Earlier this year, I wondered whether it was time to give up my hope that researchers were close to developing a Bruton tyrosine kinase (BTK) inhibitor – a treatment that could pump the brakes on multiple sclerosis (MS) progression, particularly in primary progressive MS (PPMS). The US Food and Drug Administration (FDA) had just decided not to approve the experimental BTK inhibitor tolebrutinib in its current form. But the findings of a phase 3 trial of fenebrutinib recently rekindled my hopes.
In the FENtrepid study, presented at this year’s meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), Genentech’s oral BTK inhibitor reduced the risk of disability progression by 12% compared with ocrelizumab (Ocrevus®), also produced by Genentech.
In early March, there were other positive results for fenebrutinib. The phase 3 FENhance 1 study, which tested the experimental disease-modifying therapy (DMT) in relapsing MS (RMS), met its primary endpoint, reducing the annualized relapse rate (ARR) by 51% compared with teriflunomide over a period of at least 96 weeks. That was similar to the results of FENhance 2, which showed a 59% reduction in ARR. As Genentech noted in a news release, “Together, these results equate to approximately one relapse every 17 years.”
In the FENtrepid study, fenebrutinib showed consistent clinical benefit as early as week 24, notably in upper limb function. The agent “has the potential to be a high-efficacy, oral treatment option that acts directly in the brain, targeting progressive biology, and may slow disability,” Amit Bar-Or, MD, director of the Center for Neuroinflammation and Neurotherapeutics at the University of Pennsylvania in Philadelphia, said in a news release.
Benefit in Both Remitting and Primary Progressive MS
The mechanism behind BTK inhibitors such as fenebrutinib shows why they have the potential to treat both PPMS and RMS. According to an April 2023 Nature Reviews Neurology review, BTK inhibitors work by penetrating the blood-brain barrier and suppressing B-cell activation.
In the announcement of the FENhance results, Genentech explained that targeting B cells helps control the acute inflammation that causes relapses. At the same time, targeting microglia inside the brain addresses the chronic damage thought to drive long-term disability progression.
According to Levi Garraway, MD, PhD, the company’s chief medical officer, “These pivotal results, together with . . . earlier data, provide convincing evidence that fenebrutinib can become the first high-efficacy oral treatment for RMS and PPMS.”
People With PPMS Need More Treatment Options
I certainly hope Dr. Garraway is right. Ocrevus (ocrelizumab) is the only DMT approved by the FDA to treat PPMS. Patients have been waiting more than a decade for another option to emerge from the research pipeline.
Rituxam (rituximab) and Kesimpta (ofatumumab), both commonly used to treat RMS, are sometimes used off-label for progressive forms. But getting insurance to cover their cost can be difficult.
There’s also another BTK inhibitor in that progressive MS pipeline: orelabrutinib. Researchers at Zenas BioPharma are conducting a pair of phase 3 trials, one in PPMS and 1one in secondary progressive MS (SPMS). Results for both are expected in the spring or summer of 2030.
According to the National Multiple Sclerosis Society, only 10% to 15% of people with MS carry a PPMS diagnosis. In addition, 50% of people diagnosed with RMS will probably transition to SPMS. I suspect there’s just not much return on investment for DMTs that treat progressive MS, and that’s a real shame. Let’s hope fenebrutinib and orelabrutinib researchers are able to change that paradigm.
Do you agree with me that fewer treatments are being researched for progressive MS than for the relapsing form because profit is likely from the latter?
(A version of the post first appeared on the Rare Disease Advisor website.)
