Natalizumab Treatment Strategies in Multiple Sclerosis

Natalizumab is a humanised monoclonal antibody directed against the α4‐integrin component of very late antigen‐4 (VLA‐4), which plays a central role in lymphocyte adhesion and migration across the blood–brain barrier. By blocking VLA‐4, natalizumab markedly reduces inflammatory lesion formation, relapse rate and accrual of disability in relapsing–remitting multiple sclerosis (RRMS). Its high efficacy is tempered by the risk of progressive multifocal leukoencephalopathy (PML), necessitating vigilant risk stratification and monitoring of John Cunningham virus (JCV) serostatus. Strategies to optimise benefit–risk include extended interval dosing (EID) to reduce PML risk while retaining efficacy, therapeutic drug monitoring to personalise dosing intervals, and structured protocols for treatment interruption or switching to alternative disease‐modifying therapies. Real‐world registries and cohort studies have informed long‐term safety profiles, rates of secondary progressive conversion and rebound phenomena after discontinuation. Practical approaches now integrate patient‐specific factors such as prior immunosuppression, JCV index, tolerability and radiological activity to guide initial choice of natalizumab, interval adjustments and exit strategies, thereby maximising global clinical benefit for people with MS.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Research from all publishers

Extended interval dosing (EID) has been examined for neuroprotective as well as anti‐inflammatory outcomes. A longitudinal cohort study comparing EID with standard interval dosing (SID) over more than three years found no significant differences in annualised rates of whole‐brain, ventricular or thalamic atrophy, nor any correlation between serum natalizumab concentration and atrophy measures. This suggests that spacing infusions beyond four weeks preserves both anti‐inflammatory efficacy and structural integrity of the CNS. Real‐world registry data from a national treatment registry encompassing over 1,500 patients treated up to 14 years confirmed a sustained reduction in annualised relapse rate from baseline, a favourable safety profile and an 86% rate of no adverse events during follow‐up. Conversion to secondary progressive multiple sclerosis occurred in just over 20% of patients, underscoring the long‐term stabilising effect of natalizumab on relapsing disease. For patients at elevated PML risk, pilot studies have evaluated switching from EID‐natalizumab to B‐cell–depleting therapy. In a 96-week follow-up of high-risk individuals, transition to ocrelizumab yielded comparable relapse rates, radiological stability and disability progression to those maintained on natalizumab EID, with a higher proportion achieving no evidence of disease activity (NEDA-3) and no serious safety signals. This supports a tailored exit strategy to mitigate PML risk without compromising disease control.

Natalizumab Treatment Strategies in Multiple Sclerosis publication trend

The graph below shows the total number of articles in natalizumab treatment strategies in multiple sclerosis across all publications each year (not limited to Nature Index journals).

Technical terms

Relapsing–remitting multiple sclerosis (RRMS): A form of MS characterised by episodes of neurological dysfunction (relapses) followed by periods of partial or complete recovery (remissions).

Extended interval dosing (EID): Administration of natalizumab at intervals longer than the standard four weeks, typically every six to eight weeks, aimed at reducing infection risk while maintaining efficacy.

Standard interval dosing (SID): The approved four-week infusion schedule for natalizumab, established in pivotal clinical trials.

Progressive multifocal leukoencephalopathy (PML): A rare but serious brain infection caused by JCV reactivation in immunocompromised patients, monitored via serological and MRI surveillance.

Very late antigen-4 (VLA-4): An integrin receptor on leukocytes that mediates adhesion to vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells, critical for CNS infiltration of immune cells.

References

1. Switch to ocrelizumab in MS patients treated with natalizumab in extended interval dosing at high risk of PML: A 96-week follow-up pilot study. Frontiers in Immunology (2023).
2. Real-world use of natalizumab in Austria: data from the Austrian Multiple Sclerosis Treatment Registry (AMSTR). Journal of Neurology (2023).
3. Exploring the effects of extended interval dosing of natalizumab and drug concentrations on brain atrophy in multiple sclerosis. Multiple Sclerosis Journal (2024).