Press Release: Tolebrutinib phase 3 data published in NEJM demonstrate benefit on disability progression in multiple sclerosis

Core Insights - Tolebrutinib has shown positive results in delaying disability progression in patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS), a condition currently lacking approved treatment options [1][6] - The HERCULES phase 3 study results were published in the New England Journal of Medicine (NEJM) and presented at major neurology conferences, indicating a significant advancement in multiple sclerosis treatment [1][2] Tolebrutinib Efficacy - In the HERCULES study, tolebrutinib delayed the time to onset of 6-month confirmed disability progression (CDP) by 31% compared to placebo, with a hazard ratio of 0.69 and a p-value of 0.003 [3][6] - The GEMINI 1 and 2 studies did not demonstrate superiority in reducing annualized relapse rate (ARR) compared to teriflunomide, with ARR of 0.13 for tolebrutinib and 0.12 for teriflunomide in GEMINI 1, and 0.11 for both groups in GEMINI 2 [4][17] Safety Profile - Tolebrutinib was generally well-tolerated, with liver enzyme elevations observed in 4.0% of participants compared to 1.6% in the placebo group in the HERCULES study [5][7] - A small proportion (0.5%) of participants experienced significant ALT increases (>20xULN), all occurring within the first 90 days of treatment [5][7] Regulatory Status - Tolebrutinib is under priority review by the US FDA with a target action date of September 28, 2025, and a regulatory submission is also under review in the EU [6][8] - The drug has previously received breakthrough therapy designation from the FDA based on positive phase 3 study results [12] Mechanism of Action - Tolebrutinib is a Bruton's tyrosine kinase (BTK) inhibitor designed to target neuroinflammation behind the blood-brain barrier, addressing the underlying pathology of progressive multiple sclerosis [11][13] - This mechanism allows it to modulate both B-lymphocytes and disease-associated microglia, potentially transforming the treatment landscape for multiple sclerosis [11][13]