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The HERCULES Trial on Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis - Article Summary

Summary Author: Bhavik Patel


Background:

Multiple sclerosis (MS) is a chronic disease where the immune system attacks the brain and spinal cord. Over time, many people with MS enter a stage called secondary progressive MS (SPMS), during which symptoms steadily worsen, often without relapses or new MRI lesions. For people in this “non-relapsing” phase, there have been no approved treatments that slow progression - until now. The HERCULES trial, published in The New England Journal of Medicine in 2025, shows that the oral drug tolebrutinib significantly reduced the risk of disability worsening in adults with non-relapsing SPMS. This represents the first major breakthrough for a population that previously had no effective disease-modifying therapy.


Study Overview:

  • Design: Phase 3, double-blind, randomized, placebo-controlled

  • Population: 1,131 adults with non-relapsing SPMS (mean age 49; 62% women)

  • Sites: 264 trial locations in 31 countries

  • Intervention:

    • Tolebrutinib, 60 mg taken once daily (n = 754)

    • Placebo (n = 377)

  • Duration: Median follow-up of 133 weeks

  • Primary Endpoint: confirmed disability progression (CDP), defined as an increase in the Expanded Disability Status Scale (EDSS) that was sustained for ≥6 months


Results:

  • Confirmed Disability Progression ≥6 Months:

    • Tolebrutinib group: 22.6%

    • Placebo group: 30.7%

  • Hazard Ratio: 0.69 (95% CI, 0.55–0.88); p = 0.003

  • Safety Profile:

    • Serious adverse events: 15.0% (tolebrutinib) vs 10.4% (placebo)

    • Liver enzyme elevations were more common in the tolebrutinib group

    • Most non-serious adverse effects were mild (e.g. headache, upper respiratory symptoms)

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Conclusions:

This is the first every study shown to slow disability progression in non-relapsing SPMS. Tolebrutinib is an oral BTK inhibitor that targets brain-resident immune cells involved in chronic inflammation and neurodegeneration, and its oral formulation is potentially more convenient than infusion-based therapies. These findings open the door for treatment in advanced-stage MS, where options have been scarce.


Limitations and Next Steps:

  • Patients with recent relapses or active MRI lesions were excluded, limiting generalizability

  • Further follow-up on tolebrutinib is needed to evaluate long-term safety and real-world efficacy

  • Additional studies may explore impact on cognitive function and quality of life


Main Takeaway

The HERCULES trial demonstrates that tolebrutinib has a significantly lower risk of disability for patients with non-relapsing SPMS when compared to placebo, redefining treatment goals for patients and providers alike.


References:

Vermersch P, Miller DH, Montalban X, et al. Tolebrutinib in nonrelapsing secondary progressive multiple sclerosis. N Engl J Med; 392(19): 1883-1892. Apr 8 2025. https://doi.org/10.1056/NEJMoa2415988.

 
 
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