Emerging Therapeutic Options in Progressive Multiple Sclerosis (Podcast)

“Nonrelapsing secondary progressive multiple sclerosis (MS) has been the hardest form of MS to find therapies for because patients with this form of the disease don’t have peripherally driven inflammation. There is something else driving their disease that we have not historically been able to treat,” says Robert Fox, MD, a neurologist with Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research.

Yet that appears to be changing with recent findings of the phase 3 HERCULES trial of the CNS-penetrant BTK inhibitor tolebrutinib (N Engl J Med. 2025;392:1883-1892), for which Dr. Fox serves as first and corresponding author. The study yielded the first evidence that a medication can delay confirmed disability progression in patients with nonrelapsing secondary progressive MS.

That and other developments in the management of progressive MS are the focus of the latest episode of Cleveland Clinic’s Neuro Pathways podcast. As the episode’s featured guest, Dr. Fox discusses the following topics, among others:

The recent evolution in our understanding of progressive MS phenotypes

Clinical hallmarks of progressive MS and key diagnostic principles

• The dearth of treatment options for progressive MS, including the limitations of ocrelizumab in this setting
• The rationale for use of CNS-penetrant BTK inhibitors for progressive MS, including details of the HERCULES trial
• Ongoing trials of other BTK inhibitors and a new drug class, CD40 ligand inhibitors

Click the podcast player above to listen to the 29-minute episode now or read on for a few excerpted passages. Check out more Neuro Pathways episodes at clevelandclinic.org/neuropodcast or wherever you get your podcasts.

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Excerpts from the podcast

Robert Fox, MD: The BTK inhibitors have approval for a number of lymphomas and lymphoid blood disorders. They also have an effect on immune function, so they can alter how lymphocytes function. Additionally, they can alter microglia, the resident immune cells within the brain. They also may have an impact on other brain cells as well. As a result, these agents have attracted interest in recent years for treating both the peripheral immune dysfunction that we think drives relapsing MS and also the central compartmentalized inflammation that we believe is driving, or at least contributing to, progressive MS….

Another thing that’s attractive about the BTK inhibitors is that they cross the blood-brain barrier and get into the brain. The hope has been that their impact on the brain would decrease inflammation related to secondary progressive MS….

In terms of clinical trial evidence with the BTK inhibitors in MS, the HERCULES trial of tolebrutinib is the first positive trial in nonrelapsing secondary progressive MS, demonstrating 31% slowing of disability progression….

One thing that’s important to realize is that the BTK inhibitors do have some risks, most notably that they can irritate the liver. Some patients experience liver irritation, and about one in 200 patients will have a very severe elevation of liver enzymes. And if this liver enzyme elevation is not identified and caught quickly, it can be fatal. The good news is that all cases of severe liver enzyme elevation have been seen in the first three months of treatment. As a result, very intensive monitoring of liver enzymes is going to be needed for the first three months of therapy, after which monitoring can be less frequent. If severe liver enzyme elevations are found, the management is very straightforward: the drug should be stopped.