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

CNM-Au8 在肌萎缩侧索硬化症 (ALS) 中的中等规模扩展访问协议。

• 批准号: 10835565
• 负责人: Eric Anderson
• 金额: $ 1119.22万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-25 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10835565
• 关键词: ALS patients; Address; Adenosine Triphosphate; Adverse event; Affect; Amyotrophic Lateral Sclerosis; Biological Markers; Blood - brain barrier anatomy; Brain; Calcium; Cells; Cessation of life; Characteristics; Chemicals; Clinic; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Collaborations; Country; Creatinine; Data; Data Science; Data Set; Disease; Disease Progression; Dose; Eligibility Determination; Energy Metabolism; Enrollment; Enteral Feeding; Evaluation; Event; Frequencies; Genetic; Goals; Health Services; Homeostasis; Impairment; Improve Access; Infrastructure; Investigation; Light; Measures; Metabolism; Methods; Mitochondria; Modeling; Monitor; Motor Neurons; Multicenter Trials; Neurodegenerative Disorders; Neurons; Neuroprotective Agents; Nicotinamide adenine dinucleotide; Oral; Oral Administration; Outcome Measure; Oxidative Stress; Participant; Patients; Persons; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Placebo Control; Plasma; Population; Property; Protocols documentation; RNA Processing; Randomized; Resources; Safety; Sampling; Serious Adverse Event; Serum; Specific qualifier value; Spinal Cord; Statistical Models; Surface; Suspensions; Time; Tracheostomy procedure; Training; United States; Universities; Venous blood sampling; Visit; amyotrophic lateral sclerosis therapy; arm; cohort; experience; glutamatergic signaling; gradient boosting; improved; individual patient; innovation; machine learning model; medical specialties; nanoGold; nanocrystal; nanomedicine; neurofilament; neuron loss; neuroprotection; open label; pre-clinical; preclinical study; prediction algorithm; predictive modeling; primary outcome; programs; proteostasis; rural area; rural setting; safety assessment; secondary outcome; survival prediction; telehealth; ubiquitin C-terminal hydrolase; virtual

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.

抽象的 哥伦比亚大学，克莱恩和突触正在合作并采取创新的方法 为生活在所有50个州的肌萎缩性侧索硬化症（PAL）的人提供服务 - 包括在偏远/农村地区的那些 - 访问CNM-AU8®，一种耐受性良好的神经保护 正在研究用于治疗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。调查此机制 疾病表明，运动神经元在ALS中基本受损。能量的迹象 运动神经元的损伤先于临床表现，能量损害是 影响线粒体功能，谷氨酸能信号传导，钙稳态，RNA的事件 CNM-AU8是口头 施用血脑屏障渗透剂，催化活性金纳米晶体的悬浮液 通过提高细胞内能量代谢产物来保护神经元免受死亡的影响， 临床前研究使用几个 独立的遗传或化学诱导的神经退行性疾病模型具有 在多个神经元亚型中表现出强大的神经保护特性。两个阶段2 随机，安慰剂对照，并行组，多中心试验研究了安全性和 CNM-AU8在ALS中的功效。与这些试验相关的每个试验的开放标签扩展（OLE）是 正在进行。虽然这两个试验都无法满足主要和次要结果，但两者的结果 研究始终证明了对疾病的预定探索终点的好处 进展和生存。 CNM-AU8也始终显示出有利的安全性和耐受性 在所有研究中的概况，迄今为止，没有与CNM-AU8有关的严重不良事件。哥伦比亚， Clene和Sentapticure提案是多中心，中型扩展的访问程序 CNM-AU8在100个好朋友中的持续投资。一种创新的方法最多将使用10 在全国范围内经验丰富的ALS试验中心，与克莱恩建立了关系。它 还将通过突触通过虚拟诊所注册，以便在所有50个州中纳入患者。这 这项研究的主要目的是评估不符合临床试验的一系列PAL中的安全性。 对生存和对疾病进展的临床测量的潜在影响将被预先指定 并使用多个独立的，经过验证的统计模型进行评估，这些模型经过大型培训 临床试验和现实世界ALS数据集。疾病进展的生物标志物，例如血浆 将分析神经丝轻链（NFL），UCHL1和血清肌酐水平以增强 并证实了临床结果的解释。