BTK Inhibitor Tolebrutinib Shows Greater Effectiveness in Multiple Sclerosis with Higher Paramagnetic Rim Lesion Counts

A post-hoc, late-breaking analysis of several phase 3 trials assessing tolebrutinib (Sanofi), an investigational Bruton tyrosine kinase (BTK) inhibitor, suggested that the agent has greater efficacy in patients with multiple sclerosis who have higher number of paramagnetic rim lesions (PRLs).¹

The research comprised data from the HERCULES study of patients with non-relapsing secondary progressive MS (nrSPMS) as well as GEMINI 1 and 2, two identical trials of patients with relapsing MS (RMS). In HERCULES, treatment with tolebrutinib demonstrated a 54% attenuated risk in 6-month confirmed disability worsening (CDW) among patients with at least 4 baseline PRLs, the highest quartile group observed. In GEMINI, a similar risk mitigation was observed with a 46% and 49% risk reduction in participants with 1-3 and at least 4 PRLs, respectively.

These data were presented by lead author Jiwoh Oh, MD, PhD, staff neurologist and medical director of the Barlo Multiple Sclerosis Program, St. Michaels Hospital, University of Toronto, at the 2025 Americas Committee for Treatment & Research in Multiple Sclerosis (ACTRIMS) Forum, held February 27-March 1, in West Palm Beach, Florida. Overall, the analysis comprised 653 of the original 3004 patients across the studies who had PRL imaging data available.

Oh and colleagues manually identified PRLs on SWI images generated from 3D-gradient echo phase images (6 echoes ranging from 4.9 to 41 ms, 0.8-mm isotropic resolution). In HERCULES, 40% of participants had 0 PRLs at baseline, 36% had 1-3 PRLs, and 24% had at least 4 PRLs, with similar distributions observed in the GEMINI study. All told, results revealed a numerically similar risk of 6-month CDW associated with the GEMINI trials and of 6-month CDP for the HERCULES trial among tolebrutinib-treated patients with PRLs in both studies vs participants without PRLs.

"This finding has several clinical and clinical trial implications, particularly for trial design in the future. If we want to enrich clinical trial populations for people more likely to accumulate disability, pearls could be considered as a measure to help with this—though, of course, these findings need to be validated," Oh told NeurologyLive^® in a recent interview.

"To get a better idea, we need to assess the longitudinal data, but this does suggest that what we’re thinking about the relationship between 'pearls' and disability holds up prospectively," Oh said. "That’s important because many smaller studies have shown a correlation between an individual’s pearl count and motor as well as cognitive disability. The fact that this was demonstrated in a two- to three-year clinical trial is significant—showing prospectively that having a certain number of pearls greatly increases the risk of developing disability is a critical finding."

READ MORE: BTK Inhibitor Orelabrutinib Shows Promising Efficacy in Phase 2 Study of Relapsing-Remitting Multiple Sclerosis

An investigational agent, tolebrutinib was awarded breakthrough therapy designation for patients with nrSPMS in December 2024 using data from HERCULES as the basis for the decision. After randomly assigning patients 2:1 to either tolebrutinib or placebo, results showed that those time to onset of CDP, the primary end point, was reduced by 31% for those on active treatment in comparison with placebo (HR, 0.69; 95% CI, 0.55-0.88; P = .0026). On a secondary end point, the number the patients who experienced confirmed disability improvement increased by nearly 2-fold, 10%, for those treated with tolebrutinib relative to the placebo group (HR, 1.88; 95% CI, 1.10-3.21; nominal P = .021).²

"Like any research study, this has several strengths, particularly that it was conducted within multiple large phase 3 clinical trials and evaluated pearls prospectively. However, before drawing definitive conclusions, it’s important to validate these relationships in other clinical trials. We also need to assess whether this apparent accentuated treatment effect holds in other relevant clinical trials," Oh said. "There are multiple other BTK inhibitors and experimental therapies under evaluation that may target some of the disease mechanisms relevant to MS progression. Validation in external studies and different settings is necessary before we can definitively say that 'pearls' should be used as prognostic or treatment effect biomarkers."

HERCULES and GEMINI differed in a few ways, with the former including patients with nrSPMS and the latter comprising those with RMS. In HERCULES, patients were randomly assigned to either tolebrutinib or placebo whereas in the GEMINI trials, participants were randomized in both studies 1:1 to receive either tolebrutinib and placebo daily or 14mg teriflunomide (Aubagio; Sanofi) and placebo. In GEMINI, tolebrutinib failed to meet its primary end point of reducing annualized relapse rate (ARR) in comparison with teriflunomide; however, it did show positive data on a key secondary end point of pooled 6-month CDW, significantly delaying the time to onset of worsening.³

"As for the effect of tolibrutinib on 'pearls', I don’t think we can say definitively without the longitudinal data. However, the fact that individuals with a greater number of pearls seemed to show a better treatment effect suggests that tolibrutinib, which we know can penetrate the central nervous system at bioactive concentrations, may beneficially affect cells relevant to progressive disease biology," Oh said.

Tolebrutinib also currently remains in development for patients with primary progressive MS, a subgroup of MS with significant therapeutic needs. The ongoing phase 3, randomized, double-blind, PERSEUS study (NCT04458051), which primarily tests effects of the agent in delaying disability progression, is expected to have data released in the second half of 2025. Spanning 277 study locations, the study also has several secondary objectives, including MRI lesions, cognitive performance, physical function, and quality of life.

Tolebrutinib, a highly selective, oral, irreversible BTK inhibitor, targets the BTK enzyme in immune cells, particularly B cells. What distinguishes tolebrutinib from other BTK inhibitors is its targeting of BTK with a high degree of selectivity, which helps to minimize off-target effects and reduce adverse events, particularly in the central nervous system. Because of its irreversible build, it binds permanently to the BTK enzyme, which may provide sustained therapeutic effects with a potentially lower risk of relapse in conditions like MS.

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REFERENCES
1. Oh J, Fox RJ, Arnold DL, et al. LB1.1. Paramagnetic Rim Lesions as a Prognostic and Predictive Biomarker in the Tolebrutinib Phase 3 Trials for Disability Outcomes. Presented at: 2025 ACTRIMS Forum; February 27-March 1; West Palm Beach, FL. ABSTRACT LB1.1
2. Fox RJ, Bar-Or A, Traboulsee A, et al. Efficacy and Safety of Tolebrutinib Versus Placebo in Non-Relapsing Secondary Progressive Multiple Sclerosis: Results from the Phase 3 HERCULES Trial. Presented at: 2024 ECTRIMS; September 18-20; Copenhagen, Denmark. Abstract 4027.
3. GEMINI 1 and 2 Trials. Presented at: ECTRIMS Congress; September 18-20, 2024; Copenhagen, Denmark. Abstract 4026/O135