#ECTRIMS2021 – Trial Analyses Support Evobrutinib for Relapsing MS

Treatment with evobrutinib, an experimental therapy for relapsing forms of multiple sclerosis (MS), reduced the size of inflammation-associated brain lesions in a Phase 2 clinical trial, data show.

The oral medication was also found to be generally safe and well tolerated, according to an analysis of trial data in MS and other autoimmune diseases.

Findings will be shared in a series of presentations at the 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), taking place virtually Oct. 13–15. The research was supported by Merck KGaA (known as EMD Serono in the U.S. and Canada), which is developing evobrutinib.

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Merck is currently running two identically designed Phase 3 trials, EVOLUTION RMS 1 and 2 (NCT04338022 and NCT04338061), to further test evobrutinib in people with relapsing forms of MS. These trials have now finished enrolling participants, the company announced.

“The breadth of our data at ECTRIMS, paired with the rapid enrollment in our evobrutinib Phase III EVOLUTION RMS clinical trial program, further exemplifies a commitment to continue breaking boundaries in the science of MS,” Danny Bar-Zohar, global head of development for the healthcare business of Merck KGaA, Darmstadt, Germany, said in a press release.

Evobrutinib is an investigational oral MS therapy that works by blocking the activity of the Bruton’s tyrosine kinase (BTK) protein, which is involved in the activation of immune cells, most notably B-cells.

By blocking BTK, evobrutinib is thought to reduce immune activity, thus lowering the inflammation that causes damage to the nervous system (the brain and spinal cord) in MS.

Its efficacy and safety were evaluated in a Phase 2 clinical trial (NCT02975349) that enrolled 267 people with relapsing MS, which includes relapsing-remitting MS and active secondary progressive MS.

Results showed that evobrutinib significantly reduced relapse rates and brain lesions at 48 weeks compared with a placebo, and this reduction was sustained for about two years.

Researchers at Merck and other institutions will now share new analyses from this trial, in two oral presentations at ECTRIMS.

Evobrutinib’s effect on slowly expanding lesions, a specific type of brain injury visible on MRI scans, was discussed in one presentation, “Effects of evobrutinib, a Bruton’s tyrosine kinase inhibitor, on slowly expanding lesions: an emerging imaging marker of chronic tissue loss in multiple sclerosis.”

Slowly expanding lesions (SELs) lead to irreversible damage to brain cells over time. They are thought to be driven by certain immune cells called microglia and macrophages, whose activity can be blocked  with evobrutinib.

Trial results showed that, relative to a placebo, treatment with evobrutinib significantly reduced the size of SELs in a dose-dependent manner: at the lowest dose tested, SELs were on average 136.5 cubic millimeters (mm³) smaller than seen with the placebo. At the highest tested dose, the difference was 474.5 mm³.

Further analyses showed that the dose-dependent effect of evobrutinib on SELs was significant among subgroups of patients with longer disease duration or more severe disability, and among those with relapsing-remitting MS.

“Evobrutinib reduces SEL volume in a dose-dependent manner in relapsing MS,” the investigators concluded. “The reduction is especially apparent in patients with more advanced disease.”

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The effect of evobrutinib in people with different levels of neurofilament light chain (NfL) in their blood was presented in another session, “Evobrutinib significantly reduces relapses and magnetic resonance imaging outcomes in patients with multiple sclerosis: association with baseline neurofilament light chain levels.”

NfL is a protein that is important for the structure of neurons (nerve cells). When these cells are damaged, NfL gets released into the blood. As such, measuring blood NfL may be a way to assess damage to the nervous system in MS and other diseases.

The analysis included 162 participants in the Phase 2 trial whose NfL levels were measured at the trial’s start. Statistical analyses showed that patients with high NfL levels tended to also have more severe disease, including more relapses and brain lesion accumulation over time.

However, treatment with evobrutinib significantly reduced the risk of disease relapse, regardless of initial NfL levels. The medication’s effect at lessening brain lesions also was consistent in people with lower or higher NfL levels.

A third presentation, “Safety profile characterisation of evobrutinib in over 1000 patients from phase II clinical trials in multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus,” showed analyzed data from the MS trial combined with two other Phase 2 clinical trials that tested evobrutinib in other autoimmune diseases

These included a 12-week study that enrolled 390 participants with rheumatoid arthritis (NCT03233230), and a 52-week study that enrolled 480 people with systemic lupus erythematosus (NCT02975336).

Of the 1,083 total patients analyzed, rates of adverse events (side effects) were similar among those given evobrutinib (66.2%) or a placebo (62.4%). Rates of serious adverse events were also comparable, about 12% in both groups.

BTK inhibitors are known to cause increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), two markers of damage to the liver.

However, “elevations in ALT and AST were asymptomatic and reversible” in the pooled analysis, the researchers concluded, adding that evobrutinib “was generally well tolerated across indications.”