tolebrutinib (SAR442168) / Sanofi - LARVOL DELTA

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

Re-defining progression in multiple sclerosis. (PubMed, Curr Opin Neurol) - "Pathological processes that underpin MS progression are detectable early in RRMS, evolve throughout the disease course and correlate with disability accumulation. Progression in MS should not be defined dichotomously - the focus instead should be on recognizing progressive components based on clinical measures and biomarkers early in the disease to better individualize treatment strategies."

Journal • CNS Disorders • Inflammation • Metabolic Disorders • Multiple Sclerosis

Cleveland Clinic-Led Trial is the First to Show a Delay in Confirmed Disability Progression in Non-relapsing Secondary Progressive Multiple Sclerosis (Cleveland Clinic) - P3 | N=1,131 | HERCULES (NCT04411641) | Sponsor: Sanofi | "The first peer-reviewed results of the Phase 3 HERCULES trial published online today in the New England Journal of Medicine and were simultaneously presented during a clinical trials plenary session at the American Academy of Neurology 2025 Annual Meeting....For the primary endpoint, the cumulative incidence of six-month confirmed disability progression was 22.6% in the tolebrutinib group versus 30.7% in the placebo group, which was a 31% reduction with tolebrutinib compared to placebo. In addition, the drug demonstrated a positive effect across several of its secondary endpoints in disability progression and MRI-related measures: A similar degree of risk reduction was observed in the time to three-month confirmed disability progression. A higher proportion of patients achieved improvement in disability with therapy, with a six-month confirmed disability improvement rate of 8.6% versus 4.5% with placebo."

P3 data • Multiple Sclerosis

Press Release: Tolebrutinib regulatory submission accepted for priority review in the US for patients with multiple sclerosis (GlobeNewswire) - "The US Food and Drug Administration (FDA) is evaluating under priority review the regulatory submission of tolebrutinib to treat non-relapsing secondary progressive multiple sclerosis (nrSPMS) and to slow disability accumulation independent of relapse activity in adult patients. The target action date for the FDA decision is September 28, 2025. A regulatory submission is also under review in the EU...The regulatory submissions in the US and the EU are supported by the results from the phase 3 studies HERCULES in nrSPMS and GEMINI 1 and 2 in relapsing MS (RMS)."

EMA filing • FDA filing • PDUFA • Priority review • Multiple Sclerosis

Update on novel multiple sclerosis treatments: from dismal defeat to scintillating success. (PubMed, Curr Opin Neurol) - "Multiple strategies are being investigated in MS to address progressive disability, myelin repair, neural protection and treatment refractory disease. Some of these strategies have successfully completed clinical trials giving hope that some of the most vexing aspects of MS will soon have new treatment options."

Journal • CNS Disorders • Multiple Sclerosis

Tolebrutinib Versus Teriflunomide in Relapsing Multiple Sclerosis: Efficacy and Safety Results from the Phase 3 GEMINI 1 and 2 Trials (AAN 2025) - P3 | "Tolebrutinib showed a clear reduction in disability accumulation versus teriflunomide despite no difference in relapses. Results are consistent with the hypothesis that acute focal inflammation and smoldering neuroinflammation are two distinct biological processes."

Clinical • P3 data • CNS Disorders • Inflammation • Multiple Sclerosis

Tolebrutinib Versus Placebo in Non-relapsing Secondary Progressive Multiple Sclerosis: Efficacy and Safety Results from the Phase 3 HERCULES Trial (AAN 2025) - P3 | "HERCULES is the first trial to demonstrate a slowing of disability accumulation in people with nrSPMS, a population with an urgent need for treatments that delay progression."

Clinical • P3 data • CNS Disorders • Infectious Disease • Inflammation • Multiple Sclerosis • Respiratory Diseases

Paramagnetic Rim Lesions as a Prognostic and Predictive Biomarker in the Tolebrutinib Phase 3 Trials for Disability Outcomes (ACTRIMS Forum 2025) - "Abstract is embargoed at this time."

Biomarker • Late-breaking abstract • P3 data

How Does Fenebrutinib Work? Exploring Kinetic and Mechanistic Features That Influence BTK Potency, Selectivity and Pharmacology (ACTRIMS Forum 2025) - P2, P3 | "Fenebrutinib (FEN) is being developed because it is a potent and highly selective noncovalent reversible BTKi that has shown efficacy in several diseases, including a Ph 2 RMS study (NCT05119569) and is currently in Ph 3 trials in RMS (NCT04586010, NCT04586023) and PPMS (NCT04544449).Objectives: Define the BTK binding mechanisms and selectivities of FEN and irreversible covalent inhibitors remibrutinib (REMI), tolebrutinib (TOL) and evobrutinib (EVO); compare their projected relative rates of BTK inhibition at clinical-dose concentrations reported in human CSF. Using biochemical kinetic competition binding assays, we defined binding mechanisms to BTK and to an off-target BMX, a related cytoplasmic protein tyrosine kinase. Fenebrutinib’s slowly reversible binding mechanism allows for potent, selective BTK inhibition and illustrates how kinetic and mechanistic features of drug-target interactions impact pharmacology. Fenebrutinib’s properties and observed..."

CNS Disorders • Hematological Disorders • Immunology • Multiple Sclerosis

Baseline Characteristics Across Major Clinical Trials in Progressive Multiple Sclerosis: Insights from ORATORIO, EXPAND, MS-STAT2, HERCULES, and CALLIPER (ACTRIMS Forum 2025) - "Several major trials have explored therapies in this domain, including ORATORIO (ocrelizumab, primary progressive MS, PPMS), EXPAND (siponimod, secondary progressive MS, SPMS), MS-STAT2 (simvastatin, SPMS), and HERCULES (tolebrutinib, non-relapsing SPMS, nrSPMS). The data from this cohort could provide valuable insight into understanding the effects of vidofludimus calcium in a non-active and progressive population. Any impact of vidofludimus calcium on 24-week confirmed disability worsening in this group may therefore primarily reflect its influence on compartmentalized pathology within the CNS. Top line data of the study is expected in April 2025."

Clinical • CNS Disorders • Inflammation • Multiple Sclerosis • NR4A2 • STAT2

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

Trial completion date • CNS Disorders • Multiple Sclerosis

Long Term Safety and Efficacy Study of Tolebrutinib (SAR442168) in Participants With Relapsing Multiple Sclerosis (clinicaltrials.gov) - P2 | N=125 | Completed | Sponsor: Sanofi | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Multiple Sclerosis

Press Release: Tolebrutinib designated Breakthrough Therapy by the FDA for non-relapsing secondary progressive multiple sclerosis (GlobeNewswire) - "The US Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to tolebrutinib for the treatment of adults with non-relapsing secondary progressive multiple sclerosis (nrSPMS). This is based on positive results from the HERCULES phase 3 study..."

Breakthrough therapy • CNS Disorders • Immunology • Multiple Sclerosis

BTK regulates microglial function and neuroinflammation in human stem cell models and mouse models of multiple sclerosis. (PubMed, Nat Commun) - "We further identify a BTK-dependent transcriptional signature in vitro, using the BTKi tolebrutinib, in mouse microglia, human induced pluripotent stem cell (hiPSC)-derived microglia, and a complex hiPSC-derived tri-culture system composed of neurons, astrocytes, and microglia, revealing modulation of neuroinflammatory pathways relevant to MS. Finally, we demonstrate that in MS tissue BTK is expressed in B-cells and microglia, with increased levels in lesions. Our data provide rationale for targeting BTK in the CNS to diminish neuroinflammation and disability accumulation."

Journal • Preclinical • CNS Disorders • Inflammation • Multiple Sclerosis

Efficacy and Safety of Tolebrutinib in Non-Relapsing SPMS: Phase 3 HERCULES Results (AECF 2024) - No abstract available

Clinical • P3 data • Multiple Sclerosis

Efficacy and Safety of Tolebrutinib Vs Teriflunomide in RMS: Phase 3 GEMINI Trials (AECF 2024) - No abstract available

Clinical • P3 data

Bruton’S tyrosine kinase (btk) is a druggable therapeutic target for neuroprotection in parkinson’s disease (Neuroscience 2024) - "In summary, our findings suggest that BTK drives inflammasome activation and neuropathology in PD and that BTK inhibition represents a promising therapeutic strategy for disease modification in PD. Our current studies are evaluating the therapeutic efficacy of second-generation CNS-targeted BTK inhibitor, PRN2675, an analog of the clinical-stage drug Tolebrutinib (Sanofi Genzyme) which displays superior CNS permeability, target coverage and BTK occupancy compared to previous generation BTK inhibitors such as Ibrutinib."

CNS Disorders • Parkinson's Disease • BTK • NLRP3

Press Release: Tolebrutinib demonstrated a 31% delay in time to onset of confirmed disability progression in non-relapsing secondary progressive multiple sclerosis phase 3 study (GlobeNewswire) - P3 | N=1,131 | HERCULES (NCT04411641) | Sponsor: Sanofi | "Positive results from the HERCULES phase 3 study in people with non-relapsing secondary progressive multiple sclerosis (nrSPMS) demonstrated that tolebrutinib delayed the time to onset of 6-month confirmed disability progression (CDP) by 31% compared to placebo (HR 0.69; 95% CI 0.55-0.88; p=0.0026). Further analysis of secondary endpoints demonstrated that the number of participants who experienced confirmed disability improvement increased by nearly two-fold, 10% with tolebrutinib compared to 5% with placebo (HR 1.88; 95% CI 1.10 to 3.21; nominal p=0.021)...Study results will form the basis for future discussions with global regulatory authorities with submissions starting in H2 2024...The PERSEUS phase 3 study in primary progressive MS is currently ongoing with study results anticipated in H2 2025."

P3 data • Regulatory • CNS Disorders • Immunology • Multiple Sclerosis

The GEMINI 1 and 2 phase 3 study results of tolebrutinib… (GlobeNewswire) - P3 | N=974 | GEMINI 1 (NCT04410978) | P3 | N=899 | GEMINI 2 (NCT04410991) | Sponsor: Sanofi | "Both studies did not meet their primary endpoints of statistically significant improvement in annualized relapse rates (ARR) compared to Aubagio. However, in the key secondary endpoint, a pooled analysis of data from GEMINI 1 and 2, tolebrutinib delayed the time to onset of 6-month confirmed disability worsening (CDW) by 29% (HR 0.71; 95% CI: 0.53-0.95; nominal p=0.023). The results of the 29% delay in CDW endpoint in participants with RMS are in line with the 31% delay in CDP observed in participants with nrSPMS."

P3 data • CNS Disorders • Immunology • Multiple Sclerosis

Primary Progressive Multiple Sclerosis (PPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (PERSEUS) (clinicaltrials.gov) - P3 | N=766 | Active, not recruiting | Sponsor: Sanofi | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Multiple Sclerosis

Efficacy and Safety of Tolebrutinib Versus Placebo in Non-Relapsing Secondary Progressive Multiple Sclerosis: Results from the Phase 3 HERCULES Trial (ECTRIMS 2024) - P3 | "The presented HERCULES trial results will provide a comprehensive assessment of tolebrutinib efficacy and safety in participants with nrSPMS."

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

Efficacy and Safety of Tolebrutinib Versus Teriflunomide in Relapsing Multiple Sclerosis: Results from the Phase 3 GEMINI 1 and 2 Trials (ECTRIMS 2024) - P3 | "The presented phase 3 GEMINI 1 and 2 trial results will provide a comprehensive assessment of tolebrutinib efficacy and safety in participants with relapsing MS."

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