Targeting Disability, Not Relapses: BTK Inhibitors Arrive in Progressive MS

Bottom Line: For the first time, randomized trials have slowed disability in progressive MS by targeting the CNS-compartmentalized inflammation that peripheral therapies never reach. Tolebrutinib (Cenrifki) won EU approval for non-relapsing secondary progressive MS but was rejected by the FDA over severe drug-induced liver injury; the reversible BTK inhibitor fenebrutinib is now positive across relapsing and primary progressive disease. These are progression drugs, not relapse drugs — and the class's future turns on balancing brain penetrance against hepatotoxicity.

Tolebrutinib's European approval for non-relapsing secondary progressive multiple sclerosis — and its rejection by the FDA — open a new chapter in MS therapeutics. Behind it sits an entire class of Bruton tyrosine kinase inhibitors, and a hard lesson about the trade-off between reaching the brain and protecting the liver.

For three decades, disease-modifying therapy in multiple sclerosis has been a triumph of relapse prevention. From the interferons to the high-efficacy anti-CD20 antibodies, our best drugs suppress the focal inflammatory attacks that punctuate the relapsing phase, and they do so extraordinarily well. Yet the patients who trouble us most are often not the ones having relapses. They are the ones who, years after their last attack, continue to lose function — the slow, relentless accrual of disability that proceeds independent of relapse activity (PIRA) and defines the progressive phase. For non-relapsing secondary progressive MS (nrSPMS), we have had, in practical terms, nothing to offer.

That is beginning to change. In June 2026 the European Commission approved tolebrutinib — marketed as Cenrifki — as the first therapy indicated specifically to slow disability accumulation in secondary progressive MS without recent relapses. Three months earlier, the U.S. Food and Drug Administration had declined to approve the same drug for the same indication. The transatlantic split is not a bureaucratic curiosity; it is a clean illustration of the central tension in this new class.

Two diseases in one, and why our drugs miss half of it

The relapsing and progressive phases of MS are driven by different immunology. Relapses reflect focal, peripherally driven inflammation that breaches the blood–brain barrier — waves of lymphocytes entering the CNS, producing the enhancing lesions and clinical attacks that our therapies target. Progression is something else: a compartmentalized, “smoldering” inflammation sequestered largely behind an intact barrier. Its pathology is now well described — chronic active lesions with iron-laden microglia at their expanding rims (the paramagnetic rim lesions increasingly visible on MRI), ectopic meningeal B-cell follicles, and diffuse microglial activation throughout the normal-appearing white matter.

This is the problem our best drugs cannot solve. Anti-CD20 monoclonal antibodies are large molecules that deplete circulating B cells superbly but penetrate the CNS poorly; they quiet the periphery while the intrathecal fire burns on. That is the therapeutic gap Bruton tyrosine kinase (BTK) inhibitors were designed to fill.

Why BTK

BTK is a signaling enzyme that sits downstream of the B-cell receptor and of Fc receptors on myeloid-lineage cells — including microglia. Inhibiting it does two things at once. In B cells, it dampens activation, maturation, and antibody production without depleting the cells, a more modulatory approach than wholesale anti-CD20 depletion. In microglia and macrophages, it blunts the innate-immune signaling that sustains chronic lesion activity. Critically, several BTK inhibitors are small, brain-penetrant molecules that achieve meaningful CSF exposure — so, unlike the antibodies, they can act inside the compartment where progression lives. Tolebrutinib was engineered explicitly for this purpose, and early imaging work showed it could quiet chronically inflamed white-matter lesions.

One structural distinction matters for what follows: tolebrutinib, evobrutinib, and remibrutinib are covalent (irreversible) inhibitors, whereas fenebrutinib is reversible and more selective — a difference that appears to track with both efficacy and off-target liability.

The tolebrutinib evidence, read as a whole

No single trial makes the case; the pattern across three does.

• HERCULES (nrSPMS; 1,131 patients randomized 2:1 to tolebrutinib or placebo over ~48 months) met its primary endpoint: a 31% delay in time to 6-month confirmed disability progression (HR 0.69; 95% CI 0.55–0.88; p=0.003), with progression in 22.6% on tolebrutinib versus 30.7% on placebo. More striking, confirmed disability improvement roughly doubled (10% vs 5%; HR 1.88) — a direction of effect we almost never see in progressive MS.
• GEMINI 1 and 2 (relapsing MS; tolebrutinib vs teriflunomide) failed their primary endpoint. Annualized relapse rates were essentially identical (~0.12 in both arms). Yet the same trials showed a 29% reduction in 6-month confirmed disability worsening. The failure is the point: BTK inhibition does not out-suppress relapses, but it slows disability.
• PERSEUS (primary progressive MS) was negative on its primary endpoint, and Sanofi will not pursue a PPMS indication.

Read together, the message is coherent: the drug does not treat relapses, and — for tolebrutinib — does not help primary progressive disease, but in the specific setting of secondary progression without relapses, it moves disability. A progression-targeted mechanism should look exactly this selective.

The safety problem, stated plainly

Efficacy is only half the story, and the other half is the liver. BTK inhibition carries a class risk of hepatotoxicity, and tolebrutinib's is the most severe seen to date. In 2022 the FDA placed a partial clinical hold across five tolebrutinib trials — the two GEMINI studies, HERCULES, PERSEUS, and URSA (in generalized myasthenia gravis) — after cases of drug-induced liver injury (DILI). Many early cases occurred in patients with pre-existing risk factors, and enzymes typically recovered after the drug was stopped; Sanofi responded by intensifying liver-function monitoring and excluding higher-risk patients.

But the signal did not disappear. In its December 2025 complete response letter, the FDA characterized the hepatotoxicity risk as “substantial and unusually high” for drug-development programs in general and for MS therapies in particular. Across roughly 2,700 participants, six cases met Hy's Law criteria — the laboratory signature of potentially fatal DILI — including one death after liver transplantation. The risk concentrates in the early months of treatment, which is why any real-world use demands frequent, scheduled transaminase monitoring, particularly at initiation. Serious adverse events in HERCULES occurred in 15.0% of the tolebrutinib group versus 10.4% on placebo.

This is the fulcrum on which the two regulators tipped opposite ways. The EMA judged that, for a population with no approved therapy, the benefit outweighed the risk with mandated monitoring. The FDA judged that a severe, occasionally fatal liver risk overrode an efficacy benefit it viewed as modest — while explicitly leaving the door open to a better-defined, lower-risk population.

The class is bigger than one drug

Tolebrutinib is the first BTK inhibitor to reach a regulator's desk in progressive MS, but it may not be the most important. The class has now sorted itself into instructive successes and failures:

• Fenebrutinib (Roche/Genentech), the lone reversible inhibitor, has posted the strongest data of any BTK agent. It met its primary endpoint in both relapsing-MS trials (FENhance 1 and 2, versus teriflunomide) and, in FENtrepid, became the first BTK inhibitor to succeed in primary progressive MS — non-inferior to ocrelizumab on disability progression. Roche has emphasized a very low on-treatment relapse rate; its liver-safety profile, while not free of DILI signals, has so far proven manageable enough to continue development. If approved, fenebrutinib would be the first agent positioned across relapsing and primary progressive disease.
• Remibrutinib (Novartis), a covalent inhibitor already approved in chronic urticaria, is in the phase 3 REMODEL I/II relapsing-MS program and a phase 3b switch study (RESHAPE) from ocrelizumab, with a secondary-progressive study now launching. Its MS efficacy readouts are still pending.
• Evobrutinib (Merck KGaA) is the cautionary tale: it failed both EVOLUTION relapsing-MS trials against teriflunomide, and its program was deprioritized — an early, unambiguous signal that relapse endpoints are the wrong yardstick for this class.

The through-line is now hard to miss. Every BTK inhibitor tested has struggled to beat existing drugs on relapses, and the two that have moved disability (tolebrutinib in nrSPMS, fenebrutinib across the spectrum) did so on progression endpoints. These are progression drugs. The open question is which molecule best threads the needle between CNS penetrance and hepatic safety — and on current evidence, the reversible agent looks favored.

What it means at the bedside

Where it is available, tolebrutinib is the first disease-modifying option for nrSPMS — a real advance for patients we have long counseled with little to offer. It also demands candor. The absolute benefit is modest (roughly an 8-percentage-point reduction in 6-month progression over about four years). The monitoring burden is substantial and non-negotiable. And the hepatic risk, though uncommon, can be catastrophic. The right candidate is the patient still accruing disability without relapses, with preserved hepatic reserve and the reliability to sustain frequent laboratory follow-up; the wrong candidate is anyone with existing liver risk who cannot.

For U.S. clinicians, the practical answer for now is watchful patience: tolebrutinib is not available, fenebrutinib and remibrutinib are moving toward filing, and the class's ultimate place — and its safest member — will be clearer within a year or two.

The larger shift

The conceptual advance is larger than any single approval. For the first time, large randomized trials have moved disability in progressive MS by targeting the CNS-compartmentalized inflammation we have described for years but never treated. Tolebrutinib proved the principle and paid for it in the liver; fenebrutinib suggests the principle can be realized more safely and more broadly. Whether “targeting disability, not relapses” becomes the organizing strategy of the next decade will depend not on whether these drugs work — they do — but on whether we can deliver their benefit without the risk that gave the FDA pause.