The European Commission has approved Cenrifki (tolebrutinib) for adults with secondary progressive multiple sclerosis (SPMS) without relapses in the last two years, characterized by developer Sanofi as marking the EU entry of the first disease-targeting oral therapy approved in the EU for non-relapsing SPMS (nrSPMS).
The approval also highlights a divergence in regulatory outcomes between major markets. Although tolebrutinib received Breakthrough Therapy designation and Priority Review in the US based on data from the Phase III HERCULES study, the FDA ultimately declined to approve the therapy despite an extended review process and discussions that included an expanded access program for eligible nrSPMS patients. The EC’s positive decision therefore makes Europe the first major market to endorse the drug’s benefit-risk profile in non-relapsing SPMS, following first approvals in the UAE and Australia.
The EC’s approval carries conditions: patients require liver monitoring throughout treatment due to an identified risk of drug-induced liver injury (DILI), and therapy must be initiated by a physician experienced in MS management. Sanofi said it will launch Cenrifki commercially in Germany this year under a Risk Management Program.
Cenrifki is an oral, once-daily, brain-penetrant Bruton’s tyrosine kinase (BTK) inhibitor designed to suppress smoldering neuroinflammation — a process thought to drive progressive disability accumulation independently of acute relapses. By penetrating the central nervous system, tolebrutinib aims to inhibit BTK-dependent activation of microglia and B cells within the brain and spinal cord, addressing inflammatory activity that standard peripheral immunosuppression may not reach.
The approval rests primarily on the HERCULES Phase III study (NCT04411641), a double-blind, randomized trial in patients with nrSPMS defined by an Expanded Disability Status Scale score of 3.0–6.5, no clinical relapses in the prior 24 months, and documented disability accumulation in the preceding 12 months. Participants were randomized 2:1 to tolebrutinib or placebo for up to approximately 48 months. The primary endpoint was six-month confirmed disability progression (CDP). HERCULES demonstrated a 31% reduction in the risk of six-month confirmed disability progression compared with placebo.. Supporting data came from the GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) Phase III studies in relapsing MS, which compared tolebrutinib against teriflunomide on annualized relapse rate.
The most common adverse events reported across the clinical program were COVID-19 and upper respiratory tract infections. Significant liver enzyme elevations were observed, and DILI is listed as an identified risk, necessitating structured monitoring protocols.
SPMS without active relapses has historically been among the most difficult MS subtypes to treat, as most approved disease-modifying therapies demonstrate efficacy principally through reduction of relapse frequency and associated inflammatory lesions — endpoints that are largely irrelevant in the non-relapsing population. The BTK inhibitor mechanism offers a distinct approach by targeting resident CNS immune cells rather than peripheral lymphocyte trafficking, which underpins the rationale for activity in progressive disease. Tolebrutinib joins a competitive BTK inhibitor landscape in MS that includes fenebrutinib (Roche) and orelabrutinib (China-based InnoCare Pharma), though neither currently holds an EU approval for SPMS. Ocrelizumab (Ocrevus, Roche) and siponimod (Mayzent, Novartis) hold approvals for SPMS subtypes in the EU, but neither is specifically indicated for the non-relapsing population addressed by Cenrifki’s label.
This article was generated with AI assistance and reviewed and edited by the AllSci editorial team
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