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Clinical Trial
. 2024 Mar 12;102(5):e208058.
doi: 10.1212/WNL.0000000000208058. Epub 2024 Feb 9.

Effect of Evobrutinib on Slowly Expanding Lesion Volume in Relapsing Multiple Sclerosis: A Post Hoc Analysis of a Phase 2 Trial

Douglas L Arnold  1 , Colm Elliott  1 , Emily C Martin  1 , Yann Hyvert  1 , Davorka Tomic  1 , Xavier Montalban  1
Affiliations
Clinical Trial

Effect of Evobrutinib on Slowly Expanding Lesion Volume in Relapsing Multiple Sclerosis: A Post Hoc Analysis of a Phase 2 Trial

Douglas L Arnold et al. Neurology. .

Abstract

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.

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Conflict of interest statement

D.L. Arnold has received personal fees for consulting from Albert Charitable Trust, Alexion, Biogen, Celgene, F. Hoffmann-La Roche Ltd., Frequency Therapeutics, Genentech, Med-Ex Learning, the healthcare business of Merck KGaA, Darmstadt, Germany, Novartis, Receptos and Sanofi-Aventis; grants from Biogen and Novartis; and has an equity interest in NeuroRx Research. C. Elliott has received speaker honoraria from EMD Serono and is an employee of NeuroRx Research. E.C. Martin is an employee of EMD Serono. Y. Hyvert is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany. D. Tomic is an employee of Ares Trading SA, Eysins, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany, and received stock or an ownership interest from Novartis. X. Montalban has received personal compensation for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion, Biogen, Celgene/Receptos, F. Hoffmann-La Roche, Genzyme, Medday, the healthcare business of Merck KGaA, Darmstadt, Germany, EMD Serono, NervGen, Novartis, TG Therapeutics and Sanofi-Genzyme; his institution has received compensation for consultancy for Biogen, F. Hoffmann-La Roche, Medday, the healthcare business of Merck KGaA, Darmstadt, Germany, EMD Serono and Novartis, and research support from Abbvie, Biogen, F. Hoffmann-La Roche, Medday, the healthcare business of Merck KGaA, Darmstadt, Germany, Novartis, Sanofi and Teva. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Example of a SEL Shown at 3 Time Points Over 48 Weeks
(A–C) and (G–I) show the same axial slice on T1-weighted and T2-weighted images, respectively, at screening, week 20, and week 48. (D–F) and (J–L) shows a zoomed-in region of interest corresponding to the red box in (A–C) and (G–I) highlighting the SEL. An animated version of this figure is more appropriate for data visualization and is available in Video 1. SEL = slowly expanding lesion.
Figure 2
Figure 2. Evobrutinib Treatment Groups vs Placebo/Evobrutinib 25 mg QD or DMF Treatment Group vs Placebo/Evobrutinib 25 mg QD
(A) Absolute SEL volume. (B) SEL volume as a percentage of baseline T2 lesion volume (stratified analyses). BID = twice daily; DMF = dimethyl fumarate; QD = once daily; SEL = slowly expanding lesion. *p value <0.05. †Evobrutinib or DMF treatment groups vs placebo/evobrutinib 25 mg QD (n = 42). ‡Evobrutinib or DMF treatment groups vs placebo/evobrutinib 25 mg QD (n = 38). §Patients switched from placebo to evobrutinib 25 mg QD for the second 24-week treatment period. SEL analysis set.
Figure 3
Figure 3. Evobrutinib Treatment Groups vs DMF
(A) Absolute SEL volume. (B) SEL volume as a percentage of baseline T2 lesion volume (stratified analyses). BID = twice daily; DMF = dimethyl fumarate; QD = once daily; SEL = slowly expanding lesion. †Evobrutinib treatment groups vs DMF 240 mg BID (n = 50). SEL analysis set.
Figure 4
Figure 4. SEL Volume by Tertiles of Baseline T2 Lesion Volume
(A) Absolute SEL volume. (B) SEL volume as a percentage of baseline T2 lesion volume. BID = twice daily; DMF = dimethyl fumarate; EOT = end of treatment; QD = once daily; SEL = slowly expanding lesion. SEL analysis set. Tertiles of baseline T2 lesion volume in overall population—tertile 1: ≤8,000 mm3 (≤8 cm3); tertile 2: 8,000–19,000 mm3 (8–19 cm3); and tertile 3: ≥19,000 mm3 (≥19 cm3). SEL volume based on MRI assessments from baseline through week 48/EOT.
See this image and copyright information in PMC

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