Emerging MS Treatments Offer New Hope for Progressive Disease

A wave of new treatments under investigation could reshape the landscape for multiple sclerosis (MS), particularly for patients with progressive forms of the disease—where current therapies fall short. A recent review analyzed 67 clinical trials exploring therapies that go beyond traditional immunomodulation, targeting myelin repair, neuroprotection, and central nervous system (CNS)–resident immune cells.¹

According to the Multiple Sclerosis International Federation, approximately 2.9 million people worldwide are living with MS—a significant increase from 2.3 million in 2013. | Image credit: Juan Gärtner - stock-adobe.com

According to the Multiple Sclerosis International Federation, approximately 2.9 million people worldwide are living with MS—a significant increase from 2.3 million in 2013.² This rise is largely attributed to better diagnostic tools and longer life expectancy among individuals with MS.

One of the most closely watched drug classes in development is Bruton tyrosine kinase inhibitors (BTKis). Tolebrutinib, a BTKi that can cross the blood-brain barrier, showed a significant effect in slowing confirmed disability progression (CDP) in individuals with nonrelapsing secondary progressive MS (nrSPMS).¹ The drug acts on microglia, macrophages, and B cells inside the CNS, suggesting a mechanism that may address progression independent of relapses. Despite the encouraging data, concerns over liver toxicity remain under investigation.

Other BTKis are also in late-stage trials. Evobrutinib failed to outperform teriflunomide in reducing relapses, but early results for fenebrutinib and remibrutinib point to potential in limiting lesion activity.

Efforts to repair myelin and protect nerves are also gaining traction. Although no remyelination therapy has shown significant benefit in phase 3 trials yet, researchers are optimistic about compounds like clemastine fumarate and metformin, which are being studied in combination for their potential to stimulate myelin repair. Novel agents PIPE-307 and PIPE-791, targeting CNS receptor pathways, are also being tested for neuroprotective effects.

Immune modulation continues to be a key area of interest. Vidofludimus calcium is in phase 3 trials for relapsing MS and phase 2 for progressive MS, with early indications of a better safety profile than current standards. Frexalimab is being evaluated in both relapsing and nonrelapsing SPMS. Simvastatin, once considered a possible low-cost option for progressive MS, failed to slow disability in a recent phase 3 study.

Targeting B cells with newer-generation therapies is another focus. Several monoclonal antibodies are in development, including LY3541860, a nondepleting anti-CD19 agent; RO7121932, which uses brain-shuttle technology to improve CNS penetration; and obexelimab, aimed at reducing lesion burden in relapsing MS.

Researchers are also exploring the potential of the gut microbiome and dietary supplements. N-acetyl cysteine is being tested in progressive MS for its impact on brain and spinal cord atrophy. A phase 2 study is also examining the effects of conjugated linoleic acid combined with probiotics in relapsing MS.

On the cell therapy front, autologous hematopoietic stem cell transplantation continues to show potential for inducing remission in relapsing MS by resetting the immune system. Mesenchymal stem cells, delivered intravenously or via intrathecal injection, are being investigated for their regenerative and protective properties. CAR T cell therapy has also been used on a compassionate basis in MS cases.

Although current MS therapies have brought significant improvements for relapsing disease, the progressive forms have remained harder to treat. With several new therapies advancing through trials—particularly BTKis like tolebrutinib—experts are hopeful that the next generation of MS treatments could finally deliver solutions for slowing or halting progression and restoring function.

A second review (Sabatino, et al), published in Annals of Neurology around the same time, echoes many of these themes and highlights how MS treatment has evolved from symptom management to the pursuit of prevention and repair.³ The authors credited monoclonal antibody therapies—especially anti-CD20 agents like ocrelizumab and ofatumumab—with transforming care in relapsing MS, while acknowledging their limited impact in progressive forms. Sabatino, et al emphasized the growing role of CNS-compartmentalized inflammation, driven by microglia, in driving “silent progression” even in the absence of relapses. The authors also pointed to future directions such as CAR T cell therapies and potential primary prevention strategies, including targeting Epstein-Barr virus and presymptomatic biomarkers.

References

1. Cree B, Hartung H-P. Update on novel multiple sclerosis treatments: from dismal defeat to scintillating success. Curr Opin Neurol. 2025;38(3):226-235. doi:10.1097/WCO.0000000000001363

2. Number of people with MS. MS International Federation’s Atlas of MS. Accessed August 7, 2025. https://atlasofms.org/map/global/epidemiology/number-of-people-with-ms

3. Jeremias S. Advances in MS therapies reshape the treatment landscape. AJMC^®. Published August 7, 2025. Accessed August 8, 2025. https://www.ajmc.com/view/advances-in-ms-therapies-reshape-the-treatment-landscape