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Fingolimod

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Fingolimod
Clinical data
Trade namesGilenya
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth (capsules)
ATC code
Legal status
Legal status
Identifiers
  • 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC19H33NO2
Molar mass307.471 g/mol g·mol−1
3D model (JSmol)
  • OCC(N)(CCc1ccc(cc1)CCCCCCCC)CO
  • InChI=1S/C19H33NO2/c1-2-3-4-5-6-7-8-17-9-11-18(12-10-17)13-14-19(20,15-21)16-22/h9-12,21-22H,2-8,13-16,20H2,1H3 checkY
  • Key:KKGQTZUTZRNORY-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Fingolimod (INN, trade name Gilenya, Novartis) is an immunomodulating drug, mostly used for treating multiple sclerosis (MS).[1] It has reduced the rate of relapses in relapsing-remitting multiple sclerosis by approximately one-half over a two-year period.[2] Fingolimod is a sphingosine-1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction.

Medical uses

Fingolimod is used in the treatment of the relapsing form of multiple sclerosis. Its effect in those with primary progressive MS is not clear. May also be used in chronic inflammatory demyelinating polyneuropathy.[1] It was originally proposed as an antirejection medication indicated after transplantation but it failed to show any significant benefit in post-transplantation clinical trials.

Side effects

The most common side effects of fingolimod have been head colds, headache, and fatigue. A few cases of skin cancer have been reported, which has also been reported in patients taking natalizumab (Tysabri), an approved MS drug.[3] Fingolimod has also been associated with potentially fatal infections, bradycardia and, recently, a case of hemorrhaging focal encephalitis, an inflammation of the brain with bleeding.[4] Two people died: one due to brain herpes infection, and a second one due to zoster. It is unclear whether the drug was responsible for the events.[5] At least three cases of progressive multifocal leukoencephalopathy had also occurred as of 2015.[6]

Fingolimod has also been known to cause macular edema, resulting in decreased vision.[7][8]

The European Medicines Agency has advised doctors to increase their level of monitoring of people after the first dose of the medicine. This includes electrocardiogram (ECG) monitoring before treatment and then continuously for the first six hours after the first dose, and measurement of blood pressure and heart rate every hour.[9]

Structure and mechanism

It is derived from myriocin (ISP-1), a metabolite of the fungus Isaria sinclairii. It is a structural analogue of sphingosine and is phosphorylated by sphingosine kinases in the cell (most importantly sphingosine kinase 2).[10][11][12] The molecular biology of phospho-fingolimod is thought to lie in its activity at one of the five sphingosine-1-phosphate receptors, S1PR1.[13] Phospho-fingolimod causes the internalization of S1P receptors, which sequesters lymphocytes in lymph nodes, preventing them from moving to the central nervous system and cause a relapse in multiple sclerosis.

The unphosphorylated moiety of fingolimod, which is the predominant form of the drug in the body, is also an active molecule. Unphosphorylated fingolimod impairs the ability of cytotoxic CD8 T cells to kill their target cells by a different mechanism that involves the arachidonic acid pathway, which is unrelated to sphigosine phosphate receptors.[14] This has implications to both increasing susceptibility to viral infections as well as enhancing its therapeutic efficacy in multiple sclerosis.[14]

Finally, fingolimod has been also found to have other molecular targets and functions. Fingolimod has been reported to be a cannabinoid receptor antagonist,[15] a cPLA2 inhibitor [16] and a ceramide synthase inhibitor.[17][18] It has also been reported to stimulate the repair process of glial cells and precursor cells after injury.[19]

History

First synthesized in 1992 by Yoshitomi Pharmaceuticals, fingolimod was derived from an immunosuppressive natural product, myriocin (ISP-I) through chemical modification. Myriocin was isolated from the culture broth a type of entomopathogenic fungus (Isaria sinclairii) that was an eternal youth nostrum in traditional Chinese medicine.[20] Showing positive results in both in vitro (mixed lymphocyte reaction) and in vivo screening (prolonging rat skin graft survival time), myriocin was modified through a series of steps to yield fingolimod, code named at the time FTY720. [21]

Structure activity relationship (SAR) studies on myriocin homologs and partially synthetic derivatives showed that the configuration at the carbon bearing the 3-hydroxy group or the 14-ketone, the 6-double bond, and the 4-hydroxy group were not important for its activity and simplification of the structure of ISP-I was done in an attempt to reduce toxicity and improve drugability.[20]

Elimination of side chain functionalities and removal of chiral centers was part of the simplification process and an intermediate compound (ISP-I-28) with the carboxylic acid of myriocin transformed to a hydroxymethyl group was generated. ISP-I-28 was found to be less toxic and more effective at lengthening rat skin allograft time than ISP-1.

Approval

On September 21, 2010, fingolimod became the first oral disease-modifying drug approved by the Food and Drug Administration to reduce relapses and delay disability progression in patients with relapsing forms of multiple sclerosis.[22][23] Novartis announced on March 10, 2011 that it had received a notice of compliance from Health Canada and that the drug would be available April 1, 2011 at pharmacies.[24][25] On March 17, 2011, the European Medicines Agency approved the drug for use in the European Union.[26]

The US Patent and Trademark Office (USPTO)'s trial and appeal board quashed Novartis's patent claims stating they were obvious (and hence not inventions that merit patent protection).[27]

Research

Organ transplant

In a previous phase III clinical trial of kidney transplantation, fingolimod was found to be no better than the existing standard of care.[28][29] Fingolimod is studied in human models in vitro and in animal kidney transplantation.[29][30][31][31]

Multiple sclerosis

In two Phase III clinical trials, fingolimod reduced the rate of relapses in relapsing-remitting multiple sclerosis by over half compared both to placebo and to the active comparator interferon beta-1a.[32]

A double-blind randomized control trial comparing fingolimod to placebo[33] found the drug reduced the annualized frequency of relapses to 0.18 relapses per year at 0.5 mg/day or 0.16 relapses per year at 1.25 mg/day, compared to 0.40 relapses per year for those patients taking the placebo. The probability of disease progression at 24 month followup was lower in the fingolimod groups compared to placebo (hazard ratio 0.70 at 0.5 mg and 0.68 at 1.25 mg). Fingolimod patients also had better results according to MRI imaging of new or enlarged lesions at 24 month followup. Side effects leading to discontinuation of the study drug were more common in the higher dose group (14.2% of patients) than at the lower dose (7.5%) or placebo (7.7%). Serious adverse events in the fingolimod group included bradycardia, relapse, and basal-cell carcinoma. Seven episodes of bradycardia occurred during the monitoring period after administration of the first dose, and were asymptomatic in six of these cases. There was a higher rate of lower respiratory tract infections (including bronchitis and pneumonia) in the fingolimod groups (9.6% at 0.5 mg, 11.4% at 1.5 mg) than the placebo group (6.0%). Other adverse events reported on the study drug included macular edema, cancer, and laboratory abnormalities.[34]

Heart failure and arrhythmia

Fingolimod is a candidate therapeutic drug for the treatment of heart failure and arrhythmias. Heart failure is a leading cause of hospitalization and death in many countries, and an ever-increasing health burden worldwide.[35][36][37] Pathogenic hypertrophy of the myocardium is a cardinal sign leading to heart failure and is associated with an increased risk of cardiac morbidity and mortality.[35][38] Cardiac arrhythmias are disturbances in cardiac rhythm that often arise as a lethal complication of heart failure. This occurs due to the progressive ischemic/reperfusion injury the heart faces.[39]

Many signaling pathways, including pathways involving P21-activated kinase-1 (Pak1), play a role in the pathogenesis of heart failure and arrhythmias.[38] The cardioprotective effects of fingolimod have been attributed to Pak1 activation.[35][40][41] Studies using animal models have shown promising results for fingolimod as a potential therapeutic drug for arrhythmias and prevention of hypertrophy and heart failure[35][40][41][42]

P21-activated kinases (Paks) are a family of serine/threonine protein kinases involved in the G-protein signaling pathway activated by Cdc42 and Rac1. Cdc42 and Rac1 are GTPases that upon activation by extracellular stimuli lead to activation of Pak.[43] Paks are widely expressed in mammalian tissue and at least three Pak isoforms exist in the heart, including Pak14. Pak1 has been shown to regulate many cellular functions in the heart including cell growth, survival, and motility.[35][44] Pak1 has also been implicated in the regulation of vital cardiac processes such as hypertrophy and contractility.[45]

Previous studies have shown that Pak1 activation contributes to the pathogenesis of cardiac hypertrophy through multiple mechanisms.[44][45][46][47][48][49] Contrary to this, a recent study has discovered Pak1 plays a cardioprotective role during the pathogenesis of cardiac hypertrophy and thus heart failure.[35] A knock-out mouse model and myocyte cell culture experiments have identified Pak1 as a key player in a signaling cascade relaying antihypertrophic signals within the heart. This effect is a result of a c-Jun N-terminal kinase (JNK)-dependent cascade directly downstream of Pak1 activation. Results of this study revealed fingolimod as a potential antihypertrophic cardiac treatment through its activation of Pak1 and the resultant antihypertrophic effects seen in animal models.[35]

A study using ex vivo rat hearts and myocyte cell culture has also identified fingolimod as a candidate drug for preventing cardiac arrhythmias resulting from ischemic/reperfusion injury.[40][41] Fingolimod prevents arrhythmias through the activation of Pak1 and its downstream effectors. These include upregulation of protein phosphatase 2 (PP2A) and subsequent dephosphorylation of troponin I (TnI,) and activation of the sphingosine-1-phosphate (S1P) signaling cascade.[41] The latter inhibits cardiac pacemaker rate by altering the activity of acetylcholine-regulated potassium channels (KACh).[50]

See also

References

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