Non-covalent inhibitors reversibly bind to different BTK-specific pockets.41,44 As an example of a non-covalent BTK inhibitor, BIIB091 (Biogen) is an orthosteric, reversible adenosine triphosphate competitor, which sequesters tyrosine 551, an important BTK phosphorylation site, leading to an inactive conformation.44 A phase II trial examining BIIB091 in RMS is planned and yet to recruit, while fenebrutinib is undergoing a phase III clinical trial for people with RMS or PPMS,45ClinicalTrials.gov identifiers: NCT05798520, NCT04586010, NCT04544449. The gene discussed is BTK; the disease is primary progressive multiple sclerosis.