The Road to Remyelination in Multiple Sclerosis: Breakthroughs, Challenges, and Considerations for Future Trial Design.

Despite major advances in multiple sclerosis (MS) treatment, disability accumulation independent of relapse activity remains a significant challenge. Chronic demyelination is a key driver of neurodegeneration and disease progression, highlighting remyelination as a promising therapeutic strategy. Collective evidence from several phase II clinical trials now indicates that remyelination is feasible in patients with MS. However, several drug development programs have yielded less robust responses than anticipated, which has limited translation of therapies into clinical practice. This underscores the need for refined trial methodologies, including careful selection of patient populations, validation of biomarkers, and implementation of functional outcomes that accurately capture remyelination effects. In this review, we summarize the current understanding of remyelination mechanisms, assess the therapeutic landscape, and discuss strategies to improve clinical trial design. Addressing key questions-such as the optimal timing, patient selection, and methods of measurement-will be crucial for advancing the field and ushering in a new wave of MS therapeutics.