Personalized Extended Interval Dosing Reduces John Cunningham Virus Seroconversion Rate for Natalizumab

Zoé L. E. van Kempen

In a recently published study of patients with relapsing-remitting multiple sclerosis (RRMS), data showed that the seroconversion rate for John Cunningham virus (JCV) was substantially lower among patients on natalizumab (Tysabri; Biogen) with low trough concentrations resulting from personalized extended interval dosing (EID). Overall, these findings underscored the importance of personalized EID for natalizumab-treated patients, potentially allowing for more consistent safety for a longer period of time.

Natalizumab, marketed since 2004, is the only disease-modifying treatment for MS that does not induce systemic immune suppression; however, its major drawbacks include the risk of progressive multifocal leukoencephalopathy (PML), a potentially fatal infection of the brain caused by JCV. This study combined two overlapping Dutch patient cohorts treated with intravenous (IV) natalizumab to assess JCV seroconversion during periods of high (≥15 µg/mL) and low (<15 µg/mL) trough concentrations.

Led by senior author Zoé L. E. van Kempen, a neurologist and research at the MS Center Amsterdam, the annual seroconversion rate of 8.4% observed in patients during periods of high trough concentrations (n = 226) was 2.32 times higher than the seroconversion rate of 4.8% in patients during periods of low trough concentrations (n = 252; 95% CI, 1.32-4.08; P = .0035). Notably, there was no association between natalizumab treatment duration and JCV seroconversion (ß = 0.02; 95% CI, –0.05 to 0.10), suggesting that the risk of seroconversion does not increase or decrease with longer treatment duration.

Among a cohort of 357 patients with RRMS, 105 were observed with only high natalizumab trough concentrations, 131 were observed with only low natalizumab trough concentrations, and 121 were observed with both high and low natalizumab trough concentrations. The cohort’s total observation period was 1304.8 patient-years (mean, 3.7 years), during which 85 patients (23.8%) seroconverted, yielding an annual rate of 6.5 per 100 person-years.

READ MORE: First-Ever Case Report Highlights Potential for Acute Retinal Necrosis While on Dimethyl Fumarate

In the study, there were no cases of PML observed, and 15 patients (4.2%) showed variable JCV serostatuses and were thus considered JCV negative. During high trough concentrations, the cohort accumulated 631.2 patient-years (mean 2.79 years per patient), with 53 patients (23.5%) seroconverting, corresponding to an annual rate of 8.40%; by comparison, the low trough concentration group accrued 673.6 patient-years (mean 2.67 years per patient).

Additional data from the study showed that age, sex, and treatment during COVID-19 were not associated with JCV seroconversion in the analysis. Study authors noted that the overall annual seroconversion rate found in this cohort of 6.51% was slightly lower compared with the seroconversion rates found in other cohorts, possibly due to the fact that it includes many patients on EID.

Prior to this study, the NOVA trial, a large-scale study in which patients were randomized to receive natalizumab either every 4 weeks or every 6 weeks, showed that most patients could be safely treated every 6 weeks without compromising efficacy.² Based on the variability in trough concentrations among EID patients, van Kempen et al defined observation periods by natalizumab trough concentrations rather than treatment intervals.

"Based on the results of the NOVA trial, we recommend initiating EID with 6-week intervals and suggest further extending the intervals in patients who still have high trough concentrations at 6 weeks to reach a trough concentration below 15 µg/mL, for example, by aiming for a trough concentration between 5 and 10 µg/mL," the study authors wrote.

"This strategy would minimize the risk of JCV seroconversion while preserving treatment efficacy by maintaining concentrations above the minimum effective level. Personalised EID of natalizumab starting at 6 weeks and targeting a trough concentration of 5 µg/mL is currently being studied in the next phase of the NEXT-MS trial, known as the SUPERNEXT (NCT04225312), with results expected in 2027."

REFERENCES
1. Gelissen LMY, Toorop AA, Schipper PM, et al. Low natalizumab trough concentrations are associated with reduced seroconversion of the John Cunningham virus in natalizumab-treated patients with multiple sclerosis. Neurol, Neurosurg, & Psych. Published online March 25, 2025. doi:10.1136/jnnp-2024-335761
2. Foley JF, Defer G, Ryerson LZ, et al. Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial. Lancet Neurol 2022;21:608–19. doi:10.1016/S1474-4422(22)00143-0