RESTORE Study: Effects of a 24-Week Natalizumab Treatment Interruption on Immune Parameters and Multiple Sclerosis Magnetic Resonance Imaging Disease Activity (P06.168)

Objective: Determine the effects of a 24-week interruption of natalizumab treatment on pharmacodynamic and immune parameters, and magnetic resonance imaging (MRI) disease activity using placebo or alternative immunomodulatory therapy (AIT) in patients with MS. Background As progressive multifocal leukoencephalopathy (PML) risk increases with longer natalizumab treatment duration, particularly beyond 2 years, some physicians may interrupt therapy based on theoretical considerations. This study assessed return of immune function and MRI disease activity following natalizumab discontinuation. Design/Methods: RESTORE is a randomized, partially placebo-controlled study to evaluate the effect of a 24-week interruption in natalizumab treatment on immune parameters and multiple sclerosis (MS) disease activity. Enrolled patients received natalizumab for at least the preceding 12 months, had no relapses, and had no gadolinium-enhancing lesions on screening brain MRI. Patients were randomized 1:1:2 to either continue natalizumab or to switch to placebo or open-label AIT. Evaluations were performed at least every 4 weeks for 24 weeks and at the final study visit at week 52. Results: Throughout treatment interruption, good concordance was seen between serum natalizumab concentration, alpha-4 integrin saturation, and serum soluble vascular cell adhesion molecule (sVCAM) concentration. Binding of fluorescently labeled VCAM to circulating lymphocyte subsets increased during treatment interruption, indicating increasingly available alpha-4 integrin molecules and increased adhesion interactions. Four months after natalizumab cessation, serum natalizumab and sVCAM concentrations, alpha-4 receptor saturation, CD49d expression, and circulating lymphocyte subsets, including CD34+ cells, reached stable levels consistent with those observed for patients not treated with natalizumab. Returning disease activity as identified by brain MRI paralleled the immune reconstitution kinetics. Conclusions: Within 4 months of natalizumab treatment interruption, pharmacokinetic, pharmacodynamic, and immune parameters returned to levels consistent with non–natalizumab-treated patients. Details on the return of MRI disease activity will be provided. Supported by: Biogen Idec Inc. and Elan Pharmaceuticals, Inc. Disclosure: Dr. Cree has received personal compensation for activities with Biogen Idec, Genzyme Corporation, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Cree has received research support from EMD Serono. Dr. De Seze has received personal compensation for activities with Bayer Schering, Biogen Idec, LFB, Merck Serono, Novartis, Sanofi-Aventis, and Teva Neuroscience.Dr. De Seze has received personal compensation in an editorial capacity for Elsevier. Dr. Fox has received personal compensation for activities with Avanir, Biogen Idec, EMD Serono, and Novartis. Dr. Fox has received research support from Biogen Idec and Genentech, Inc. Dr. Gold has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received (royalty or license fee or contractual rights) payments from Biogen Idec. Dr. Gold has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience. Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Genzyme Corporation, Merck Serono, Novartis, Sanofi-Aventis and Teva as a speaker and/or consultant. Dr. Jeffery has received personal compensation for activities with Berlex Labortories, GlaxoSmithKline Inc., Pfizer Inc, Serono, Inc. and Teva Neuroscience as a consultant.Dr. Jeffery has received research support from Berlex Labortories, Pfizer Inc, Serono, Inc. and Teva Neuroscience. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Kaufman has received personal compensation for activities with Biogen Idec, Acorda Therapeutics, Bayer Pharmaceuticals, Novartis, Serono, Inc., Teva Neuroscience, Department of Defense as a consultant, researcher and/or speaker. Dr. Kaufman has received personal compensation in an editorial capacity for Medlink Neurology. Dr. Kaufman has received research support from Biogen Idec. Dr. Montalban has received personal compensation for activities with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG. Dr. Montalban has received research support from Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG. Dr. Weinstock-Guttman has received personal compensation for activities with Acorda Therapeutics, Biogen Idec, Serono, Inc., Novartis, Pfizer Inc, Teva Neuroscience as a speaker and/or participant on an advisory board. Dr. Weinstock-Guttman has received research support from Acorda Therapeutics, Biogen Idec, Serono Inc., Novartis, Pfizer Inc, Teva Neuroscience, National Multiple Sclerosis Society, the National Institutes of Health, ITN, Teva Neuroscience, Aspreva-Roche, Acorda Therapeutics and Shire Pharmaceuticals. Dr. Natarajan has received personal compensation for activities with Biogen Idec as an employee. Dr. Subramanyam has received personal compensation for activities with Biogen Idec as an employee. Dr. Subramanyam holds stock and/or stock options in Biogen Idec. Dr. Plavina has received personal compensation for activities with Biogen Idec as an employee.Dr. Plavina holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Plavina was involved as an investigator. Dr. Woodworth has received personal compensation for activities with Biogen Idec as an emlployee. Dr. Woodworth holds stock and/or stock options in Biogen Idec. Dr. Duda has received personal compensation for activities with Biogen Idec as an employee.