MS drug fenebrutinib shows ‘unprecedented results’ in trials
BTK inhibitor tested in relapsing, primary progressive forms of disease
Genentech‘s experimental oral therapy fenebrutinib has become the first Bruton’s tyrosine kinase (BTK) inhibitor to show positive Phase 3 results in both relapsing forms of multiple sclerosis (MS) and primary progressive MS (PPMS), the company announced.
In what Genentech called “unprecedented results,” two late-stage trials testing the therapy in these indications have met their primary goals.
FENhance 2 (NCT04586023) demonstrated that fenebrutinib was significantly better than Aubagio (teriflunomide) at reducing relapse rates in people with relapsing forms of MS, while FENtrepid (NCT04544449) found that the therapy was at least as effective as Ocrevus (ocrelizumab) at slowing disability progression in people with PPMS.
A third trial called FENhance 1 (NCT04586010), which is designed similarly to FENhance 2, is still ongoing, with results expected in mid-2026. Genentech plans to use findings from all three trials to support regulatory applications for fenebrutinib.
“Fenebrutinib substantially reduced the number of relapses in [relapsing] MS and slowed disability progression in PPMS,” Levi Garraway, MD, PhD, chief medical officer and head of global product development at Roche, the parent company of Genentech, said in a company press release. “These unprecedented results suggest that fenebrutinib could potentially become a best-in-disease medicine as the first high-efficacy, oral treatment for people with [relapsing forms of MS] or PPMS.”
Fenebrutinib designed to block BTK, a key enzyme
MS is a chronic disorder in which inflammation damages healthy cells in the brain and spinal cord. Most people with MS are diagnosed with relapsing forms of the disease, which are marked by relapses where symptoms suddenly worsen, followed by periods of remission where symptoms ease. A minority of patients instead develop PPMS, which is marked by gradual worsening of symptoms from the onset of the disease, independent of relapse activity.
The vast majority of MS treatments are specifically indicated to treat relapsing forms of MS. Treatments for PPMS are much more limited. Currently, only Ocrevus and its under-the-skin formulation Ocrevus Zunovo (ocrelizumab and hyaluronidase-ocsq), both sold by Genentech, are approved in the U.S. for PPMS.
Fenebrutinib is designed to block BTK, an enzyme with a key role in the activation of B-cells and microglia — immune cells involved in MS. By inhibiting BTK, the therapy aims to reduce inflammatory immune cell activity, thus slowing disease progression.
While fenebrutinib isn’t the first BTK inhibitor to enter Phase 3 clinical testing for relapsing forms of MS, it is the first to have positive results in this MS type. Prior Phase 3 trials of Sanofi’s tolebrutinib and EMD Serono’s evobrutinib in relapsing forms of MS failed to meet their main goals of showing that those therapies were significantly better than Aubagio at reducing relapse rates.
Some benefits were seen in the tolebrutinib studies, however, and that therapy is now being considered for approval in the U.S., with a decision expected next month. Nonetheless, fenebrutinib is the first therapy in its class to meet its main goal in Phase 3 trials for relapsing MS.
With the positive results from FENhance 2, fenebrutinib has become the first BTK inhibitor to outperform Aubagio at reducing annual relapse rates over about two years of treatment.
PPMS trial meets its main goal
The PPMS trial FENtrepid was designed to show that fenebrutinib was non-inferior (or at least as effective as) to Ocrevus in delaying the onset of confirmed disability progression after 120 weeks, or about 2.5 years. That goal was met, making fenebrutinib the first BTK inhibitor to achieve its main goal in Phase 3 clinical testing for PPMS.
Genentech reported that a numerical benefit favoring fenebrutinib was observed as early as six months and lasted for the duration of the trial.
“These pivotal results for fenebrutinib may offer new hope for people living with MS, and they reaffirm our enduring commitment to the MS community,” Garraway said.
Liver safety data from the studies were consistent with earlier studies of fenebrutinib, and additional safety data are still being analyzed.
According to Genentech, full data from the two studies will be presented at upcoming medical meetings.
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