Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, characterised by the progressive degeneration of upper and lower motor neurons. Its progression leads to severe and debilitating motor impairment. Current pharmacological therapies, while not curative, are primarily designed to attenuate and alleviate its associated symptoms. Despite recent therapeutic approvals, existing studies have only evaluated these therapies in isolation, leaving the therapeutic hierarchy of performance for patients unresolved. This study provides the first comparative evaluation of the four approved ALS therapies (Riluzole, Edaravone, AMX0035, and Tofersen).

Methods: A systematic review and (network) meta-analysis synthesis were conducted in accordance with the PRISMA 2020 guidelines. To identify relevant research articles, database searches were conducted on PubMed, COCHRANE Library, Embase, ICTRP, CT.gov. Pairwise (PMA) and Network (NMA) meta- analyses were conducted to examine the individual efficacy of each of the included therapies (assessing functional outcomes, respiratory function, and muscle strength) and to comparatively assess these therapies, respectively.

Results: Of the 1,442 articles, 10 met the inclusion criteria. The PMA found that all the therapies displayed improved functional outcomes relative to placebo. On respiratory function decline, only AMX0035 and Tofersen showed a statistically significant beneficial effect. For muscle strength decline, only Edaravone was found to exert a statistically significant effect. The NMA, as assessed by ALSFRS-R scores, ranked the efficacy of AMX0035 first, followed by Edaravone and Tofersen, although overall differences were not statistically significant for all included therapies - Riluzole: n/a.

Conclusion: The efficacy of current ALS therapies although appear to confer beneficial effects, the limited sample size warrants cautious interpretation of the results. Nonetheless, the combination therapy, AMX0035, being revealed as the most effective treatment highlights the therapeutic potential of combination approaches targeting multiple pathological mechanisms in ALS.

Nevin Essel Boakye is a second-year graduate-entry medical student at the University of Nottingham. He recently completed a BSc in Biomedical Science at the University of Leicester, graduating with First- Class Honours. His dissertation - “The Efficacy of Current Pharmacological Therapies for ALS: A Systematic Review and Meta-analysis”- ranked in the top 5% of his cohort and sparked a deep interest in evidence-based approaches to neurological disease. Originally from Ghana and raised in London, Nevin brings a strong foundation in clinical science and a lived understanding of resilience, having self-funded both degrees through part-time work. He aspires to pursue a surgical career, with particular interest in neurosurgery or orthopaedics. This will be his first academic presentation, marking the start of a journey into clinical research and academic surgery.