Sanofi's Tolebrutinib Faces Phase 3 Failure in PPMS and FDA Delays in nrSPMS

Sanofi's tolebrutinib failed the primary endpoint in the Phase 3 PERSEUS trial for primary progressive multiple sclerosis (PPMS), which measured delay in six-month composite confirmed disability progression; Sanofi will not pursue regulatory approval for PPMS.1 2 3 5 7

The FDA delayed its review of tolebrutinib for non-relapsing secondary progressive MS (nrSPMS) to the end of Q1 2026, originally set for December 28, 2025.1 2 3 5

Sanofi shares fell 6% following the announcement of the trial failure and regulatory delay.2

Tolebrutinib, a BTK inhibitor acquired via Sanofi's $3.7bn purchase of Principia Biopharma in 2021, has faced prior setbacks including Phase 3 failures in 2024 and liver injury concerns.2 3

Sanofi stated the PERSEUS results will aid understanding of MS biology, with safety consistent with prior studies; no specific data released.1 2 3

Earlier, tolebrutinib succeeded in the HERCULES Phase 3 trial for nrSPMS, delaying progression by 31%, but faced issues like liver enzyme elevations in 4.1% of patients.3

In January 2026, FDA issued a Complete Response Letter (CRL) citing high risk of severe drug-induced liver injury (DILI), uncertainties in benefits, and no favorable benefit-risk profile for nrSPMS.4