July 22, 2025 – A promising new drug could soon transform treatment for one of the most challenging types of multiple sclerosis – and with FDA approval expected in the coming months, it's being hailed as the start of a new chapter in MS treatment, offering long-awaited hope to patients with limited options.
The new drug, called tolebrutinib – and a growing pipeline of others like it – is designed to penetrate the brain and spinal cord, targeting the way MS damages the nervous system, not just the inflammatory flare-ups.
"It's really exciting," said Michael D. Kornberg, MD, PhD, a neurologist at Johns Hopkins University School of Medicine who was not involved in the drug's development, "because of the effect that it has on patients, but also because it provides proof of principle that this is an aspect of the disease that we can target."
About a million Americans live with progressive MS, an autoimmune disease that attacks the central nervous system and can lead to worsening disability, ranging from memory and thinking problems to muscle weakness and mobility issues. The cause is unknown, but it likely involves genetic and environmental factors.
Usually, it begins with relapses – sudden flare-ups or "crises" when the immune system becomes overactive and "attacks somewhere new in the brain or spinal cord," said Kornberg. Each attack leaves a new scar and produces new symptoms.
The inflammation clears up and people recover, either completely or incompletely, until the next flare-up.
But often, the condition happens without these relapses and remissions, and disability steadily worsens from the start. This is called non-relapsing secondary progressive MS (nrSPMS), and it's the hardest type to treat because most therapies target inflammation, which is less prominent in this form of MS.
Tolebrutinib promises to change that, and thanks to an FDA breakthrough therapy designation – a special status that fast-tracks promising drugs for serious conditions – it could be available to patients by the end of September.
A Paradigm Shift in MS Treatment
Currently, the go-to treatments for relapsing forms of MS are disease-modifying therapies (DMTs). They work in different ways, but the shared effect is the same: They all reduce the inflammation that drives relapses.
But they're limited in their ability to act directly on the immune cells involved in the nerve-damaging process. As such, they've revealed a more subtle driver of long-term disability: the slow, neuroinflammation that is largely independent of relapses and fuels nrSPMS's ongoing nerve damage.
Patients with nrSPMS are "typically treated with DMTs just to prevent any superimposed relapses that can contribute to further disability," said Kornberg. But the benefits are limited, and for a person with progressive MS, it's a race between the DMT's modest effectiveness and the unstoppable momentum of the underlying nerve damage.
That's where tolebrutinib comes in. Unlike existing MS treatments, the new drug is a small molecule designed to pass through the blood-brain barrier, a highly selective membrane that shields the central nervous system from toxins and pathogens in the blood. That allows tolebrutinib to penetrate the brain and spinal cord, which is where the long-term damage in MS happens, slowing the relentless decline caused by the disease.
In a phase III clinical trial, patients taking the drug went significantly longer before their symptoms progressed permanently – about 31% longer than the control group. Further, a higher percentage of patients taking tolebrutinib saw improvement in their disability (8.6%) compared to those on a placebo (4.5%).
The Promise of BTK Inhibitors
Tolebrutinib, which was developed by biotech company Principia Biopharma before Sanofi acquired the drug in 2017, targets the central nervous system. There, it inhibits an enzyme called Bruton's tyrosine kinase (BTK), a protein expressed in immune cells in the brain and spinal cord. These immune cells, or microglia, become overactive in MS patients, releasing proteins called cytokines that trigger widespread inflammation, drawing aggressive immune cells from the blood into the brain. They also eat away at myelin, the protective sheath that insulates nerve fibers and ensures proper communication between brain and body.
When myelin breaks down, patients have fatigue, muscle stiffness, weakness, and loss of coordination, among other symptoms.
"What's different about tolebrutinib and other BTK inhibitors that penetrate the brain is it can turn off those inflamed microglia," said Kornberg. "That is why it has an effect on progression."
Beyond tolebrutinib, a pipeline of other BTK inhibitors is advancing. Key competitors include fenebrutinib, made by Roche, which inhibits BTK reversibly (while tolebrutinib does so irreversibly). This may give the drug a better safety profile and potentially fewer side effects. Other notable BTK inhibitors include remibrutinib (developed by Novartis), which is more focused on relapsing forms of MS.
What Does This Mean for Patients?
What many MS patients, even those on effective medications, worry about is long-term disability getting worse, said Veronica Cipriani, MD, a neuroimmunologist at UChicago Medicine and assistant professor of neurology at the University of Chicago.
Patients want to know whether tolebrutinib will prevent future disability, and Cipriani, who did not take part in the trial, thinks it will. "Not only is [tolebrutinib] going to help patients who already have SPMS and that have had MS for 20 or 30 years … but it could potentially help patients who are having clinical disability progression early on in their disease course," she said.
Still, tolebrutinib has side effects, including serious ones.
Around 4% to 5.6% of patients enrolled in the phase III trial saw significant increases in liver enzymes, which typically mean there's inflammation or damage within liver cells. Most cases got better without medical aid, but one person in the study needed a liver transplant and died due to postoperative complications related to liver failure.
After that, the trial monitored liver enzymes more often. "Once the studies instituted a robust monitoring program, there was a very small risk of severe liver injury," said Kornberg. Still, "it's important to know this is going to be a risk," he said.
The exact recommendation for clinical use is pending FDA approval (targeted for Sept. 28, 2025), but patients can expect to have their liver enzymes tested "quite intensively for the first 12 weeks or so," said Erik Wallstroem, MD, PhD, senior vice president and global head of neurology and ophthalmology development at Sanofi. "If there is significant liver enzyme elevation, the recommendation is to discontinue treatment."
Tolebrutinib also presents a risk to the peripheral immune system, as a patient's overall immune response would be dampened while on the drug. This could increase the risk of respiratory infections (such as the flu, common cold, and COVID-19) and urinary tract infections. But "the effects on the immune system also seem to be quickly reversible if you stop the medication," said Kornberg. "I think that that's something we're going to be able to mitigate against with appropriate monitoring."
