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DMTs for MS
The Evolving Disease-Modifying Therapy Landscape in Multiple Sclerosis

Released: January 22, 2025

Expiration: January 21, 2026

Jiwon Oh
Jiwon Oh, MD, PhD, FRCPC
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Key Takeaways
  • The treatment landscape for multiple sclerosis (MS) has expanded exponentially during the past several decades, with nearly 30 disease-modifying therapies now available.
  • Additional therapies targeting progressive MS disease mechanisms and biomarkers to guide personalized treatment are still needed.

Introduction
The past 25-30 years have been an incredibly exciting time regarding multiple sclerosis (MS) treatment. Injectable therapies for MS were first introduced in the mid to late 1990s, and in 2004, the first monoclonal antibody was tested and approved for the treatment of MS, marking a historic milestone for the field. Additional monoclonal antibodies and other highly efficacious agents have continued to expand the treatment armamentarium, with new options being added almost yearly, so that we now have nearly 30 available disease-modifying therapies (DMTs) in most parts of the world. MS is noteworthy among other common chronic neurologic diseases like Parkinson’s disease, Alzheimer’s disease, and motor neuron disease in that we have had profound developments in the treatment landscape that have resulted in dramatically improved outcomes in people living with MS over time. 

Current Treatment Landscape
Among the available DMTs for MS treatment, most are used to treat relapsing forms of MS. A noteworthy recent development is the introduction of dedicated therapies for progressive subtypes of MS, including active secondary progressive MS (SPMS) and primary progressive MS (PPMS). The widespread availability of highly effective treatments for relapsing disease activity in people with MS has led to the identification of different clinical needs and questions.

Unmet Clinical Needs
One of the biggest challenges healthcare professionals (HCPs) are facing right now is that, with the wide array of treatment options, it is still unclear which treatment option will be ideal for any individual patient. Thus, we are far from delivering optimal personalized medicine, which is an important goal in MS clinical care. In the future, emerging technologies, including advanced MRI measures and biological measures, will likely enable us to achieve this goal.

In MS clinical care, facilitating the delivery of personalized medicine is a high priority because it is a highly heterogeneous disease and individual patients can have dramatically different clinical presentations, disease courses, and responses to disease-modifying treatment. For a patient who presents in their 20s or early 30s for the first time with an MS relapse followed by complete clinical recovery, our ability to select the optimal therapy for an individual patient, considering their disease activity, disease course, life circumstances, personal preferences, and medical comorbidities, remains elusive. At the current time, HCPs must use their best clinical judgment given available tools, such as MRI and laboratory-based measures including oligoclonal bands in cerebrospinal fluid, to try to prognosticate how an individual will respond to specific disease-modifying treatments. Newer tools, such as advanced MRI measures and fluid biomarkers (including neurofilament light and glial fibrillary acidic protein), have the potential to provide more prognostic information to help guide more personalized decisions, but these tools require validation and HCPs need to be able to easily access these tools before they can be used widely in clinical practice.

Another major unmet clinical need concerns the relative lack of treatment options for progressive subtypes of MS. At present, only 2 of the nearly 30 different MS therapies are specific for progressive MS: siponimod for active forms of SPMS and ocrelizumab for PPMS. Moreover, although clearly effective, both of these therapies are modestly beneficial at best. Thus, it is clear that more effective treatments targeting the biological processes underlying progressive disease are needed.

Emerging Therapies
Bruton tyrosine kinase inhibitors (BTKis) are a novel class of therapy that may have the potential to address some of the unmet clinical needs in the MS field. BTKis have the ability to modulate B-cells and microglia, which are cells that are highly relevant to both relapsing and progressive disease mechanisms in MS. In addition, a number of BTKis can cross the blood–brain barrier and achieve biologically active concentrations within the central nervous system; this raises the possibility that BTKis may be able to beneficially modulate microglia within the central nervous system, which are a key driver of progressive disease mechanisms. Recently, positive results from the phase III HERCULES clinical trial, which evaluated the efficacy and safety of tolebrutinib in nonrelapsing SPMS, were presented at the European Committee for Treatment and Research in Multiple Sclerosis 2024 meeting. This was the first evaluation of a DMT in a nonrelapsing SPMS population, with tolebrutinib clearly showing a benefit over placebo on the primary endpoint of confirmed disability worsening. Moreover, although the phase III relapsing MS (RMS) clinical trials of tolebrutinib vs teriflunomide (GEMINI I and II) did not meet their primary endpoints, the secondary endpoints of these trials were of interest because tolebrutinib reduced disability progression in comparison with teriflunomide, even though there was no difference in reduction of relapses.

Taken together, these results are exciting and mark another milestone in the field, because they suggest that it is possible to develop agents targeting pathologic processes confined within the central nervous system that drive progressive disease, which current therapies do not modulate to a meaningful extent. Results from other BTKi clinical trials have been reported in the recent past, including the phase II FENOPTA trial that evaluated fenebrutinib vs placebo in RMS. In FENOPTA, fenebrutinib demonstrated a clear ability to substantially reduce T1 gadolinium-enhancing lesions vs placebo at 12 weeks, and the effect was sustained for up to 48 weeks in the long-term extension study. Results from additional phase III trials of BTKis are eagerly anticipated, including: PERSEUS (tolebrutinib in PPMS); FENHANCE I and II (fenebrutinib in RMS); FENTREPID (fenebrutinib in PPMS); and REMODEL I and II (remibrutinib in RMS). In addition, upcoming phase III trial results on high-dose ocrelizumab vs regular-dose ocrelizumab in RMS (MUSETTE) will also be of high interest for the field. Based on the many phase III clinical trials that will be reporting results in the next 1-2 years, it seems likely that the treatment landscape in MS will continue to expand and evolve, and there is hope that some of these novel treatments will address current unmet clinical needs.

Your Thoughts?
What do you consider the most important unmet clinical needs in the treatment of MS? Join the discussion by posting a comment below.

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