In the course of a 24-week cessation of treatment with the humanized monoclonal antibody, natalizumab, in patients with RRMS, pharmacokinetic, pharmacodynamic, and serum immune parameters normalized by 4 months.
SAN DIEGO — In the course of a 24-week cessation of treatment with the humanized monoclonal antibody, natalizumab, in patients with relapsing-remitting multiple sclerosis (RRMS), pharmacokinetic, pharmacodynamic, and serum immune parameters normalized by 4 months, according to research presented at the Fourth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and America’s Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Natalizumab treatment duration has been associated with the development of progressive multifocal leukoencephalopathy (PML), a rare but often lethal and untreatable disorder of the central nervous system characterized by large white-matter lesions that occur in immunocompromised patients. The RESTORE study was designed to investigate the effects of natalizumab interruption on MS disease activity.
Natalizumab works by directly binding to the alpha 4-integrin submit of very late activation antigen-4 (VLA-4), which reduces the availability of unblocked alpha-4, leading to an inhibition of immune cell extravasation across the blood-brain barrier.
Hans-Peter Hartung, MD, of the Heinrich-Heine University in Düsseldorf, Germany, and colleagues conducted the randomized, partially placebo-controlled exploratory RESTORE study. The objective was to evaluate the effects of a 24-week treatment interruption on MS disease activity in 175 patients who had been relapse-free after treatment with natalizumab for a year or more and had no gadolinium-enhancing (Gd+) lesions on baseline MRI scan.
Patients received either natalizumab, placebo, or in an open-label fashion, an alternative immunomodulatory therapy, such as interferon beta-1a (IFNbeta-1a), glatiramer acetate, or methylprednisolone. Rescue treatment with natalizumab or high-dose corticosteroids was allowed if patients experienced a clinical relapse, 1 new Gd+ lesion over 0.8 cubic centimeters in volume, or 2 or more gadolinium lesions.
After 4 months of natalizumab treatment interruption, serum concentrations of natalizumab and soluble vascular cell adhesion molecule (sVCAM), alpha-4 integrin receptor saturation, CD49d (alpha-4 integrin) expression, and circulating lymphocyte subsets, including CD34 hematopoietic cells, were consistent with results obtained from patients who had never been treated with natalizumab. It is important to note, however, that as these pharmacokinetic, pharmacodynamic, and immune parameters normalized, MRI and disease activity returned.
“Within 4 months of natalizumab treatment interruption, pharmacokinetic, pharmacodynamic, and immune parameters returned to baseline levels similar to those in non-natalizumab-treated patients,” the authors concluded.
This research was supported by Biogen Idec Inc. and Elan Pharmaceuticals, Inc.