AAN 2026 | The role of BTK in MS pathophysiology and developments in BTK-targeting therapies

Yeah, so Bruton’s tyrosine kinase is an enzyme that is present in critical cells that are involved in the inflammatory pathways in multiple sclerosis, particularly in B cells and also microglial cells in the CNS. In the role of MS, in a sense, BTK plays a role in amplifying the response of autoreactive cells, but also, in a sense, contributes to the activation of the cells, antibody production, antigen presentation, indirectly through the amplification of B cell responses. Perhaps the most interesting portion of the BTK role in MS is how the activation of microglial cells is also dependent, in a sense, on the BTK role in MS, is how the activation of microglial cells is also dependent, in a sense, on the BTK pathway, so it becomes an attractive target when you’re looking at addressing inflammation in MS because, in a sense, it sits at the intersection of two different types of processes: acute peripherally activated immune responses as well as more compartmentalized central nervous system responses. Yeah, so in the last few years, we have had some disappointments with some of the readouts from some of the early BTK inhibitors, with evobrutinib, particularly when it truly failed to demonstrate superiority to Aubagio. However, most recently, we are starting to see some movement in terms of some hints of benefits when you’re looking at both acute inflammatory responses measured by the traditional outcomes of relapses and acute lesions on the brain MRI, as well as the perhaps unmet need in MS, which is targeting chronic inflammation. You know, in a sense, it’s suspected by its role in microglial activation. So I will say that over time, you know, we are learning that some of those outcomes have been met. I think one of the key learning lessons from the BTK inhibitor experience is that not only is the class itself, the mechanism valid, but also the nuance between the different molecules within the BTK inhibitor space might matter more. So the type of binding, whether it’s covalent or non-covalent binding, the selectivity for BTK itself, which may be relating to safety profile and tolerability, as well as the dose and the CNS penetration. I think those aspects are going to matter a lot when you start looking into how the clinical efficacy actually matters and relates to the mechanism of action.

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