Sanofi’s Cenrifki (tolebrutinib) approved in the EU as the first disability-targeting medicine for secondary progressive multiple sclerosis without relapses

EU Approves Sanofi's Cenrifki for Non-Relapsing SPMS

Sanofi's Cenrifki (tolebrutinib), an oral Bruton's tyrosine kinase inhibitor, has received European Commission approval for treating secondary progressive multiple sclerosis (SPMS) without relapses in the last two years. This marks Cenrifki as the first disability-targeting medicine for this patient population in the EU. The approval is primarily based on positive results from the Phase 3 HERCULES study in non-relapsing SPMS (nrSPMS), which demonstrated a significant delay in disability progression. Supporting data came from the GEMINI 1 and 2 Phase 3 studies in relapsing MS. While Cenrifki showed a consistent safety profile, common adverse events included COVID-19 and upper respiratory infections, with drug-induced liver injury (DILI) identified as a safety risk requiring strict monitoring. Sanofi plans to launch Cenrifki commercially in Germany this year.

• The European Commission has granted marketing authorization for Sanofi's Cenrifki (tolebrutinib) for secondary progressive multiple sclerosis (SPMS) without relapses in the last two years. This approval, following a positive opinion from the European Medicines Agency's CHMP, positions Cenrifki as the first disability-targeting medicine in the EU specifically designed to address the underlying processes of MS disability accumulation in this patient group, representing a significant advancement for an area with high unmet medical need.
• The approval is primarily supported by the HERCULES Phase 3 study (NCT04411641) in non-relapsing SPMS. This double-blind, randomized study demonstrated that Cenrifki significantly delayed the onset of six-month confirmed disability progression (CDP), its primary endpoint. Patients in HERCULES had an EDSS score between 3.0 and 6.5, no clinical relapses for 24 months, and documented disability accumulation in the prior 12 months, highlighting its efficacy in a specific, progressive MS population.
• Cenrifki is an oral, brain-penetrant Bruton's tyrosine kinase inhibitor that targets smoldering neuroinflammation, a key driver of disability progression in MS. Its safety profile was consistent across the clinical program, with common adverse events including COVID-19 and upper respiratory tract infections. However, significant liver enzyme elevations were observed, and drug-induced liver injury (DILI) is an identified safety risk, necessitating strict adherence to liver monitoring requirements and prompt management.
• The EU approval is also supported by data from the GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) Phase 3 studies in relapsing multiple sclerosis. Beyond the EU, Cenrifki is already approved in Australia and the United Arab Emirates for similar SPMS indications. Sanofi plans to make Cenrifki commercially available in Germany this year, emphasizing a careful introduction supported by a Risk Management Program and Patient Support Program, underscoring its commitment to addressing neurological diseases.

Cenrifki's Clinical Foundation: HERCULES and Supporting Studies

The evidence base for non-active secondary progressive multiple sclerosis (SPMS) — defined by the absence of relapses in the preceding two years — is characterised by heterogeneous trial designs, inconsistent primary endpoint results, and evolving patient selection criteria. Key trials have spanned natalizumab, interferon-beta agents, siponimod, and simvastatin, each employing EDSS-anchored disability progression as the primary outcome while increasingly incorporating composite and patient-reported measures. The table below summarises the core design parameters and endpoints across the pivotal studies in this population.

Secondary endpoints across trials have included T25FW, 9HPT, Single Digit Modalities Test, Sloan Low Contrast Visual Acuity, modified Rankin Scale, BICAMS, and patient-reported outcomes covering walking, fatigue, and disease impact. Health economic analyses are incorporated in MS-STAT2. Methodological consensus identifies EDSS as having poor responsiveness in progressive MS (effect size 0.2–0.3 over two years on placebo), supporting the move toward composite and patient-reported endpoint strategies in future trial design.

Understanding Cenrifki's BTK Inhibition and Safety Considerations

Tolebrutinib's safety and tolerability profile has been characterized across multiple clinical stages, from early phase trials through large Phase 3 programs spanning relapsing and progressive MS populations. Across these studies, the drug has generally demonstrated an acceptable safety profile, though notable differences in adverse event rates have emerged when compared to active comparators and across disease subtypes.

• Phase 2b trial (relapsing MS, n=130): Over 16 weeks, tolebrutinib was well tolerated across all dose cohorts (5 mg, 15 mg, 30 mg, and 60 mg once daily). The most frequently reported non-serious adverse event was headache, occurring in 3–13% of participants depending on dose group. Only one serious adverse event was recorded — a hospitalization for MS relapse in the 60 mg cohort — and no safety-related discontinuations or treatment-related deaths occurred.

• Long-term extension study (relapsing MS, ~2-year follow-up, n=125): Of 129 participants completing the core study, 125 enrolled in the extension (Part A), 124 entered Part B, and 114 remained on study as of February 18, 2022. The most common treatment-emergent adverse events were COVID-19 (21%, n=26/125) and headache (14%, n=17/125). An acceptable safety profile was maintained over the 2-year period, alongside durable effects on MRI measures, annualized relapse rate, and Expanded Disability Status Scale scores.

• Phase 3 GEMINI 1 & 2 trials (relapsing MS; n=974 and n=899; median follow-up 139 weeks): The overall proportion of participants experiencing adverse events was broadly similar between tolebrutinib 60 mg once daily and teriflunomide 14 mg once daily. However, minor bleeding events were more frequent in the tolebrutinib group, including petechiae (4.5% vs. 0.3%) and heavy menses (2.6% vs. 1.0%). Tolebrutinib did not demonstrate superiority over teriflunomide in reducing annualized relapse rates.

• Phase 3 HERCULES trial (nonrelapsing secondary progressive MS; n=1,131; median follow-up 133 weeks): Serious adverse events occurred in 15.0% of participants in the tolebrutinib group versus 10.4% in the placebo group. Elevations in alanine aminotransferase to more than 3× the upper limit of normal were observed in 4.0% of the tolebrutinib group compared with 1.6% in the placebo group, signaling a hepatic safety signal warranting monitoring in this population.

• BTK inhibitor class-level considerations: As an irreversibly binding BTK inhibitor, tolebrutinib shares class-relevant adverse effect considerations, including off-target kinase inhibition. Within the broader BTKi class, dermatological toxicities, diarrhea, bleeding, and invasive fungal infections typically emerge early and may subside over time, while cardiovascular adverse events — including hypertension and various forms of cardiac disease — tend to persist with continued treatment.

Cenrifki's Approval: A New Era for Non-Relapsing Progressive MS

The recent European Commission approval of Sanofi's Cenrifki (tolebrutinib) for non-relapsing secondary progressive multiple sclerosis (nrSPMS) marks a significant milestone, addressing a critical therapeutic gap for patients facing relentless disability progression. For years, this patient population has had limited options, with existing disease-modifying therapies primarily targeting relapsing forms of MS. Cenrifki emerges as the first approved medicine in the EU specifically designed to slow disability accumulation in nrSPMS, offering a new beacon of hope.

Tolebrutinib is an oral, brain-penetrant Bruton's tyrosine kinase (BTK) inhibitor, a class of drugs gaining prominence for their ability to modulate both peripheral B cells and central nervous system (CNS) resident immune cells, notably microglia. This dual action is crucial, as chronic neuroinflammation within the CNS is a key driver of progressive MS. The pivotal Phase 3 HERCULES study demonstrated a significant reduction in the risk of confirmed disability progression, underscoring the drug's potential. Intriguingly, studies indicate that tolebrutinib's benefit on disability progression appears to be uncoupled from its effect on relapse rates, suggesting a distinct mechanism focused on the underlying neurodegenerative processes rather than just acute inflammatory attacks.

This strategic approval positions Sanofi as a leader in a specialized, high-need segment of the MS market. However, the journey ahead is not without considerations. The identified risk of drug-induced liver injury (DILI) necessitates careful patient monitoring, and common adverse events like infections and minor bleeding require proactive management. Furthermore, while Cenrifki is first-in-class for nrSPMS, the broader BTK inhibitor landscape for MS is rapidly evolving, with several other compounds in advanced clinical development. Future data from these competitors will shape the long-term market dynamics. Nevertheless, Cenrifki's approval represents a substantial step forward, offering a targeted approach to a previously intractable aspect of MS and potentially reshaping how progressive forms of the disease are managed.