medwireNews: Tolebrutinib, an oral Bruton’s tyrosine kinase (BTK) inhibitor, significantly reduces disability accrual in patients with nonrelapsing secondary progressive multiple sclerosis (MS), but it is not superior to teriflunomide in reducing relapse rates in patients with the relapsing form of the condition, show two separate studies published in The New England Journal of Medicine.
Targeting inflammation in the CNS to slow disability worsening
The first – the phase 3 HERCULES trial – considered the potential of tolebrutinib to reduce MS progression that is occurring independently of relapse activity because the brain-penetrant agent targets chronic inflammation in disease-associated microglia cells and B cells in the central nervous system (CNS), which are thought to be the drivers of disability accrual, as well as in the periphery, the researchers explain.
Robert Fox (Cleveland Clinic, Ohio, USA) and co-authors found that over a median follow-up of 133 weeks, 754 eligible patients randomly assigned to take daily tolebrutinib 60 mg were a significant 31% less likely to have disability progression sustained for 6 months than the 377 patients taking placebo, with rates of 22.6% versus 30.7%.
Confirmed disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) score of at least 0.5 points or 1.0 point, depending on whether the baseline score was up to 5 points or more than 5 points, respectively. The scale ranges from 0 to 10 points, where a higher score denotes greater disability.
The trial involved patients with a current diagnosis of secondary progressive MS, despite previously receiving disease-modifying treatment such as interferons and glatiramer acetate, and no clinical relapses in the preceding 2 years.
The participants (mean age 48.9 years, 61.5% women) had a disease duration of 7.9 and 8.4 years, respectively and they all had documented evidence of disability progression in the previous 12 months. The baseline EDSS score was 3.0–6.5 points (mean 5.6 points) and 12.7% of patients had one or more gadolinium-enhancing lesions on T1-weighted magnetic resonance imaging (MRI).
In addition to reducing disability accrual, tolebrutinib treatment was associated with fewer new or enlarging brain lesions on MRI than with placebo, with a mean annualized rate of 1.84 versus 2.95, which the researchers say is “consistent with the effect of tolebrutinib on peripheral B lymphocytes.”
Potential safety considerations
Adverse events (AEs) occurred in 81.5% of patients in the tolebrutinib arm and 78.1% of those in the placebo arm and led to discontinuations in 3.9% and 2.9% of patients, respectively. Those AEs more common with tolebrutinib than placebo were COVID-19 (25.5 vs 22.7%), nasopharyngitis (9.3 vs 6.9%), and influenza (5.6 vs 3.5%). Serious AEs occurred in a respective 15.0% and 10.4% of patients, and there were three deaths: two in the tolebrutinib group – one due to liver failure considered related to the drug – and one in the placebo group resulting from a fall.
As previously seen with BTK inhibitors, increases in alanine aminotransferase levels to more than three times the upper limit of normal occurred in more tolebrutinib-treated than placebo-treated patients, at a rate of 4.0% versus 1.6%.
The researchers note, however, that most of these increases “were mild to moderate, and the majority resolved without sequelae.”
Comparable relapse rate reduction vs teriflunomide
The second study encompassed two phase 3 trials – GEMINI 1 and GEMNI 2 – involving 1873 patients with relapsing MS who were randomly assigned to receive daily tolebrutinib 60 mg or teriflunomide 14 mg.
The median follow-up of the two trials was 139 weeks, during which, in GEMINI 1, the annualized relapse rate was a similar 0.13 and 0.12 in 486 patients receiving tolebrutinib and 488 receiving teriflunomide, respectively. And for GEMINI 2, the rate was 0.11 in both the tolebrutinib (n=447) and teriflunomide (n=452) groups, giving an equal pooled rate across the trials of 0.12 for both treatments.
Relapse was defined as new or worsening neurological symptoms and a clinically relevant change in EDSS score, which was a mean of 2.4 points at baseline.
The patients were an average of 37 years old (18–55 years), and all had an EDSS score of 5.5 points or below, and at least two relapses in the preceding 2 years with at least one in the previous year, or at least one gadolinium-enhancing brain lesion on T1-weighted MRI within the previous year.
The researchers also note that in a pooled subanalysis, disability worsening sustained for at least 6 months was less common with tolebrutinib than with teriflunomide, at a rate of 8.3% versus 11.3%. However, no formal hypothesis testing was conducted for this outcome due to the nonsignificant result for the primary endpoint, and so this “will require further study,” they say.
Commenting on this secondary outcome and the disability accrual findings in the HERCULES trial in a related editorial, Peter Calabresi (Johns Hopkins University School of Medicine, Baltimore, Maryland, USA) says that they show “tolebrutinib may target chronic inflammation in the central nervous system.”
AEs in the pooled GEMINI trials were reported in 84.9% of patients in the tolebrutinib arm and 86.3% of those in the teriflunomide arm, primarily COVID-19, nasopharyngitis, and headache, with serious AEs occurring in a respective 9.8% and 8.2%.
While minor bleeding was not an event of special interest, Jiwon Oh (St Michael’s Hospital, Toronto, Ontario, Canada) and fellow authors highlight that it occurred in a higher percentage of patients in the tolebrutinib than teriflunomide group, with rates of petechiae and heavy menses reported in a respective 4.5% versus 0.3%, and 2.6% versus 1.0%.
Editorialist Calabresi says that if BTK inhibitors are approved for progressive MS, “clinicians will need to grapple with when and how to use these drugs, which may have less robust antiinflammatory activity than the available monoclonal antibodies, but which could be directly targeting the pathogenesis of insidious progression in persons with multiple sclerosis.”
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2025 Springer Healthcare Ltd, part of Springer Nature
N Engl J Med 2025; 392: 1883–1892
N Engl J Med 2025; 392: 1893–1904
N Engl J Med 2025; 392: 1966–1968
