Medicine & Research

When I first began treating patients with multiple sclerosis, I remember the swift wave of hope injected into a medical field that historically did not offer much optimism. The tired neurology notion was that we “diagnose and adios,” because there were few perceived effective treatments for neurologic conditions. As I entered neurology training, the surge of effective therapeutics was happily overwhelming and contrary to this tired notion. I saw physicians speak with greater hope with their patients after diagnosing such a life-altering condition as MS, bolstered with the knowledge of readily available therapeutics to modify the course of their patient’s condition.
 
Treating MS began with the interferon era, then came the rise of oral therapies, and most recently the infusion era with increasingly higher efficacy disease-modifying treatments that are largely better tolerated than prior iterations. We are now in a treatment era in which relapses are quite rare after patients are started on high-efficacy medications. 

Controlling relapsing disease is finally a confident gold standard in MS that we can reliably achieve for most of our patients. This therapeutic revolution in MS has truly modified the disease. The therapeutic era must now do the same for treating progressive MS disease. Treatment with Bruton’s tyrosine kinase inhibitors are driving this conversation further.

Finding direction

Treating progression in MS is tough. Clinicians historically have had little direction on how best to treat patients when symptoms and MRI changes do not vary as clearly as they do in relapsing forms of MS. One of the major barriers in treating progression is that we do not have a well-defined meaning of what progression in MS truly means. Is it worsened weakness on top of existing weakness? Worsened twenty-five-foot walk? Biomarker changes? MRI changes? Each of these datapoints can look stable but we still can see patients progressively worsen anyway. We do not treat MRIs, labs, composite scores; we treat people. 

The year 2017 was the beginning of an era of treating MS progression. With the results from the ORATORIO trial, we finally received the first FDA-approved medication for primary progressive MS: ocrelizumab. Clinicians finally had some direction on treating progressive forms of MS. While not robust, this trial showed the rate of disability and MRI lesions was reduced in primary progressive MS with use of ocrelizumab versus placebo. Gradually other disease-modifying therapies have received FDA expanded approvals for progressive forms of MS. 

Our treatment options for patients with progression have expanded, bringing more optimism and purpose to slowing progression’s gradual decline. We have tried several of these DMTs to slow progression with frustrating 
results. MRI lesions can look stable, the biomarkers can look stable, yet our patients can continue to have worsening symptoms. 

Treating progression is tough. We can more confidently prevent relapses, but not progression. The story of treating all components of this disease is incomplete. 

Seeking a holy grail

Enter the Bruton’s tyrosine kinase inhibitors, which include evobrutinib, oralebrutinib, tolebrutinib, remebrutinib, and fenebrutinib. This class of medication was originally an FDA-approved oral therapy for lymphoproliferative disorders, taken twice daily. Like many other oncologic medications that have found utility in treatment of MS (i.e. cladribine, ofatumumab), BTK inhibitors have had promising potential use in treating MS because of their effects on immune cell signaling. BTK inhibitors offer a mechanism of action by interrupting B cell lymphocyte signaling and affect the critical cell players in progressive MS disease including dendritic cells, microglia, and macrophages. 

Unlike anti-CD20 therapies such as ocrelizumab, ofatumumab, ublituximab, and rituximab, BTKis do not fully deplete B cells. Instead, they modulate B-cell activity, reducing inflammatory signaling. This class also appears to cross the blood-brain barrier more effectively than prior DMTs, which largely act within the peripheral immune system.

More importantly, BTKis seem to have a role in modulating neuronal microglia to reduce inflammatory signals and possibly promote remyelination of damaged neurons. This unique mechanism of action is aimed at achieving one of the holy grails in MS: a single treatment for both preventing relapses and promoting remyelination. This idea has created a clinical trial surge of multiple BTKis to show efficacy for relapses and slowing progression. 

Many trials are looking at different dosing patterns and comparisons of BTKis with existing FDA-approved medications for MS. To date, most data show one consistent finding: relapses and new MRI lesions are consistently reduced with this class of medications. 

Future unclear

While excellent to see, controlling MS relapses is the pre-existing standard for MS DMTs and hardly novel. We need something for slowing and stopping progression. At the writing of this article, trial endpoints for delaying MS progression have not been convincingly met for FDA approval of BTKis. 

In December 2025, the FDA declined tolebrutinib for use in MS, citing an unclear clinical benefit and safety concerns with liver injury. Within the medication class, transient liver enzyme elevation appears to be a 
consistent side effect of BTKis that needs better parameters for monitoring. Unclear benefits and possible significant side effects have paused our optimism for incorporating BTKi into MS treatment.

While the story of treating progression is incomplete, I think the ongoing BTKi trials will be one of our best next MS educators by having the medical community firmly concentrate on defining the meaning of progression in MS and refining a better target of how to treat it.
 
Just as we have revolutionized our treatment of relapsing MS disease, I expect us to revolutionize progression. We may just be in the “interferon era” of treating progression, which is a necessary step for improving the quality of patient lives and meaningful outcomes. 

The future role of BTKis in our treatment algorithm is unclear. We do not have approval for the use of BTKis in MS, but I expect we will.