Innovations In Clinical Neuroscience

MAY-JUN 2017

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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Innovations in CLINICAL NEUROSCIENCE [ V O L U M E 1 4 , N U M B E R 5 – 6 , M A Y – J U N E 2 0 1 7 ] 28 ABSTRACT The treatment of multiple sclerosis continues to evolve. However, even with the introduction of B-cell depleting monoclonal antibodies, disability progression continues unabated since B- cell therapies are unable to cross the blood brain barrier and thus are unable to address the disease that lurks within the brain. In this commentary, the author explores the research and practice of using B-cell depleting monoclonal antibody therapies in MS. The author provides discussion on the blood brain barrier as the primary limitation to the effectiveness of MS therapies. The author briefly reviews the pathophysiological role of B-cells in MS and the implications that B-cell migration to the brain has on MS disease progression and treatment. The author discusses potential drug development strategies for MS that combine blood brain barrier crossing molecules with peripherally acting B-cell depleting monoclonal antibodies. INTRODUCTION Rapid strides have been made in the treatment of multiple sclerosis (MS) since the United States Food and Drug Administration (FDA) approved Betaseron ® (Schering AG and Bayer HealthCare), the first drug approved for MS treatment, in 1993. Despite this, treatment options for worsening MS, characterized by accumulating disability on Expanded Disability Status scores (EDSS) and/or cognitive decline, offer disappointing results. This is particularly worrisome for African-American patients, who have higher EDSS, greater gait abnormalities at diagnosis, and possibly more primary progressive (PPMS) variants, compared to Caucasian patient cohorts. 1 The progression of disability in patients with relapsing-remitting MS (RRMS), which eventually transitions into secondary progressive MS (SPMS), has been a poorly understood phenomenon from a mechanistic perspective, and no specific drugs have been developed that counteract or arrest the progression of disability over time. This is likely due to the poor penetration of the blood brain barrier (BBB) by these drugs, particularly the B-cell depleting monoclonal antibodies (MAbs). Currently, four MAbs have been approved for MS therapy—natalizumab, alemtuzumab, daclizumab, and ocrelizumab. This brief review and commentary describes and discusses potential drug combination strategies that might improve treatment outcomes in MS. By combining BBB-crossing molecules (e.g., siponimod, cyclophosphamide, or laquinimod) with peripherally acting MAbs, we might be able to develop MS therapies that effectively limit or halt disease progression and improve overall treatment outcomes. BBB, MS, and MAbs Molecular weight. Unlike nearly all other blood vessels in the body, the endothelial cells of the BBB are held together by tight junctions, and in order for a drug to enter the central nervous system (CNS), it must take the trans- cellular route. The tight junctions, coupled with numerous efflux by JAGANNADHA AVASARALA, MD, PhD Dr. Avasarala is Associate Professor of Neurology, Division of Neurology, Department of Medicine, University of South Carolina School of Medicine, Greenville Health System, Greenville, South Carolina. Innov Clin Neurosci. 2017;14(5–6):28–30 FUNDING: No funding was received for the preparation of this article. FINANCIAL DISCLOSURES: The author has no conflicts of interest relevant to the content of this article. ADDRESS CORRESPONDENCE TO: Jagannadha Avasarala, MD, PhD, Associate Professor of Neurology, Division of Neurology, Department of Medicine, University of South Carolina School of Medicine, Greenville Health System, 701 Grove Road, Greenville, SC 29605; Phone: 864-395-8252; Fax: 864- 454-4514; email: javasarala@ghs.org KEYWORDS: Blood-brain barrier, monoclonal antibodies, multiple sclerosis, laquinimod, cyclophosphamide, siponimod, disability status, combination therapies, drug development C O M M E N T A R Y IT'S TIME FOR COMBINATION THERAPIES in Multiple Sclerosis

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