Fenebrutinib for multiple sclerosis

Last updated March 5, 2025, by Marisa Wexler, MS
Fact-checked by Ines Martins, PhD

What is fenebrutinib for MS?

Fenebrutinib is an oral therapy being tested for relapsing forms of multiple sclerosis (MS) and primary progressive MS (PPMS).

The therapy is being developed by Roche subsidiary Genentech to ease disease-driving inflammation, with the aim of reducing relapses and lesions and slowing disability progression. It is administered twice daily, in the form of oral tablets.

Therapy snapshot

How does fenebrutinib work in MS?

Fenebrutinib is an oral small molecule designed to reduce disease activity and slow disability progression in people with MS. It works by preventing certain immune cells from driving disease-related inflammation and causing nerve cell damage.

The therapy belongs to a class of compounds called Bruton’s tyrosine kinase (BTK) inhibitors. BTK is an enzyme that’s critical to the inflammatory activity of B-cells and microglia, two types of immune cells that are known to contribute to disease inflammation in both relapsing and progressive forms of MS.

Fenebrutinib has been found to be able to cross the blood-brain barrier, a semi-permeable membrane that tightly regulates what substances from the blood can access the brain and spinal cord. Crossing it is often a challenge for brain-targeting therapies.

Unlike other BTK inhibitors being developed for MS, fenebrutinib has the unique property of binding to its target in a reversible manner. This may make it safer than other therapies of the same class, according to researchers.

How will fenebrutinib be administered in MS?

Fenebrutinib is available in film-coated tablets. In early clinical trials involving people with other autoimmune diseases, the therapy was administered orally at doses ranging from 50 mg once daily to 200 mg twice daily.

Ongoing clinical trials in MS are testing it at a dose of 200 mg, or two 100 mg tablets, taken twice daily. The total daily dose is 400 mg, or four tablets.

If data from those trials are positive, this will likely be the recommended dosing regimen for fenebrutinib in MS.

Fenebrutinib in MS clinical trials

Genentech launched a Phase 2 trial called FENopta (NCT05119569) in 2022 to investigate the therapy in people with relapsing types of MS. Earlier trials in healthy volunteers and people with other autoimmune diseases had shown that fenebrutinib was generally safe and well tolerated.

FENopta trial

The FENopta trial is testing fenebrutinib against a placebo in 109 adults with relapsing-remitting MS and active secondary progressive MS whose symptoms had started within the previous 10 years.

Participants were randomly assigned to receive 200 mg fenebrutinib or a placebo (two 100 mg tablets, twice a day) for up to 12 weeks, or about three months.

The trial’s main goal was to determine the effect of treatment on the development of new MS lesions with active inflammation, as measured by brain MRI scans at weeks four, eight, and 12. This goal was met, with fenebrutinib reducing by 90% the number of new inflammatory brain lesions after three months compared with the placebo.

The decrease was evident within four weeks of starting treatment, when patients taking fenebrutinib had 22% fewer new lesions than those on the placebo. By eight weeks, rates were 92% lower with fenebrutinib. The number of new or enlarging lesions after 12 weeks was also significantly reduced, by 95%.

After completing the main trial, 99 patients chose to enter an open-label extension phase, in which all are receiving fenebrutinib for up to 192 weeks, or about 3.5 years.

Data showed that 96% of treated patients were free from MS relapses after 48 weeks, or nearly one year, in the extension. No changes in disability levels were observed during that period, as assessed by the Expanded Disability Status Scale (EDSS), a commonly used measure.

Fenebrutinib also continued to suppress MRI activity during the extension portion of FENopta, with 99% of patients free from inflammatory brain lesions after 48 weeks. Total lesion volume was reduced threefold over this period relative to the end of the main trial.

FENhance trials

To continue studying fenebrutinib in relapsing forms of MS, Genentech launched two identically designed Phase 3 clinical trials: FENhance 1 (NCT04586010) and FENhance 2 (NCT04586023).

These trials are testing the medication against the approved MS treatment Aubagio (teriflunomide) in about 1,500 adults with relapsing-remitting MS (RRMS) or active secondary progressive MS (SPMS). All of the patients in the study had experienced their first symptoms of MS within 10 years of enrollment. Treatment with either twice-daily fenebrutinib or daily Aubagio will be given for 96 weeks.

The main goal in both trials is to evaluate whether fenebrutinib can outperform Aubagio at reducing relapse rates after 96 weeks. Additional measures, such as disability progression, number of lesions, and changes in brain volume and cognitive function will also be assessed.

These Phase 3 studies were placed on a partial hold by the U.S. Food and Drug Administration in November 2023 after two treated patients showed signs of possible treatment-related liver injury. The trials continued, but new enrollment was stopped at U.S. sites for all three studies.

Participants who complete these trials in the U.S. and elsewhere may be invited to enter an open-label extension study in which all would receive fenebrutinib for another 96 weeks. That extension phase will be confirmed following a risk-benefit analysis of the trial’s early results, which is expected in late 2025.

FENtrepid trial

Another Phase 3 trial, FENtrepid (NCT04544449), was launched to investigate fenebrutinib in people with PPMS. A total of 985 adults who experienced disability progression in the past year were enrolled and randomly assigned to receive the experimental therapy or Ocrevus (ocrelizumab) for at least 120 weeks. Ocrevus is the only therapy approved for PPMS.

The main goal is to assess the effects of treatment on 12-week confirmed disability progression, which is defined as an increase in EDSS levels that’s confirmed at an appointment at least three months later.

Other measures of disability progression, as well as changes in brain volume and cognitive function and patient-reported evaluations of disease impact, are also being assessed.

FENtrepid was also placed on a partial hold that prevented more patients from being enrolled in the U.S., but the trial continued as planned in other clinical sites. Top-line data are expected in early 2026.

Participants who complete FENtrepid may be given the option to join an open-label extension part and receive the therapy for another 96 weeks. As in the FENhance trials, this extension is dependent on positive risk-benefit results observed in the trial’s primary analysis.

Common side effects of fenebrutinib

Fenebrutinib has shown a generally positive safety profile, with one serious side effect reported during MS clinical trials.

The most common side effects reported in a Phase 2 trial and its extension part included:

• elevated levels of liver enzymes
• urinary tract infection
• COVID-19
• pharyngitis, or sore throat.

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