Annual 12-Week Dosing Gap of Natalizumab: Clinical Efficacy, Blood Biomarkers, and CSF Cell Composition.

Objective: Natalizumab (NTZ) is a highly effective therapy for multiple sclerosis (MS); however, its use is limited by the risk of a rare potentially severe opportunistic brain infection, progressive multifocal leukoencephalopathy (PML). Alternative dosing strategies are evaluated to reduce PML risk while still maintaining efficacy, which include extending the dosing interval (EID) or a lesser-known annual dosing gap (aGAP), which is the focus of this prospective observational single-site cohort study. We evaluated whether aGAP affects the efficacy of NTZ, which biomarkers could be useful for a personalized dosing strategy, and potential cellular mechanisms that might contribute to reducing the risk of PML during aGAP.

Methods: Clinical assessments, quantifications of NTZ, neurofilament light chain (NfL), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were performed for ten study participants of a clinical trial (NCT04048577); CSF single-cell RNA-sequencing data from nine participants (15 samples) were analyzed together with 48 healthy and 35 MS controls.

Results: Although NTZ serum levels were decreased below EID levels and sVCAM-1 levels were increased, aGAP was not associated with MS activity as measured by EDSS and MRI. After aGAP, while CSF cell counts remained stable, the CSF immune cell composition changed and NfL values were increased 3 months post gap. CSF proportions of CD4, CD8, and natural killer cell subsets increased towards levels of untreated MS patients, while B-cell proportions remained unchanged.

Interpretation: The differential CSF composition associated with sVCAM-1 serum level changes suggests that selective immune cell trafficking may occur during aGAP, potentially contributing to PML prevention.