Fingolimod

from Wikipedia, the free encyclopedia
Structural formula
Structure of fingolimod
General
Non-proprietary name Fingolimod
other names
  • FTY-720
  • 2-amino-2- (2- (4-octylphenyl) ethyl) propane-1,3-diol
Molecular formula C 19 H 33 NO 2
External identifiers / databases
CAS number
PubChem 107970
ChemSpider 97087
DrugBank DB08868
Wikidata Q425137
Drug information
ATC code

L04 AA27

Drug class

Immunosuppressant

Mechanism of action

Sphingosine-1-phosphate - analogue

properties
Molar mass 307.47 g mol −1
Physical state

firmly

Melting point
  • 121-124 ° C (free base)
  • 105 ° C (hydrochloride)
pK s value

7.82 ( conjugated acid )

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS hazard labeling
no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Fingolimod (trade name Gilenya ; manufacturer Novartis ) is a drug from the group of immunosuppressants that is used in the treatment of multiple sclerosis (MS) .

The drug is a synthetic replica of the natural active ingredient Myriocin . Myriocin comes from the mushroom Isaria sinclairii . Fingolimod acts as sphingosine-1-phosphate - analogue . It retains an important subgroup of white blood cells called lymphocytes in the lymph nodes , thereby reducing the number of lymphocytes that can migrate to the central nervous system and damage nerve tracts in patients with MS.

Application areas (indications)

Multiple sclerosis (MS)

Fingolimod is approved in the European Union (EU) for the treatment of patients with highly active, relapsing-remitting MS as an alternative therapy after treatment with interferon-beta or in patients with rapidly progressing, severe MS. In Switzerland , the drug is approved for the treatment of patients with relapsing-remitting MS to reduce the frequency of relapses and to delay the progression of the disability.

In November 2018, Novartis received approval for the therapy of children and adolescents with multiple sclerosis.

In the completed Phase II study , 281 MS patients were treated. After six months, magnetic resonance imaging showed a reduction in the number of active lesions of up to 80% ( median ; on average up to 60%) and a reduction in the relapse rate of around 50% compared to placebo . In an 18-month, open-label follow-up study, it was shown that the positive effects found persisted over this period.

In development phase III , since 2006, it has been investigated in patients with a relapsing-remitting form whether the effects observed in phase II remain stable over a longer period and whether treatment with fingolimod can slow the development of the disability associated with MS. These studies demonstrated effectiveness in terms of relapse rate and disability progression.

By the end of 2014, fingolimod had been studied unsuccessfully as a treatment option for patients with primary progressive multiple sclerosis.

Kidney transplant

Novartis also tested fingolimod in combination with ciclosporin to suppress the rejection reaction after kidney transplantation . (In clinical trials of phase III, however, side effects showed macula - edema ) especially in diabetic patients with predisposition to diabetic retinopathy . In addition, there was a slight functional impairment in the freshly transplanted kidneys . Since fingolimod suppression of rejection was no better than that in the control group with mycophenolate mofetil , the development of fingolimod for transplant medicine was discontinued.

Adverse effects (side effects)

Fingolimod lowers the number of white blood cells. This effect is desirable for the treatment of MS. However, white blood cells are also required to fight off infection . Treatment with fingolimod could make you more susceptible to infections. Existing infections could worsen. In 2008, two cases of serious infections with fingolimod were reported. An MS patient died of chicken pox , while a second patient has a life-threatening herpes - encephalitis developed. In both cases, however, there were circumstances that influenced the course of the infection may adversely: The first patient was the same time as high glucocorticoid - cans treated while the antiviral treatment of the second patient was started with delay.

The FDA warned in 2013 of the increased risk of developing progressive multifocal leukoencephalopathy (PML) with fingolimod. In January 2016, the manufacturer Novartis drew attention to the PML risk in a Rote-Hand-Brief (RHB) .

In a RHB from September 2019, Novartis drew attention to the fact that, due to the risk of congenital malformations in fetuses, fingolimod is contraindicated during pregnancy and in women of childbearing potential who are not using effective contraception.

An overview of the RHB in recent years can be found on the website of the drug commission of the German medical profession.

Cardiac side effects are also described: Long-term treatment can lead to a moderate increase in blood pressure . After taking fingolimod for the first time, a marked drop in heart rate ( bradycardia ) and decrease in atrioventricular conduction can be observed. This effect usually disappears after a few hours and does not reappear if the drug is taken continuously. After individual cases of severe cardiovascular disorders became known, appropriate therapy monitoring was recommended as a measure in January 2012: heart rate, blood pressure and ECG must be continuously checked for all patients within the first 6 hours after the start of therapy, and monitoring must also be carried out if necessary beyond that. According to a risk-benefit assessment by the European Medicines Agency (EMA), fingolimod should, if possible, not be administered at the same time as drugs that slow the heart rate and, if possible, should not be used in patients with certain heart diseases. In January 2013, the manufacturer Novartis again sent a revised recommendation in a ( Rote-Hand-Brief ), when the monitoring should be repeated analogous to the initial administration of fingolimod.

In November 2013, the manufacturer informed Novartis in a Rote-Hand-Brief about two cases of haemophagocytic syndrome (HPS) resulting in death in patients treated with fingolimod.

In some patients, swelling has been observed in the central visual area of ​​the fundus ( macular edema ). Macular edema can cause visual disturbances.

Pharmacological properties

Mechanism of action (pharmacodynamics)

In contrast to many previously available immunosuppressive drugs, fingolimod does not kill the immune cells or prevent them from multiplying. Instead, fingolimod inhibits the migration of lymphocytes from the lymphoid organs into the blood, thus lowering the number of inflammatory lymphocytes that could damage the central nervous system.

After ingestion, fingolimod is converted to FTY720 phosphate (FTY720-P) by the enzyme sphingosine kinase-2, which then binds to the sphingosine-1-phosphate (S1P) receptors S1P1, S1P3, S1P4, and S1P5 present on cell surfaces can. The S1P1 receptor on T and B lymphocytes is essential for the mechanism of action of FTY720-P. S1P1 receptors are 'internalized' by FTY720-P, that is, shifted from the cell membrane into the interior of the cell and broken down. This degradation is responsible for the inhibition of the S1P1-dependent migration of lymphocytes from the lymph nodes into the blood and the resulting reduced migration of inflammatory cells into peripheral organs and the central nervous system.

Early benefit assessment

Since 2011 - in Germany - newly approved drugs with new active ingredients have had to undergo an early benefit assessment by the Federal Joint Committee (G-BA) based on Section 35a SGB ​​V ( AMNOG ) if the pharmaceutical manufacturer wants to achieve a higher sales price than just the fixed amount . Only if there is an additional benefit can the pharmaceutical manufacturer negotiate a price with the umbrella association of statutory health insurance companies. This also applies to fingolimod. The G-BA passed a resolution on the "additional benefit" of fingolimod at the end of March 2012. According to the G-BA, the active substance fingolimod was confirmed to have a slight additional benefit through a statistically significant reduction in flu-like symptoms in patients with a progressive, severe relapsing-remitting course. However, the validity of the decision was limited to three years due to an increased risk profile and weak evidence of benefits. In a new benefit assessment in March 2016, IQWiG came to the conclusion: no indication of additional benefit in the new area of ​​application . The Federal Joint Committee (G-BA), however, takes the final decision on the extent of the additional benefit.

History

In the early 1990s, a Japanese team of researchers from the University of Kyoto discovered the immunosuppressive effects of myriocin. Myriocin was chemically changed to FTY720 (fingolimod) and thus better tolerated. In 1997, the Japanese company Yoshitomi licensed fingolimod to Novartis . The drug was first clinically tested in combination with cyclosporine to suppress the rejection reaction after kidney transplantation ; later, however, the development of fingolimod for transplant medicine was discontinued.

The drug was first approved for MS in 2010 in Russia and the USA. In 2011 fingolimod was also approved in Switzerland and the EU.

Trade names

Fingolimod's trade name is Gilenya . Novartis had previously announced the name Gilenia , but later changed it to its current form.

Web links

Commons : Fingolimod  - collection of images, videos and audio files

Individual evidence

  1. ↑ a b Sanghee Kim, Hyeseung Lee, Minhee Lee, Taeho Lee: Efficient Synthesis of the Immunosuppressive Agent FTY720. In: Synthesis . 2006, pp. 753-755. doi: 10.1055 / s-2006-926342 .
  2. ↑ Entry on fingolimod. In: Römpp Online . Georg Thieme Verlag, accessed on December 28, 2014.
  3. ^ FDA memorandum fingolimod. P. 11 (PDF; 4.5 MB)
  4. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
  5. ↑ Novartis receives recommendation for EU approval of therapy for the treatment of children and adolescents with multiple sclerosis (MS) , Novartis PM dated September 25, 2018, accessed on March 20, 2019
  6. ↑ Novartis announces EU approval of Gilenya® for children and adolescents with MS, making it the first and only oral disease-modifying treatment for these patients in Europe , PM Novartis November 29, 2018, accessed March 20, 2019
  7. ↑ L. Kappos, J. Antel et al. a .: Oral fingolimod (FTY720) for relapsing multiple sclerosis. In: The New England Journal of Medicine . Volume 355, Number 11, September 2006, pp. 1124-1140, doi: 10.1056 / NEJMoa052643 . PMID 16971719 .
  8. ↑ P. O'Connor, G. Comi et al. a .: Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study. In: Neurology. Volume 72, number 1, January 2009, pp. 73-79, doi: 10.1212 / 01.wnl.0000338569.32367.3d . PMID 19122034 .
  9. ↑ JA Cohen, F. Barkhof u. a .: Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. In: The New England Journal of Medicine . Volume 362, Number 5, February 2010, pp. 402-415, doi: 10.1056 / NEJMoa0907839 . PMID 20089954 .
  10. ↑ L. Kappos, EW Radue et al. a .: A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. In: The New England Journal of Medicine . Volume 362, Number 5, February 2010, pp. 387-401, doi: 10.1056 / NEJMoa0909494 . PMID 20089952 .
  11. ↑ Primary progressive multiple sclerosis: fingolimod disappoints in phase III study. DMSG , December 1, 2014.
  12. ↑ a b K. Garber: Infections cast cloud over Novartis' MS therapy. In: Nature Biotechnol. 26, 2008, pp. 844-845. PMID 18688218 .
  13. ^ FDA Drug Safety Communication .
  14. ↑ Fingolimod (Gilenya®): Risks in connection with the effects on the immune system , website of the Drug Commission of the German Medical Association (AkdÄ), accessed on October 30, 2019
  15. ↑ Fingolimod (Gilenya®): New contraindication for use during pregnancy and for women of childbearing age who do not use an effective contraceptive method , website of the Drug Commission of the German Medical Association (AkdÄ), accessed on October 30, 2019
  16. ↑ AKdA , looking for RHB's on the website of AKdA
  17. ↑ Rote-Hand-Brief on more stringent cardiovascular monitoring . (PDF; 674 kB), January 26, 2012, retrieved from the website of the Drugs Commission of the German Medical Association (AkdÄ).
  18. ↑ European Medicines Agency gives new advice to better manage risk of adverse effects on the heart with Gilenya, retrieved from the EMA website.
  19. ↑ Rote-Hand-Brief with updates on cardiovascular monitoring (PDF; 2.2 MB) retrieved from the website of the Drugs Commission of the German Medical Association (AkdÄ).
  20. ↑ Red Hand Letter from Novartis in January 2013 (PDF; 120 kB) Accessed January 8, 2013 .
  21. ↑ Red Hand Letter from Novartis in November 2013 (PDF; 535 kB) Accessed November 15, 2013 .
  22. ^ V. Brinkmann, MD Davies, CE Heise et al.: The immune modulator FTY720 targets sphingosine 1-phosphate receptors. In: J Biol Chem . 277, 2002, pp. 21453-21457. PMID 11967257
  23. ↑ a b c M. Matloubian, C. Lo, G. Cinnamon et al .: Lymphocyte egress from thymus and peripheral lymphoid organs is sphingosine 1-phosphate receptor-1 dependent. In: Nature . 427, 2004, pp. 355-360. PMID 14737169 .
  24. ^ A b V. Brinkmann, JG Cyster, T. Hla: FTY720: Sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. In: Am J Transplant. 4, 2004, pp. 1019-1025. PMID 15196057
  25. ^ V. Brinkmann: Sphingosine 1-phosphate receptors in health and disease: Mechanistic insights from gene deletion studies and reverse pharmacology. In: Pharm Ther. 115, 2007, pp. 84-105. PMID 17561264
  26. ↑ Active ingredient: Fingolimod G-BA: Information archive | Early benefit assessment (Section 35a SGB V), accessed on March 29, 2012.
  27. ↑ Early benefit assessment: G-BA makes six further decisions , G-BA press release of March 29, 2012.
  28. ↑ BMG: Announcement of a resolution (PDF; 2.2 MB), publication in the Federal Gazette ( BAnz AT 04.05.2012 B3 ).
  29. ↑ Fingolimod in multiple sclerosis: no hint of added benefit in the new indication. IQWiG press release of March 1, 2016, accessed on March 1, 2016.
  30. ^ Novartis AG: Novartis announces Russian regulatory approval for Gilenya . (PDF; 119 kB) Press release. September 10, 2010. Accessed September 29, 2010.
  31. ↑ Novartis AG: Novartis receives FDA approval for Gilenya (PDF; 40 kB). Press release. September 22, 2010. Accessed September 29, 2010.