tolebrutinib (SAR442168) / Sanofi - LARVOL DELTA

Tolebrutinib for secondary progressive multiple sclerosis: A summary from the Institute for Clinical and Economic Review's California Technology Assessment Forum. (PubMed, J Manag Care Spec Pharm) - No abstract available

Journal • CNS Disorders • Multiple Sclerosis

Tolebrutinib: First Approval. (PubMed, Drugs) - "The drug is under regulatory review in the USA and the EU. This article summarizes the milestones in the development of tolebrutinib leading to this first approval for MS."

Journal • CNS Disorders • Multiple Sclerosis

NEW TREATMENTS OF MULTIPLE SCLEROSIS (WCN 2025) - "This teaching course will provide a comprehensive overview of the latest advancements in MS treatment, including B-cell depleting therapies (e.g., ocrelizumab), cladribine, Bruton's tyrosine kinase (BTK) inhibitors, and sphingosine-1-phosphate (S1P) receptor modulators, with a focus on their mechanisms, clinical applications, emerging indications, and safety considerations...BTK inhibitors (e.g., evobrutinib, tolebrutinib), currently in phase III trials, target both peripheral and CNS-resident immune cells, showing promise for progressive MS. S1P receptor modulators (e.g., fingolimod, siponimod) regulate lymphocyte trafficking and are approved for RMS and secondary progressive MS (SPMS)...Additionally, this course will explore smoldering MS pathology, including chronic active lesions and neurodegeneration, and discuss whether emerging therapies, particularly BTK inhibitors, can address progression beyond relapse suppression. Through case discussions and trial data,..."

CNS Disorders

Effects of Tolebrutinib on MSQoL-54 in the HERCULES Phase 3 trial in nrSPMS (ECTRIMS 2025) - P3 | "These analyses suggest that tolebrutinib may preserve several key HRQoL domains over time in people with nrSPMS."

P3 data • CNS Disorders • Multiple Sclerosis

Blood Immunoglobulin Levels and Immune Cell Populations in the Phase 3 GEMINI Trials of Tolebrutinib in Relapsing Multiple Sclerosis (ECTRIMS 2025) - P3 | "In the phase 3 GEMINI 1 and 2 trials (NCT04410978; NCT04410991) involving participants with relapsing MS, tolebrutinib reduced the risk of disability worsening versus teriflunomide. Mean immune cell counts, immunoglobulin levels and platelet count remained within normal ranges in participants treated with tolebrutinib in the GEMINI 1 and 2 trials. These findings support the safety profile of tolebrutinib as an immunomodulatory agent that does not appear to deplete circulating leukocytes, immunoglobulins or platelets."

Clinical • Immune cell • P3 data • CNS Disorders • Multiple Sclerosis

Subgroup Analyses of the Phase 3 Tolebrutinib in nrSPMS HERCULES Trial (ECTRIMS 2025) - "Compared to placebo, tolebrutinib demonstrated an overall consistent effect on disability accumulation across all subgroups."

P3 data • CNS Disorders • Multiple Sclerosis

Effects of Tolebrutinib on Progression Independent of Relapse Activity in the Phase 3 GEMINI Relapsing MS Trials (ECTRIMS 2025) - P3 | "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."

P3 data • Multiple Sclerosis

Tolebrutinib treatment induces complex alterations of the peripheral immune-regulatory network in the blood of patients with non-relapsing secondary progressive MS – results from the TOLEDYNAMIC study (ECTRIMS 2025) - P3 | "Our data reveal that in vivo inhibition of BTK via Tolebrutinib induces complex shifts in the differentiation programme of B cells as well as T helper cell subsets which may contribute to the recently discovered effects on disease progression in non-relapsing secondary progressive MS."

Clinical • Multiple Sclerosis

Blood Immunoglobulin Levels and Immune Cell Populations in the Phase 3 HERCULES Trial of Tolebrutinib in Non-Relapsing Secondary Progressive Multiple Sclerosis (ECTRIMS 2025) - P3 | "Mean immune cell counts, immunoglobulin levels and platelet count remained within normal ranges in participants treated with tolebrutinib in the HERCULES trial. These findings support the safety profile of tolebrutinib as an immunomodulatory agent that does not appear to deplete circulating leukocytes, immunoglobulins or platelets."

Clinical • Immune cell • P3 data • CNS Disorders • Multiple Sclerosis

Tolebrutinib Plasma Exposure and Efficacy Response in the Phase 3 HERCULES Trial in nrSPMS (ECTRIMS 2025) - "These findings suggest that higher exposures were associated with greater effects in slowing disability accumulation."

Clinical • P3 data • Multiple Sclerosis

Tolebrutinib influences B cell and monocyte phenotype and function in treatment-naïve relapsing-remitting and progressive forms of multiple sclerosis (ECTRIMS 2025) - "In B cells and activated monocytes derived from treatment-naïve RRMS and SPMS patients, tolebrutinib significantly increased IL-10 levels while decreasing TNF, IL-12, and the expression of co-stimulatory molecules and microRNAs involved in antigen presentation and effector function. These results suggest that tolebrutinib limits both innate and adaptive immune responses that are associated with relapse activity and disease progression in MS."

CNS Disorders • Inflammation • Multiple Sclerosis • CD14 • CD80 • CD86 • IFNG • IL10 • IL12A • IL6 • MIR155 • MIR223

Multiple sclerosis updates and the safety and efficacy of Bruton tyrosine kinase inhibitors in it: A systematic review. (PubMed, Dis Mon) - "With good safety and efficacy profiles in treating relapsing multiple sclerosis, both of the BTKis (Evobrutinib and Tolebrutinib) show promise. Both have promise as oral treatments of the future, but Tolebrutinib might have better effects on the central nervous system. To confirm long-term results and determine their role in progressive MS, more phase III trials are necessary."

Journal • CNS Disorders • Immunology • Infectious Disease • Inflammation • Multiple Sclerosis

…The PERSEUS phase 3 study in primary progressive MS is ongoing with study results anticipated in H2 2025 (PRNewswire)

P3 data • Multiple Sclerosis

Press Release: Update on the US regulatory review of tolebrutinib in non-relapsing, secondary progressive multiple sclerosis (GlobeNewswire) - "Based on the submission of additional analyses during the review, the FDA has determined that the additional information constituted a major amendment to the NDA and extended the target action date accordingly. The revised target action date for the FDA decision is December 28, 2025."

PDUFA • Multiple Sclerosis

Dose-finding Study for SAR442168 in Relapsing Multiple Sclerosis (clinicaltrials.gov) - P2 | N=130 | Completed | Sponsor: Sanofi | Phase classification: P2b ➔ P2

Phase classification • CNS Disorders • Multiple Sclerosis

Baseline characteristics in the tolebrutinib Phase 3 primary progressive multiple sclerosis PERSEUS clinical trial (EAN 2025) - No abstract available

Clinical • P3 data • CNS Disorders • Multiple Sclerosis

Paramagnetic rim lesions as a prognostic and predictive biomarker in Tolebrutinib Phase 3 trials for disability outcomes (EAN 2025) - P3 | "Background and aims: Tolebrutinib, a brain-penetrant Bruton's tyrosine kinase inhibitor that, in phase-3 trials, reduced disability accumulation by 31% and 29% relative to placebo and teriflunomide in non-relapsing secondary progressive multiple sclerosis (MS) and relapsing MS, respectively. This post-hoc analysis suggests greater impact of tolebrutinib in those with higher number of PRLs."

Biomarker • P3 data • CNS Disorders • Multiple Sclerosis

In a landmark regulatory achievement that reflects the UAE’s leadership in accelerating access to innovative therapies, the Emirates Drug Establishment has announced the approval of ’Tolebrutinib’ as the world’s first oral treatment for non-relapsing secondary progressive multiple sclerosis (Devdiscourse) - "The approval was based on a scientific study conducted in collaboration with the National Multiple Sclerosis Society."

Approval • Multiple Sclerosis

Tolebrutinib for non-relapsing secondary progressive multiple sclerosis: a critical therapeutic gap. (PubMed, Med) - "Results from the HERCULES trial1 showed that tolebrutinib, a brain-penetrant BTKi, reduced by 31% the risk of disability progression in non-relapsing secondary progressive MS patients, with a good safety profile. Tolebrutininb may represent a major advance for this MS population with no treatment currently approved."

Journal • CNS Disorders • Multiple Sclerosis

Targeting smouldering neuroinflammation in multiple sclerosis: insights from tolebrutinib clinical trials. (PubMed, Lancet Reg Health Eur) - No abstract available

Journal • CNS Disorders • Inflammation • Multiple Sclerosis

Next generation Bruton's tyrosine kinase inhibitors - characterization of in vitro potency and selectivity. (PubMed, Eur J Pharmacol) - "BTKi ranked in their selectivity as follows (most selective to least): remibrutinib, fenebrutinib, evobrutinib, orelabrutinib, rilzabrutinib and tolebrutinib. These data suggest that next generation BTKi show important differences in their in vitro target binding and selectivity when compared under the same conditions."

Journal • Preclinical • Allergy • Immunology

CDSCO Panel Approves Sanofi's Protocol Amendment To Study Tolebrutinib (Medical Dialogues) - "This came after the firm presented protocol amendment 14, version 01, dated 31-Oct-2024, protocol no. EFC16035. This is a phase 3, randomized, double-blind, efficacy and safety study comparing SAR442168 to placebo in participants with primary progressive multiple sclerosis (PERSEUS)...At the SEC meeting for Neurology and Psychiatry held on 28th February 2025, the expert panel reviewed protocol amendment 14, version 01 dated 31-Oct-2024 protocol no. EFC16035....After detailed deliberation, the committee recommended the approval of the protocol amendment as presented by the firm."

Clinical protocol • Multiple Sclerosis

AAN 2025: Sanofi’s tolebrutinib likely to be first BTK inhibitor for the treatment of MS (Yahoo Finance) - "During the Plenary Session, Sanofi also reported that tolebrutinib failed to meet the primary endpoint of reducing annualised relapse rate over teriflunomide in patients with RMS in the GEMINI studies. A pooled analysis of GEMINI 1 and GEMINI 2 for a key secondary endpoint, not controlled for multiplicity, showed that tolebrutinib delayed the time to onset of six-month confirmed disability worsening by 29% versus teriflunomide. But the number of new Gd-enhancing T1 lesions was higher in the tolebrutinib arm and the number of new or enlarging T2 lesions was similar between both treatment arms....Tolebrutinib was generally well-tolerated in the HERCULES, GEMINI 1, and GEMINI 2 trials."

Retrospective data • Multiple Sclerosis

Tolebrutinib versus Teriflunomide in Relapsing Multiple Sclerosis. (PubMed, N Engl J Med) - P3 | "Tolebrutinib was not superior to teriflunomide in decreasing annualized relapse rates among participants with relapsing multiple sclerosis. (Funded by Sanofi; GEMINI 1 and GEMINI 2 ClinicalTrials.gov numbers, NCT04410978 and NCT04410991, respectively.)."

Journal • CNS Disorders • Inflammation • Multiple Sclerosis

Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis. (PubMed, N Engl J Med) - P3 | "In participants with nonrelapsing secondary progressive multiple sclerosis, the risk of disability progression was lower among those who received treatment with tolebrutinib than among those who received placebo. (Funded by Sanofi; HERCULES ClinicalTrials.gov number, NCT04411641.)."

Journal • CNS Disorders • Inflammation • Multiple Sclerosis