Feb 25, 2023 – Isabella Ciccone, MPH
A preclinical assessment of evobrutinib showed it demonstrated superior efficacy in targeting compartmentalized neuroinflammation in multiple sclerosis compared with anti-CD20 treatment.
Jorge Alvarez, BSc, PhD
New data from a preclinical assessment onevobrutinib (EMD Serono), a highly selective central nervous system (CNS)-penetrant Bruton tyrosine kinase (BTK) inhibitor, demonstrated superior efficacy compared with anti-CD20 treatment for targeting compartmentalized neuroinflammation in multiple sclerosis (MS).1 The findings support the BTK inhibitor as a promising therapy for persistently targeting neuroinflammation and disease progression in MS.
Evobrutinib reduced both disease severity (65% reduction; P <.0001) and immunopathological parameters of disease (56% reduction; P <.01) in progressive-like experimental autoimmune encephalitis mice (pEAE) compared with anti-CD20 (clone: SA271G2) treatment. The favorable effects of evobrutinib paralleled with a significant gain in body weight and decrease in cumulative disease score in comparison with anti-CD20 treatment (54% disease score reduction; P <.001).
The results were presented in a poster at the annual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum held February 23-25, 2023, in San Diego, California, by senior author Jorge Alvarez, BSc, PhD, assistant professor, University of Pennsylvania School of Veterinary Medicine.
Alvarez and colleagues wrote, “The observed improvements in clinical, immunological, and neuropathological parameters of disease 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.”1
Assessments were conducted preclinically for comparing the therapeutic potential of evobrutinib and anti-CD20 antibody treatment on MS progression using a pEAE mouse model. Additionally assessed with the pEAE mice were clinical outcomes and their correlation with CNS immunopathological parameters to reiterate the main aspects of disease progression in MS.
The BTK inhibitor significantly reduced the number and activation of lymphoid and myeloid cells, lessening neuroinflammation, Alvarez et al noted. In addition, evobrutinib significantly reduced the extent of submeningeal demyelination both in the brain (44% reduction; P <.01) and the spinal cord (42% reduction; P <.01).
“In MS, compartmentalized neuroinflammation often starts early and is characterized by an accumulation of persistent B cell-rich aggregates within the CNS. Such compartmentalized neuroinflammation is predictive of both poor clinical outcomes and rapid disability progression,” Alvarez and colleagues noted.1 “B cells located in the CNS may be protected from established MS therapies such as anti-CD20 antibodies. Recently, CNS-penetrant small molecules directed against BTK, which plays a critical role in B cell activation, proliferation, and survival, have emerged with the potential to target compartmentalized neuroinflammation.”
Evobrutinib is currently being evaluated in 2 pivotal phase 3 studies, both expected to conclude in September 2023. The trials—evolutionRMS 1 (NCT04338022) and evolutionRMS 2 (NCT04338061)––are multicenter, randomized, parallel-group, double-blind, double- dummy, active-controlled studies comparing evobrutinib and teriflunomide (Aubagio; Sanofi) in adults with relapsing MS.
Previously, at the 2022 ACTRIMS Forum, held February 24-26, in West Palm Beach, Florida, Alvarez presented data from pEAE mice displaying the benefits of targeting BTK to reduce CNS-compartmentalized inflammation in MS in the “Cutting Edge Developments” session.2 Alvarez and his colleagues specifically looked at clinical outcomes that correlated with CNS immunopathological parameters that recapitulated key aspects of MS.