tolebrutinib (SAR442168) / Sanofi - LARVOL DELTA

Subgroup Analysis of the Phase 3 Tolebrutinib HERCULES Trial: Disability Accumulation Outcomes in North American Participants (ACTRIMS Forum 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.STUDY FUNDING: Sanofi."

P3 data • 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

Efficacy and Safety of Tolebrutinib Versus Placebo in Primary Progressive Multiple Sclerosis: Results From the Phase 3 PERSEUS Trial (ACTRIMS Forum 2026) - "Abstract is embargoed at this time."

Clinical • Late-breaking abstract • P3 data • CNS Disorders • Multiple Sclerosis

Presenter: 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

Tolebrutinib outcomes not as hoped for progressive MS (Multiple Sclerosis Australia) - "There is currently only one disease modifying therapy (DMT) approved in Australia for people with primary progressive MS, however, this is not available on the pharmaceutical benefits scheme (PBS)...Tolebrutinib is also under review by the Therapeutic Goods Administration (TGA) for treating non-relapsing secondary progressive MS in Australia."

Reimbursement • Multiple Sclerosis

Efficacy and safety of Bruton's tyrosine kinase inhibitors compared to Teriflunomide in relapsing multiple sclerosis: A systematic review and meta-analysis. (PubMed, Mult Scler Relat Disord) - "Compared with teriflunomide, BTK inhibitors were associated with a reduced risk of short-term disability progression, whereas no differences were observed in relapse rates, MRI activity, or safety outcomes."

Journal • Retrospective data • Review • CNS Disorders • Multiple Sclerosis

A CENTRALLY-ACTING BTK INHIBITOR AMELIORATES AGGRESSIVE MSA-C SUPPRESSING PROINFLAMMATORY MICROGLIA AND PHOSPHORYLATED Α-SYNUCLEIN FORMATION (ADPD 2026) - "Tolebrutinib and remibrutinib, respectively centrally and peripherally-acting Bruton's tyrosine kinase inhibitors (BTKi), were orally administered to Tg mice 4 times a week from 18 to 26 weeks of age, and clinicopathologically evaluated. Single-cell RNA sequencing revealed a unique microglia cluster that highly expresses Toll-like receptor 2, transglutaminase 2, arginase-1, and various inflammatory cytokines compared with other clusters. A centrally-acting BTKi could be a novel therapy for MSA-C by suppressing proinflammatory microglia like SAM."

IO biomarker • Ataxia • CNS Disorders • Inflammation • Movement Disorders • Multiple System Atrophy • Solid Tumor • ITGAM • PLP1 • SNCA • TGM2 • TLR2

Primary Progressive Multiple Sclerosis (PPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (PERSEUS) (clinicaltrials.gov) - P3 | N=767 | Completed | Sponsor: Sanofi | Trial primary completion date: Jul 2025 ➔ Nov 2025 | Active, not recruiting ➔ Completed

Trial completion • Trial primary completion date • CNS Disorders • Multiple Sclerosis • Plasma NfL

Sanofi SA…announced that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) for the New Drug Application of tolebrutinib, which was being evaluated for non-relapsing secondary progressive multiple sclerosis. (Investing.com) - "'The French pharmaceutical company received the regulatory setback for tolebrutinib, a drug candidate that had been in development for this specific form of multiple sclerosis. A Complete Response Letter from the FDA indicates that the agency has completed its review of a drug application but cannot approve it in its current form."

CRL • Multiple Sclerosis

Press Release: Sanofi provides update on tolebrutinib in primary progressive multiple sclerosis (Sanofi Press Release) - "Results from the PERSEUS phase 3 study (clinical study identifier: NCT04458051) showed that tolebrutinib did not meet its primary endpoint in delaying time to 6-month composite confirmed disability progression (cCDP) in participants with primary progressive multiple sclerosis (PPMS), which represents 10% of the overall multiple sclerosis patient population. Based on these results, Sanofi will not pursue regulatory registration for PPMS...Preliminary analysis showed the safety profile was consistent with previous tolebrutinib studies."

P3 data • Regulatory • Multiple Sclerosis

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