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Reversibility of the Effects of Natalizumab on Peripheral Immune Cell Dynamics in MS Patients

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Reversibility of the Effects of Natalizumab on Peripheral Immune Cell Dynamics in MS Patients Reversibility of the effects of natalizumab on peripheral immune cell dynamics in MS patients Tatiana Plavina, PhD ABSTRACT Kumar Kandadi Objective: To characterize the reversibility of natalizumab-mediated changes in pharmacokinet- Muralidharan, PhD ics/pharmacodynamics in patients with multiple sclerosis (MS) following therapy interruption. Geoffrey Kuesters, PhD Methods: Pharmacokinetic/pharmacodynamic data were collected in the Safety and Efficacy of Daniel Mikol, MD, PhD Natalizumab in the Treatment of Multiple Sclerosis (AFFIRM) (every 12 weeks for 116 weeks) Karleyton Evans, MD and Randomized Treatment Interruption of Natalizumab (RESTORE) (every 4 weeks for 28 weeks) Meena Subramanyam, studies. Serum natalizumab and soluble vascular cell adhesion molecule–1 (sVCAM-1) were PhD measured using immunoassays. Lymphocyte subsets, a4-integrin expression/saturation, and vas- Ivan Nestorov, PhD cular cell adhesion molecule–1 (VCAM-1) binding were assessed using flow cytometry. Yi Chen, MS 3 Qunming Dong, PhD Results: Blood lymphocyte counts (cells/L) in natalizumab-treated patients increased from 2.1 9 3 9 Pei-Ran Ho, MD 10 to 3.5 10 . Starting 8 weeks post last natalizumab dose, lymphocyte counts became 3 Diogo Amarante, MD significantly lower in patients interrupting treatment than in those continuing treatment (3.1 9 3 9 p 5 Alison Adams, PhD 10 vs 3.5 10 ; 0.031), plateauing at prenatalizumab levels from week 16 onward. All a Jerome De Sèze, MD measured cell subpopulation, 4-integrin expression/saturation, and sVCAM changes demon- Robert Fox, MD strated similar reversibility. Lymphocyte counts remained within the normal range. Ex vivo z Ralf Gold, MD VCAM-1 binding to lymphocytes increased until 16 weeks after the last natalizumab dose, Douglas Jeffery, MD then plateaued, suggesting reversibility of immune cell functionality. The temporal appearance Ludwig Kappos, MD of gadolinium-enhancing lesions was consistent with pharmacodynamic marker reversal. Xavier Montalban, MD, Conclusions: Natalizumab’s effects on peripheral immune cells and pharmacodynamic markers were PhD reversible, with changes starting 8 weeks post last natalizumab dose; levels returned to those Bianca Weinstock- observed/expected in untreated patients z16 weeks post last dose. This reversibility differentiates Guttman, MD natalizumab from MS treatments that require longer reconstitution times. Characterization of the time Hans-Peter Hartung, MD course of natalizumab’s biological effects may help clinicians make treatment sequencing decisions. Bruce A.C. Cree, MD, Classification of evidence: This study provides Class III evidence that the pharmacodynamic markers PhD, MAS of natalizumab are reversed z16 weeks after stopping natalizumab. Neurology® 2017;89:1584–1593 GLOSSARY Correspondence to AFFIRM 5 Safety and Efficacy of Natalizumab in the Treatment of Multiple Sclerosis; CTS 5 Clinical Trials Services; EID 5 extended Dr. Plavina: interval dosing; Gd1 5 gadolinium-enhancing; MS 5 multiple sclerosis; NK 5 natural killer; PD 5 pharmacodynamics; PK 5 phar- [email protected] macokinetics; RESTORE 5 Randomized Treatment Interruption of Natalizumab; RRMS 5 relapsing-remitting multiple sclerosis; sVCAM-1 5 soluble vascular cell adhesion molecule–1; VCAM-1 5 vascular cell adhesion molecule–1; WBC 5 white blood cell. A number of therapies for relapsing-remitting multiple sclerosis (RRMS) are currently available; each has a distinct mechanism of action and benefit/risk profile and exhibits a different temporal pattern with respect to reversibility of the drug’s overall biological effects. Given the expansive and complex RRMS treatment landscape, when patients experience treatment failure and Supplemental data at Neurology.org From Biogen (T.P., K.K.M., G.K., D.M., K.E., M.S., I.N., Y.C., Q.D., P.-R.H., D.A.), Cambridge, MA; Ashfield Healthcare Communications (A.A.), Middletown, CT; Hôpital Civil (J.D.S.), Strasbourg, France; Mellen Center for Multiple Sclerosis (R.F.), Cleveland Clinic, OH; St. Josef Hospital (R.G.), Ruhr University, Bochum, Germany; Piedmont HealthCare (D.J.), Mooresville, NC; Neurologic Clinic and Policlinic (L.K.), Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital and University of Basel, Switzerland; Vall d’Hebron University Hospital (X.M.), Barcelona, Spain; Jacobs MS Center and Pediatric MS Center of Excellence (B.W.-G.), Jacobs Neurological Institute, Buffalo, NY; Department of Neurology (H.-P.H.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany; and University of California San Francisco Multiple Sclerosis Center (B.A.C.C.). Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was funded by Biogen. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. 1584 Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. alternative therapies are being considered, clinicaltrials.gov).10 Details of the study design and patient pop- 10 treatment sequencing is an important issue. ulation were previously published. Patients were randomized 2: 1 to receive 300 mg natalizumab or placebo IV every 4 weeks for Understanding the temporal nature of the bio- up to 116 weeks. logical effect of individual therapies may facil- RESTORE was a randomized, multicenter, partially blinded, itate treatment selection. parallel-group exploratory study conducted between March 2010 12 Natalizumab is a recombinant humanized and November 2011 (NCT01071083; clinicaltrials.gov). De- a tails of the study design and patient population were previously monoclonal antibody that targets the 4sub- published.12,13 Patients who had received 300 mg natalizumab IV unit of the a4b1integrinonmononuclearleu- for $12 months prior to trial entry were randomized (1:1:2) to kocytes and is approved for the treatment of natalizumab, placebo, or alternate therapy (IM interferon-b-1a 1 [Avonex; Biogen, Cambridge, MA], glatiramer acetate [Copax- relapsing multiple sclerosis (MS). When bound one; Teva Neuroscience, Kansas City, MO], or methylpredniso- by natalizumab, a4b1 integrin is blocked from lone). Administration of natalizumab and placebo was double-blind; binding to vascular cell adhesion molecule–1 alternative therapies were administered open-label. Randomiza- (VCAM-1), disrupting the homing and traf- tion occurred at week 0 (in which all patients received their last natalizumab infusion). At week 28, patients discontinued ficking of mononuclear leukocytes across acti- placebo or alternate therapy and restarted open-label natalizu- – vated vascular endothelium of the CNS.2 4 mab.12 Patients who experienced 1 new gadolinium-enhancing The pharmacodynamics (PD), the drug (Gd1) lesion of .0.8 cm3 in volume, $2Gd1 lesions of any $ effect on biological systems, of natalizumab size, or 1 clinical relapses could receive high-dose corticosteroid treatment or restart open-label natalizumab treatment at the in- include increased saturation/occupancy by na- vestigator’s discretion. Patients who received open-label natalizu- talizumab of its target, a4-integrin (CD49d), mab during the treatment interruption period proceeded directly on the surface of circulating lymphocytes2,5,6; to the open-label follow-up period. decreased surface expression of a4-integrin on Primary research question. This analysis was conducted to lymphocytes; and decreased serum concentra- characterize the timing of the PK and PD changes, including 7–9 changes in peripheral immune cells, upon natalizumab treatment tion of soluble VCAM-1 (sVCAM-1). Na- initiation and interruption. talizumab use is also associated with increased Classification of evidence. This study provides Class III evi- levels of peripheral immune cells, although dence that the PD markers of natalizumab’s activity are reversed these levels remain within the normal range z16 weeks after stopping natalizumab. for all investigated cell types except CD341 Assessments. In AFFIRM, samples for PK and limited PD eval- 5,10,11 progenitor cells. uations (total lymphocyte and white blood cell [WBC] counts) Natalizumab is highly efficacious at reducing were taken from all patients at baseline (prenatalizumab) and both clinical and radiologic disease activity.10 prior to infusion at weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, and 120. A cohort of 31 patients (natalizumab, n 5 20; placebo, Upon natalizumab treatment interruption, dis- n 5 11) from a subset of US sites underwent weekly measure- ease activity returns, with the earliest MRI lesions ment of a4-integrin saturation following the first dose of nata- observed 12 weeks after the last natalizumab lizumab; a4-integrin saturation was also measured every 24 weeks dose.12,13 However, the time course of reversibil- in a separate subset of 21 patients (natalizumab, n 5 15; placebo, ’ n 5 6). Blood for hematology and serum chemistry were analyzed ity of natalizumab seffectsonimmunecellsis at a central laboratory (Covance Central Laboratory Services, not well-characterized. Data from 2 large clinical Indianapolis, IN; Covance, Geneva, Switzerland; or Sonic Trials trials allowed assessment
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