Low natalizumab trough concentrations are associated with reduced seroconversion of the John Cunningham virus in natalizumab-treated patients with multiple sclerosis

Abstract

Background: Natalizumab is a highly effective drug for patients with relapsing-remitting multiple sclerosis (MS). A disadvantage of this treatment is the risk of progressive multifocal leukoencephalopathy in patients who are seropositive for the John Cunningham virus (JCV). JCV seroconversion rates increase under natalizumab treatment compared with non-natalizumab using controls. The aim of this study was to assess whether lower natalizumab trough concentrations are associated with reduced JCV seroconversion compared with higher natalizumab trough concentrations.

Methods: Two overlapping cohorts of patients treated with intravenous natalizumab in the Netherlands were combined for this study. JCV seroconversion was assessed during periods of high (≥15 µg/mL) and low (<15 µg/mL) natalizumab trough concentrations. Low trough concentrations were mainly the result of trough concentration guided personalised extended interval dosing (EID). The seroconversion rates during high and low trough concentrations were compared using a generalised linear mixed model with a Poisson link function.

Results: A total of 357 patients from 21 hospitals in the Netherlands were included. 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 to 4.08, p=0.0035).

Conclusions: The seroconversion rate observed in patients with MS with low trough concentrations was substantially lower compared with those with high trough concentrations during natalizumab treatment. This emphasises the importance of personalised EID, where intervals between infusions are prolonged to achieve lower natalizumab trough concentrations, to increase drug safety.

Keywords: MULTIPLE SCLEROSIS.

Figure 1. Examples of how the observation periods of each patient were defined. The first example (a) represents a case in which only one trough concentration was measured. Since the treatment interval remained unchanged throughout the observation period, this period is considered a high trough concentration observation period. JCV tests are usually done every 6 months, resulting in an observation period of 24 months for this patient. The second example (b) is a patient observed from the start of natalizumab treatment. Initially, the patient had high trough concentrations, which decreased as the treatment intervals were extended. If two consecutive measurements below 15 µg/mL were observed, the observation period with low trough concentrations was considered to have started at the last measurement showing a trough concentration of 15 µg/mL or higher, since extended interval dosing was always initiated right after a trough concentration measurement. Therefore, the trough concentration of 15 µg/mL, after which the 6-week interval regimen was started, marks the transition from the high to the low trough concentration observation period in this patient. A threshold of 15 µg/mL was chosen because most patients in the NEXT-MS trial were participating in the personalised dosing group aiming for a trough concentration of approximately 10 µg/mL. In this study group, treatment intervals of patients were extended if a trough concentration was ≥15 µg/mL. The third example (c) shows a similar trend of decreasing trough concentrations as the treatment intervals were extended. It demonstrates that a single measurement above 15 µg/mL during the low trough concentration period is acceptable, as long as the mean trough concentration throughout the period remains below 15 µg/mL. An observation period starts with two consecutive measurements below or above 15 µg/mL. JCV, John Cunningham virus; NEXT-MS, Natalizumab personalized EXTended interval dosing in MS; NTZ, natalizumab.

Figure 2. Inclusion and exclusion process. AMSC, Amsterdam Multiple Sclerosis Cohort; JCV, John Cunningham virus; NEXT-MS, Natalizumab personalized EXTended interval dosing in MS.

Figure 3. Kaplan-Meier survival curves to visualise differences in JCV seroconversion across both groups over time. In this figure, JCV seroconversion during the observation period is considered as the event. The graphs begin at 1.00, indicating that 100% of the patients started the observation period without JCV seroconversion. JCV, John Cunningham virus.