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      Patient Preference and Adherence (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the growing importance of patient preference and adherence throughout the therapeutic process. Sign up for email alerts here.

      34,896 Monthly downloads/views I 2.314 Impact Factor I 3.8 CiteScore I 1.14 Source Normalized Impact per Paper (SNIP) I 0.629 Scimago Journal & Country Rank (SJR)

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      Patient experience and practice trends in multiple sclerosis – clinical utility of fingolimod

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          Abstract

          Targeting sphingosine-1-phosphate pathway with orally available immune-modulatory fingolimod (Gilenya™) therapy ameliorates relapsing–remitting multiple sclerosis (RRMS) by decreasing relapse rate as shown in FREEDOMS and TRANSFORMS. Fingolimod has also been shown to be superior to interferon-beta therapy as evidenced by TRANSFORMS. Albeit multiple benefits in treatment of multiple sclerosis including high efficacy and ease of administration, potential untoward effects such as cardiotoxicity, risk of infection, and cancer exist, thus mandating careful screening and frequent monitoring of patients undergoing treatment with fingolimod. This review outlines mechanism of action, observations, side effects, and practice guidelines on use of fingolimod in treatment of RRMS.

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          The immune modulator FTY720 targets sphingosine 1-phosphate receptors.

          Volker Brinkmann, Michael D Davis, Christopher E. Heise … (2002)
          Immunosuppressant drugs such as cyclosporin have allowed widespread organ transplantation, but their utility remains limited by toxicities, and they are ineffective in chronic management of autoimmune diseases such as multiple sclerosis. In contrast, the immune modulating drug FTY720 is efficacious in a variety of transplant and autoimmune models without inducing a generalized immunosuppressed state and is effective in human kidney transplantation. FTY720 elicits a lymphopenia resulting from a reversible redistribution of lymphocytes from circulation to secondary lymphoid tissues by unknown mechanisms. Using FTY720 and several analogs, we show now that FTY720 is phosphorylated by sphingosine kinase; the phosphorylated compound is a potent agonist at four sphingosine 1-phosphate receptors and represents the therapeutic principle in a rodent model of multiple sclerosis. Our results suggest that FTY720, after phosphorylation, acts through sphingosine 1-phosphate signaling pathways to modulate chemotactic responses and lymphocyte trafficking.
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            FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation.

            Ji Choi, Shannon E Gardell, Deron R. Herr … (2011)
            Sphingosine 1-phosphate (S1P), a lysophospholipid, has gained relevance to multiple sclerosis through the discovery of FTY720 (fingolimod), recently approved as an oral treatment for relapsing forms of multiple sclerosis. Its mechanism of action is thought to be immunological through an active phosphorylated metabolite, FTY720-P, that resembles S1P and alters lymphocyte trafficking through receptor subtype S1P(1). However, previously reported expression and in vitro studies of S1P receptors suggested that direct CNS effects of FTY720 might theoretically occur through receptor modulation on neurons and glia. To identify CNS cells functionally contributing to FTY720 activity, genetic approaches were combined with cellular and molecular analyses. These studies relied on the functional assessment, based on clinical score, of conditional null mouse mutants lacking S1P(1) in CNS cell lineages and challenged by experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. All conditional null mutants displayed WT lymphocyte trafficking that responded normally to FTY720. In marked contrast, EAE was attenuated and FTY720 efficacy was lost in CNS mutants lacking S1P(1) on GFAP-expressing astrocytes but not on neurons. In situ hybridization studies confirmed that astrocyte loss of S1P(1) was the key alteration in functionally affected mutants. Reductions in EAE clinical scores were paralleled by reductions in demyelination, axonal loss, and astrogliosis. Receptor rescue and pharmacological experiments supported the loss of S1P(1) on astrocytes through functional antagonism by FTY720-P as a primary FTY720 mechanism. These data identify nonimmunological CNS mechanisms of FTY720 efficacy and implicate S1P signaling pathways within the CNS as targets for multiple sclerosis therapies.
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              Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis.

              Jeffrey A Cohen, Jerold Chun (2011)
              Until recently, all approved multiple sclerosis (MS) disease treatments were administered parenterally. Oral fingolimod was approved in September 2010 by the US Food and Drug Administration to reduce relapses and disability progression in relapsing forms of MS. In the clinical trials that led to approval, fingolimod reduced not only acute relapses and magnetic resonance imaging lesion activity but also disability progression and brain volume loss, suggesting preservation of tissue. Fingolimod's mechanism of action in MS is not known with certainty. Its active form, fingolimod-phosphate (fingolimod-P), is a sphingosine 1-phosphate receptor (S1PR) modulator that inhibits egress of lymphocytes from lymph nodes and their recirculation, potentially reducing trafficking of pathogenic cells into the central nervous system (CNS). Fingolimod also readily penetrates the CNS, and fingolimod-P formed in situ may have direct effects on neural cells. Fingolimod potently inhibits the MS animal model, experimental autoimmune encephalomyelitis, but is ineffective in mice with selective deficiency of the S1P₁ S1PR subtype on astrocytes despite normal expression in the immune compartment. These findings suggest that S1PR modulation by fingolimod in both the immune system and CNS, producing a combination of beneficial anti-inflammatory and possibly neuroprotective/reparative effects, may contribute to its efficacy in MS. In clinical trials, fingolimod was generally safe and well tolerated. Its interaction with S1PRs in a variety of tissues largely accounts for the reported adverse effects, which were seen more frequently with doses 2.5 to 10x the approved 0.5 mg dose. Fingolimod's unique mechanism of action distinguishes it from all other currently approved MS therapies. Copyright © 2011 American Neurological Association.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Patient Prefer Adherence
                Journal ID (iso-abbrev): Patient Prefer Adherence
                Journal ID (publisher-id): Patient Preference and Adherence
                Title: Patient preference and adherence
                Publisher: Dove Medical Press
                ISSN (Electronic): 1177-889X
                Publication date Collection: 2015
                Publication date (Electronic): 21 May 2015
                Volume: 9
                Pages: 685-693
                Affiliations
                [1 ]Stanford Healthcare, Multiple Sclerosis Center, Stanford University School of Medicine, Stanford University, Stanford, CA, USA
                [2 ]Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford University, Stanford, CA, USA
                Author notes
                Correspondence: May H Han, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford University, 1201 Welch Road, Stanford, CA 94305, USA, Email mayhan@ 123456stanford.edu
                Article
                Publisher ID: ppa-9-685
                DOI: 10.2147/PPA.S57354
                PMC ID: 4446999
                SO-VID: 6e26924c-69fc-4b55-be8d-3a20ff63b478
                Copyright © © 2015 Lee and Han. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License
                License:

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Categories
                Subject: Review

                ScienceOpen disciplines: Medicine
                Keywords: sphingosine-1-phosphate,rrms,freedoms,transforms,side effects,ifnβ
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: sphingosine-1-phosphate, rrms, freedoms, transforms, side effects, ifnβ

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