A Systematic Approach to Identify Neuroprotective Interventions for Motor Neuron Disease
Authors:   The Writing Committee for Repurposing Living Systematic Review – Motor Neuron Disease (ReLiSyR-MND), Wong Charis , Gregory Jenna M. , Liao Jing , Egan Kieren , Vesterinen Hanna M. , Khan Aimal Ahmad , Anwar Maarij , Beagan Caitlin , Brown Fraser , 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 Danielle , 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 , Macleod Malcolm R. 
Published: April 2022

Background

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.

Objectives

Here we detail a systematic, structured, and unbiased evidence-based approach to guide selection of drugs for clinical evaluation in the Motor Neuron Disease – Systematic Multi-arm Adaptive Randomised Trial (MND-SMART, clinicaltrials.gov registration number: NCT04302870), an adaptive platform trial.

Methods

We conducted a two-stage systematic review and meta-analysis to identify potential neuroprotective interventions. In stage one, we identified drugs from the clinical literature tested in at least one study in MND or in two or more cognate diseases with potential shared pivotal pathways (Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, or multiple sclerosis). We scored and ranked 66 drugs thus identified using a predefined framework evaluating safety, efficacy, study size and quality of studies. In stage two, we conducted a systematic review of the MND preclinical literature describing efficacy of these drugs in animal models, multicellular eukaryotic models and human induced pluripotent stem cell studies; 17 of these drugs were reported to improve survival in at least one preclinical study. An expert panel then shortlisted and ranked 22 drugs considering stage one and stage two findings, mechanistic plausibility, safety and tolerability, findings from previous clinical trials in MND, and feasibility for use in clinical trials.

Results

Based on this process, the panel selected memantine and trazodone for testing in 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 induced pluripotent stem cells.

STRENGTHS AND LIMITATIONS OF THIS STUDY

We described a systematic, evidence-based approach towards drug repurposing in motor neuron disease (MND), specifically for Motor Neuron Disease – Systematic Multi-arm Adaptive Randomised Trial (MND-SMART), a phase III multi-arm multi-stage clinical trial in MND.

Systematic reviews of clinical studies in neurodegenerative diseases and MND preclinical studies provided a robust evidence base to inform expert panel decisions on drug selection for clinical trials.

Providing a contemporary evidence base using traditional systematic reviews is challenging given their time-consuming and labour-intensive nature.

Incorporation of machine learning and automation tools for systematic reviews, and data from experimental drug screening can be helpful for future drug selection.