Biological and clinical stability after switching from intravenous to subcutaneous natalizumab in RRMS under standard and extended dosing

Abstract

INTRODUCTION: Natalizumab (NTZ) is a high-efficacy therapy for relapsing-remitting multiple sclerosis (RRMS) that can be administered intravenously (IV) or subcutaneously (SC). While switching from IV to SC NTZ is increasingly common in clinical practice, evidence on pharmacodynamic stability, particularly under extended interval dosing (6 weeks), remains limited. This study aimed to evaluate CD49d receptor occupancy (RO), serum neurofilament light chain (sNfL) levels, and clinical outcomes in RRMS patients switching from IV to SC NTZ while maintaining either 4- or 6-week dosing intervals. METHODS: We conducted a multicenter, ambispective, observational study including RRMS patients who had received IV NTZ for at least 6 months on a 4w or 6w schedule and subsequently switched to SC NTZ while maintaining the same dosing interval. CD49d RO was assessed in CD4+, CD8+, and CD19+ lymphocyte subsets before the first, third, and seventh SC administrations. sNfL levels and clinical outcomes (relapses, MRI activity, EDSS score) were also evaluated. Mixed models for repeated measures were applied. RESULTS: A total of 48 patients were included (4w: n=20; 6w: n=28). CD49d RO remained stable over time within both dosing schedules across all lymphocyte subsets. A significant difference between groups was observed only in CD19+ cells at the third administration (LS mean difference 13.08, SE = 4.10; p=0.028; 95% CI: 4.90-21.26) without clinical correlation. sNfL levels showed no significant differences at any timepoint within or between groups. Clinically, patients remained stable, with no new MRI activity or disability progression during the follow-up. CONCLUSION: Switching from IV to SC NTZ while maintaining either standard (4w) or extended (6w) dosing intervals preserves pharmacodynamic stability, as reflected by sustained CD49d RO, stable sNfL levels, and consistent clinical outcomes. These findings support SC administration as a reliable alternative to IV NTZ, including in extended interval dosing strategies.