Selecting amantadine as the 3rd experimental arm for MND-SMART using a data-driven framework

<h3></h3> There is a pressing need to identify effective disease modifying treatments for motor neuron disease (MND). Motor Neuron Disease-Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART; NCT04302870) is a phase III multi-arm multi-stage trial testing a pipeline of candidate drugs. Building upon systematic reviews to inform initial drug selection, we aimed to develop and implement a multimodal data-driven framework to inform ongoing selection. We gathered, synthesised, integrated and reported evidence from published literature through Repurposing Living Systematic Review (ReLiSyR-MND), in vitro high throughput drug screening, pathway and network analysis, and mining drug, chemical and clinical trial registry databases. We identified candidate drugs (ReLiSyR: 303, drug screening: 287, network analysis: 1144). We longlisted 49 drugs and synthesised further evidence across domains. We shortlisted 9 drugs and selected amantadine for evaluation in MND-SMART. Amantadine showed good efficacy and safety across 59 clinical publications, reduced TDP-43 aggregates on in vitro screening and was predicted to be active on multiple targets associated with MND. Amantadine was added as the third experimental arm of MND-SMART in April 2023. We demonstrated the feasibility and synergistic benefits of a systematic, multimodal, data-driven framework to inform drug selection for MND clinical trials, with potential for application across other disease areas.