ECTRIMS 2023: Fenebrutinib lowers new lesions in relapsing MS

Treatment with the investigational therapy fenebrutinib significantly reduced the number of new inflammatory lesions visible on MRI scans in people with relapsing forms of multiple sclerosis (MS).

Pharmacological data from the study suggest the anti-inflammatory experimental medication can get into the brain and spinal cord at levels high enough to block the activity of immune cells that drive MS.

Amit Bar-Or, MD, chief of the multiple sclerosis division at the Perelman School of Medicine, University of Pennsylvania, presented the findings this month at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

His talk was titled “Cerebrospinal fluid and MRI analyses of fenebrutinib treatment in multiple sclerosis reveal brain penetration and early reduction of new lesion activity: results from the phase II FENopta study.” The work was funded by Roche, which is developing fenebrutinib through Genentech, its subsidiary.

“These interesting results raise the possibility that fenebrutinib slows MS disease progression in part by acting directly within the brain,” Levi Garraway, MD, PhD, Genetech’s chief medical officer and head of global product development, said in a company press release.

“These findings, along with the consistent safety profile observed, bring us one step closer to our goal of developing medicines to slow, stop, and ideally prevent disease progression,” said Ashish Pradhan, MD, executive director and disease area lead of neuroimmunology at Genentech, in an email to Multiple Sclerosis News Today.

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Fenebrutinib’s effect on relapsing MS

Fenebrutinib is an oral medicine made to reduce the activity of B-cells and microglia, immune cells with a central role in driving MS. It targets Bruton’s tyrosine kinase, or BTK, a protein needed for the cells’ inflammatory activity.

The medication is being investigated in 106 people with relapsing forms of MS in a Phase 2 clinical trial called FENopta (NCT05119569). The patients, whose symptoms started up to 10 years before screening, were randomly assigned to take 200 mg of fenebrutinib or a placebo, twice daily for 12 weeks, or about three months.

The study’s main goal is to evaluate its effect on new lesions with active inflammation visible on brain MRI scans. Secondary measures include the number of new or enlarging brain lesions, the proportion of patients free of any new lesion — with or without inflammation — and safety.

Taking fenebrutinib for 12 weeks led to a 90% reduction in the number of new inflammatory lesions compared with a placebo. The decrease was evident within four weeks of starting treatment, when patients taking fenebrutinib had 22% fewer new lesions. By eight weeks, rates were already 92% lower with fenebrutinib.

Patients taking fenebrutinib also had 49% fewer new or enlarging lesions at four weeks. This difference grew to 90% fewer lesions at eight weeks and 95% at 12 weeks.

The rate of new inflamed lesions was 69% lower with fenebrutinib than a placebo, according to collective data from weeks four, eight, and 12, while the rate of new or enlarging lesions was 74% lower.

“The results of the FENopta study demonstrate superior reduction in new MRI lesions in the brain with fenebrutinib compared to placebo in adults with [relapsing MS],” Pradhan said.

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Fenebrutinib levels in CSF

Analyses of cerebrospinal fluid (CSF) — the liquid that surrounds the brain and spinal cord — from 11 patients at week 12 indicated all of them had fenebrutinib levels that should be sufficient to reduce immune cells’ inflammatory activity.

“Fenebrutinib was present in the CSF at levels that are sufficient to reduce … activation of both B-cells and microglia [in cell cultures], and this certainly suggests that it may impact mechanisms that we now consider important in the context of chronic, progressive disease biology,” Bar-Or said.

Data from four patients whose CSF and blood samples were available suggested the therapy was present in the spinal fluid at 6.1 times higher levels than in blood. This is different from other MS medications, particularly antibody-based therapies, which are mainly found outside the brain, Bar-Or noted.

“Early findings from FENopta indicate that [fenebrutinib] is brain penetrant and has the potential to modulate MS-related pathophysiological processes,” the researchers said.

This finding “is significant because if a medicine can enter the brain to act directly on chronic inflammation, which can lead to disease progression, then it has the potential to reduce this inflammation and slow disability progression for patients,” Pradhan said.

Safety data from the study were generally positive and no serious side effects were reported. Two patients given fenebrutinib had severely elevated values of liver enzymes, but didn’t show any notable symptoms of liver problems. Rates of infections, which are often a concern for immune-suppressing MS therapies, were similar in patients given fenebrutinib or a placebo.

“These data, which we are currently confirming in pivotal trials of both relapsing and progressive MS, suggest that fenebrutinib may have the potential to counteract acute and chronic inflammation within the brain to reduce disease activity in people with MS,” Garraway said.

Roche is running two global Phase 3 clinical trials called FENhance 1 (NCT04586010) and FENhance 2 (NCT04586023) that are testing fenebrutinib against the approved treatment Aubagio (teriflunomide) in people with relapsing MS. The studies are recruiting people with relapsing-remitting MS (RRMS) or active secondary progressive MS (SPMS) at sites worldwide.

Another Phase 3 study called FENtrepid (NCT04544449) is testing fenebrutinib in people with primary progressive MS (PPMS). The study, which has finished recruiting, is comparing fenebrutinib against Ocrevus (ocrelizumab), the only approved PPMS therapy.

Note: The Multiple Sclerosis News Today team is providing in-depth coverage of the 9th joint ECTRIMS-ACTRIMS meeting Oct. 11-13. Go here to see the latest stories from the conference.