Taking a More Targeted Approach to Treating Progressive MS Using BTK Inhibition

Jorge Alvarez, BSc, PhD

In the “Cutting Edge Developments” session of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2022, held February 24-26, in West Palm Beach, Florida, new data highlighted the benefits of targeting Bruton’s tyrosine kinase (BTK) to reduce central nervous system (CNS)-compartmentalized inflammation. BTK inhibition, which has gained momentum in recent years, may be a promising therapy to improve treatment options for patients with multiple sclerosis (MS).

Using a progressive-like experimental autoimmune encephalitis (pEAE) mouse model, investigators found a robust expression of BTK—an enzyme critically involved in B-cell activation, proliferation, and survival—with treatment of evobrutinib (EMD Sorono), an investigational BTK inhibitor. Additionally, this expression was also especially found within leptomeningeal infiltrates, which have been previously documented as predictive of poor clinical outcome and rapid disability progression in MS.

"In relapsing-remitting MS, there is this pathology, mostly the demyelination of white matter sometimes in the cortex and very little involvement of the submeningeal pathology," senior author Jorge Alvarez, BSc, PhD, assistant professor, University of Pennsylvania School of Veterinary Medicine, said in his presentation. "This contrasts what is seen in progressive MS, where you have, in addition to this pathology in the parenchyma, this underlined super meningeal pathology that we know is associated with an accumulation of immune cells in the meninges. In particular, these aggregates of B-cells have shown to be important in driving submeningeal pathology as well as shown to be predictive of an aggressive disease with rapid, unrelenting progression of disability."

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Alvarez and his colleagues specifically looked at clinical outcomes that correlated with CNS immunopathological parameters that recapitulated key aspects of MS. The pEAE mice were observed in 2 phases, the acute and the progressive. Daily oral evobrutinib resulted in a significant reduction in not only the peak of the disease in the acute phase, but more profoundly later in the disease process. Additionally, BTK was highly expressed by CD19 B-cells and also colocalized with Iba1 and with CD11b microglia/myeloid cells.

"When we look at the pathology, we see these major clusters in the spinal cord, accumulation of the myelination in the tissue, and other areas that are heavily infiltrated by immune cells in this model,” Alvarez said. “When we compare it to the BTK inhibitor, you see that there is an obvious reduction in the number of infiltrating cells and not so much edema and demyelination when we look at the spinal cord of different areas of the brain."

The effects of evobrutinib on reducing disease severity and improving immunopathological parameters remained consistent regardless of being treated in either prophylactic or therapeutic paradigms. The level of acute attack was reduced following treatment, with stabilization of the disease for up to 20 days post-onset. This correlated with changes in body weight and the decrease in maximum disease score as compared to the vehicle control-treated pEAE mice.

"All of this tells us that BTK inhibition is a good target for CNS-compartmentalized inflammation for future studies. What we are doing is understanding what BTK is doing in those immune cells that are in the tissue. We are also interested in treating later on in the disease, try to try replicate more of what will be seen in cases of MS," Alvarez added.

When asked about whether he and his colleagues could identify which cell type is being exerted to show this beneficial effect, Alvarez noted that they are unsure currently, but that they are looking to conduct future assays to further examine. He was also asked about if the research distinguished the impact on submeningeal vs perivascular pathology, to which he said they had not, but that "we are able to see the impact on both compartments separately. I believe that in our case with the BTK inhibitor, we are seeing an impact on both of those compartments, not only on B-cell compartments."

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 in adults with relapsing MS.

For more coverage of ACTRIMS Forum 2022, click here.

REFERENCES
1. Kebir H, Li C, May MJ, Church ME, Boschert U, Alvarez JI. Effectiveness of the Bruton’s tyrosine kinase inhibitor evobrutinib in a novel model for compartmentalized neuroinflammation in multiple sclerosis. Presented at: ACTRIMS Forum 2022; February 24-26; West Palm Beach, Florida. Abstract CE1.3