Abstract
Oral fingolimod (Gilenya™), a sphingosine 1-phosphate (S1P) receptor agonist, is the first oral agent and the first in a novel class of disease-modifying therapies (DMTs) to be approved for use in the US for the treatment of relapsing forms of multiple sclerosis (MS). In the EU, fingolimod is approved for use as a single-agent DMT in selected patients with highly-active, relapsing-remitting (RR) MS. This article reviews the pharmacological properties and clinical use of the drug in patients with RRMS.
Fingolimod is rapidly converted in vivo to the active moiety S-fingolimodphosphate, which binds with high affinity to S1P receptors, thereby sequestering lymphocytes in the lymph nodes and preventing their egress into the peripheral circulation. As a consequence, there is a reduction in the infiltration of auto-aggressive lymphocytes into the CNS. Fingolimod-phosphate also acts as a functional antagonist, as its binding to S1P receptors results in their internalization and degradation, thereby downregulating S1P receptors on the lymphocyte cell surface. Since fingolimod crosses the blood: brain barrier, it also potentially acts at S1P receptors on neural cells in the CNS to mitigate neuropathological processes associated with MS.
In large multinational trials in adult patients with RRMS, oral fingolimod 0.5mg/day was more effective than oral placebo (FREEDOMS) and recommended dosages of intramuscular interferon-β (IFNβ)-1a (TRANSFORMS) in reducing the annualized relapse rate and was also generally more effective at slowing progression of neurological disability and at reducing the burden and activity of disease. Fingolimod was generally well tolerated in these trials of up to 2 years’ duration, with most adverse events being manageable and of mild to moderate severity; there were two deaths from opportunistic infections, albeit these occurred with fingolimod 1.25mg/day (higher than the recommended dosage). Limited long-term data indicated that no new safety concerns had arisen after 5 years of fingolimod treatment. However, further clinical experience is required to fully determine the long-term safety profile of fingolimod, particularly with regard to any potentially serious or life-threatening adverse events. In the absence of robust pharmacoeconomic studies and of head-to-head trials comparing fingolimod with other formulations of IFNβ and glatiramer acetate, the relative position of fingolimod with respect to other DMTs remains to be fully determined. In the meantime, given its convenient once-daily oral treatment regimen and better efficacy than intramuscular IFNβ-1a, fingolimod is a valuable emerging option for the treatment of adult patients with relapsing forms of MS.
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Various sections of the manuscript reviewed by: H.-P. Hartung, Department of Neurology, Heinrich-Heine-Universitä, Dusseldorf, Germany; J. Hong, Department of Neurology, Baylor College of Medicine, Houston, TX, USA; B.C. Kieseier, Department of Neurology, Heinrich-Heine-Universitä, Dusseldorf, Germany; T. Menge, Department of Neurology, Heinrich-Heine-Universitä, Dusseldorf, Germany; F. Patti, Department of G.F. Ingrassia, Multiple Sclerosis Centre of Catania University, Catania, Italy; M. Ryan, Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, KY, USA.
Data Selection
Sources: Medical literature (including published and unpublished data) on ‘fingolimod’ was identified by searching databases since 1996 (including MEDLINE and EMBASE and in-house AdisBase), bibliographies from published literature, clinical trial registries/databases and websites (including those of regional regulatory agencies and the manufacturer). Additional information (including contributory unpublished data) was also requested from the company developing the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘fingolimod’ and (‘multiple sclerosis’ or ‘relapsing remitting multiple sclerosis’ or ‘multiple sclerosis relapsing remitting’). Searches were last updated 6 July 2011.
Selection: Studies in patients with relapsing remitting multiple sclerosis who received fingolimod. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Fingolimod, sphingosine 1-phosphate receptor agonists, multiple sclerosis, relapsing-remitting multiple sclerosis, immunosuppressants, immunomodulators, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.
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Scott, L.J. Fingolimod. CNS Drugs 25, 673–698 (2011). https://doi.org/10.2165/11207350-000000000-00000
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DOI: https://doi.org/10.2165/11207350-000000000-00000