Paramagnetic rim lesions predict effectiveness of tolebrutinib

Results of a post hoc analysis of 3 phase 3 trials of tolebrutinib suggest that paramagnetic rim lesions (PRLs) are associated with an increased risk of disability accumulation. Tolebrutinib has a greater impact on patients with MS with higher numbers of PRLs. These findings are consistent with the CNS bioactive mechanism of action of tolebrutinib.

The brain-penetrant Bruton’s tyrosine kinase (BTK) inhibitor tolebrutinib produced promising results in the phase 3 trials HERCULES (NCT04411641), GEMINI 1 (NCT04410978), and GEMINI 2 (NCT04410991) [1,2]. Dr Jiwon Oh (University of Toronto, Canada) and co-workers wanted to know if PRLs are associated with response to tolebrutinib [3]. She explained that PRLs are chronic active lesions that have a demyelinated core with axonal loss and an inflammatory demyelinating rim with iron-laden microglia and macrophages. They are present across the spectrum of MS [4]. PRLs have been shown to correlate with disability accumulation and are resistant to approved therapies.

Baseline PRLs were evaluated as a prognostic and predictive biomarker for disability accumulation and treatment response in the GEMINI and HERCULES trials. In GEMINI, participants with relapsing MS were randomised 1:1 to tolebrutinib 60 mg once daily or teriflunomide 14 mg once daily. In HERCULES, participants with secondary progressive MS were randomised 2:1 to tolebrutinib 60 mg once daily or placebo. In all, 631 (34%) and 437 (39%) participants of GEMINI and HERCULES, respectively, had PRL imaging.

Overall, 653 participants (61%) had PRLs. In GEMINI, the proportion of participants with 0, 1–3, or ≥4 PRLs at baseline was 38%, 35%, and 27%, respectively, with similar proportions in HERCULES. “In all 3 studies, the treatment effect of tolebrutinib was much more evident in patients with PRLs,” said Dr Oh. In both studies, the risk of 6-month confirmed disability worsening (CDP) increased with the amount of baseline PRLs in all groups. In GEMINI, the CDP risk was mitigated by tolebrutinib, with a relative risk reduction of -18%, -46%, and -49% in participants with 0, 1–3 and ≥4 PRLs, respectively. In HERCULES, tolebrutinib was associated with a +17%, -15% and -54% risk, respectively.

Meet the Trialist: Read our interview with Dr Oh.

1. Fox RJ, et al. Abstract O136, ECTRIMS 2024, 18–20 September, Copenhagen, Denmark.
2. Oh J, et al. Abstract O135, ECTRIMS 2024, 18–20 September, Copenhagen, Denmark.
3. Oh, J, et al. Paramagnetic rim lesions as a prognostic and predictive biomarker in the tolebrutinib Phase 3 trials for disability outcomes. LB1.1, ACTRIMS 2025, 27 February–01 March 2025, West Palm Beach, FL, USA.
4. Dal-Bianco A, et al. Ther Adv Neurol Disord. 2024 Dec 19:17:17562864241306684.

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Posted on 28 March 2025