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Effect of Evobrutinib on Slowly Expanding Lesion Volume in Relapsing Multiple Sclerosis: A Post Hoc Analysis of a
Douglas L Arnold1, Colm Elliott1, Emily C Martin1
1From the Montreal Neurological Institute (D.L.A.), McGill University; NeuroRx Research (D.L.A., C.E.), Montreal, Quebec, Canada; EMD Serono (E.C.M.), Billerica, MA; The Healthcare Business of Merck KGaA (Y.H.); Ares Trading SA (D.T.), Eysins, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany; and Centre d'Esclerosi Múltiple de Catalunya (Cemcat) (X.M.), Hospital Universitario Vall d'Hebron, Barcelona, Spain.
Background And Objectives:
Chronic active lesions (CALs) are demyelinated multiple sclerosis (MS) lesions with ongoing microglia/macrophage activity, resulting in irreversible neuronal damage and axonal loss. Evobrutinib is a highly selective, covalent, CNS-penetrant, Bruton tyrosine kinase inhibitor. This post hoc analysis evaluated the effect of evobrutinib on slowly expanding lesion (SEL) volume, an MRI marker of CALs, assessed baseline-week 48 in a phase 2, double-blind, randomized trial (NCT02975349) in relapsing MS (RMS).
Methods:
In the 48-week, double-blind trial, adult patients received evobrutinib (25 mg once daily [QD], 75 mg QD, or 75 mg twice daily [BID]), placebo (switched to evobrutinib 25 mg QD after week 24), or open-label dimethyl fumarate (DMF) 240 mg BID. SELs were defined as slowly and consistently radially expanding areas of preexisting T2 lesions of ≥10 contiguous voxels (∼30 mm3) over time. SELs were identified by MRI and assessed by the Jacobian determinant of the nonlinear deformation from baseline to week 48. SEL volume analysis, stratified by baseline T2 lesion volume tertiles, was based on week 48/end-of-treatment status (completers/non-completers). Treatment effect was analyzed using the stratified Hodges-Lehmann estimate of shift in distribution and stratified Wilcoxon rank-sum test. Comparisons of evobrutinib and DMF vs placebo/evobrutinib 25 mg QD were made. Subgroup analyses used pooled treatment groups (evobrutinib high dose [75 mg QD/BID] vs low dose [placebo/evobrutinib 25 mg QD]).
Results:
The SEL analysis set included 223 patients (mean [SD] age: 42.4 [10.7] years; 69.3% female; 87.4% relapsing/remitting MS). Mean (SD) SEL volume was 2,099 (2,981.0) mm3 with evobrutinib 75 mg BID vs 2,681 (3,624.2) mm3 with placebo/evobrutinib 25 mg QD. Median number of SELs/patient ranged from 7 to 11 across treatments. SEL volume decreased with increasing evobrutinib dose vs placebo/evobrutinib 25 mg QD, and no difference with DMF vs placebo/evobrutinib 25 mg QD was noted. SEL volume significantly decreased with evobrutinib 75 mg BID vs placebo/evobrutinib 25 mg QD (-474.5 mm3 [-1,098.0 to -3.0], p = 0.047) and vs DMF (-711.6 [-1,290.0 to -149.0], p = 0.011). SEL volume was significantly reduced for evobrutinib high vs low dose within baseline Expanded Disability Status Scale ≥3.5 and longer disease duration (≥8.5 years) subgroups.
Discussion:
Evobrutinib reduced SEL volume in a dose-dependent manner in RMS, with a significant reduction with evobrutinib 75 mg BID. This is evident that evobrutinib affects brain lesions associated with chronic inflammation and tissue loss.
Trial Registration Information:
ClinicalTrials.gov number: NCT02975349. Submitted to ClinicalTrials.gov on November 29, 2016. First patient enrolled: March 7, 2017.
Classification Of Evidence:
This study provides Class II evidence that evobrutinib reduces the volume of SELs assessed on MRI comparing baseline with week 48, in patients with RMS.
Insights
Evobrutinib significantly reduced slowly expanding lesion volume in relapsing multiple sclerosis (RMS) patients. This Bruton tyrosine kinase inhibitor shows promise in treating chronic active lesions associated with MS.
Area of Science:
- Neuroscience
- Immunology
- Radiology
Background:
- Chronic active lesions (CALs) in multiple sclerosis (MS) involve ongoing microglia/macrophage activity, leading to irreversible damage.
- Evobrutinib, a selective Bruton tyrosine kinase inhibitor, penetrates the central nervous system.
- Slowly expanding lesions (SELs) are MRI markers of CALs.
Purpose of the Study:
- To evaluate the effect of evobrutinib on SEL volume in patients with relapsing MS (RMS).
- To assess SEL volume changes from baseline to week 48 in a phase 2 clinical trial.
Main Methods:
- A 48-week, double-blind trial involving RMS patients treated with evobrutinib (25 mg QD, 75 mg QD, or 75 mg BID), placebo, or dimethyl fumarate (DMF).
- SELs were identified via MRI and quantified using Jacobian determinant analysis.
- Treatment effects on SEL volume were analyzed using stratified statistical methods.
Main Results:
- Evobrutinib demonstrated a dose-dependent reduction in SEL volume compared to placebo.
- Evobrutinib 75 mg BID significantly reduced SEL volume versus placebo and DMF.
- Significant SEL volume reduction was observed in subgroups with higher baseline Expanded Disability Status Scale and longer disease duration.
Conclusions:
- Evobrutinib effectively reduces SEL volume in RMS patients in a dose-dependent manner.
- The 75 mg BID dose of evobrutinib showed a significant reduction in SEL volume.
- Evobrutinib impacts brain lesions linked to chronic inflammation and tissue loss in MS.
