BTKis target a group of proteins found on a variety of immune cells involved in the pathogenesis of Multiple Sclerosis (MS), including mediators of inflammation locally in the Central Nervous System (CNS). By targeting these proteins, the hope is that these medications will be able to decrease the activation of immune cells within the central nervous system directly, and could prevent inflammatory activity in people with MS. BTKis have several theoretical advantages over some of the current high-efficacy medications in MS.
1) Broad effects across multiple types of cells and types of MS: Our immune system consists of two broad categories: the adaptive and innate immune systems. The adaptive immune system is specific and targeted, where our bodies learn to fight off viruses and bacteria using targeted antibodies after we have been exposed to them. The innate immune system is much more broad, and attempts to create inflammation more generally to fight off threats. While the two are very much interconnected, we think that the adaptive immune system plays a greater role in relapses while the innate immune system may, in some people, be a driver of progression. By affecting cells in both of these systems (B-cells and microglia) we hope that these medications can impact multiple forms of MS.
2) These medications can, in some cases, penetrate and act directly in the central nervous system. Many medications that we use in MS are unable to effectively cross into the central nervous system from the blood stream, which may limit their ability to act directly where the immune system dysregulation is occurring.
3) They do not deplete cells, but instead modulate their activity. As a result, it is possible that they could leave more function of the immune system intact, creating less risks of infections.
4) They are taken orally (through tablets).
What is left to see is how effective and safe these medications will be in trials. As of yet, data have been mixed but with some promising results. Though we are still in the early stages, a few of the medications being investigated have shown results, some of which we will discuss below.
Tolebrutinib
A CNS-penetrant BTK inhibitor being developed by Sanofi, which has been studied broadly in relapsing remitting MS as well as forms of progressive multiple sclerosis. One of its trials, the HERCULES trial, is a phase 3 study in non-relapsing secondary progressive MS which showed about a 30% reduction in disability progression. This was statistically significant when compared to a placebo. Its main adverse effect was a risk of serious liver injury which was mitigated with close monitoring. This medication may be particularly relevant to adults with non-relapsing progressive disease who may not be able to tolerate medications with more significant immunosuppressive effects or who may not have had success with other treatments. A review of its approval by the FDA was recently extended to near the end of December, and so we may find out more by that time.
Fenebrutinib
Fenebrutinib is a selective CNS-penetrant BTK inhibitor being developed by Genentech and which completed a promising phase 2 trial in relapsing patients compared to a placebo which showed a 69% relative reduction in new activity seen on MRI over 12 weeks. Phase 3 trials are now underway and are being done broadly in both relapsing remitting and progressive forms of multiple sclerosis. Importantly, Fenebrutinib is being compared to ocrelizumab in Primary Progressive MS, which will provide the first head-to-head data between a BTK inhibitor and B-cell depleters. Results from these trials are pending, with data expected at the end of 2025.
A few others to note:
Remibrutinib is a treatment which was recently approved for use in urticaria which has shown promise in models, however data are now being collected in trials in Multiple Sclerosis specifically. Evobrutinib is a BTK which was investigated in phase 3 trials which was shown not to be superior to teriflunomide in preventing relapses.