Medicine & Research

A new treatment for MS is being researched. What is this potential treatment? How does it work? The drugs being studied are BTK inhibitors. Let's examine what BTK is, so we can understand how these drugs that inhibit it might be helpful in MS. Bruton's tyrosine kinase, or BTK, is an enzyme that plays an important role in the immune response. It transmits signals that are critical for the activation of B cells. BTK also plays a part in signaling myeloid cells, including microphages and microglial cells. This signaling leads to the secretion of proinflammatory cytokines. Inhibiting BTK pathways related to the development of autoimmune diseases, such as MS. 

BTK inhibitors, the treatment being studied, are designed to selectively block this enzyme that is important for the activation of B cells and microglia. B cells and the cells of the myeloid lineage are important drivers in the development of multiple sclerosis, thus BTKi could provide therapeutic benefit for MS. These drugs have been previously used in other areas such as graft versus host disease, lymphomas, and leukemia. One of the first BTKis to be approved was ibrutinib. This first-generation drug was approved in 2013 for lynphocitic luekemia and chronic GVHD.

While it works well and has had significant progress in affecting BTK, it also affects other kinases and B cell malignancies, leading to off-target activity and significant side-effect profile. This has led the pharmaceutical researchers to look for alternatives with ibrutinib's efficacy but more specific targeting. There are two types of BTK inhibitors: irreversible inhititors and reversible inhibitors. Irreversible inhibitors have a higher rate of inhibitory potency and selectively compared to reversible inhibitors.

For research in the treatment of MS, irreversible inhibitors have recently been at the forefront because of their potential advantages over the biologic disease-modifying therapy options. These inhibitors can selectively target B cells, wiping out those that harm the immune systems of people with MS while leaving normal B cells alone. This shows an advantage over disease-modifying therapies such as ocralizumab and rituximab, as they wipe out all the B cells, leaving a greater chance of infection. Currently, there are studies being conducted using BTKis to aid the treatment of relapsing-remitting MS, primary-progressive MS, and secondary-progressive MS. 

One of the newest drugs, evobrutinib, is the first covalent and irreversible BTKi to be evaluated for the treatment of MS. Compared to placebo, it is shown to considerable reduce the neurofilament light chain levels and decrease the number of gadolinium-enhancing lesions. These neurofilament chains show a correlation with the development of gadolinium enhanced lesions to indicate if the DMT is effective. During relapses, levels of NfL are elevated as much as 10 times compared to NfL levels during remission.

Elevated levels of the neurofilament light chains have been correlated to poorer neurologic function including decreased cognitive performance, manual dexterity and walking speed. This reduction of NfLs suggest that evobrutinib may reduce the possible tissue damage linked to MS. During the Phase-II studies, the most common side effects were the common cold and the increased level of liver enzymes. Additionally, as an oral, twice-a-day tablet, the patient burden could be significantly reduced compared to the side effects of other DMTs.

Another covalent irreversible BTK inhibitor that is currently being tested in trials, tolebrutinib, has been shown to be effective in reducing new, active brain lesions. This medication is being studied in relasping-remitting MS, in both primary and active secondary progressive MS. By blocking Bruton's tyrosine kinase, B cell activation is decreased, thus interfering with microphages, and preventing the loss of myelin sheaths within the brain. 

This oral, once-a-day tablet, is reporting minimal side-effects with the main reports of headaches, chest infections, and increased risks of getting the common cold. Although early data appear promising, further trials will be required to confirm the efficacy and safety of BTK inhibitors use for treatment of MS.