Tolebrutinib

An oral BTK inhibitor that crosses into the brain to target both peripheral immune cells and brain-resident microglia. Phase 3 HERCULES trial showed 31% delay in disability progression in non-relapsing secondary progressive MS. FDA issued a Complete Response Letter on December 23, 2025, citing severe liver injury risk and benefit-risk concerns; the EU approved it as Cenrifki in June 2026.

Tolebrutinib blocks an enzyme called BTK in both immune cells and brain cells, preventing them from triggering inflammation. The drug crosses the blood-brain barrier to reach the central nervous system, allowing it to reduce both relapses and long-term disability.

The most serious concern is severe liver injury. In Sanofi's Phase 3 program, six cases met Hy's Law criteria for serious drug-induced liver injury (DILI) out of approximately 2,700 patients, including one fatal case after liver transplant. The FDA noted that the risk of fatal DILI from tolebrutinib appears to be among the highest in the BTK inhibitor class. Other side effects included headaches and respiratory infections.

Tolebrutinib is taken as an oral pill once daily. The drug crosses into the brain, unlike many other MS treatments. The FDA declined approval in December 2025, so tolebrutinib is not available in the United States; in the EU it is marketed as Cenrifki.

Tolebrutinib is currently in crl clinical trials for Multiple Sclerosis. It has not yet received FDA approval.

BTK (Bruton's tyrosine kinase) is an enzyme found in both B cells and microglia (immune cells resident in the brain). BTK inhibitors like tolebrutinib block this enzyme, reducing inflammation from both peripheral immune cells and brain-resident cells. This dual action is significant because current MS therapies mainly target peripheral immunity but do not address the chronic, smoldering inflammation inside the brain driven by microglia, which is thought to contribute to disability progression.

The FDA issued a Complete Response Letter on December 23, 2025, mainly because of severe drug-induced liver injury (DILI). 6 patients in the Phase 3 program met Hy's Law criteria, including one fatal case after a liver transplant. The FDA said the risk of fatal DILI from tolebrutinib appears to be among the highest in the BTK inhibitor class. It also raised efficacy concerns, including that missing pre-trial MRI history made it impossible to separate active from non-active SPMS, and concluded that 'a favorable benefit-risk profile could not be established for any patient subpopulation.' No U.S. resubmission had been announced as of September 2026.

The HERCULES Phase 3 trial enrolled patients with non-relapsing secondary progressive MS and showed that tolebrutinib reduced 6-month confirmed disability progression by 31% compared to placebo. This is noteworthy because non-relapsing SPMS (progressive disease without active relapses) has been one of the hardest MS populations to treat, and few therapies have shown benefit in this group. The positive efficacy result was offset by the liver safety signal.

Tolebrutinib was specifically designed to penetrate the blood-brain barrier, unlike many other drugs that primarily work in the peripheral blood. This CNS penetration allows it to directly inhibit BTK in microglia, the brain's resident immune cells that drive chronic neuroinflammation in progressive MS. This brain-penetrant property is what makes BTK inhibitors a potentially transformative drug class for progressive MS, where peripheral immunosuppression alone has been insufficient.

Not by prescription in the United States. As of September 2026, tolebrutinib is not FDA-approved following the December 23, 2025 Complete Response Letter, although Sanofi has described a U.S. expanded access program. It is approved in the European Union, where the European Commission cleared it on June 23, 2026 as Cenrifki for secondary progressive MS without relapses, and it holds provisional approval in the United Arab Emirates. Patients with progressive MS in the U.S. should discuss currently approved treatment options with their neurologist.