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

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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.