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Published on: December 9, 2015
Pharmacokinetics and Pharmacodynamics of Natalizumab 6-Week Dosing vs Continued 4-Week Dosing for Relapsing-Remitting
John F Foley1, Gilles Defer1, Lana Zhovtis Ryerson1
1From the Rocky Mountain MS Clinic (J.F.F.), Salt Lake City, UT; Department of Neurology (G.D.), Centre Hospitalier Universitaire de Caen, France; Hackensack Meridian Medical Group - Neurology (L.Z.R.), Jersey Shore University Medical Center, Neptune City, NJ; Mellen MS Center (J.A.C.), Neurological Institute, Cleveland Clinic, OH; Montréal Neurological Institute (D.L.A.), McGill University; NeuroRx Research (D.L.A.), Montréal, Quebec, Canada; Department of Neuroscience (H.B.), Central Clinical School, Monash University, Melbourne, Victoria, Australia; University of Alabama at Birmingham (G.R.C.), School of Public Health; Blizard Institute (G.G.), Barts and The London School of Medicine and Dentistry; Queen Mary University of London (G.G.), United Kingdom; Department of Neurology (J.K.), Amsterdam University Medical Centers, Vrije Universiteit, Netherlands; Department of Neurology with Institute of Translational Neurology (H.W.), University of Münster, Germany; Biogen (K.L., L.D., M.T., K.F., J.S., T.L.), Cambridge, MA; and Ashfield MedComms (H.E.), Middletown, CT.
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.
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