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US neurologists favorably view BTK inhibitors as potential MS therapies

But Spherix surveys across 2023 may not reflect recent setbacks in clinical trials

More than one-third of neurologists in the U.S. believe Bruton’s tyrosine kinase (BTK) inhibitors could be of pivotal significance as a future treatment of multiple sclerosis (MS), according to findings of a recent Spherix Global Insights’ survey.

“Through Spherix’s quarterly RealTime Dynamix market tracker, neurologists and MS specialists have expressed an increasing level of enthusiasm for these investigational therapies over time,” the company stated in a press release. RealTime Dynamix issues reports on market trends based on surveys of healthcare providers.

But this enthusiasm may be tempered by recent clinical trial data and concerns regarding these potential oral therapies, as neurologists also are placing more emphasis on treatment efficacy and safety than on convenience of use, Spherix noted.

Respondents’ heightened interest in these types of inhibitors also extended to AB Science’s masitinib, a selective tyrosine kinase inhibitor now in Phase 3 clinical trials as a possible treatment for progressive types of MS.

A BTK inhibitor blocks an enzyme controlling B-cells and microglia

BTK inhibitors are small molecules that block the BTK enzyme, which controls how immune B-cells and microglia grow, survive, and become activated to help mount an immune response. As both these immune cell types are thought to contribute to MS, inhibiting BTK is expected to reduce the inflammation and nerve cell damage seen in patients.

BTK inhibitors in development also are taken by mouth, a convenient method of administration and one considered to lead to better therapy adherence than approved MS antibody-based therapies, which are mostly infused into the bloodstream.

However, recent setbacks have been noted for two BTK inhibitors in pivotal Phase 3 clinical testing for MS.

In late November, the U.S. Food and Drug Administration (FDA) placed a partial hold on Genentech’s ongoing Phase 3 clinical program in the U.S. after two patients experienced elevations in liver enzyme levels, a sign of potential treatment-related liver damage.

Two of these trials, called FENhance 1 (NCT04586010) and FENhance 2 (NCT04586023), are testing fenebrutinib in people with relapsing MS, while FENtrepid (NCT04544449) is investigating the therapy in primary progressive MS patients.

Then in early December, EMD Serono (known as Merck KGaA outside North America) announced a failure to meet main study goals in its two Phase 3 clinical trials of evobrutinib. Results in the EVOLUTION RMS1 (NCT04338022) and EVOLUTION RMS2 (NCT04338061) trials did not show the medication can outperform Aubagio (teriflunomide) at reducing relapse rates.

The FDA also placed a partial hold on the EVOLUTION trials in April due to two cases of patients with elevations in liver enzymes.

Spherix to ask about positive changes in views of BTK inhibitors for MS

Likewise, signs of liver injury led a 2022 FDA partial hold on four trials of tolebrutinib, another BTK inhibitor aiming to treat MS. Affected trials were GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) investigating tolebrutinib in relapsing forms of MS, the HERCULES (NCT04411641) study in adults with nonactive SPMS, and PERSEUS (NCT04458051) testing tolebrutinib against a placebo in primary progressive MS.

Many neurologists and MS specialists surveyed across 2023 — the number of respondents was not given in the release — said that the treatment’s anticipated efficacy will be their main consideration in prescribing a BTK inhibitor, should one or more be approved.

“Twice the number of neurologists [emphasized] their anticipated efficacy, rather than favorable safety, as the driver for prescribing this new mechanism of action once it enters the market,” Spherix stated.

The company plans to assess if the recent fenebrutinib and evobrutinib setbacks change perceptions of these two potential medications, the broader class of BTK inhibitors, and the entire MS treatment landscape in next year’s RealTime Dynamix reports.

It also noted that the unfavorable BTK developments “potentially [pave] the way for masitinib to emerge as a standout oral option in the landscape.”


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