Failed, inconclusive or interrupted trials in multiple sclerosis: 2020-2024 update

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by inflammation, demyelination, and neuronal loss, with significant public health impact. Despite important therapeutic advances, major unmet needs remain, mainly in targeting neurodegeneration, blocking progression independent of relapse activity and fostering remyelination. Several compounds tested to address some of these processes yielded negative or inconclusive results, forcing researchers, clinicians and industry to look for alternative molecules to alter key underlying pathways. The aim of this study was to examine trials that failed due to negative or inconclusive results between October 2019 and October 2024. A literature review was conducted using MEDLINE, clinical trial databases, and international conference proceedings to identify both published and unpublished failed phases I-III and randomized controlled trials, which were analyzed based on their primary study endpoints. Studies that focused solely on secondary outcomes of MS, such as spasticity or cognitive impairment, were excluded. 17 distinct investigational agents were identified, spanning across seven therapeutic classes: immune- active agents, neuroprotective/metabolic modulators, remyelination antibodies, hormones, antivirals, vitamins/ nutraceuticals, and regenerative growth factors. Although some compounds demonstrated biological activity—such as reduced MRI lesion counts with Bruton’s tyrosine kinase inhibitors or improved visual evoked potentials with remyelination antibodies—none met their pre-specified primary endpoints in adequately powered settings. Safety concerns, heterogeneous patient populations and insensitive traditional endpoints further limited trial success. In conclusion, while many novel therapies have demonstrated mechanistic promise in MS, key challenges remain in producing durable outcomes on disability accumulation, ensuring drug tolerability, promoting sustained repair and achieving commercial viability.