Ongoing phase 2 agents for multiple sclerosis: could we break the phase 3 trial deadlock?

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system. While disease-modifying therapies have significantly improved the management of relapsing MS, progressive MS remains a major clinical challenge. This review provides a general overview of recent and ongoing phase 2 clinical trials investigating treatments for MS, summarizing emerging results when available. The trials are categorized based on the desired therapeutic effect: immunomodulatory treatments, neuroprotection and remyelination. A comprehensive literature search was conducted using databases such as PubMed and ClinicalTrials.gov to identify relevant studies, with a focus on promising therapies that address both inflammatory and neurodegenerative processes in MS. Despite promising results from phase 2 trials, many phase 3 trials fail to demonstrate significant efficacy. This discrepancy is partly due to limitations in biomarkers, which often lack disease specificity and fail to predict long-term outcomes. Additionally, smaller, narrowly focused phase 2 trials may overestimate efficacy, leading to challenges when transitioning to larger, more inclusive phase 3 trials. Recruitment of patients with less aggressive disease further complicates phase 3 success. Addressing these challenges requires the refinement of biomarkers, adoption of unified definitions for outcomes like progression independent of relapse activity (PIRA), and trial designs that better capture the complexity of MS progression.