Cenrifki (tolebrutinib) / Sanofi - LARVOL DELTA

Tolebrutinib in nonrelapsing SPMS: regulatory divergence and the limits of relapse based labels. (PubMed, Mult Scler Relat Disord) - No abstract available

Journal • CNS Disorders • Hepatology • Liver Failure • Multiple Sclerosis

Tolebrutinib liver safety: A detailed overview. (PubMed, Mult Scler Relat Disord) - P3 | "This overview summarizes tolebrutinib liver safety data, characterizes DILI cases, describes mechanistic and biomarker findings, and demonstrates the impact of enhanced monitoring on early detection and risk mitigation. CLINICALTRIALS.GOV IDENTIFIERS: NCT04410978, NCT04410991, NCT04411641, NCT04458051, NCT06372145."

Journal • CNS Disorders • Hepatology • Liver Failure • Multiple Sclerosis • Transplantation

Mechanistically resolved prediction of compound hepatotoxicity using primary human liver spheroids-Application to recent real-world cases. (PubMed, Drug Metab Dispos) - "Cholestatic liability was identified using bile acid coexposure with accurate classification of chlorpromazine and bosentan and confirmation of bile salt export pump downregulation. Importantly, the model also recapitulated hepatotoxicity signals observed in recent clinical development, including for Bruton's tyrosine kinase inhibitors (tolebrutinib and evobrutinib), oral glucagon-like peptide-1 receptor agonists (danuglipron vs orforglipron), synergistic toxicity on azelaprag-tirzepatide coexposure and enhanced sensitivity to the IL-17A inhibitor LY3509754 on coculture with nonparenchymal liver cells...The model maintains stable CYP expression and metabolic activity, captures the impact of nonparenchymal cells on hepatic clearance, and detects mitochondrial, cholestatic, and interaction-driven toxicity, including recent real-world clinical cases. These findings support 3-dimensional human liver spheroids as translational new approach methodologies for integrating..."

Journal • Real-world evidence • Hepatology • Liver Failure • Metabolic Disorders • IL17A

Effect of Tolebrutinib on Disability in Relation to MRI Activity: A Post-Hoc Analysis of HERCULES and GEMINI Phase 3 Trials (EAN 2026) - P3 | "This post-hoc analysis suggests that tolebrutinib decreases the risk of disability accumulation in participants with nrSPMS and RMS in both those who develop focal lesions while receiving treatment and those who do not."

P3 data • Retrospective data • CNS Disorders • Multiple Sclerosis

Emerging Role of BTK Inhibitors in Multiple Sclerosis: From Immunobiology to Clinical Translation. (PubMed, Brain Sci) - "BTK inhibitors reduce inflammatory disease activity in relapsing MS and have emerging efficacy in progressive MS phenotypes; however, continued monitoring for hepatotoxicity is warranted. Optimization of CNS penetrance and pharmacologic selectivity may influence long-term clinical positioning."

Journal • Review • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis

Sanofi’s Cenrifki (tolebrutinib) approved in the EU as the first disability-targeting medicine for secondary progressive multiple sclerosis without relapses (GlobeNewswire) - "This follows the positive opinion by the European Medicines Agency's Committee for Medicinal Products for Human Use. The approval is based on results from the HERCULES phase 3 study (clinical study identifier: NCT04411641) in non-relapsing SPMS (nrSPMS), with supporting data from the GEMINI 1 (clinical study identifier: NCT04410978) and GEMINI 2 (clinical study identifier: NCT04410991) phase 3 studies in relapsing multiple sclerosis (RMS)....Sanofi will make Cenrifki commercially available in Germany this year..."

EMA approval • Launch Europe • Multiple Sclerosis

Early Anti-CD20 and CNS Penetrant BTK Inhibition to Enhance OPC-Driven Remyelination in Multiple Sclerosis. (PubMed, CNS Neurol Disord Drug Targets) - "Supporting data include disability slowing with tolebrutinib in non-relapsing secondary progressive MS, heterogeneous relapse outcomes across BTKi molecules, and class safety signals that favour BTKi as an add-on rather than a replacement for anti-CD20 therapy...Patient selection bifurcates into active relapsing MS, suited to upfront anti-CD20 therapy to maximise salvageable substrate, and non-reversing SPMS or PPMS, enriched for PRL and SEL burden, where CNS-penetrant BTKi is prioritised. Success is defined as a decrease in CAL burden and an increase in rem."

Journal • CNS Disorders • Inflammation • Multiple Sclerosis • Solid Tumor

Blood Levels of Immune Cells, Immunoglobulins, and Platelets in the Phase 3 HERCULES and GEMINI Trials of Tolebrutinib in nrSPMS and RMS (CMSC 2026) - P3 | "In phase 3 pivotal trials, tolebrutinib treatment reduced the risk of disability accumulation versus placebo in non-relapsing secondary progressive MS (nrSPMS), and versus teriflunomide in relapsing MS (RMS) though not superior in reducing annualized relapse rate (primary endpoint). Mean levels of immune cells, immunoglobulins, and platelets remained stable overall and within normal ranges in participants treated with tolebrutinib over the duration of the HERCULES and GEMINI trials. These findings support the safety profile of tolebrutinib as an immunomodulatory agent that does not deplete circulating leukocytes, immunoglobulins, or platelets."

Immune cell • P3 data • CNS Disorders • Multiple Sclerosis

MSBenefiT: A Randomized Open Label Trial Exploring the Soluble and Imaging Biomarker Dynamic Responses to Tolebrutinib Compared to Rituximab Treatment in Patients with Multiple Sclerosis (MS) (clinicaltrialsregister.eu) - P2/3 | N=60 | Not yet recruiting | Sponsor: Region Stockholm SLSO

Biomarker • New P2/3 trial • CNS Disorders • Multiple Sclerosis

Tolebrutinib Administration with Food: Clinical Trial Evidence and Implications for Dosing Guidelines (CMSC 2026) - "Administration of tolebrutinib with a meal is required for optimal exposure. Patients should be advised to take tolebrutinib at the same time and with the same meal (breakfast, lunch, or dinner) each day. Adherence to meal-related administration guidelines for tolebrutinib may help maximize treatment benefits, potentially supporting more favorable disability outcomes."

Clinical • CNS Disorders • Multiple Sclerosis

Subgroup Analysis of the Phase 3 Tolebrutinib HERCULES Trial: Disability Accumulation Outcomes in North American Participants (CMSC 2026) - P3 | "Tolebrutinib demonstrated a significant effect on disability accumulation versus placebo in participants with nrSPMS, with consistent benefit observed for participants residing in North America, including the US."

P3 data • CNS Disorders • Multiple Sclerosis

Indirect Treatment Comparison of Brain Volume Loss with Tolebrutinib Versus Other Therapies In Relapsing Multiple Sclerosis: A Network Meta-Analysis (CMSC 2026) - "For tolebrutinib, ublituximab, and cladribine, percent change in BVL from 6 months to end of study (EOS) was extracted, while change from baseline to EOS was used for all other comparators...Relative to other approved DMTs in RMS, tolebrutinib showed numerically lower change in BVL across most comparisons, except with ponesimod 20 mg and alemtuzumab 12 mg, where trends favored the comparator. Tolebrutinib 60 mg was associated with less BVL versus placebo, peginterferon 125 µg Q2W and glatiramer acetate 40 mg TIW and showed numerically favorable BVL outcomes compared with most established RMS therapies, suggesting a potential beneficial effect on BVL."

Retrospective data • CNS Disorders • Multiple Sclerosis

Bruton's Tyrosine Kinase Inhibitors in Multiple Sclerosis: Mechanistic Considerations Across Relapsing and Progressive Disease. (PubMed, Molecules) - "Second-generation BTK inhibitors, including evobrutinib, tolebrutinib, fenebrutinib, remibrutinib, and orelabrutinib, have advanced through Phase II-III development in MS. This review integrates molecular pharmacology and the most recent clinical evidence available through 2026 to examine how pharmacologic properties translate into stage-dependent therapeutic positioning. We also consider safety constraints within a disease-stage-specific benefit-risk framework, aiming to clarify the evolving role of BTK inhibition in MS."

Journal • Review • CNS Disorders • Inflammation • Multiple Sclerosis

Bruton's Tyrosine Kinase Inhibitors in Multiple Sclerosis. (PubMed, Drugs) - "In particular, tolebrutinib has demonstrated efficacy against disability progression in non-relapsing secondary progressive MS, while fenebrutinib has recently shown promise in both relapsing and primary progressive MS. However, adverse events include elevated liver enzymes, which can reach life-threatening levels. This review highlights the role of BTK in immune signaling and the rationale for BTK inhibition in MS, discusses the evolution of BTK inhibitors for MS and other indications, summarizes findings from Phase 2 and Phase 3 trials in RMS and PMS, and explores practical questions around the potential use of BTK inhibitors in real-world practice."

Journal • Review • CNS Disorders • Inflammation • Multiple Sclerosis

Uncoupling Relapse Reduction and Disability Progression: Evidence From Tolebrutinib Studies. (PubMed, Neurol Clin Pract) - "Tolebrutinib was the only therapy to show a benefit on CDW without a measurable effect on relapses, highlighting a dissociation between disability worsening and relapse suppression not observed with other DMTs."

Journal • CNS Disorders • Multiple Sclerosis

Safety Comparison of Teriflunomide and Next-generation BTK Inhibitors in Relapsing Multiple Sclerosis: Network Meta-analysis of Randomized Controlled Trials (AAN 2026) - "Results Mortality was lower with tolebrutinib than teriflunomide (OR 0.50, CI 0.05-5.58), while evobrutinib had similar rates (OR 1.01, CI 0.06-16.14). Conclusions BTK inhibitors demonstrated less alopecia events and no increased ALT levels as compared to teriflunomide, whereas evobrutinib has more overall adverse events. These results point to targeted monitoring of patients and highlight the need for more."

Retrospective data • Alopecia • CNS Disorders • Immunology • Infectious Disease • Multiple Sclerosis

Bruton’s Tyrosine Kinase Inhibitors in Multiple Sclerosis: A Meta-analysis With Reconstructed Individual Patient Data (AAN 2026) - "Design/Methods A literature search was conducted through PubMed, Scopus, and WOS to identify RCTs evaluating BTK inhibitors (Tolebrutinib; Evobrutinib) in MS. Event-specific analyses revealed a lower risk of alopecia and gastrointestinal effects compared with teriflunomide (RR=0.49,0.48; respectively), as well as a higher risk of ALT elevation compared with placebo (RR=2.58). Conclusions BTK inhibitors showed potential in reducing MRI lesions and disability progression, improving confirmed disability, and demonstrated acceptable safety profile; however, further studies are needed to confirm these findings."

Retrospective data • Alopecia • CNS Disorders • Immunology • Multiple Sclerosis

Blood Levels of Immune Cells, Immunoglobulins, and Platelets in the Phase Three HERCULES and GEMINI Trials of Tolebrutinib in Non-relapsing Secondary Progressive Multiple Sclerosis and Relapsing Multiple Sclerosis (AAN 2026) - P3 | "In phase 3 pivotal trials, tolebrutinib treatment reduced the risk of disability accumulation versus placebo in non-relapsing secondary progressive MS (nrSPMS), and versus teriflunomide in relapsing MS (RMS) though not superior in reducing annualized relapse rate (primary endpoint). Conclusions Mean levels of immune cells, immunoglobulins, and platelets remained stable overall and within normal ranges in participants treated with tolebrutinib over the duration of the HERCULES and GEMINI trials. These findings support the safety profile of tolebrutinib as an immunomodulatory agent that does not deplete circulating leukocytes, immunoglobulins, or platelets."

Immune cell • CNS Disorders • Multiple Sclerosis

Effects of Tolebrutinib on Progression Independent of Relapse Activity in the Phase Three GEMINI Relapsing MS Trials (AAN 2026) - P3 | "Conclusions Tolebrutinib-treated participants experienced fewer PIRA events in comparison to teriflunomide. These GEMINI PIRA data support the observation in HERCULES that tolebrutinib targets drivers of disability accumulation independent of effects on relapsing biology."

Multiple Sclerosis

Subgroup Analysis of the Phase Three Tolebrutinib HERCULES Trial: Disability Accumulation Outcomes in North American Participants (AAN 2026) - P3 | "A limitation of this analysis is the small sample size of the subgroups. Conclusions Tolebrutinib demonstrated a significant effect on disability accumulation versus placebo in nrSPMS, with consistent benefit observed for participants residing in North America, including the US."

CNS Disorders • Multiple Sclerosis

Discussant: Efficacy and Safety of Tolebrutinib Versus Placebo in Primary Progressive Multiple Sclerosis: Results from the Phase 3 PERSEUS Trial (AAN 2026) - No abstract available

Clinical • P3 data • CNS Disorders • Multiple Sclerosis

Subgroup Analyses of the Phase Three Tolebrutinib in Non-relapsing Secondary Progressive Multiple Sclerosis (nrSPMS) HERCULES Trial (AAN 2026) - "The adjusted annualized adjudicated relapse rate during the trial was low for both tolebrutinib (0.033; 95% CI: 0.024 to 0.045) and placebo (0.032; 95% CI: 0.021 to 0.049), as expected. Conclusions Compared to placebo, tolebrutinib demonstrated an overall consistent effect on disability accumulation across all subgroups."

CNS Disorders • Multiple Sclerosis

Press Release: Sanofi’s Cenrifki (tolebrutinib) recommended for EU approval by the CHMP to treat secondary progressive multiple sclerosis without relapses (The Manila Times) - "The positive CHMP opinion is based on data from the HERCULES phase 3 study (clinical study identifier: NCT04411641) in non-relapsing SPMS, with supporting data from the GEMINI 1 (clinical study identifier: NCT04410978) and GEMINI 2 (clinical study identifier: NCT04410991) phase 3 studies in relapsing multiple sclerosis (RMS)...Additional submissions for Cenrifki are currently under review with regulatory authorities worldwide."

CHMP • Filing • Multiple Sclerosis

Presenter: Efficacy and Safety of Tolebrutinib Versus Placebo in Primary Progressive Multiple Sclerosis: Results from the Phase 3 PERSEUS Trial (AAN 2026) - P3 | "In phase 3 pivotal trials, tolebrutinib treatment reduced the risk of disability accumulation versus placebo in non-relapsing secondary progressive MS and versus teriflunomide in relapsing MS.Design/PERSEUS (NCT04458051) is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven trial. Enrollment criteria included age 18-55 years, diagnosis of PPMS per the 2017 McDonald criteria, Expanded Disability Status Scale (EDSS) score of 2.0-6.5 at screening, positive CSF findings, and either no access, intolerance, or perceived lack of efficacy to ocrelizumab...The presented PERSEUS trial results will provide an assessment of tolebrutinib efficacy and safety in people with PPMS."

Clinical • P3 data • CNS Disorders • Multiple Sclerosis

A Study to Investigate Long-term Safety and Tolerability of Tolebrutinib in Participants With Multiple Sclerosis. (clinicaltrials.gov) - P3 | N=2500 | Recruiting | Sponsor: Sanofi | Active, not recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Multiple Sclerosis