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The BTK inhibitor race for multiple sclerosis

The BTK inhibitor race for multiple sclerosis

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By Newzino Staff | |

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

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

Overview

The FDA just rejected Sanofi's tolebrutinib for progressive multiple sclerosis 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 stunning Phase 3 victories, 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. Only one looks likely to reach the finish line first.

What's at stake: 2.8 million people worldwide have MS, and 45% suffer from progressive forms that steadily worsen regardless of relapses. 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 alone expected to grow from $1.3 billion to $5.1 billion by 2034. BTK inhibitors represent the first drugs that cross the blood-brain barrier to target the microglia driving neurodegeneration—a fundamentally different approach than existing immunosuppressants.

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
Status: 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
Status: 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
Status: Reviewing BTK inhibitor safety across multiple programs

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

Timeline

  1. FDA Rejects Tolebrutinib for US Market

    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.

Scenarios

1

Roche Sweeps the Market with Fenebrutinib Approval in 2026

Discussed by: Leerink analysts, BioPharma Dive coverage, clinical trial experts

Roche resolves the FDA clinical hold by demonstrating the liver enzyme elevations are manageable and reversible upon discontinuation. After FENhance 1 data arrives in mid-2026, Roche files for approval and becomes the first company with a BTK inhibitor approved for both relapsing and progressive MS. Analysts predict $1+ billion in annual sales. This would cement Roche's MS dominance while Sanofi struggles to address FDA concerns. Fenebrutinib's success in trials where competitors failed, combined with Roche's regulatory experience, makes this the most likely outcome.

2

Sanofi Overcomes FDA Objections, Wins Approval in Late 2026

Discussed by: Multiple Sclerosis News Today analysis, progressive MS advocacy groups

Sanofi successfully addresses the FDA's concerns in the complete response letter—likely related to safety monitoring protocols or additional efficacy analyses—and resubmits with satisfactory data. The agency approves tolebrutinib for non-relapsing progressive MS by Q4 2026, recognizing the massive unmet need. However, Sanofi's commercial position remains weak: the drug failed in relapsing MS and primary progressive MS, limiting its market. Roche likely still files fenebrutinib first, forcing Sanofi to compete on price and convenience.

3

Class-Wide Liver Toxicity Kills BTK Inhibitors for MS

Discussed by: FDA safety reviewers, hepatology experts, Nature Reviews Drug Discovery

The FDA determines that severe liver toxicity is an unacceptable class effect after reviewing data across all BTK inhibitor programs. Both Roche and Sanofi fail to gain U.S. approval. The UAE pulls tolebrutinib from market. This would mirror the fate of other promising MS therapies that failed due to safety concerns. The 2.8 million MS patients worldwide remain without effective progressive disease treatments. However, this seems unlikely given that most liver elevations resolved after stopping the drugs and no patients showed clinical symptoms.

4

Novartis Leapfrogs Both Rivals with Remibrutinib

Discussed by: Industry observers, BioCentury analysis

While Sanofi and Roche struggle with FDA safety concerns, Novartis quietly advances remibrutinib through its REMODEL Phase 3 trials with a cleaner safety profile. Novartis learns from competitors' regulatory mistakes, designs superior liver monitoring protocols, and files first with convincing safety data. This would represent a stunning upset in a race where Novartis has maintained a low profile. However, remibrutinib is further behind in development and lacks the extensive safety database of its competitors, making this a long-shot scenario.

Historical Context

Rituximab's OLYMPUS Trial Failure in Progressive MS

2008-2009

What Happened

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.

Outcome

Short Term

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

Long Term

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 It's Relevant Today

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.

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

2015-2018

What Happened

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.

Outcome

Short Term

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

Long Term

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 It's Relevant Today

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.

Tysabri's Black Box Warning and Market Recovery

2005-2006

What Happened

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.

Outcome

Short Term

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

Long Term

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 It's Relevant Today

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.

17 Sources:
+11
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