Evobrutinib reduces volume of slowly expanding lesions

The highly selective Bruton’s tyrosine kinase (BTK) inhibitor evobrutinib reduced the volume of slowly expanding lesions (SEL) in a phase 2 trial. This effect was dose-dependent and especially apparent in more advanced multiple sclerosis (MS). This is the first evidence that a BTK inhibitor impacts brain lesions associated with chronic inflammation and tissue loss.

Evobrutinib is a highly selective BTK inhibitor that targets B cells, macrophages, and microglia. In a phase 2 trial (NCT02975349) in patients with relapsing MS, 75 mg twice-daily evobrutinib reduced T1 gadolinium-enhancing lesions versus placebo during weeks 12 through 24 [1].

The current study focused on the effect of evobrutinib versus a comparator on an emerging MRI biomarker: SELs, also referred to as “smouldering lesions” [2]. SELs are chronically active, demyelinated MS lesions, likely driven by sustained microglia/macrophage activity. They can be detected in vivo as of the past few years. In this study, SELs were defined as radially expanding areas of pre-existing T2 lesions of ≥10 contiguous voxels, around 30 mm³ in size. Evobrutinib at doses of 25 mg once daily (n=50), 75 mg once daily (n=51), and 75 mg twice daily (n=53) was compared with placebo/evobrutinib 25 mg once daily (n=53). SEL volume was analysed after 48 weeks or after end of treatment in RMS patients, both among those who completed or discontinued the study. Prof. Douglas Arnold (McGill University, Canada) shared the results.

Evobrutinib was found to decrease SEL volume relative to the comparator in a dose-dependent manner:

• 25 mg once daily, -136.5 mm³ (P=0.505);
• 75 mg once daily, -246.0 mm³ (P=0.192);
• 75 mg twice daily, -474.5 mm³ (P=0.047).

In pooled, high-dose groups (75 mg once daily and 75 mg twice daily), SEL volume was significantly reduced compared with low-dose groups (placebo and evobrutinib 25 mg once daily) in the following subgroups:

• baseline EDSS ≥3.5: -652.0 mm³ (P=0.020);
• relapsing-remitting MS: -317.0 mm³ (P=0.025);
• disease duration ≥8.5 years; -729.3 mm³ (P=0.040).

This is the first evidence that a BTK inhibitor impacts brain lesions associated with chronic inflammation and tissue loss, probably via microglia.

1. Montalban X, et al. N Engl J Med. 2019;380(25):2406–17.
2. Arnold D, et al. Effects of Evobrutinib, a Bruton’s Tyrosine Kinase Inhibitor, on Slowly Expanding Lesions: An Emerging Imaging Marker of Chronic Tissue Loss in Multiple Sclerosis. S14.009, AAN 2022, 02–07 April, Seattle, USA.

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Posted on 2 June 202225 March 2024