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The BTK inhibitor race for multiple sclerosis

The BTK inhibitor race for multiple sclerosis

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Pharma giants compete to crack progressive MS with brain-penetrating drugs

December 28th, 2025: FDA Rejects Tolebrutinib for US Market

Overview

Updated May 16

The FDA rejected Sanofi's tolebrutinib for progressive MS on December 28, 2025—a crushing blow for a drug that had won Breakthrough Therapy status and became the first BTK inhibitor approved anywhere in the world. Meanwhile, Roche's rival drug fenebrutinib is racing toward approval after strong Phase 3 results, and Merck's evobrutinib crashed out entirely. Three pharma giants bet billions that brain-penetrating BTK inhibitors could finally slow the relentless neurodegeneration that leaves MS patients in wheelchairs, and only one looks likely to reach the finish line first.

What's at stake: 2.8 million people worldwide have MS, with 45% suffering from progressive forms that steadily worsen regardless of relapses, and no effective treatments exist for non-relapsing progressive MS. The global MS drug market is projected to hit $43 billion by 2032, with progressive MS growing from $1.3 billion to $5.1 billion by 2034. BTK inhibitors are the first drugs that cross the blood-brain barrier to target the microglia driving neurodegeneration—a fundamentally different approach than existing immunosuppressants.

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Key Indicators

31%
Disability progression reduction in tolebrutinib's HERCULES trial
First drug to show significant slowing of disability in non-relapsing progressive MS
3 of 3
Tolebrutinib Phase 3 trial failures
GEMINI 1, GEMINI 2 (relapsing MS), and PERSEUS (primary progressive MS) all missed primary endpoints
$5.1B
Projected progressive MS market by 2034
Growing at 14.84% annually from $1.29 billion in 2024
0%
Approved treatments for non-relapsing progressive MS before 2025
Massive unmet medical need affecting hundreds of thousands of patients

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People Involved

Houman Ashrafian
Houman Ashrafian
Executive Vice President, Head of Research & Development, Sanofi
Leading Sanofi's response to FDA rejection
 Levi Garraway
Levi Garraway
Chief Medical Officer and Head of Global Product Development, Roche
Overseeing fenebrutinib's path to approval

Organizations Involved

Sanofi
Sanofi
Pharmaceutical Company
Seeking FDA guidance after tolebrutinib rejection

French pharmaceutical giant with €43 billion in annual revenue and a struggling MS franchise.
Roche / Genentech
Roche / Genentech
Pharmaceutical company
Leading the BTK inhibitor race, awaiting final trial data

Swiss pharmaceutical giant that already dominates MS with Ocrevus, its $5 billion blockbuster.
FDA Center for Drug Evaluation and Research
FDA Center for Drug Evaluation and Research
Federal Regulatory Agency
Reviewing BTK inhibitor safety across multiple programs

The gatekeeper for new drug approvals, currently scrutinizing BTK inhibitor liver toxicity.

Timeline

April 2023 December 2025

15 events Latest: December 28th, 2025 · 8 months ago Showing 8 of 15
Tap a bar to jump to that date

  1. FDA Rejects Tolebrutinib for US Market

    Latest Regulatory

    Complete response letter denies approval for non-relapsing progressive MS despite breakthrough designation and UAE approval.

  2. Tolebrutinib PERSEUS Trial Fails

    Clinical Trial

    Misses primary endpoint in primary progressive MS, Sanofi withdraws PPMS regulatory submissions.

  3. Sanofi Submits Expanded Access Protocol

    Regulatory

    At FDA's request, Sanofi submits expanded access protocol for tolebrutinib in nrSPMS to provide eligible patients access to investigational therapy.

  4. FDA Halts Fenebrutinib Trials

    Regulatory

    Clinical hold on fenebrutinib due to liver enzyme elevations with elevated bilirubin in two patients.

  5. Roche Sweeps Phase 3 Trials

    Clinical Trial

    Fenebrutinib meets primary endpoints in both FENhance 2 (relapsing MS) and FENtrepid (primary progressive MS).

  6. FDA Delays Tolebrutinib Decision

    Regulatory

    Review extended from September 28 to December 28 to accommodate additional analyses.

  7. UAE Grants First Tolebrutinib Approval

    Regulatory

    World's first BTK inhibitor approval for MS, covering non-relapsing secondary progressive MS.

  8. Fenebrutinib Two-Year Data Impresses

    Clinical Trial

    Roche reports sustained disease suppression through 96 weeks, maintaining safety profile.

  9. Tolebrutinib Wins FDA Priority Review

    Regulatory

    FDA accepts tolebrutinib NDA for Priority Review with September 28 target action date.

  10. FDA Grants Tolebrutinib Breakthrough Status

    Regulatory

    Breakthrough Therapy designation recognizes potential to address critical unmet need in progressive MS.

  11. Merck Abandons Evobrutinib

    Business

    Evobrutinib fails Phase 3 EVOLUTION trials, Merck exits BTK inhibitor race entirely after safety and efficacy setbacks.

  12. Tolebrutinib GEMINI Trials Fail

    Clinical Trial

    Both GEMINI 1 and 2 miss primary endpoint for relapsing MS, showing no improvement over Aubagio.

  13. Roche's Fenebrutinib Dominates in Early Results

    Clinical Trial

    Near-complete disease suppression in relapsing MS, significantly outperforming competitor drugs at 48 weeks.

  14. Tolebrutinib HERCULES Trial Success

    Clinical Trial

    First BTK inhibitor shows 31% reduction in disability progression for non-relapsing progressive MS, breakthrough result.

  15. FDA Halts Merck's Evobrutinib Program

    Regulatory

    FDA partial clinical hold due to liver enzyme elevations in two patients, first major BTK inhibitor safety signal.

Historical Context

3 moments from history that rhyme with this story — and how they unfolded.

2005-2006

Tysabri's Black Box Warning and Market Recovery

Biogen's natalizumab (Tysabri) was pulled from market just three months after approval when three patients developed progressive multifocal leukoencephalopathy (PML), a fatal brain infection. The drug had shown dramatic efficacy in MS trials, but the safety signal was devastating. After a year-long investigation, the FDA allowed Tysabri back on market in 2006 with severe restrictions and a risk management program requiring patient registries and monitoring.

Then

Tysabri's withdrawal triggered panic about MS drug safety and wiped billions from Biogen's market cap.

Now

Despite the black box warning, Tysabri became a blockbuster generating $2+ billion annually because doctors and patients accepted the risk for a highly effective therapy.

Why this matters now

The BTK inhibitor liver toxicity concerns are serious but appear manageable compared to Tysabri's fatal PML risk. If fenebrutinib or tolebrutinib show clear efficacy, the FDA may approve them with enhanced monitoring requirements rather than outright rejection.

2008-2009

Rituximab's OLYMPUS Trial Failure in Progressive MS

Roche's rituximab, already approved for rheumatoid arthritis and cancer, entered Phase III trials for primary progressive MS in 439 patients. Despite being a B-cell depleting therapy similar to the later-approved ocrelizumab, rituximab failed to meet its primary endpoint of reducing disability progression at 96 weeks. The trial showed only a non-significant trend toward benefit, leading to abandonment of the progressive MS indication.

Then

Roche shelved rituximab for progressive MS but learned critical lessons about trial design and patient selection.

Now

These lessons informed development of ocrelizumab, which became the first drug approved for primary progressive MS in 2017 and now generates $5+ billion annually.

Why this matters now

Progressive MS trials have a brutal history of failure. Even Roche, now leading with fenebrutinib, has experienced crushing defeats. The difference: Roche learned from rituximab's failure to design better trials.

2015-2018

High-Dose Biotin (MD-1003) Collapses in Phase 3

French company MedDay's high-dose biotin showed promising Phase II results in progressive MS, with some patients experiencing dramatic improvements in disability. The company rushed into Phase 3 trials SPI2 and MS-ON, generating enormous patient hope. Both trials failed spectacularly in 2018, showing no benefit over placebo. Patients who had experienced improvements on biotin during open-label phases saw those gains evaporate when properly controlled studies ran.

Then

MedDay's stock crashed, and the MS community faced bitter disappointment after being told a vitamin could reverse disability.

Now

The failure reinforced that progressive MS requires rigorous Phase 3 evidence and that promising Phase 2 signals often don't replicate, raising the bar for future therapies.

Why this matters now

Tolebrutinib showed genuine Phase 3 success in HERCULES, unlike biotin's false promise. But it also shows that even drugs with real efficacy data can fail regulatory approval for safety or other concerns.

Sources

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Sanofi NeurologyLive Practical Neurology The Pharma Letter Roche Multiple Sclerosis News Today New England Journal of Medicine Clinical Trials Arena FierceBiotech PMC Nature Reviews Neurology Nasdaq Roche Sanofi NeurologyLive New England Journal of Medicine Multiple Sclerosis News Today