Phase 3 Trial Data Shows Fenebrutinib Curbs Chronic Active Lesions in Multiple Sclerosis

At the joint ACTRIMS-ECTRIMS medical meeting in Toronto in October 2026, researchers unveiled Phase 3 clinical trial data demonstrating that the experimental oral drug fenebrutinib directly reduces chronic active brain lesions in people with multiple sclerosis. The findings represent the first prospective demonstration of a therapy curbing chronic neuroinflammation in late-stage trials.[1][2]

Fenebrutinib, developed by Roche and Genentech, belongs to a new class of medications known as Bruton's tyrosine kinase inhibitors. Unlike older treatments that primarily manage acute flare-ups, this drug is designed to cross the blood-brain barrier and address the underlying mechanisms that drive long-term disability.[1][2][3]

"The field is quite interested in both SELs and PRLs because both are imaging biomarkers of chronic active lesions, which we know are a dominant driver of progressive disease biology," said Dr. Jiwon Oh of the University of Toronto, who presented the findings.[1]

Slowly expanding lesions and paramagnetic rim lesions serve as magnetic resonance imaging markers for chronic smoldering inflammation in the brain. These lesions are strongly associated with the gradual worsening of physical and cognitive symptoms in multiple sclerosis patients, regardless of their specific diagnosis.[1][2]

Targeting chronic brain inflammation

Most existing multiple sclerosis therapies effectively suppress the acute immune attacks that cause sudden relapses, but they struggle to halt the slow, continuous nerve damage occurring behind the intact blood-brain barrier. Fenebrutinib aims to fill this therapeutic gap by inhibiting specific immune cells within the central nervous system.[1][3]

The drug works by blocking the activation of B cells, which drive acute inflammation, as well as microglia, the resident immune cells in the brain implicated in chronic tissue damage. Because fenebrutinib is a reversible and non-covalent inhibitor, it binds and then releases the target enzyme, potentially offering a safer profile than irreversible alternatives.[1][2][3]

"Progressive MS biology occurs from disease onset in almost everybody with MS, regardless of the initial clinical presentation," Oh explained during the late-breaking session. "When PRLs have been evaluated, they seem to be present in most people early in the disease course."[1]

Identifying a treatment that can halt this early and continuous progression remains the greatest unmet need in multiple sclerosis care. The new imaging data suggests that fenebrutinib actively suppresses the cellular mechanisms responsible for this steady accrual of disability.[1][2]

Phase 3 trial results in relapsing disease

The presentation highlighted pooled data from the FENhance 1 and 2 clinical trials, which enrolled approximately 1,500 adults aged 18 to 55 with relapsing forms of multiple sclerosis. Participants were randomly assigned to receive either daily oral fenebrutinib or the standard therapy teriflunomide.[2][4]

Over a 96-week period, patients taking fenebrutinib experienced a 30.5% relative reduction in the volume of slowly expanding lesions compared to those on teriflunomide. The treatment also significantly curtailed the formation of new inflammatory boundaries around existing nerve damage.[1][2]

Specifically, participants treated with fenebrutinib had 62% lower odds of accumulating new paramagnetic rim lesions compared to the control group. This sharp reduction in rim lesions provides concrete imaging evidence that the drug successfully quiets chronic active inflammation.[1][2]

Beyond the imaging biomarkers, the broader clinical outcomes in the relapsing multiple sclerosis cohort proved highly favorable. Across the pooled FENhance studies, 75% of patients receiving fenebrutinib showed no evidence of disease activity at the two-year mark.[3]

Achieving no evidence of disease activity means these patients experienced zero clinical relapses, zero new magnetic resonance imaging activity, and zero worsening of their baseline disability. This represented a 70% improvement over the outcomes seen in the teriflunomide group.[3]

Impact on primary progressive multiple sclerosis

Researchers also presented data from the FENtrepid trial, which evaluated fenebrutinib in nearly 1,000 patients aged 18 to 65 with primary progressive multiple sclerosis. This form of the disease involves a steady decline in function from the outset, without distinct relapse and remission phases.[2][5]

Participants in the FENtrepid study received either fenebrutinib or ocrelizumab, the current standard of care and the only approved medicine for primary progressive multiple sclerosis. The trial tracked their disability progression and brain imaging markers over a 120-week period.[1][2][5]

In this progressive cohort, fenebrutinib demonstrated a 27.5% relative reduction in the volume of slowly expanding lesions compared to ocrelizumab. However, the difference in the net accumulation of paramagnetic rim lesions between the two therapies did not reach statistical significance.[1][2]

"Addressing long-term disability progression to preserve people's independence remains a critical challenge in neuroinflammatory diseases," said Dr. Levi Garraway, chief medical officer at Roche. "Our recent data indicate that fenebrutinib can inhibit disease activity inside and outside the central nervous system."[3]

The path to regulatory approval

The United States Food and Drug Administration recently accepted a New Drug Application for fenebrutinib under priority review. The application seeks approval for the drug to treat both relapsing and primary progressive forms of multiple sclerosis based on these Phase 3 results.[2]

If cleared by regulators, fenebrutinib would become the first Bruton's tyrosine kinase inhibitor approved for multiple sclerosis. It would also serve as the first highly effective oral treatment available for patients living with the primary progressive form of the disease.[2][3]

The multiple sclerosis treatment landscape has shifted dramatically over the past decade, with highly effective infusion therapies becoming the standard of care. An oral medication capable of matching or exceeding those results while simultaneously targeting chronic brain inflammation could fundamentally alter prescribing practices.[1][3]

While the efficacy data appears robust, the broader class of Bruton's tyrosine kinase inhibitors has faced regulatory scrutiny over potential liver toxicity. Several competing experimental drugs in the same class have been placed on partial clinical holds by the FDA following elevated liver enzyme reports.[3]

Roche has maintained that fenebrutinib's reversible binding mechanism may spare patients from the severe liver complications seen with other candidates. Preliminary safety assessments from the FENhance and FENtrepid trials have remained consistent with earlier studies, showing no outsized hepatic risks to date.[2][3]

As the FDA evaluates the comprehensive clinical package, the multiple sclerosis community awaits a decision that could introduce a powerful new tool. The prospect of an oral therapy that directly tackles the chronic inflammation driving long-term disability represents a major milestone in neurological research.[1][2][3]