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      The Development of Cladribine Tablets for the Treatment of Multiple Sclerosis: A Comprehensive Review

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          Abstract

          Cladribine is a purine nucleoside analog initially developed in the 1970s as a treatment for various blood cancers. Due to the molecule’s ability to preferentially reduce T and B lymphocytes, it has been developed into an oral formulation for the treatment of multiple sclerosis (MS). The unique proposed mechanism of action of cladribine allows for the therapy to be delivered orally over two treatment-week cycles per year, one cycle at the beginning of the first month and one cycle at the beginning of the second month of years 1 and 2, with the potential for no further cladribine treatment required in years 3 and 4. This review summarizes the clinical development program for cladribine tablets in patients with MS, including the efficacy endpoints and results from the 2-year phase III CLARITY study in patients with relapsing–remitting MS (RRMS), the 2-year CLARITY EXTENSION study, and the phase III ORACLE-MS study in patients with a first clinical demyelinating event at risk for developing MS. Efficacy results from the phase II ONWARD study, in which cladribine tablets were administered as an add-on to interferon-β therapy in patients with RRMS, are also summarized. A review of all safety data, including lymphopenia, infections, and malignancies, is provided based on data from all trials in patients with MS, including the initial parenteral formulation studies. Based on these data, cladribine tablets administered at 3.5 mg/kg over 2 years have been approved across the globe for various forms of relapsing MS.

          Enhanced Digital Features To view enhanced digital features for this article, go to 10.1007/s40265-020-01422-9

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          Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria

          The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers.
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            Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria

            New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use. Ann Neurol 2011
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              Defining the clinical course of multiple sclerosis

              Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.
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                Author and article information

                Contributors
                krammohan@med.miami.edu
                Journal
                Drugs
                Drugs
                Drugs
                Springer International Publishing (Cham )
                0012-6667
                1179-1950
                28 November 2020
                28 November 2020
                2020
                : 80
                : 18
                : 1901-1928
                Affiliations
                [1 ]GRID grid.26790.3a, ISNI 0000 0004 1936 8606, Multiple Sclerosis Center, , University of Miami, ; Miami, FL USA
                [2 ]GRID grid.36425.36, ISNI 0000 0001 2216 9681, Multiple Sclerosis Comprehensive Care Center, , Stony Brook University, ; Stony Brook, NY USA
                [3 ]GRID grid.39009.33, ISNI 0000 0001 0672 7022, Merck KGaA, ; Darmstadt, Germany
                [4 ]GRID grid.39009.33, ISNI 0000 0001 0672 7022, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, ; Darmstadt, Germany
                [5 ]GRID grid.39009.33, ISNI 0000 0001 0672 7022, EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, ; Darmstadt, Germany
                [6 ]Comprehensive MS Center, Jefferson University, Philadelphia, PA USA
                Article
                1422
                10.1007/s40265-020-01422-9
                7708385
                33247831
                f752b546-3473-4dc9-acad-0e9f992d7d89
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Funding
                Funded by: EMD Serono, Inc. (an affiliate of Merck KGaA, Darmstadt, Germany)
                Categories
                Review Article
                Custom metadata
                © Springer Nature Switzerland AG 2020

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