，导致神经元死亡。CNM-AU8是一种口服 血脑屏障穿透剂、催化活性金纳米晶给药悬浮液 研究表明，通过提高细胞内能量代谢产物的水平来保护神经元免于死亡， 烟酰胺腺嘌呤二核苷酸和三磷酸腺苷。临床前研究使用了几个 独立的遗传或化学诱导的神经退行性疾病模型 在多种神经元亚型中显示出强大的神经保护特性。两个阶段2 随机、安慰剂对照、平行组、多中心试验，调查安全性和 CNM-AU8治疗ALS的疗效观察与每个试验相关联的开放标签扩展(OLE)是 正在进行中。虽然两项试验都未能达到主要和次要结果，但两项试验的结果 研究一致证明，在疾病的预先指定的探查终点上有好处 进步和生存。CNM-Au8也一直表现出良好的安全性和耐受性 所有研究的概况，到目前为止还没有与CNM-AU8相关的严重不良事件。哥伦比亚, Clene和Synapticure提出了一项多中心、中等规模的扩展接入计划， 100例PAL中CNM-AU8的继续调查。一种创新的方法将使用多达10 全国有经验的肌萎缩侧索硬化症试验中心，与克莱恩建立了关系。它 还将通过Synapticure的虚拟诊所注册，以实现所有50个州的患者纳入。这个 这项研究的主要目的是评估一组不符合临床试验条件的PAL的安全性。 对存活率和疾病进展的临床测量的潜在影响将预先指定 并使用多个独立的、经过验证的统计模型进行评估，这些模型在 临床试验和真实的肌萎缩侧索硬化数据集。疾病进展的生物标志物，如血浆 将分析神经丝轻链(NFL)、UCHL1和血清肌酐水平，以提高 并证实了对临床结果的解释。

ABSTRACT Columbia University, Clene, and Synapticure are partnering and taking an innovative approach to provide persons living with amyotrophic lateral sclerosis ALS (pALS) across all 50 states— including those in remote/rural areas—access to CNM-Au8®, a well-tolerated neuroprotective drug being investigated for treatment of ALS. ALS is a progressive neurodegenerative disease affecting motor neurons of the brain and spinal cord. Investigations of the mechanism of this disease have revealed that motor neurons are energetically impaired in ALS. Signs of energetic impairment in motor neurons precede clinical manifestations, and energetic impairment is key to the events affecting mitochondrial function, glutamatergic signaling, calcium homeostasis, RNA processing/function, and proteostasis, leading to neuronal death. CNM-Au8 is an orally administered suspension of blood-brain barrier penetrant, catalytically active gold nanocrystals shown to protect neurons from death by raising intracellular levels of energy metabolites, nicotinamide adenine dinucleotide, and adenosine triphosphate. Preclinical studies using several independent genetic or chemically induced models of neurodegenerative disease have demonstrated robust neuroprotective properties across multiple neuronal subtypes. Two Phase 2 randomized, placebo-controlled, parallel group, multicenter trials investigated the safety and efficacy of CNM-Au8 in ALS. Open label extension (OLE) associated with each of these trials are ongoing. While both trials failed to meet primary and secondary outcomes, results from both studies consistently demonstrated benefit on prespecified exploratory endpoints of disease progression and survival. CNM-Au8 also consistently showed favorable safety and tolerability profile across all studies, with no serious adverse events related to CNM-Au8 to date. Columbia, Clene, and Synapticure propose a multicenter, intermediate-size Expanded Access Program for the continued investigation of CNM-Au8 in 100 pALS. An innovative approach will use up to 10 experienced ALS trial centers across the country that have established relationship with Clene. It will also enroll via virtual clinic by Synapticure to enable inclusion of patients in all 50 states. The primary aim of this study is to evaluate safety in a cohort of pALS that are not clinical trial eligible. Potential effects on survival and on clinical measures of disease progression will be pre-specified and assessed using multiple independent, validated statistical models that are trained on large clinical trial and real-world ALS datasets. Biomarkers of disease progression, such as plasma Neurofilament Light Chain (NfL), UCHL1, and serum creatinine levels will be analyzed to enhance and corroborate the interpretation of clinical results.