Abstract Details

Title The Bruton’s Tyrosine Kinase Inhibitor Evobrutinib Demonstrates Superior Efficacy in Targeting Compartmentalized Neuroinflammation Compared to Anti-CD20 Treatment.

Topic Multiple Sclerosis

Presentation(s) S16 - MS Clinical Trials and Therapeutics (1:36 PM-1:48 PM)

Poster/Presentation
Number 004

Background In MS, compartmentalized neuroinflammation often starts early and is characterized by an accumulation of persistent B cell rich aggregates. Compartmentalized neuroinflammation is predictive of both poor clinical outcomes and rapid disability progression. B cells within the CNS may be protected from established MS therapies such as anti-CD20 antibodies. CNS-penetrant small molecules directed against BTK – with its critical role in B cell activation, proliferation, and survival – have emerged to potentially target chronic neuroinflammation.

Objective To evaluate the efficacy of evobrutinib, a central nervous system (CNS)-penetrant Bruton’s tyrosine kinase inhibitor (BTKi), versus anti-CD20 treatment, on compartmentalized neuroinflammation and disease outcomes in a novel mouse model recapitulating key features of disease progression in multiple sclerosis (MS).

Design/Methods Preclinical assessments compared the therapeutic potential of evobrutinib and anti-CD20 antibodies on MS progression using the experimental autoimmune encephalomyelitis mouse model with features of progression (pEAE). Clinical outcomes and their correlation with CNS immunopathological parameters were assessed in pEAE mice to recapitulate key aspects of MS disease progression.

Results Evobrutinib, versus anti-CD20 (clone: SA271G2) treatment, reduced disease severity (65% reduction; P<0.0001) and immunopathological parameters of disease (56% reduction; P<0.01) in pEAE mice. The beneficial effects of BTKi were paralleled by body-weight gain and a decrease in maximum disease score versus anti-CD20 treatment. Evobrutinib lessened neuroinflammation by significantly reducing the number and activation of lymphoid and myeloid cells as well as the extent of submeningeal demyelination both in the brain (44% reduction; P<0.01) and the spinal cord (42% reduction; P<0.01).

Conclusions The improvements in clinical, immunological, and neuropathological parameters of disease observed in pEAE mice treated with evobrutinib illustrate the importance of compartmentalized neuroinflammation for disease progression. The limited effect of anti-CD20 treatment confirms the insufficient disease inhibition potential of antibody-based therapies when targeting intrathecal B cells. These findings support the notion that evobrutinib targets persistent neuroinflammation in MS.

Authors/Disclosures
PRESENTER	No disclosure on file
Hania Kebir, PhD (University of Pennsylvania)	Ms. Kebir has received research support from Fonds de Recherche du Québec-Santé. Ms. Kebir has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Ursula Boschert Shafaatian (C/o Serono)	Ursula Boschert has nothing to disclose.