Abstract Details

Title The Bruton’s Tyrosine Kinase Inhibitor Evobrutinib Ameliorates Meningeal Inflammation in Experimental Autoimmune Encephalomyelitis (EAE)

Topic Multiple Sclerosis

Presentation(s) P3 - Poster Session 3 (12:00 PM-1:00 PM)

Poster/Presentation
Number 9-016

Objective To test the effect of evobrutinib, a highly-selective BTK inhibitor, as a potential therapy targeting meningeal inflammation in a mouse model of MS.

Background

Leptomeningeal inflammation in MS is associated with worse clinical outcomes and greater cortical pathology. Both B cells and myeloid cells are found in areas of meningeal inflammation. We previously demonstrated that, in the relapsing-remitting EAE model in SJL mice, ultra-high field contrast-enhanced MRI could identify and track areas of meningeal inflammation. Bruton’s tyrosine kinase (BTK) mediates signaling through B cell receptor and Fc receptor pathways and leads to B cell and myeloid cell proliferation and activation. We therefore hypothesized that a BTK inhibitor could target meningeal inflammation in EAE.

Design/Methods We immunized 7-8-week-old female SJL/J mice with PLP_139-151 peptide and CFA to induce EAE. Animals were weighed and disease severity scored starting at 7 days post-immunization and at 6 weeks underwent Gadolinium-enhanced MRI. Mice demonstrating the presence of meningeal contrast enhancement were randomized to receive daily oral doses by gavage of evobrutinib [10 mg/kg] or vehicle control between Weeks 6–10 post-immunization. MRI was repeated at Weeks 8 and 10 to assess meningeal inflammation, and brain tissues were collected for histopathological analysis.

Results At baseline, both vehicle (n=16) and evobrutinib (n=19) groups had a similar number of areas of meningeal contrast enhancement (median: 10.5 vs 11; p=0.25). Following treatment, a greater reduction in the number of areas of meningeal contrast enhancement was identified in the evobrutinib group vs the vehicle group (median change: -3 vs 0.5; p=0.003). Histopathological analyses to define changes in immune cell composition and effects on surrounding cortex are ongoing.

Conclusions

An amelioration of established meningeal inflammation in the relapsing-remitting EAE model was observed with evobrutinib treatment, suggesting the potential utility of this agent to target this phenomenon in MS patients.

Authors/Disclosures
Sol Kim PRESENTER	No disclosure on file
Ursula Boschert Shafaatian (C/o Serono)	Ursula Boschert has nothing to disclose.
Roland Grenningloh	Roland Grenningloh has received personal compensation for serving as an employee of EMD Serono.
Pavan Bhargava, MD, FAAN (Johns Hopkins University)	The institution of Dr. Bhargava has received research support from EMD Serono. The institution of Dr. Bhargava has received research support from Amylyx pharmaceuticals. The institution of Dr. Bhargava has received research support from Genentech. The institution of Dr. Bhargava has received research support from GSK.

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