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LETTER
Year : 2011  |  Volume : 3  |  Issue : 3  |  Page : 460-461  

Fingolimod: The first oral drug approved by food and drug administration; A breakthrough in treatment of multiple sclerosis


1 Department of Neurosurgery, JIPMER, Puducherry- 605 006, India
2 Department of Neurosurgery, Dr. Achanta Lakshmipathi Neurosurgical Centre, Post Graduate Institute of Neurological Surgery, V.H.S Hospital, Taramani, Chennai- 600 113, India
3 Department of Obstetrics and Gynecology, JIPMER, Puducherry- 605 006, India
4 Department of Neurology, Dr Ram ManoharLohia Institute of Medical Sciences, VibhootiKhand, Gomti Nagar, Lucknow, Uttar Pradesh- 226 010, India

Date of Web Publication3-Sep-2011

Correspondence Address:
Manish Singh
Department of Neurosurgery, JIPMER, Puducherry- 605 006
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-7406.84467

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How to cite this article:
Singh M, Cugati G, Singh P, Singh AK. Fingolimod: The first oral drug approved by food and drug administration; A breakthrough in treatment of multiple sclerosis. J Pharm Bioall Sci 2011;3:460-1

How to cite this URL:
Singh M, Cugati G, Singh P, Singh AK. Fingolimod: The first oral drug approved by food and drug administration; A breakthrough in treatment of multiple sclerosis. J Pharm Bioall Sci [serial online] 2011 [cited 2019 Apr 26];3:460-1. Available from: http://www.jpbsonline.org/text.asp?2011/3/3/460/84467

Sir,

The French neurologist Jean-Martin Charcot (1825-1893) was the first person to recognize multiple sclerosis (MS) as a distinct disease in 1868 by summarizing previous reports and adding his own clinical and pathological observations. [1] Since then, five disease-modifying treatments for MS have been approved by regulatory agencies of various countries: (1) Interferon beta-1a, (2) interferon beta-1b, (3) glatiramer acetate, is a non-interferon, non-steroidal immunomodulator, (4) mitoxantrone is an immunosuppressant, (5) natalizumab is a humanized monoclonal antibody immunomodulator, all of them are either immunomodulator or immunosuppressant, and have to be given in injectable form, in daily or weekly doses. [2] These drugs only alter the course of the disease and do not reverse the neurological damage, which already has happened during disease process. [2]

A new drug, fingolimod, was recently approved by Food and Drug Administration (FDA) of United States on September 22, 2010. [3],[4] It can be given by oral route in once daily dose and has potential disease-modifying effects in most common relapsing forms of MS. [3],[5],[6] It can reduce relapses and delay neurological damage progression. [3],[5],[6]

Fingolimod (FTY720) is asphingosine-1-phosphate receptor modulator, [3],[5] which is present on the surface of thymocytes, lymphocytes, and neural cells. [3],[5] Phosphorylated fingolimod acts as a functional antagonist of the sphingosine-1-phosphate receptor, inducing receptor internalization and rendering T and B cells insensitive to a signal necessary for come out from secondary lymphoid tissues. [5] It sequestrates inflammatory cells in lymph nodes, away from the central nervous system (CNS). [3] This leads to reduction of inflammatory cells in CNS, which can cause damage to myelin sheath. [3] Fingolimod is lipophilic in nature, easily crosses the blood-brain barrier, and is phosphorylated within the CNS. It interacts with sphingosine-1-phosphate receptors on neural cells. Fingolimod may have neuroprotective or reparative effects. [5] It also enhances myelination and protects axons from damage. [3]

It is structural analog of sphingosine and phosphorylated by sphingosine kinase to form the active phosphate moiety. [3],[5] This active phosphate moiety of fingolimod binds to the sphingosine-1-phosphate receptor. [3,5] It is hydroxylated by cytochrome CYP4F2. Ketoconazole interact with fingolimod and inhibit the oxidative metabolism by liver microsomes. [3] Its bioavailability after an oral dose is 93% and T max is 12 to 16 hours. [3] The recommended dose of fingolimod tablet is 0.5 mg/day through oral route, which is approved by US FDA. [3],[4]

The side effect of fingolimod are headache, influenza-like illness, nasopharyngitis, bronchitis, pneumonia, and fatigability. [3],[6] A sudden reduction in the heart rate, severe bradycardia, atrioventricular blockade, macular edema, and life-threatening infections like disseminated primary Varicella zoster and herpes simplex encephalitis have been reported in literature. [3],[5],[6] Localized skin cancers (basal-cell carcinomas, melanomas) and breast cancer have also been reported. [5],[6]

Two large Phase III Clinical Trials were conducted to evaluate the efficacy and safety of fingolimod in relapsing-remitting MS. [3],[5],[6]

  1. The FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis) trial, in which 1 272 patients were involved and were randomized to receive placebo or either 0.5 or 1.25 mg of oral fingolimod daily. It was double-blind, placebo-controlled, 24-month duration trial, which showed significant reduction in the annual relapse rate of relapsing-remitting type of MS with both doses of fingolimod compared with placebo, both clinically and radiologically. [3],[6]
  2. TRANSFORMS (Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis): It was 12-month duration, phase 3, multicenter, randomized, double-blind, double-dummy, parallel-group study and 1 292 patients were randomized to receive placebo or either 0.5 or 1.25 mg of oral fingolimod daily or interferon beta-1a, 30 μg, given intramuscularly once a week. Results showed significant reduction in the annual relapse rate of relapsing-remitting type of MS with both doses of fingolimod compared with the interferon beta-1a group, both clinically and radiologically. [3],[5]


Fingolimod is the first oral drug available for treatment of MS, which showed better results than interferon beta-1a for treatment of MS in the trial done previously but still having risk of life-threatening and serious complications like severe bradycardia, atrioventricular blockade, macular edema life-threatening infections, and skin or breast carcinoma. [3],[5],[6] These should be monitored when fingolimod is started for the treatment of MS. [3],[5],[6]

 
   References Top

1.Compston A. The 150th anniversary of the first depiction of the lesions of multiple sclerosis. J NeurolNeurosurg Psychiatry 1988;51:1249-52.  Back to cited text no. 1
    
2.Compston A, Coles A. Multiple sclerosis. Lancet 2008;372:1502-17.  Back to cited text no. 2
[PUBMED]  [FULLTEXT]  
3.Sharma S, Mathur AG, Pradhan S, Singh DB, Gupta S. Fingolimod (FTY720): First approved oral therapy for multiple sclerosis. J PharmacolPharmacother 2011;2:49-51.  Back to cited text no. 3
    
4.FDA approves first oral drug to reduce MS relapses. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm226755.htm. [Last cited in 2010].  Back to cited text no. 4
    
5.Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010;362:402-15.   Back to cited text no. 5
[PUBMED]  [FULLTEXT]  
6.Kappos L, Radue EW, O′Connor P, Polman C, Hohlfeld R, Calabresi P, et al. A placebo controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362:387-401.  Back to cited text no. 6
[PUBMED]  [FULLTEXT]  



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