Fingolimod

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Fingolimod
Fingolimod structure.svg
Fingolimod-3D-balls-by-AHRLS-2011.png
Clinical data
Trade names Gilenya
AHFS/Drugs.com Monograph
MedlinePlus a611006
License data
Pregnancy
category
  • AU:D
Routes of
administration 		By mouth
Drug class Immunosuppressants
ATC code
Legal status
Legal status
Identifiers
  • 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C19H33NO2
Molar mass 307.478 g·mol−1
3D model (JSmol)
  • CCCCCCCCC1=CC=C(C=C1)CCC(CO)(CO)N
  • 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 Yes check.svgY
  • Key:KKGQTZUTZRNORY-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Fingolimod, sold under the brand name Gilenya, is an immunomodulating medication, used for the treatment of multiple sclerosis. [2] Fingolimod is a sphingosine-1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction. It has been reported to reduce the rate of relapses in relapsing-remitting multiple sclerosis by approximately one-half over a two-year period. [3]

Contents

Medical uses

Fingolimod is used in the treatment of the relapsing form of multiple sclerosis. Its effect in those with primary progressive multiple sclerosis is not clear. It may also be used in chronic inflammatory demyelinating polyneuropathy. [2]

Adverse effects

The most common side effects of fingolimod have been head colds,[ vague ] headache, [4] increased gamma-glutamyl transfer (≤15%), diarrhea (13%), nausea (13%), abdominal pain (11%) [4] and fatigue. A few cases of skin cancer have been reported, which has also been reported in patients taking natalizumab (Tysabri), an approved multiple sclerosis drug. [5] Fingolimod has also been associated with potentially fatal infections, bradycardia and, in 2009, a case of hemorrhaging focal encephalitis, an inflammation of the brain with bleeding. [6] Two people died: one due to brain herpes infection, and a second one due to herpes zoster. It is unclear whether the drug was responsible for the events. [7] At least three cases of progressive multifocal leukoencephalopathy had also occurred as of 2015. [8]

Fingolimod has also been known to cause macular edema, resulting in decreased vision. [9] [10] Therefore, frequent surveillance eye examinations are required while taking this medication.

In the United States, fingolimod must be dispensed with a medication guide that contains important information about its uses and risks. [11] Serious risks include slowing of the heart rate, especially after the first dose. [11] Fingolimod may increase the risk of serious infections. [11] Patients should be monitored for infection during treatment and for two months after discontinuation of treatment. [11] A rare brain infection that usually leads to death or severe disability, called progressive multifocal leukoencephalopathy (PML) has been reported in patients being treated with the drug. [11] PML cases usually occur in patients with weakened immune systems. [11] Fingolimod can cause vision problems. [11] It may increase the risk for swelling and narrowing of the blood vessels in the brain (posterior reversible encephalopathy syndrome). [11] Other serious risks include respiratory problems, liver injury, increased blood pressure and skin cancer. [11] Fingolimod may cause harm to a developing fetus; health care professionals should advise women of child-bearing age of the potential risk to the fetus and to use effective contraception. [11]

The European Medicines Agency (EMA) stated that the multiple sclerosis medicine fingolimod (Gilenya) must not be used in pregnant women and in women able to have children who are not using effective contraception. [12]

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). [13] [14] [15] The molecular biology of phospho-fingolimod is thought to lie in its activity at one of the five sphingosine-1-phosphate receptors, S1PR1. [16] Phospho-fingolimod causes the internalization of S1P receptors, which sequesters lymphocytes in lymph nodes, preventing them from moving to the central nervous system and causing a relapse of 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, which involves the arachidonic acid pathway, which is unrelated to sphingosine phosphate receptors. [17] This has implications both for increasing susceptibility to viral infections as well as enhancing therapeutic efficacy in multiple sclerosis. [17]

Additionally, fingolimod shifts macrophages to an anti-inflammatory M2 phenotype. It modulates their proliferation, morphology, and cytokine release via inhibition of the transient receptor potential cation channel, subfamily M, member 7. (TRPM7). [18]

Finally, fingolimod has also been found to have other molecular targets and functions. Fingolimod has been reported to be a cannabinoid receptor antagonist, [19] a cPLA2 inhibitor [20] and a ceramide synthase inhibitor. [21] [22] It has also been reported to stimulate the repair process of glial cells and glial precursor cells after injury. [23]

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. [24] 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. [25] A recent review highlights the synthetic methods, mode of action and potential applications of this molecule. [26] 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 drug ability. [24]

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.

In September 2010, fingolimod became the first oral disease-modifying drug approved by the U.S. Food and Drug Administration (FDA) to reduce relapses and delay disability progression in patients with relapsing forms of multiple sclerosis. [27] [28] In April 2011 Novartis said that the drug would be available in Canadian pharmacies. [29] [30] In March 2011, the European Medicines Agency approved the drug for use in the European Union. [31]

In 2016, a systematic review concluded that treatment of people relapsing-remitting multiple sclerosis is effective in reducing the probability of acute inflammatory relapses, with potentially little or no effect on disability progression, compared to placebo. [32] The risk/benefit profile compared to other disease-modifiying therapies being unclear due to a lack of direct comparisons. [32]

In December 2019, generic fingolimod was approved in the United States for the treatment of relapsing forms of multiple sclerosis in adults. [11] The FDA granted approvals of generic fingolimod applications to HEC Pharm Co. Limited, Biocon Limited and Sun Pharmaceutical Industries Limited. [11]

On 19 July 2019, fingolimod received fast approval for use in China. [33]

Society and culture

In 2015, after a challenge at the US Patent and Trademark Office by a generic competitor, the patent office quashed Novartis's patent claims stating they were obvious. Novartis appealed and the federal circuit upheld the patent office decision in April 2017, leaving a high likelihood of generics coming to market by 2019. [34]

In January 2020, a panel of judges at the Court of Appeal for the Federal Circuit called into question the validity of the last remaining orange book patent protecting Gilenya. [35]

In October 2022, the Supreme Court turned down a request by Novartis to block the launch of generic versions of Gilenya in the United States. [36] [37]

In April 2023, the U.S. Supreme Court declined to hear Novartis's request to revive a key patent on Gilenya that had been invalidated by a lower court. [38]

Research

Clinical trials are ongoing to prevent neuropathic pain in patients with breast cancer treated with paclitaxel. [39] Recently, the fingolimod molecule has been incorporated in mRNA delivery vehicles to increase targeting of lymphocytes expressing the S1P1 receptor in pre-clinical models. [40]

Related Research Articles

<span class="mw-page-title-main">Immunosuppressive drug</span> Drug that inhibits activity of immune system

Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.

Daclizumab is a therapeutic humanized monoclonal antibody which was used for the treatment of adults with relapsing forms of multiple sclerosis (MS). Daclizumab works by binding to CD25, the alpha subunit of the IL-2 receptor of T-cells.

<span class="mw-page-title-main">Natalizumab</span> Medication used to treat multiple sclerosis and Crohns disease

Natalizumab, sold under the brand name Tysabri among others, is a medication used to treat multiple sclerosis and Crohn's disease. It is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin. It is given by intravenous infusion. The drug is believed to work by reducing the ability of inflammatory immune cells to attach to and pass through the cell layers lining the intestines and blood–brain barrier.

<span class="mw-page-title-main">Cladribine</span> Pharmaceutical drug

Cladribine, sold under the brand name Leustatin, among others, is a medication used to treat hairy cell leukemia and B-cell chronic lymphocytic leukemia. Cladribine, sold under the brand name Mavenclad, is used for the treatment of adults with highly active forms of relapsing-remitting multiple sclerosis.

<span class="mw-page-title-main">Alemtuzumab</span> Medication used to treat chronic lymphocytic leukemia (CLL)

Alemtuzumab, sold under the brand names Campath and Lemtrada among others, is a medication used to treat chronic lymphocytic leukemia (CLL) and multiple sclerosis. In CLL, it has been used as both a first line and second line treatment. In MS it is generally only recommended if other treatments have not worked. It is given by injection into a vein.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system (CNS). Several therapies for it exist, although there is no known cure.

<span class="mw-page-title-main">Glatiramer acetate</span> Medication

Glatiramer acetate, sold under the brand name Copaxone among others, is an immunomodulator medication used to treat multiple sclerosis. Glatiramer acetate is approved in the United States to reduce the frequency of relapses, but not for reducing the progression of disability. Observational studies, but not randomized controlled trials, suggest that it may reduce progression of disability. While a conclusive diagnosis of multiple sclerosis requires a history of two or more episodes of symptoms and signs, glatiramer acetate is approved to treat a first episode anticipating a diagnosis. It is also used to treat relapsing-remitting multiple sclerosis. It is administered by subcutaneous injection.

<span class="mw-page-title-main">Myriocin</span> Chemical compound

Myriocin, also known as antibiotic ISP-1 and thermozymocidin, is a non-proteinogenic amino acid derived from certain thermophilic fungi.

Sphingosine-1-phosphate (S1P) is a signaling sphingolipid, also known as lysosphingolipid. It is also referred to as a bioactive lipid mediator. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcohol, which is sphingosine.

<span class="mw-page-title-main">Belimumab</span> Pharmaceutical drug

Belimumab, sold under the brand name Benlysta, is a human monoclonal antibody that inhibits B-cell activating factor (BAFF), also known as B-lymphocyte stimulator (BLyS). It is approved in the United States and Canada, and the European Union to treat systemic lupus erythematosus and lupus nephritis.

Ocrelizumab, sold under the brand name Ocrevus, is a medication used for the treatment of multiple sclerosis (MS). It is a humanized anti-CD20 monoclonal antibody. It targets CD20 marker on B lymphocytes and is an immunosuppressive drug. Ocrelizumab binds to an epitope that overlaps with the epitope to which rituximab binds.

<span class="mw-page-title-main">Ofatumumab</span> Medication

Ofatumumab is a fully human monoclonal antibody to CD20, which appears to provide rapid B-cell depletion. Under the brand name Kesimpta, it is approved for the treatment of multiple sclerosis in the United States as well as in the European Union and other regions. Under the brand name Arzerra, it is approved for the treatment of certain types of chronic lymphocytic leukemia (CLL) in the United States. It is sold by Novartis under license from Genmab.

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<span class="mw-page-title-main">S1PR1</span> Protein and coding gene in humans

Sphingosine-1-phosphate receptor 1, also known as endothelial differentiation gene 1 (EDG1) is a protein that in humans is encoded by the S1PR1 gene. S1PR1 is a G-protein-coupled receptor which binds the bioactive signaling molecule sphingosine 1-phosphate (S1P). S1PR1 belongs to a sphingosine-1-phosphate receptor subfamily comprising five members (S1PR1-5). S1PR1 was originally identified as an abundant transcript in endothelial cells and it has an important role in regulating endothelial cell cytoskeletal structure, migration, capillary-like network formation and vascular maturation. In addition, S1PR1 signaling is important in the regulation of lymphocyte maturation, migration and trafficking.

<i>Isaria sinclairii</i> Species of fungus

Isaria sinclairii is a species of entomopathogenic fungus mostly infecting the underground nymphs of cicadas. It produces myriocin, from which the synthetic drug fingolimod, a treatment for multiple sclerosis, was developed.

<span class="mw-page-title-main">Ponesimod</span> Medication for the treatment of multiple sclerosis

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<span class="mw-page-title-main">Ozanimod</span> Medication

Ozanimod, sold under the brand name Zeposia, is an immunomodulatory medication for the treatment of relapsing multiple sclerosis and ulcerative colitis. It acts as a sphingosine-1-phosphate receptor (S1PR) agonist, sequestering lymphocytes to peripheral lymphoid organs and away from their sites of chronic inflammation.

<span class="mw-page-title-main">Siponimod</span> Chemical compound

Siponimod, sold under the brand name Mayzent, is a selective sphingosine-1-phosphate receptor modulator for oral use that is used for multiple sclerosis (MS). It is intended for once-daily oral administration.

There are several ways for pharmaceuticals for treating multiple sclerosis (MS) to reach the market.

<span class="mw-page-title-main">Sphingosine-1-phosphate receptor modulator</span> Drug class

Sphingosine-1-phosphate receptor modulators are a class of drugs used as immunomodulators, most notably in cases of multiple sclerosis.

References

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  22. ↑ Lahiri S, Park H, Laviad EL, Lu X, Bittman R, Futerman AH (June 2009). "Ceramide synthesis is modulated by the sphingosine analog FTY720 via a mixture of uncompetitive and noncompetitive inhibition in an Acyl-CoA chain length-dependent manner". The Journal of Biological Chemistry. 284 (24): 16090–8. doi: 10.1074/jbc.M807438200 . PMC   2713526 . PMID   19357080.
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  25. ↑ Fujita T, Yoneta M, Hirose R, Sasaki S, Inoue K, Kiuchi M, et al. (1995). "Simple compounds, 2-alkyl-2-amino-1,3-propanediols have potent immunosuppressive activity". Bioorg. Med. Chem. Lett. 5 (8): 847–52. doi:10.1016/0960-894X(95)00126-E.
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  33. ↑ "Novartis key multiple sclerosis product Gilenya approved in China". Novartis (Press release).
  34. ↑ Sagonowsky E (13 April 2017). "Novartis' Gilenya patent loss sets MS market up for battle with early generics". FiercePharma.
  35. ↑ "CAFC Oral Argument Recording".
  36. ↑ "Search - Supreme Court of the United States". U.S. Supreme Court. Retrieved 17 October 2022.
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  39. ↑ "Unlocking the Mystery of "Chemo Brain"". 2 September 2022.
  40. ↑ Testa S, Haabeth OA, Blake TR, Del Castillo TJ, Czerwinski DK, Rajapaksa R, et al. (July 2022). "Fingolimod-Conjugated Charge-Altering Releasable Transporters Efficiently and Specifically Deliver mRNA to Lymphocytes In Vivo and In Vitro". Biomacromolecules. 23 (7): 2976–2988. doi:10.1021/acs.biomac.2c00469. PMC   10199726 . PMID   35748182. S2CID   249989444.{{cite journal}}: CS1 maint: overridden setting (link)
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