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

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.[34] It can be given by oral route in once daily dose and has potential disease-modifying effects in most common relapsing forms of MS.[356] It can reduce relapses and delay neurological damage progression.[356]

Fingolimod (FTY720) is asphingosine-1-phosphate receptor modulator,[35] which is present on the surface of thymocytes, lymphocytes, and neural cells.[35] 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.[35] This active phosphate moiety of fingolimod binds to the sphingosine-1-phosphate receptor.[35] 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 Tmax 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.[34]

The side effect of fingolimod are headache, influenza-like illness, nasopharyngitis, bronchitis, pneumonia, and fatigability.[36] 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.[356] Localized skin cancers (basal-cell carcinomas, melanomas) and breast cancer have also been reported.[56]

Two large Phase III Clinical Trials were conducted to evaluate the efficacy and safety of fingolimod in relapsing-remitting MS.[356]

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.[36]

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.[35]

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.[356] These should be monitored when fingolimod is started for the treatment of MS.[356]