Experts Take a ‘Wait and See’ Approach as BTK Inhibitors Stumble in MS

MRI Scan_iStock_Shidlovski

Pictured: A neurologist examines the structure of brain tissue on an MRI/iStock, Shidlovski

A promising class of drugs called BTK inhibitors, already approved to treat certain cancers and currently in Phase III clinical trials at four different pharmaceutical companies for multiple sclerosis, has experienced multiple clinical holds and other stumbling blocks during the past two years. Yet physicians and researchers still say the drugs provide hope for a sea-change in treating “smoldering” or quietly progressive MS.

“There has been a shift in our thinking about the disease,” explained Robert Shin, director of Georgetown University’s Multiple Sclerosis and Neuroimmunology Center. “We have a lot of highly effective therapies for MS relapses or attacks,” he told BioSpace, “but people living with MS may also quietly and gradually worsen to a cane, walker or wheelchair. We call that PIRA [progression independent of relapse activity] and BTK inhibitors are a promising class of medicines that may target this quiet progression over time.”

Despite recent setbacks, “it’s too early to conclude BTK inhibitors won’t be helpful for PIRA,” Shin said. “We’re just going to have to be patient and wait for all the data to emerge.” 

About 2.9 million people suffer from MS globally, with nearly 1 million in the U.S. alone. BTK inhibitors target the Bruton’s tyrosine kinase protein, which plays an important role in the development and maturation of B cells. B cells can produce autoantibodies that attack the body’s own protective sheath around nerves. If those B cells could be quieted, MS might be quieted as well.

The efficacy of BTK inhibitors has already been demonstrated by the success of drugs such as Genentech’s Rituxan and Ocrevus. Unfortunately, those drugs wipe out all B cells, which can lead to opportunistic infections. It is thought that BTK inhibitors can remove unwanted B cells while leaving healthy ones alone to do their job. 

Raised Liver Enzymes Trigger Holds

There are currently four BTK inhibitors in Phase III clinical trials for either relapsing or progressive MS: Sanofi’s tolebrutinib, Roche’s fenebrutinib, Novartis’ remibrutinib and Merck KGaA’s evobrutinib.

A fifth, InnoCare’s orelabrutinib, was in Phase II development before Biogen dropped its collaboration with the Beijing–based biopharma.

Both tolebrutinib and orelabrutinib have had partial clinical holds (holds on new enrollment) placed by the FDA due to raised liver enzymes and potential liver injury, as did evobrutinib in April 2023 and fenebrutinib in December 2023. 

“There is nothing particularly unusual about this,” Shin said. “It’s the reason we do testing in trials, to understand how to safely administer medicines. And as is true with many medications, some individuals may have elevations in liver enzymes.”

In the case of fenebrutinib, for instance, the FDA decision was based on two cases of raised liver enzymes along with elevated bilirubin, indicating possible drug-induced liver injury. Both patients were asymptomatic and liver enzymes returned to normal once the drug was stopped, according to NeurologyLive. What we need to find out, Shin said, “is whether this is a true class effect, and all the BTK inhibitors have the same issue, or whether it is unique to certain medications, dosing regimens or individual vulnerability.” Thus far, raised liver enzymes have not been seen with remibrutinib, he noted. 

An arguably bigger blow came in early December when Merck announced that its two Phase III trials, evolutionRMS 1 and evolutionRMS 2, had failed the selected endpoints. The trials compared evobrutinib with Sanofi’s Aubagio (teriflunomide), in the hopes it would reduce relapsing-remitting MS more effectively. Instead, there was virtually no difference between the two treatment arms. In fact, Aubagio performed much better than expected.

Watching and Waiting

The Merck disappointment may not actually reflect negatively on the efficacy of BTK inhibitors, according to Jefferies analyst Brian Balchin. In a December 14 note shared with BioSpace, Balchin suggested the news actually reflects the fact that clinical trials are recruiting healthier patients with fewer relapses.

“It's just more challenging for a BTK inhibitor to show a differential effect in relapsing MS on ARR [annualized relapse rate] vs. Aubagio when studies are recruiting patients with fewer relapses at baseline and/or asymptomatic lesions and inadvertently raising the bar,” he wrote. 

In fact, he continued, studies’ inclusion criteria have become less stringent over time and there may be a tendency for researchers to recruit “patients at the bottom-end of the inflammatory activity threshold,” instead of enrolling those with a high burden of disease, who are already on effective medications. The current pool of patients for MS trials may just be healthier, Balchin said. 

He noted that confirmation of the patient cohorts enrolled in evolutionRMS 1 and evolutionRMS 2 could come at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS 2024) conference, taking place February 29 to March 2 in Florida. He expects data from Sanofi in mid-2024, Roche in 2025 and Novartis in 2026. 

Tyler Kaplan, a neurologist at the RUSH University Medical Center, agreed. “I think the big takeaway from data we have is that Aubagio performed way better than it has ever done, and that may speak more towards the patient population that was selected rather than [the] potency of either drug,” he told BioSpace.

The biggest question yet to be answered, and which will be evident once the evobrutinib data are published in full, is whether the drug showed improvement in disability progression, Georgetown’s Shin said. “The study was designed with relapse as a primary endpoint, but many of us are adopting a wait-and-see attitude because we don’t yet know whether it affects progression.”

In a 2021 article published in Nature, neurologists suggested that BTK inhibitors might not just slow down the progression of MS but even offer a functional cure. That hope is still alive. Indeed, as Kaplan explained, “progression is ultimately where a lot of people think BTKs still might shine,” although he noted that the effect could be more of a remission than a cure.

“From a fundamental mechanistic standpoint, a drug has to actually penetrate into the central nervous system to truly quiet MS, and very few MS drugs currently available can cross the blood-brain barrier and do that,” he said. BTK inhibitors can more easily cross the blood-brain barrier (BBB), Kaplan previously wrote for NeurologyLive, adding that monoclonal antibody treatments for MS do not cross the BBB and do not exert their effect directly in the CNS.

“Most effective MS drugs target the peripheral immune system and circulating immune cells in blood and lymph [nodes]," he told BioSpace. However, researchers are seeing activated immune cells called microglia in slowly expanding lesions on autopsy, "that suggests that maybe progressive MS is driven by that kind of inflammation within the CNS." 

For now, those watching this space are, like Shin, watching and waiting. “We have to keep in mind that the design of some of the other studies is different than Merck’s,” he said. “Some focus on progression, and some focus on relapsing MS. The patient populations differ as well. Though the results of the Merck trial are a bit disappointing, it is too early to conclude that BTK inhibitors won’t be helpful in MS.”

Jill Neimark is a freelance science writer based in Macon, Georgia. Reach her at

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