Uncoupling Relapse Reduction and Disability Progression: Evidence From Tolebrutinib Studies.

IF 3.7 Q3 CLINICAL NEUROLOGY

Neurology. Clinical practice Pub Date : 2026-06-01 Epub Date: 2026-04-06 DOI:10.1212/CPJ.0000000000200612

Alessio Signori, Noemi Montobbio, Francesca Bovis, Marta Ponzano, Irene Schiavetti, Alessandra Krenn, Maria Pia Sormani

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引用次数: 0

Abstract

Objectives: The aim of this study was to evaluate whether the treatment effects of tolebrutinib on confirmed disability worsening (CDW) diverge from its effects on relapse prevention compared with other disease-modifying therapies (DMTs) for relapsing multiple sclerosis (MS).

Methods: We extracted published effect estimates for annualized relapse rate (ARR) and CDW confirmed at 24 weeks from all phase 3 trials with teriflunomide as the active comparator: ASCLEPIOS (ofatumumab), OPTIMUM (ponesimod), ULTIMATE (ublituximab), EVOLUTION (evobrutinib), and GEMINI (tolebrutinib). When duplicate trials were available, pooled estimates were derived. Log-transformed estimates were used in a weighted linear regression of CDW vs ARR, with bubble size reflecting statistical precision. Tolebrutinib was excluded from the regression fit but displayed for comparison.

Results: Across 4 DMTs other than tolebrutinib, a strong linear association was observed between treatment effects on ARR and CDW (R² = 0.997), indicating that disability benefit was generally proportional to relapse reduction. By contrast, tolebrutinib deviated from this relationship, with a hazard ratio for CDW of 0.71 (95% CI 0.53-0.95) despite a relapse rate ratio of 1.03 (95% CI 0.85-1.25).

Discussion: Tolebrutinib was the only therapy to show a benefit on CDW without a measurable effect on relapses, highlighting a dissociation between disability worsening and relapse suppression not observed with other DMTs.

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解耦复发减少和残疾进展：来自托勒布替尼研究的证据。

目的：本研究的目的是评估与其他疾病改善疗法（dmt）相比，托勒布替尼对复发性多发性硬化症（MS）的治疗效果是否偏离其对残疾恶化（CDW）的预防效果。方法：我们从所有以泰瑞氟米特作为活性比较剂的3期试验中提取已发表的年化复发率（ARR）和24周时确认的CDW的效果估计：ASCLEPIOS （ofatumumab）、OPTIMUM （ponesimod）、ULTIMATE （ublituximab）、EVOLUTION （evobrutinib）和GEMINI （tolebrutinib）。当有重复试验时，得出汇总估计。对数变换估计用于CDW与ARR的加权线性回归，气泡大小反映统计精度。托勒布替尼被排除在回归拟合之外，但显示用于比较。结果：除托勒布替尼外，在4个dmt中，治疗效果对ARR和CDW之间存在很强的线性关联（R2 = 0.997），表明残疾获益通常与复发减少成正比。相比之下，托勒布替尼偏离了这一关系，尽管复发率为1.03 (95% CI 0.85-1.25)，但CDW的风险比为0.71 （95% CI 0.53-0.95）。讨论：托勒布替尼是唯一一种显示对CDW有益但对复发没有可测量影响的治疗方法，突出了残疾恶化和复发抑制之间的分离，这在其他dmt中没有观察到。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neurology. Clinical practice CLINICAL NEUROLOGY-

CiteScore

4.00

自引率

0.00%

发文量

期刊介绍： Neurology® Genetics is an online open access journal publishing peer-reviewed reports in the field of neurogenetics. The journal publishes original articles in all areas of neurogenetics including rare and common genetic variations, genotype-phenotype correlations, outlier phenotypes as a result of mutations in known disease genes, and genetic variations with a putative link to diseases. Articles include studies reporting on genetic disease risk, pharmacogenomics, and results of gene-based clinical trials (viral, ASO, etc.). Genetically engineered model systems are not a primary focus of Neurology® Genetics, but studies using model systems for treatment trials, including well-powered studies reporting negative results, are welcome.