#ACTRIMS2022 – In New Mouse Model, Evobrutinib Shows Efficacy

Researchers developed a new mouse model that more closely captures a specific type of inflammation characteristic of progressive multiple sclerosis (MS) — and found, in experiments, that treatment with an oral medication called evobrutinib can lessen disease activity.

This new mouse model may help scientists in MS to better study potential therapies for this form of the neurodegenerative disease.

The results were shared at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2022, in a presentation titled “Effectiveness of the Bruton’s Tyrosine Kinase Inhibitor Evobrutinib in a Novel Model for Compartmentalized Neuroinflammation in Multiple Sclerosis.” The research was funded in part by EMD Serono (known as Merck KGaA outside the U.S. and Canada), the company developing evobrutinib.

MS can broadly be divided into two forms: relapsing MS, characterized by periods of new or worsening symptoms (relapses) followed by times when symptoms ease (remission), and progressive MS, in which symptoms get gradually worse over time.

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These two categories are not absolute — it is possible for someone with progressive MS to experience a relapse, for example — but nonetheless, accumulating evidence suggests that these two disease courses are reflective of different disease-driving biological processes in the brain.

For example, progressive MS is usually characterized by a lot of inflammation in the meninges, or the membranes that surround the brain, and is driven mainly by immune cells called B-cells. This type of meningeal inflammation is rarely seen in relapsing MS.

In order to study progressive MS, it’s necessary to have laboratory models that accurately recapitulate these disease processes. In mice, a common model that researchers use to study MS is experimental autoimmune encephalitis, or EAE, which basically involves giving mice a small protein fragment that prompts an immune attack against the nervous system.

Although these models capture many aspects of MS, classic EAE models are more reflective of the relapsing course of the disease. Now, scientists created a new mouse model of EAE, called progressive EAE (pEAE), that aims to better reflect the development of progressive disease.

Assessments of the clinical scores of these mice scores showed that, after the induction of pEAE, there was a short “acute” phase, in which symptoms suddenly developed. After that, mice entered a progressive phase, where symptoms got gradually worse over time — similar to what happens in progressive MS patients. Similar results were seen across sexes.

Analyses of the mice’s brains showed that, over the transition from acute to progressive phases, the proportion of B-cells increased, and there was an increase in B-cell-driven inflammation at the meninges. Levels of B-cell-activating signaling molecules also increased.

“We have a novel model in which we are able to see a clinical course of disease that presents a progressive phase, in which the immune cell composition resembles that seen in MS,” Jorge Alvarez, PhD, a professor at the University of Pennsylvania and a study author, said at ACTRIMS.

Notably, B-cells in these sites of meningeal inflammation expressed high levels of a protein called Bruton’s tyrosine kinase (BTK), which is important for B-cell activation.

“B-cells that are active express BTK [at] high levels,” Alvarez said.

To address the role of BTK in this model, the researchers treated the mice with evobrutinib, an experimental BTK inhibitor that EMD Serono is developing to treat MS. Evobrutinib was given either before the induction of EAE — as a prophylactic or preventive treatment — or a few days after EAE was induced, as a therapeutic treatment.

Results showed that prophylactic evobrutinib led to a significant decrease in disease severity, as assessed by symptoms as well as changes in body weight.

“There is a significant reduction [in clinical scores], not only in the peak of disease that you see in the acute phase, but more profoundly later on in the disease process, when the animals have this progressive phase of disease,” Alvarez said.

Therapeutic treatment with evobrutinib also lessened disease activity in the acute and the progressive phases. In the progressive phase, untreated animals reached clinical scores of 4, indicating complete leg paralysis, while those that received evobrutinib had stable scores of about 1.5, which indicate limb weakness.

“We are able to reduce the level of the acute attack … and are able to stabilize disease, up to after 20 days post-onset,” Alvarez said.

Treatment with evobrutinib also resulted in an “obvious reduction” in numbers of inflammatory B-cells at the meninges and reduced the loss of myelin — the fatty sheath around nerve fibers that is attacked in MS — in the brain and spinal cord.

“When we use evobrutinib, which is a BTK inhibitor, both prophylactically and therapeutically, we are able to reduce the severity of the disease,” Alvarez concluded.

The results suggest that blocking BTK is a viable therapeutic strategy to address the specific type of inflammation that drives progressive MS, he added.

Alvarez and his team are now studying how evobrutinib impacts the immune cells in the brain and spinal cord, and whether treatment at later stages in the disease course — which more accurately replicates treatment in MS patients – also reduces disease severity.

Editor’s note: The Multiple Sclerosis News Today team is providing in-depth coverage of the ACTRIMS Forum 2022 Feb. 24–26. Go here to see the latest stories from the conference.