Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease : using systematic reviews to inform expert consensus

Wong, Charis and Gregory, Jenna M and Liao, Jing and Egan, Kieren and Vesterinen, Hanna M and Ahmad Khan, Aimal and Anwar, Maarij and Beagan, Caitlin and Brown, Fraser S and Cafferkey, John and Cardinali, Alessandra and Chiam, Jane Yi and Chiang, Claire and Collins, Victoria and Dormido, Joyce and Elliott, Elizabeth and Foley, Peter and Foo, Yu Cheng and Fulton-Humble, Lily and Gane, Angus B and Glasmacher, Stella A and Heffernan, Áine and Jayaprakash, Kiran and Jayasuriya, Nimesh and Kaddouri, Amina and Kiernan, Jamie and Langlands, Gavin and Leighton, D and Liu, Jiaming and Lyon, James and Mehta, Arpan R and Meng, Alyssa and Nguyen, Vivienne and Park, Na Hyun and Quigley, Suzanne and Rashid, Yousuf and Salzinger, Andrea and Shiell, Bethany and Singh, Ankur and Soane, Tim and Thompson, Alexandra and Tomala, Olaf and Waldron, Fergal M and Selvaraj, Bhuvaneish T and Chataway, Jeremy and Swingler, Robert and Connick, Peter and Pal, Suvankar and Chandran, Siddharthan and Macleod, Malcolm (2023) Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease : using systematic reviews to inform expert consensus. BMJ open, 13 (2). e064169. ISSN 2044-6055 (

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Objectives: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol. Methods: We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART. Results: From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART. Discussion: For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.


Wong, Charis, Gregory, Jenna M, Liao, Jing, Egan, Kieren ORCID logoORCID:, Vesterinen, Hanna M, Ahmad Khan, Aimal, Anwar, Maarij, Beagan, Caitlin, Brown, Fraser S, Cafferkey, John, Cardinali, Alessandra, Chiam, Jane Yi, Chiang, Claire, Collins, Victoria, Dormido, Joyce, Elliott, Elizabeth, Foley, Peter, Foo, Yu Cheng, Fulton-Humble, Lily, Gane, Angus B, Glasmacher, Stella A, Heffernan, Áine, Jayaprakash, Kiran, Jayasuriya, Nimesh, Kaddouri, Amina, Kiernan, Jamie, Langlands, Gavin, Leighton, D, Liu, Jiaming, Lyon, James, Mehta, Arpan R, Meng, Alyssa, Nguyen, Vivienne, Park, Na Hyun, Quigley, Suzanne, Rashid, Yousuf, Salzinger, Andrea, Shiell, Bethany, Singh, Ankur, Soane, Tim, Thompson, Alexandra, Tomala, Olaf, Waldron, Fergal M, Selvaraj, Bhuvaneish T, Chataway, Jeremy, Swingler, Robert, Connick, Peter, Pal, Suvankar, Chandran, Siddharthan and Macleod, Malcolm;