Bruton tyrosine kinase (BTK) inhibitors effectively treat certain leukemias and lymphomas, due to their ability to inhibit a protein kinase that is critical for B cell receptor signaling. These agents can inhibit antigen-triggered activation and maturation of B cells and their release of pro-inflammatory cytokines. BTK is also a key signaling protein that controls activation of monocytes, macrophages and neutrophils and its inhibition reduces the activation of these cells.
Judging from the papers presented at the recent MS Virtual 2020—the 8th Joint ACTRIMS-ECTRIMS Meeting, BTK inhibitors are showing promise in the management of multiple sclerosis (MS), as well, as researchers eye next-generation treatment options. They may prove to be effective not only in relapsing remitting multiple sclerosis, but also on progressive disease through their effect on brain macrophages and microglial cells.
Leading the way at MS Virtual 2020 was a presentation by Patrick Vermersch, MD, PhD, who summarized the results to date of masitinib’s role in primary progressive MS (PPMS) and non-active secondar progressive MS (nSPMS). The professor of neurology at Lille University in Lille, France, and his colleagues conducted a phase 3 study to assess masitinib’s efficacy at two dosage levels – 4.5 mg/kg/day (n=199) and a 6.0 mg/kg/day (n=199) -- vs placebo (n=101). The randomized, double-blinded, placebo controlled, two-parallel group trial involved adult participants with EDSS scores between 2.0 and 6.0 with either PPMS or nSPMS. Investigators looked at overall EDSS change from baseline using a variety of repeated measures, with an emphasis on determining whether participants improved, were stable, or worsened. Among the results
- In the lower-dose contingent, the odds of either a reduction in EDSS progression or increased EDSS improvement improved by 39% for patients taking masitinib, vs those receiving placebo
- Also, among those receiving the lower dose, the odds of experiencing disability progression decreased by 37% in the treatment group, compared with placebo
- Results using the higher dose of masitinib were inconclusive
Based on these results, investigators concluded that masitinib 4.5 mg/kg/day is very likely to emerge as a new treatment option for individuals with for PPMS and nSPMS.
Another MS Virtual 2020 presentation focused on fenebrutinib, an investigational, noncovalent investigational BTK inhibitor being studies as a possible treatment for MS. Investigators assessed the potency, selectivity, and kinetics of inhibition of the BTK enzyme via fenebrutinib, compared with two other BTK inhibitors, evobrutinib and tolebrutinib, in a panel of 219 human kinases.
Fenebrutinib was found to be a more potent inhibitor, compared with the other two BTK inhibitors. Additionally, fenebrutinib effectively blocked B cell and basophil activation. Moreover, fenebrutinib inhibited fewer off target kinases >50%, compared with the other two BTK inhibitors. Investigators concluded that fenebrutinib’s high selectivity and potency shows promise as a drug linked with fewer adverse events and a better treatment profile than other investigational BTK inhibitors.
These encouraging findings are leading to the initiation of three phase 3 clinical trials involving fenebrutinib, announced at MS Virtual 2020 by Stephen L. Hauser, MD, professor of neurology, and director of the UCSF Weill Institute for Neurosciences. The trials will evaluate fenebrutinib’s impact on disease progression in relapsing MS and primary progressive MS. The primary endpoint of the studies will be 12-week composite Confirmed Disability Progression, which investigators hope will provide a stronger, more thorough assessment of disability progression, vs EDSS score alone.
Other BTK inhibitors worth watching include:
- Evobrutinib: An open-label phase 2 study has shown that the drug is linked with reduced annualized relapse rate through 108 weeks
- BIIB091: Safety and tolerability has been demonstrated in phase 1, clearing the way for further investigation
- Tolebrutinib: Under assessment for its ability to inhibit microglia-driven inflammation in murine models