Secondary progressive multiple sclerosis, or SPMS, is a form of multiple sclerosis marked by gradual disability worsening over time, and that worsening may occur with relapses and new MRI activity, or without either one. For patients living with multiple sclerosis, treatment conversations can shift over time. What begins as a discussion about relapses and MRI activity may gradually become a discussion about function, progression, and what the next phase of care should look like.
For our patients and referring clinicians at Clinique Neuro-Outaouais, the current discussions around SPMS has three parts: treatment approved for active disease, investigational therapy aimed at progression, and research focused on neuroprotection and repair.
What is secondary progressive MS?
SPMS often develops after an earlier relapsing-remitting phase of multiple sclerosis. The transition is not usually defined at a single visit. Instead, it becomes clearer over time as a pattern of gradual neurological worsening emerges. A 2023 review in Neurology: Neuroimmunology & Neuroinflammation describes SPMS as a disability progression that occurs independently of relapses, with the diagnosis typically recognized after sustained decline becomes evident. The same review notes that most worsening in SPMS reflects progression independent of relapse activity, although relapses can still contribute to disability in some patients. This distinction remains important because disease activity continues to influence how treatments are discussed and selected. (Ziemssen et al., 2023).
Why treatment in SPMS is more complicated than in relapsing remitting MS
SPMS cannot be understood through relapse control alone. Disability progression is central. A 2025 review inFrontiers in Immunology describes progressive MS as involving compartmentalized neuroinflammation within the central nervous system, axonal degeneration, microglial activation, oxidative stress, mitochondrial dysfunction, iron toxicity, and deficient remyelination. Disability accumulation can result from relapse-associated worsening or progression independent of relapse activity, and that PIRA is the main driver of disability accumulation as the disease advances. This is why the therapeutic discussion in SPMS extends past standard anti-inflammatory strategies (Lublin et al., 2025).
What approved treatment options exist today?
In Canada, treatment options for secondary progressive multiple sclerosis still depend on disease activity. Siponimod is approved for patients with active SPMS, defined by the presence of relapses or imaging features that indicate inflammatory activity. The goal of treatment is to delay progression of physical disability. This distinction remains important in practice. The approval applies to active SPMS, not to all forms of secondary progressive disease (Novartis Pharmaceuticals Canada Inc., 2023).
What counts as a “new therapy” in SPMS right now?
In SPMS, a new therapy may refer to a recently approved drug, an investigational drug in phase 2 or phase 3 testing, or a treatment strategy directed at progression biology rather than relapse suppression. Those categories are not interchangeable. A positive trial result is not the same as regulatory approval, and a biologically plausible strategy is not the same as a treatment standard. In a field as nuanced as progressive MS, precision in wording is part of good clinical communication (Ziemssen et al., 2023; Lublin et al., 2025).
One investigational area drawing attention: BTK inhibitors
Why they are being studied
BTK inhibitors are under study in multiple sclerosis, including progressive forms of the disease. Tolebrutinib has been studied specifically in nonrelapsing secondary progressive multiple sclerosis. Interest in this class of drugs reflects the biology of progressive MS itself. A 2025 review in Frontiers in Immunology describes progressive MS as involving inflammatory processes within the central nervous system that can continue even in the absence of relapses. Because BTK inhibitors act on immune signaling pathways involved in these processes, they have become a focus of clinical trials in progressive MS (Lublin et al., 2025).
What has actually been reported
In progressive multiple sclerosis research, clinical trials often focus on disability progression rather than relapse reduction. Outcomes commonly measure confirmed disability progression over time using standardized neurological disability scales.
Within this context, the phase 3 HERCULES trial evaluated tolebrutinib in nonrelapsing secondary progressive multiple sclerosis. The results were published in The New England Journal of Medicine in 2025. According to the published report, participants who received tolebrutinib had a lower risk of confirmed disability progression sustained for at least six months compared with those who received placebo (Fox et al., 2025). The study also reported safety findings, including higher rates of liver enzyme elevations in the treatment group.
Sanofi stated in 2025 that tolebrutinib remained under clinical investigation and that its safety and efficacy had not been evaluated or determined by regulatory authorities at that time (Sanofi, 2025a, 2025b).
What this means for patients at Clinique Neuro-Outaouais
At Clinique Neuro-Outaouais, conversations about secondary progressive multiple sclerosis begin with a clear understanding of the individual patient’s disease progression and current level of function. SPMS often raises new questions for patients and families, particularly when they encounter headlines about emerging therapies or recent clinical trials. Our role as neurologists is to interpret that information carefully and place it in the proper clinical context. We review the available evidence, discuss approved treatment options where appropriate, and explain how ongoing research may or may not apply to a specific situation.
We are presently participating in two clinical trials that include patients with SPMS. The first, FREVIVA, is a phase 3 clinical trial where frexalimab, an antiCD40L monoclonal antibody administered intravenously every 4 weeks, is compared to a placebo in a population of SPMS patients. Recruitment is completed and the trial is ongoing. The second, the CeV study is a single center phase 3 trial looking at the impact of repetitive transcranial magnetic stimulation (rTMS) on walking speed and endurance and corroborating the improvement with electrencephalographic (EEG) changes in patients with MS induced spastic paraparesis. The recruitment is ongoing and open to MS patients of all types.
Patients referred to our neuro health clinic often want clarity about what the science currently supports,and providing that clarity is an important part of the care we provide.
References
Fox, R. J., Bar-Or, A., Traboulsee, A., Oreja-Guevara, C., Giovannoni, G., Vermersch, P., Syed, S., Li, Y., Vargas, W. S., Turner, T. J., Wallstroem, E., Reich, D. S., & HERCULES Trial Group. (2025). Tolebrutinib in nonrelapsing secondary progressive multiple sclerosis. The New England Journal of Medicine, 392(19), 1883–1892. https://doi.org/10.1056/NEJMoa2415988
Lublin, F. D., Sormani, M. P., Kappos, L., Ontaneda, D., Hauser, S. L., Fox, R. J., Reich, D. S., Arnold, D. L., Bermel, R. A., Chataway, J., Cree, B. A. C., Giovannoni, G., Lubetzki, C., Oh, J., Popescu, B. F. G., Sastre-Garriga, J., Tortorella, C., Tur, C., & Ziemssen, T. (2025). Current challenges in secondary progressive multiple sclerosis: Diagnosis, activity detection and treatment. Frontiers in Immunology, 16, Article 1543649. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1543649/full
Novartis Pharmaceuticals Canada Inc. (2023). Mayzent (siponimod) product monograph. https://www.novartis.com/ca-en/sites/novartis_ca/files/mayzent_scrip_e.pdf
Sanofi. (2025a, March 25). Press release: Tolebrutinib regulatory submission accepted in the US for non-relapsing secondary progressive multiple sclerosis and to slow disability accumulation independent of relapse activity.https://www.sanofi.com/en/media-room/press-releases/2025/2025-03-25-06-00-00-3048411
Sanofi. (2025b, April 8). Press release: Tolebrutinib phase 3 data published in NEJM demonstrate benefit on disability progression in multiple sclerosis.https://www.sanofi.com/en/media-room/press-releases/2025/2025-04-08-17-11-11-3057931
Tomizawa, Y., Hagiwara, A., Hoshino, Y., Nakaya, M., Kamagata, K., Cossu, D., Yokoyama, K., Aoki, S., & Hattori, N. (2024). The glymphatic system as a potential biomarker and therapeutic target in secondary progressive multiple sclerosis. Multiple Sclerosis and Related Disorders, 82, 105437. https://doi.org/10.1016/j.msard.2024.105437
U.S. Food and Drug Administration. (2025). Mayzent (siponimod) prescribing information.https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/209884s020lbl.pdf
Ziemssen, T., Bhan, V., Chataway, J., Chitnis, T., Cree, B. A. C., Kubala Havrdova, E., Kappos, L., Labauge, P., Miller, A., Nakahara, J., Oreja-Guevara, C., Palace, J., Singer, B., Trojano, M., Patil, A., Rauser, B., & Hach, T. (2023). Secondary progressive multiple sclerosis: A review of clinical characteristics, definition, prognostic tools, and disease-modifying therapies. Neurology: Neuroimmunology & Neuroinflammation, 10(1), Article e200064. https://doi.org/10.1212/NXI.0000000000200064
