The U.S. Food and Drug Administration (FDA) has extended the target action date for Sanofi’s tolebrutinib new drug application (NDA) by three months.
The investigational oral therapy is designed to treat non-relapsing, secondary progressive multiple sclerosis (nrSPMS) and slow disability accumulation independent of relapses.
The new target decision date is December 28, 2025. The extension follows Sanofi’s submission of additional analyses. The FDA considered this a major amendment, requiring extra review time.
Confidence from Sanofi
Sanofi said it will continue working closely with the FDA. The company remains confident in the therapy’s potential positive impact.
Tolebrutinib is also notable as the first brain-penetrant BTK inhibitor in nrSPMS to receive FDA Breakthrough Therapy Designation.
Clinical Evidence Base
The FDA’s review relies on pivotal data from three global phase 3 trials:
- HERCULES: nrSPMS patients.
- GEMINI 1 and GEMINI 2: relapsing MS (RMS) patients.
A separate PERSEUS phase 3 trial is ongoing in primary progressive MS (PPMS), with results expected in H2 2025.
HERCULES (NCT04411641)
- Double-blind, randomized phase 3 trial in nrSPMS.
- Baseline criteria:
- SPMS diagnosis.
- Expanded Disability Status Scale (EDSS) between 3.0 and 6.5.
- No relapses in past 24 months.
- Documented disability accumulation in the last 12 months. - Participants: Randomized 2:1 to tolebrutinib or placebo.
- Duration: Up to ~48 months.
- Primary endpoint: Six-month confirmed disability progression (CDP) using EDSS score.
- Secondary endpoints:
- Three-month CDP.
- MRI lesion counts (new/enlarging T2 hyperintense lesions).
- Time to confirmed disability improvement.
- Functional tests (9-hole peg test, timed 25-foot walk).
- Safety and tolerability.
GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991)
- Double-blind, randomized phase 3 trials in RMS.
- Comparator: Tolebrutinib vs. teriflunomide (14 mg daily).
- Participants randomized 1:1 to study drug or comparator.
- Duration: ~36 months.
- Primary endpoint: Annualized relapse rate.
- Secondary endpoints:
- Time to confirmed disease worsening (six months).
- MRI lesion activity (new/enlarging T2, Gd-enhancing T1 lesions).
- Safety and tolerability.
The Disease Context
Multiple sclerosis (MS) is a chronic, immune-mediated neurodegenerative disorder of the central nervous system (CNS).
- It can lead to irreversible disability over time.
- Symptoms include fatigue, cognitive impairment, balance issues, gait problems, bladder/bowel dysfunction, and sexual dysfunction.
- Disability accumulation remains a major unmet need.
nrSPMS patients no longer experience relapses but continue accumulating disability.
How Tolebrutinib Works
Tolebrutinib is an oral, brain-penetrant Bruton's tyrosine kinase (BTK) inhibitor.
- Specifically targets smoldering neuroinflammation inside the CNS.
- Aims to slow or prevent disability progression by addressing innate immunity in the brain.
- This sets it apart from current MS drugs that mainly target peripheral B and T cells.
Sanofi’s Broader Neurology Focus
Tolebrutinib reflects Sanofi’s strategy to develop disease-modifying therapies for neuroinflammatory and neurodegenerative conditions.
The company’s neurology pipeline includes programs in:
- Multiple sclerosis.
- Chronic inflammatory demyelinating polyneuropathy.
- Alzheimer’s disease.
- Parkinson’s disease.
- Age-related macular degeneration.
Several phase 3 studies are already underway.
The Road Ahead
The PERSEUS PPMS trial will deliver results in the second half of 2025, potentially reinforcing Sanofi’s case for tolebrutinib.
For now, all eyes are on December 28, 2025, the FDA’s new target date for a decision.
