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ALS（帕尔斯）患者提供- 包括那些在偏远/农村地区-获得CNM-Au 8 ®，一种耐受性良好的神经保护剂， 用于治疗ALS的药物。ALS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这一机制的研究 疾病已经揭示了运动神经元在ALS中能量受损。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 影响线粒体功能的事件、线粒体能信号传导、钙稳态、RNA 加工/功能和蛋白质稳态，导致神经元死亡。CNM-Au 8是一种口服 血脑屏障渗透剂、催化活性金纳米晶体的给药悬浮液 显示通过提高细胞内能量代谢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腺苷三磷酸。临床前研究使用了几种 神经退行性疾病的独立遗传或化学诱导模型， 在多种神经元亚型中表现出强大的神经保护特性。2项ii期 随机、安慰剂对照、平行组、多中心试验研究了 CNM-Au 8在ALS中的功效。与这些试验相关的开放标签扩展（OLE） 日至今虽然这两项试验都未能达到主要和次要结局，但两项试验的结果都表明， 研究一致证明了对预先规定的疾病探索性终点的获益 进展和生存。CNM-Au 8也始终显示出良好的安全性和耐受性 在所有研究中，迄今为止没有与CNM-Au 8相关的严重不良事件。哥伦比亚， Clene和Synapticure提出了一个多中心、中等规模的扩大使用项目， 在100例帕尔斯中继续观察CNM-Au 8。一个创新的方法将使用多达10个 全国各地经验丰富的ALS试验中心已与Clene建立了关系。它 Synapticure还将通过虚拟诊所进行注册，以使所有50个州的患者都能参与进来。的 本研究的主要目的是评价不符合临床试验条件的帕尔斯队列的安全性。 将预先规定对生存期和疾病进展临床指标的潜在影响 并使用多个独立的、经过验证的统计模型进行评估，这些模型是在大型 临床试验和真实世界ALS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）、UCHL 1和血清肌酐水平，以增强 并证实临床结果的解释。

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.