Pharmacokinetics and Pharmacodynamics of Natalizumab 6-Week Dosing vs Continued 4-Week Dosing for Relapsing-Remitting Multiple Sclerosis

Abstract

Background and objectives: Exposure to natalizumab, an efficacious treatment for relapsing-remitting multiple sclerosis (RRMS), is associated with increased risk of progressive multifocal leukoencephalopathy (PML). Compared with every-4-week (Q4W) dosing, extended-interval dosing of natalizumab is associated with decreased risk of PML. Clinical efficacy was maintained in the majority of patients switched to every-6-week (Q6W) dosing in the phase 3b NOVA clinical trial. In this article, we report pharmacokinetics (PK) and pharmacodynamics (PD) of Q6W vs Q4W dosing in NOVA.

Methods: In NOVA study Part 1, participants with RRMS (aged 18-60 years) and Expanded Disability Status Scale score <5.5, who were stable on IV natalizumab Q4W dosing for ≥12 months, were randomized to continue IV Q4W dosing or switched to IV Q6W dosing of natalizumab and followed for 72 weeks. Exploratory outcomes were measurements of trough serum natalizumab concentration, α4-integrin saturation, and soluble vascular cell adhesion molecule-1 (sVCAM-1) concentration. A mixed model of repeated measures was used to estimate mean treatment differences between groups. Patient-level PK and PD data were examined in those with relapse or radiologic disease activity.

Results: In NOVA, 486 (Q6W, n = 245; Q4W, n = 241) and 487 (Q6W, n = 246; Q4W, n = 241) participants were included in the PK and PD populations, respectively. Mean trough natalizumab concentrations ranged from 10 to 21 μg/mL (Q6W) and 33-38 μg/mL (Q4W), and mean α4-integrin saturation remained above 65.5% (Q6W) and above 77.9% (Q4W). In the Q6W group, mean sVCAM-1 levels increased 23.6% by week 24 and remained elevated throughout the study, while mean sVCAM-1 levels remained generally stable in the Q4W group. Most participants with T2 lesion activity or relapse activity, in either treatment arm, maintained trough natalizumab levels >10 μg/mL and trough α4-integrin saturation >50%.

Discussion: Compared with Q4W dosing, Q6W dosing was associated with a 60%-70% decrease in mean trough natalizumab levels and a 9%-16% decrease in mean α4-integrin saturation. At the patient level, neither natalizumab concentration nor α4-integrin saturation was consistently predictive of lesion or relapse activity, suggesting that trough natalizumab and α4-integrin saturation measurements should be interpreted with caution in clinical practice.

Trial registration information: ClinicalTrials.gov, NCT03689972; EudraCT, 2018-002145-11. Submitted 2018-09-27. First patient enrolled: 2018-12-26. https://clinicaltrials.gov/study/NCT03689972.

Figure 1. Trough Natalizumab Concentration Over Time in the PK Population (A) and Trough α4 Integrin Saturation on MNCs Over Time in the PD Population (B) and GMRs to Baseline of sVCAM-1 (C) for Q6W and Q4W

(A) Mean (SE) value of serum natalizumab C_trough over time for PK population. (B) Mean (SE) value of trough α4 integrin saturation (on MNC) over time for PD population. (C) GMR to baseline of sVCAM-1. Error bars represent 95% confidence intervals. Week 6 and 18 values were only available for the Q6W group. C_trough = trough concentrations; GMR = geometric mean ratio; MNC = mononuclear cells; N/NE = new/newly enlarging; PD = pharmacodynamic; PK = pharmacokinetic; Q4W = every 4 weeks; Q6W = every 6 weeks; SE = standard error; sVCAM = serum vascular cell adhesion molecule.

Figure 2. Natalizumab C_trough (A) and α4-Integrin Saturation on MNCs (B) for Participants With N/NE T2 Lesions

^aPatients with high T2 lesion count; one of these participants developed asymptomatic progressive multifocal leukoencephalopathy (participant no: 28) and the other participant discontinued treatment before study completion (participant no: 19). ^bN/NE T2 lesions are shown at the closest timepoint for which serum PK natalizumab or α-4 integrin saturation measurements were made. In the overall population, mean serum natalizumab C_trough ranged from 10–21 μg/mL for Q6W to 33–38 μg/mL in Q4W participants. Mean trough % α-4 integrin saturation on MNCs remained above 65.5% in Q6W participants and above 77.9% in Q4W participants. C_trough = trough concentrations; EID = extended-interval dosing; MNC = mononuclear cells; N/NE = new/newly enlarging; PK = pharmacokinetic; Q4W = every 4 weeks; Q6W = every 6 weeks; SID = standard-interval dosing.

Figure 3. Natalizumab C_trough (A) and α4-Integrin Saturation on MNCs (B) for All Participants Who Had an MS Relapse

^aRelapses are shown at the time of the visit closest to the recorded relapse. Five participants from the SID arm and 7 participants from the EID arm had relapse. Participant 06 from the EID arm had relapse at week 72, and there is no PD sample for this participant at this timepoint. In the overall population, mean serum natalizumab C_trough ranged from 10–21 μg/mL for Q6W and 33–38 μg/mL in Q4W participants. Mean trough % α-4 integrin saturation on MNCs remained above 65.5% in Q6W participants and above 77.9% in Q4W participants. C_trough = trough concentrations; EID = extended-interval dosing; MNC = mononuclear cells; PK = pharmacokinetic; Q4W = every 4 weeks; Q6W = every 6 weeks; SID = standard-interval dosing.