tolebrutinib (SAR442168) / Sanofi - LARVOL DELTA

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

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).Design/ HERCULES (NCT04411641) and GEMINI 1 and 2 (NCT04410978, NCT04410991) were phase 3, double-blind trials of tolebrutinib 60 mg once daily with food. 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 | "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 | "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

Safety Comparison of Teriflunomide and Next-generation BTK Inhibitors in Relapsing Multiple Sclerosis: Network Meta-analysis of Randomized Controlled Trials (AAN 2026) - " 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). 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

Subgroup Analyses of the Phase Three Tolebrutinib in Non-relapsing Secondary Progressive Multiple Sclerosis (nrSPMS) HERCULES Trial (AAN 2026) - "Compared to placebo, tolebrutinib demonstrated an overall consistent effect on disability accumulation across all subgroups."

CNS Disorders • Multiple Sclerosis

Bruton's Tyrosine Kinase Inhibitors in Multiple Sclerosis: A Meta-analysis With Reconstructed Individual Patient Data (AAN 2026) - "However, their efficacy and safety remain uncertain.Design/ A literature search was conducted through PubMed, Scopus, and WOS to identify RCTs evaluating BTK inhibitors (Tolebrutinib; Evobrutinib) in MS. 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

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

Tolebrutinib Phase 2b Long-Term Extension Study: Two-Year Safety, MRI, and Clinical Efficacy Outcomes in Patients With Relapsing Multiple Sclerosis Patients. (PubMed, Neurol Open Access) - "This study provides class IV evidence. It is an uncontrolled study without a comparator group."

Journal • P2b data • CNS Disorders • Infectious Disease • Multiple Sclerosis • Novel Coronavirus Disease • Pain

Tolebrutinib and the FDA. (PubMed, Mult Scler Relat Disord) - No abstract available

Journal • 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 | Active, not recruiting | Sponsor: Sanofi | Recruiting ➔ Active, not recruiting

Enrollment closed • 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) - 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...Enrollment criteria included age 18-55 years, diagnosis of PPMS according to the 2017 McDonald criteria, Expanded Disability Status Scale (EDSS) score of 2.0-6.5 at screening, positive cerebrospinal fluid findings (oligoclonal bands and/or elevated immunoglobulin G index), 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 • Late-breaking abstract • P3 data • CNS Disorders • Multiple Sclerosis

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

ACTRIMS 2026: Tolebrutinib misses main goal in PPMS Phase 3 PERSEUS trial (Multiple Sclerosis News Today) - "It did, however, show signs of benefit on MRI scans, including fewer new brain lesions and slower brain volume loss...The treatment also failed to lower the risk of three-month cCDP and had no effect on six-month confirmed disability improvement or decreases in disability...Looking only at six-month EDSS results, there was a 'little bit of a suggestion' that tolebrutinib may have slowed disability progression. However, Fox emphasized that the results were not statistically significant...The scientist noted that the observed 14% lower risk of EDSS progression with tolebrutinib was 'directionally consistent' with findings in other MS types."

P3 data • 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

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