• Jeremy Chataway, Thomas Williams, Vivien Li, Ruth Ann Marrie, Daniel Ontaneda, and Robert J Fox.
• Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK; Medical Research Council Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK; National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK. Electronic address: j.chataway@ucl.ac.uk.
• Lancet Neurol. 2024 Mar 1; 23 (3): 277301277-301.

AbstractDespite the success of disease-modifying treatments in relapsing multiple sclerosis, for many individuals living with multiple sclerosis, progressive disability continues to accrue. How to interrupt the complex pathological processes underlying progression remains a daunting and ongoing challenge. Since 2014, several immunomodulatory approaches that have modest but clinically meaningful effects have been approved for the management of progressive multiple sclerosis, primarily for people who have active inflammatory disease. The approval of these drugs required large phase 3 trials that were sufficiently powered to detect meaningful effects on disability. New classes of drug, such as Bruton tyrosine-kinase inhibitors, are coming to the end of their trial stages, several candidate neuroprotective compounds have been successful in phase 2 trials, and innovative approaches to remyelination are now also being explored in clinical trials. Work continues to define intermediate outcomes that can provide results in phase 2 trials more quickly than disability measures, and more efficient trial designs, such as multi-arm multi-stage and futility approaches, are increasingly being used. Collaborations between patient organisations, pharmaceutical companies, and academic researchers will be crucial to ensure that future trials maintain this momentum and generate results that are relevant for people living with progressive multiple sclerosis.Copyright © 2024 Elsevier Ltd. All rights reserved.

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