Reevaluating Natalizumab Dosing in RRMS: Insights from the NOVA Trial

Reevaluating dosing schedules for natalizumab in relapsing-remitting multiple sclerosis (RRMS) aims to minimize long-term risk while maintaining clinical efficacy. While conventional every-four-week (Q4W) intravenous regimen is highly effective, it carries an elevated risk of progressive multifocal leukoencephalopathy (PML).

Interest has grown in extended-interval dosing (EID)—particularly every-six-week (Q6W) administration—as a strategy to reduce cumulative exposure. In November 2024, Neurology: Neuroimmunology & Neuroinflammation published pharmacokinetic and pharmacodynamic (PK/PD) findings from the NOVA trial, offering detailed insight into the biologic effects of Q6W versus Q4W dosing in patients with stable RRMS.

The trial included 486 patients in the pharmacokinetic (PK) and 487 in the pharmacodynamic (PD) analysis populations, all of whom were relapse-free on Q4W natalizumab for at least one year. Participants were randomized to either remain on the standard regimen or switch to Q6W dosing with follow-up over 72 weeks.

As expected, Q6W dosing led to a marked reduction in trough natalizumab concentrations, averaging 10 to 21 micrograms per milliliter versus 33 to 38 in the Q4W group—a decrease of approximately sixty to seventy percent. Despite this, alpha-4 integrin saturation remained above 65.5 percent in the Q6W group and above 77.9 percent in Q4W patients, indicating sustained biologic target engagement.

Unlike trough concentration and receptor occupancy, levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) diverged significantly between groups. In the Q6W cohort, sVCAM-1 increased by 23.6 percent by week 24 and remained elevated, while levels remained largely unchanged in the Q4W arm. This is consistent with the hypothesis that EID may allow partial restoration of immune surveillance within the central nervous system. However, due to high interindividual variability, sVCAM-1 is unlikely to serve as a reliable biomarker in routine clinical practice.

Body weight was also a significant factor in drug exposure. Heavier individuals exhibited lower natalizumab concentrations and alpha-4 integrin saturation in both arms, though the clinical implications were more evident with Q6W dosing. At week 24, participants over 90 kilograms had mean trough levels of 4.4 micrograms per milliliter in the Q6W group, compared to 27.6 micrograms per milliliter in Q4W. While nearly all patients remained above the half-maximal effective concentration (2.51 micrograms per milliliter), heavier individuals had lower trough levels, suggesting a narrower pharmacologic margin.

Importantly, neither natalizumab concentration nor alpha-4 integrin saturation reliably predicted relapse or new lesion activity at the individual level. Several patients with disease activity had trough levels above 10 micrograms per milliliter and saturation above 65 percent, and disease activity was distributed across all exposure quartiles. These data suggest that PK/PD markers, while useful for understanding population-level pharmacology, should be interpreted with caution when considering individual treatment decisions.

One participant in the Q6W group developed asymptomatic PML despite maintaining natalizumab concentrations above 10 micrograms per milliliter and high receptor saturation throughout the study. This patient also had a high anti–JC virus antibody index and extended prior exposure, emphasizing the multifactorial nature of PML risk.

Taken together, the NOVA trial findings support Q6W natalizumab as a clinically effective and pharmacologically sound alternative to Q4W dosing for patients with stable RRMS. Although drug exposure was reduced, therapeutic targets were generally maintained, and the biologic activity of the drug remained intact. The elevation of sVCAM-1 levels with Q6W may signal improved immunosurveillance, potentially lowering PML risk without compromising efficacy.

Still, PK and PD measures should not be used as individualized decision-making tools due to their poor correlation with clinical outcomes. For clinicians, these results may provide reassurance that extending the dosing interval in carefully selected stable patients can be a viable option, with the added possibility of improved safety, particularly when combined with appropriate patient risk stratification and ongoing monitoring.

Reference

Foley JF, Defer G, Ryerson LZ, et al. Pharmacokinetics and Pharmacodynamics of Natalizumab 6-Week Dosing vs Continued 4-Week Dosing for Relapsing-Remitting Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2024;11(6):e200321.