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Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis.
Ann Neurol 2011; 69(5):759-77AN

Abstract

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.

Authors+Show Affiliations

Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA. cohenj@ccf.orgNo affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

21520239

Citation

Cohen, Jeffrey A., and Jerold Chun. "Mechanisms of Fingolimod's Efficacy and Adverse Effects in Multiple Sclerosis." Annals of Neurology, vol. 69, no. 5, 2011, pp. 759-77.
Cohen JA, Chun J. Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis. Ann Neurol. 2011;69(5):759-77.
Cohen, J. A., & Chun, J. (2011). Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis. Annals of Neurology, 69(5), pp. 759-77. doi:10.1002/ana.22426.
Cohen JA, Chun J. Mechanisms of Fingolimod's Efficacy and Adverse Effects in Multiple Sclerosis. Ann Neurol. 2011;69(5):759-77. PubMed PMID: 21520239.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis. AU - Cohen,Jeffrey A, AU - Chun,Jerold, PY - 2011/4/27/entrez PY - 2011/4/27/pubmed PY - 2011/6/28/medline SP - 759 EP - 77 JF - Annals of neurology JO - Ann. Neurol. VL - 69 IS - 5 N2 - 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. SN - 1531-8249 UR - https://www.unboundmedicine.com/medline/citation/21520239/Mechanisms_of_fingolimod's_efficacy_and_adverse_effects_in_multiple_sclerosis_ L2 - https://doi.org/10.1002/ana.22426 DB - PRIME DP - Unbound Medicine ER -