Current and emerging disease-modulatory therapies and treatment targets for multiple sclerosis

The treatment of multiple sclerosis (MS), the most common chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS), continues to transform. In recent years, a number of novel and increasingly effective disease-modulatory therapies (DMTs) have been approved, including oral fumarates and selective sphingosine 1-phosphate modulators, as well as cell-depleting therapies such as cladribine, anti-CD20 and anti-CD52 monoclonals. Amongst DMTs in clinical development, inhibitors of Bruton's tyrosine kinase represent an entirely new emerging drug class in MS, with three different drugs entering phase III trials. However, important remaining fields of improvement comprise tracking of long-term benefit-risk with existing DMTs and exploration of novel treatment targets relating to brain inherent disease processes underlying the progressive neurodegenerative aspect of MS, which accumulating evidence suggests start already early in the disease process. The aim here is to review current therapeutic options in relation to an improved understanding of the immunopathogenesis of MS, also highlighting examples where controlled trials have not generated the desired results. An additional aim is to review emerging therapies undergoing clinical development, including agents that interfere with disease processes believed to be important for neurodegeneration or aiming to enhance reparative responses. Notably, early trials now have shown initial evidence of enhanced remyelination both with small molecule compounds and biologicals. Finally, accumulating evidence from clinical trials and post-marketing real-world patient populations, which underscore the importance of early high effective therapy whilst maintaining acceptable tolerability, is discussed.