By Ulrike W. Kaunzner, MD
Synopsis: A recent prospective study showed that tolebrutinib slows disability progression in patients with nonrelapsing secondary progressive multiple sclerosis (SPMS). There were some safety concerns, especially hepatotoxicity. A lack of demonstrated effect on some functional outcomes warrants careful consideration and continuing study.
Sources: Fox RJ, Bar-Or A, Traboulsee A, et al; HERCULES Trial group. Tolebrutinib in nonrelapsing secondary progressive multiple sclerosis. N Engl J Med. 2025;392(19):1883-1892.
Calabrese PA. Progress toward mitigating disability in multiple sclerosis. N Engl J Med. 2025;392(19):1966-1968.
Nonrelapsing secondary progressive multiple sclerosis (SPMS) represents a stage of multiple sclerosis (MS) in which patients experience gradual and irreversible worsening of neurological function, independent of relapses. Longitudinal and meta-analytic data indicate that approximately 50% of patients with relapsing-remitting MS (RRMS) will develop SPMS within 15 to 20 years of disease onset, and up to two-thirds of patients may convert after 30 years.
More recent registry and cohort studies suggest that the rate of conversion to SPMS has declined in the era of widespread disease-modifying therapy use, but the cumulative risk remains substantial over decades of disease. This leaves a significant unmet need for treatments that can target the underlying drivers of progression, such as microglial activation, chronic active lesions, and compartmentalized inflammation within the central nervous system (CNS). Patients with nonrelapsing SPMS often feel overlooked in both research and clinical care, underscoring the urgent need for effective, targeted therapies that truly can slow or halt disability progression in this population.
Tolebrutinib is a brain-penetrant Bruton’s tyrosine kinase (BTK) inhibitor that targets both peripheral B cells and CNS resident immune cells, such as microglia, aiming to reduce relapses and slow progression in MS — particularly in nonrelapsing SPMS, where chronic inflammation drives disability. Unlike other BTK inhibitors, such as evobrutinib, which act mainly outside the CNS, tolebrutinib may address the unmet need of targeting smoldering, intrathecal inflammation linked to disease progression.
In the study by Fox et al, a total of 1,131 patients with nonrelapsing SPMS underwent randomization: 754 patients received tolebrutinib and 377 patients received placebo. The median follow-up was 133 weeks. Treatment with tolebrutinib significantly reduced the risk of confirmed disability progression sustained for at least six months compared to placebo. This effect was independent of relapse activity. Tolebrutinib also led to fewer new or enlarging brain lesions on magnetic resonance imaging (MRI), possibly because of its action on peripheral B lymphocytes and its ability to penetrate the CNS, reaching inhibitory concentrations in cerebrospinal fluid, unlike other BTK inhibitors, such as evobrutinib. Some participants experienced elevated liver enzymes. Overall, the findings suggest that tolebrutinib may help slow disability progression in patients with nonrelapsing SPMS, addressing a key unmet clinical need for patients with MS.
Commentary
Despite promising results, the tolebrutinib trial for nonrelapsing SPMS faces several important challenges. Safety, particularly liver toxicity, remains a concern. Although most cases of liver toxicity were mild, one resulted in liver transplantation.
The trial population was heterogeneous — some participants showed MRI evidence of active inflammation despite selection criteria aiming to exclude this. Many also were on first-line therapies, which may have influenced baseline disease activity. The use of a placebo rather than an active comparator limits interpretation of relative efficacy.
While the primary endpoint was met, not all functional measures improved (e.g., upper limb function in the nine-hole peg test). Reductions in MRI lesions suggest anti-inflammatory effects, possibly via BTK inhibition of B cells and microglia, but these mechanisms remain inferred. Tolebrutinib’s CNS penetration is promising but raises questions about long-term CNS-specific risks. Further research is needed to confirm long-term safety and to determine whether tolebrutinib truly addresses the neurodegenerative mechanisms of progression in SPMS.
Ulrike W. Kaunzner, MD, is Assistant Professor of Clinical Neurology, Weill Cornell Medical College.
