Sanofi’s Cenrifki (tolebrutinib) recommended for EU approval by the CHMP to treat secondary progressive multiple sclerosis without relapses

CHMP Recommends Sanofi's Cenrifki for EU Approval in Non-Relapsing SPMS

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending approval for Sanofi’s Cenrifki (tolebrutinib) in the EU. This recommendation is for treating secondary progressive multiple sclerosis (SPMS) without relapses in the last two years, addressing a significant unmet need for patients experiencing continuous disability accumulation. The positive opinion is primarily based on data from the HERCULES phase 3 study in non-relapsing SPMS, supported by findings from the GEMINI 1 and GEMINI 2 phase 3 studies in relapsing multiple sclerosis. A final decision from the European Commission is anticipated in the coming months.

• The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has recommended Cenrifki (tolebrutinib) for EU approval. This recommendation targets secondary progressive multiple sclerosis (SPMS) patients who have not experienced relapses in the past two years, offering a potential new treatment option for a debilitating condition characterized by continuous disability progression and limited therapeutic choices.
• The positive opinion is primarily supported by data from the HERCULES phase 3 study, which specifically evaluated Cenrifki in non-relapsing SPMS and demonstrated a significant delay in the onset of disability progression. Further supporting evidence comes from the GEMINI 1 and GEMINI 2 phase 3 studies in relapsing multiple sclerosis, with data presented at major conferences like ECTRIMS 2024 and AAN 2025, and published in The New England Journal of Medicine.
• Cenrifki is an oral, brain-penetrant Bruton’s tyrosine kinase (BTK) inhibitor designed to target smoldering neuroinflammation, a key driver of disability progression in MS. The safety profile has been consistent across the clinical program, with common adverse events including COVID-19 and upper respiratory tract infections. Significant liver enzyme elevations and drug-induced liver injury (DILI) are identified risks, necessitating strict liver monitoring.

Addressing the Unmet Need in Non-Relapsing SPMS

Secondary progressive multiple sclerosis without relapses represents one of the most challenging areas in MS treatment, with significant gaps in therapeutic options and clinical outcomes. The current treatment landscape reveals substantial unmet medical needs, with a high proportion of patients remaining untreated or experiencing continued disease progression despite available therapies.

• Limited therapeutic arsenal: No disease-modifying therapies are specifically approved for nonactive SPMS as of 2024, with only two clinical trials demonstrating significant reduction in disability progression in SPMS populations (EXPAND study for siponimod and European interferon beta-1b subcutaneous study)

• High rates of untreated patients: Approximately 43% of patients with nonactive progressive MS remain untreated, with rates remaining elevated at 10-38% even in recent years (2018-2021)

• Continued disability progression despite treatment: More than 50% of patients experience disability progression, including many receiving disease-modifying therapies, highlighting the inadequacy of current therapeutic approaches

• Insufficient evidence base for existing treatments: For DMTs approved for relapsing MS including active SPMS (ocrelizumab, cladribine, ofatumumab, ponesimod), efficacy data in SPMS derive only from post hoc analyses of small subgroups representing up to 15% of total study populations

• Unclear impact on relapse-independent progression: Current DMT approvals for active SPMS are largely based on assumptions that relapse rate reduction observed in RRMS translates to SPMS, while the potential to reduce relapse-independent progression remains uncertain

• Limited impact on neurodegeneration: Available disease-modifying drugs primarily target the inflammatory component of MS, with likely modest effects on the neurodegenerative aspects that drive progression in nonactive SPMS

• Physician-identified efficacy gaps: Healthcare providers cite effectiveness as the greatest unmet need (63-87%), specifically emphasizing the need for treatments that slow disease progression (32-59%)

• Diagnostic and monitoring challenges: Early detection of relapse-independent progression remains difficult, complicated by superimposed relapses and compensatory mechanisms that allow silent progression to occur undetected

Cenrifki's HERCULES Study: Design and Key Efficacy

The available literature provides limited data specifically for secondary progressive multiple sclerosis (SPMS) without relapses, as most trials include mixed populations or explicitly exclude this phenotype. The ASCEND trial with natalizumab represents the most comprehensive study targeting disability progression unrelated to relapses, while MS-STAT2 evaluates simvastatin in patients where steady progression is the predominant disease driver.

Cenrifki's Position in the BTK Inhibitor SPMS Landscape

Several BTK inhibitors are being investigated for multiple sclerosis alongside tolebrutinib, representing a competitive landscape of brain-penetrant therapies targeting both peripheral and central nervous system inflammation. These compounds share the same mechanism of action but differ in their selectivity profiles and clinical development stages.

Tolebrutinib's EU Nod: A Breakthrough for Non-Relapsing SPMS

The European Medicines Agency’s positive opinion for Sanofi’s tolebrutinib represents a significant stride forward for individuals living with non-relapsing secondary progressive multiple sclerosis (SPMS). This patient population has long faced a critical therapeutic gap, with no approved treatments specifically designed to slow the relentless accumulation of disability that characterizes this form of MS. Tolebrutinib, an oral and brain-penetrant Bruton's tyrosine kinase (BTK) inhibitor, offers a novel approach by targeting both peripheral immune cells and, crucially, immune cells within the central nervous system, such as microglia. This dual action is vital, as chronic neuroinflammation compartmentalized within the brain is understood to be a key driver of progressive MS.

Data from the HERCULES phase 3 study demonstrated that tolebrutinib significantly reduced the risk of confirmed disability progression, offering a tangible benefit where none previously existed. This positions Sanofi to potentially establish a first-in-class therapy, carving out a new market segment and providing a much-needed option for patients. The drug's ability to cross the blood-brain barrier and modulate CNS-resident immune cells differentiates it within the evolving landscape of MS treatments and the broader BTK inhibitor class.

However, as with any new therapy, important considerations exist. Clinical trials revealed a higher incidence of elevated liver enzymes with tolebrutinib, underscoring the need for careful patient monitoring. Furthermore, while effective in progressive MS, tolebrutinib did not demonstrate superiority over an active comparator in reducing annualized relapse rates in relapsing forms of MS, suggesting its primary utility may be focused on the progressive disease course. The class of BTK inhibitors also carries a known risk profile, including minor bleeding and potential cardiovascular events, which will require ongoing pharmacovigilance. Despite these considerations, the potential approval of tolebrutinib could fundamentally alter the treatment paradigm for non-relapsing SPMS, offering a new beacon of hope for patients and their clinicians.