MS: the coming (r)evolution (Part 4)
In Part 2 of this series we looked at some of the underlying mechanisms that contribute to the MS disease process. Briefly stated, a virus (Epstein-Barr virus, EBV) may initiate an autoimmune reaction in a susceptible person. An inflammatory response then induces a different type of inflammation in the brain and spinal cord. This inflammation, which involves brain cells such as microglia, can directly damage the myelin that protects nerve fibres as well as the nerves themselves, and impede healing by repair cells (such as the oligodendrocytes that produce myelin).
The severity of this process (i.e. the amount of damage) and a person’s ability to heal will be influenced by environmental factors (such as age, obesity, smoking, sun exposure) as well as the person’s genetics in ways that are not completely understood.
The goal of MS treatments is to limit damage to the brain and spinal cord. And while damage mechanisms appear to be highly complex, they do provide numerous ways for treatments to act. Many novel therapies to treat MS are currently at various stages of development. The following is a summary of some of the more promising candidates.
BTK inhibitors: This class of drugs targets an enzyme (called BTK for Bruton’s tyrosine kinase) involved in the activation of B cells (a type of immune cell) and the release of B cell products that promote inflammation. It also inhibits the activation of cells (microglia and macrophages) in the brain that actively cause nerve damage. The first of these drugs, evobrutinib, performed well in phase II testing (Montalban and colleagues. N Engl J Med 2019;380:2406-2241). Unfortunately, it came up short in phase III testing, appearing to be no better than Aubagio, so its viability as a new drug is now unclear. There are several other drugs in this class in development, such as tolebrutinib, remibrutinib and fenebrutinib. No late-stage results have been published yet.
Masitinib: This drug blocks an enzyme involved in the activation of immune cells in the brain (microglia, macrophages and mast cells). A small pilot study suggested that it may slow disability worsening in people with progressive MS (Vermersch and colleagues. BMC Neurol 2012;12:36). A phase III trial in progressive MS later showed a slightly slower rate of disability worsening (although a higher dose did not have a significant effect) (Vermersch and colleagues. Neurol Neuroimmunol Neuroinflamm 2022;9:e1148). It has been hypothesized that masitinib may protect nerve cells, but further studies are needed to test this idea.
Clemastine: This drug is an antihistamine that has been studied as a potential way of rebuilding damaged myelin. In the suitably titled ReBUILD trial, clemastine improved nerve function in the eye in people with MS with optic neuritis (Green and colleagues. Lancet 2017;390:2481-2489). Several larger studies are now underway.
Temelimab: While it is believed that Epstein-Barr virus plays a role in MS, it may not be the only virus involved. The human genome contains viral genes that can become active, producing viral proteins that the body reacts to. Of particular interest is one such embedded virus called human endogenous retrovirus (or HERV), which can produce viral proteins in the brain under certain conditions. A phase II trial found that temelimab reduced the number of neurodegenerative lesions in the brain (Hartung and colleagues. Mult Scler 2022;28:429-440). An EBV vaccine trial (called EMBOLD) recently failed but other initiatives may prove more successful. There is also the potential for antiviral therapies (drugs like the ones used to combat HIV) to be effective in MS, although these will require further study.
ATX-MS-1467 (WP1303): The autoimmune aspect of MS involves an immune reaction to the body’s own proteins; in the case of MS this appears to be the proteins that make up myelin. So there is the potential to vaccinate people to reduce their response to ‘self’ proteins – an approach that is essentially like a shot for hayfever or grass pollen. A phase II study of one such immune therapy, called ATX-MS-1467, reported that a series of injections reduced the number of inflammatory lesions in the brain (Chataway and colleagues. Neurology 2018;90:e955-e962). Drug development has been slow thus far but additional studies are planned.
Some other therapies in developed are directed at nerve growth (elezanumab), nerve cell damage (SAR443820), and oxidative damage (e.g. alpha lipoic acid).
While these different avenues of research may suggest a scattershot approach, it is important to keep in mind that different disease mechanisms may drive MS in different people – and in a person at different times in their disease. So it will become increasingly important to identify what disease mechanisms are active in an individual with MS.
We will look at how the MS revolution will change how you and your doctor evaluate your MS in Part 5 of this series.
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