Fenebrutinib (formerly known as GDC–0853 and RG7845) is an investigational oral therapy being tested in people with relapsing forms of multiple sclerosis (MS) and primary progressive MS (PPMS).
It is being developed by the Roche subsidiary Genentech.
Fenebrutinib is an oral small molecule designed to slow MS progression by preventing certain immune cells from driving the inflammation that damages nerve cells.
The therapy belongs to a class of compounds called Bruton’s tyrosine kinase (BTK) inhibitors. BTK is an enzyme that is critical to the inflammatory activity of B-cells and microglia, two types of immune cells that meaningfully contribute to disease inflammation in both relapsing and progressive forms of MS.
Fenebrutinib is known 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.
Fenebrutinib is an oral medication available in the form of 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 now testing fenebrutinib at a dose of 200 mg, or two 100 mg tablets, twice daily. The total daily dose is 400 mg, or four tablets.
The first clinical trials of fenebrutinib tested the therapy in healthy volunteers (NCT03596632), and in those with other autoimmune diseases, such as rheumatoid arthritis (NCT02833350), systemic lupus erythematosus (NCT02908100), and chronic spontaneous urticaria (NCT03693625), characterized by chronic hives.
Results have indicated that the safety profile of the investigational medication is generally comparable to that of other immune-suppressing therapies. A number of clinical trials in MS are now ongoing.
A Phase 2 clinical trial called FENopta (NCT05119569) is testing fenebrutinib against a placebo in people with relapsing types of MS. For all participants, symptoms started less than 10 years prior to enrollment.
The trial is seeking to recruit 102 adults who will be 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 main goal is to determine the effect of treatment on the development of new MS lesions with active inflammation after 12 weeks. The trial is expected to finish in late 2022.
Participants who complete this part will have the option to enter an open-label extension portion, in which all will receive fenebrutinib for up to 96 weeks.
Two identically designed Phase 3 clinical trials — FENhance 1 (NCT04586010) and FENhance 2 (NCT04586023) — also are now recruiting. Each aims to enroll 736 adults, ages 18 to 55, who experienced their first symptoms of MS within the past decade.
Participants will be randomly assigned to treatment with twice-daily fenebrutinib (four daily tablets in total) or to a daily 14 mg dose of Aubagio (teriflunomide), an approved oral therapy for relapsing MS. Treatment will be given for 96 weeks.
The main goal in both trials is to evaluate the effect of the therapy — specifically its safety and efficacy — on relapse rates after 96 weeks. Additional measures, such as disability progression, brain lesions, and changes in brain volume and cognitive function, also will be assessed.
Participants who complete these trials 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.
The trials are expected to conclude in 2025.
The FENtrepid Phase 3 trial (NCT04544449) is investigating fenebrutinib against Ocrevus (ocrelizumab) in people with PPMS. Ocrevus, given via an intravenous (into-the-vein) infusion every six months, is the only MS therapy currently approved for this patient population.
The trial, which is recruiting, aims to include 946 adults, ages 18 to 65, at more than 170 sites around the world. Patients will be randomly assigned to receive fenebrutinib (two pills twice a day) or Ocrevus for at least 120 weeks.
The main goal is to assess the effects of treatment on disability progression that is sustained for at least 12 weeks. Changes in brain volume, as well as patient-reported evaluations of disease impact and cognitive function, also are being assessed. The trial is expected to conclude in late 2025.
Participants who complete the trial and, in the opinion of the investigator, may benefit from treatment with fenebrutinib, may also be given the option to enter an open-label extension part and receive the therapy for another 96 weeks. This extension also is dependent on the results of a risk-benefit analysis of the study.
Because these MS clinical trials are all ongoing, the most common side effects of fenebrutinib in MS patients are still unknown. In clinical trials in other indications, the most commonly reported side effects were:
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Fenebrutinib is an experimental medicine that has not been approved for any indication, and that is still in clinical trials for multiple sclerosis. The therapy is believed to help reduce the inflammation that causes neurological damage in MS by blocking the activity of the Bruton tyrosine kinase protein, which is integral to the inflammatory activity of B-cells and microglial cells.
Fenebrutinib is currently being tested in multiple sclerosis patients in three Phase 3 clinical trials, all of which are expected to conclude in 2025. If the results of these studies are positive, it is possible that they could support regulatory applications seeking the therapy’s approval by the U.S. Food and Drug Administration. But it is too early to know if or when fenebrutinib could be approved to treat MS.
Current clinical trials in multiple sclerosis are not enrolling participants who are pregnant, and those with the ability to conceive are required to take measures to prevent conception while in the study. As such, it is currently unknown whether fenebrutinib can be safely taken during pregnancy.
There are not yet any data available on the potential efficacy of fenebrutinib in people with multiple sclerosis.
Neither hair loss nor weight gain was reported as side effects associated with fenebrutinib in clinical trials that enrolled participants with other inflammatory conditions. It remains unknown if these effects are experienced by people with multiple sclerosis.
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