Dimethyl fumarate

Dimethyl fumarate
Dimethyl fumarate
Names
Preferred IUPAC name
Dimethyl (2E)-but-2-enedioate
Other names
trans-1,2-Ethylenedicarboxylic acid dimethyl ester
(E)-2-Butenedioic acid dimethyl ester
Identifiers
CAS Number
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
EC Number
  • 210-849-0
KEGG
PubChem CID
UNII
InChI
  • InChI=1S/C6H8O4/c1-9-5(7)3-4-6(8)10-2/h3-4H,1-2H3/b4-3+ checkY
    Key: LDCRTTXIJACKKU-ONEGZZNKSA-N checkY
  • InChI=1/C6H8O4/c1-9-5(7)3-4-6(8)10-2/h3-4H,1-2H3/b4-3+
    Key: LDCRTTXIJACKKU-ONEGZZNKBJ
SMILES
  • O=C(OC)\C=C\C(=O)OC
Properties
Chemical formula
 C6H8O4
Molar mass 144.126 g·mol−1
Appearance White crystalline solid
Density 1.37 g/cm3
Melting point 103.5 °C (218.3 °F; 376.6 K)[1]
Boiling point 193 °C (379 °F; 466 K)[1]
Pharmacology
L04AX07 (WHO)
License data
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only [2]
  • EU: Rx-only
Hazards
GHS pictograms GHS07: Harmful
GHS Signal word Warning
GHS hazard statements
 H312, H315, H317, H319, H335
GHS precautionary statements
 P261, P264, P271, P272, P280, P302+352, P304+340, P305+351+338, P312, P321, P322, P332+313, P333+313, P337+313, P362, P363, P403+233, P405, P501
Related compounds
Related diesters
 Diethyl fumarate, dimethyl maleate, dimethyl malonate, dimethyl adipate
Related compounds
 Fumaric acid
Methyl acrylate
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)
Infobox references

Dimethyl fumarate (DMF), sold under the brand name Tecfidera among others, is a medication used to treat multiple sclerosis and psoriasis.[2][3][4]

It is the methyl ester of fumaric acid and is named after the earth smoke plant (Fumaria officinalis).[5] It was approved for medical use in the United States in 2013.[2] DMF is thought to have immunomodulatory properties without causing significant immunosuppression.[6]

DMF has also been applied as a biocide in furniture or shoes to prevent growths of mold during storage or transport in a humid climates. However, due to cases of allergic reactions after skin contact, DMF-containing consumer products are no longer authorised to be manufactured (since 1998) or imported (since 2009) in the European Union.[7] Dimethyl fumarate is approved as a generic medication in the United States as of 2020.[8]

Medical uses

In Germany, DMF is used to trea psoriasis and is available as an oral formulation mixed with related compounds (Fumaderm);[3] in the UK, it is available as a pure oral formulation (Skilarence).[9] It is also available in the U.S. as an oral formulation (Tecfidera) to treat adults with relapsing multiple sclerosis.[2]

For the treatment of psoriasis, DMF is dosed in 30 mg and 120 mg tablets, and the maximum daily dose is 720 mg. For multiple sclerosis, the doses are 120 mg and 240 mg , with a maximum daily dose of 480 mg.[7][9] A 2015 Cochrane systematic review found moderate quality evidence of a reduction in the number of people with relapsing remitting MS that had relapses over a two-year treatment period with DMF versus placebo, as well as low quality evidence of a reduction in worsening disability, and an overall need for higher quality studies with longer follow-up.[10]

Side effects

Allergy to dimethyl fumarate/dermatitis

In the treatment of psoriasis, the most common adverse events are gastrointestinal events, flushing and lymphopenia, which are usually mild. Other adverse events include progressive multifocal leukoencephalopathy (PML) and Fanconi syndrome, which are considered rare. PML is probably caused by a combination of factors. A previous infection with the John-Cunningham virus (JCV) is considered a prerequisite for the development of PML. In a PML review, all confirmed cases were of patients exposed to periods of varying lymphopenia.[11]

For multiple sclerosis, adverse effects include flushing and gastrointestinal events, such as diarrhoea, nausea and upper abdominal pain.[10] The drug label includes warnings about the risk of anaphylaxis and angio-oedema, PML, lymphopenia and liver damage.[2][12]

There is no information on how DMF affects the fetus during pregnancy; in animal tests there was fetal harm at clinically relevant doses.[2]

Pharmacology

Dimethyl fumarate is a lipophilic, highly mobile molecule in human tissue. As an α,β-unsaturated electrophilic compound, DMF is rapidly attacked by the detoxifying agent glutathione (GSH) in a Michael addition reaction.[13][14][15] Through these reactions, it is metabolised to monomethyl fumarate (MMF) prior to entering systemic distribution.[2][16] DMF has been described a prodrug.[17]

DMF is a precursor of monomethyl fumarate. Other prodrugs that metabolize to monomethyl fumarate have been developed to treat relapse-remitting multiple sclerosis, including diroximel fumarate which was approved by the FDA in October 2019.[18][19][20]

The precise mechanism of action of DMF is not clear. DMF and MMF can activate the transcription factor (Nuclear factor erythroid-derived 2)-related factor 2 (Nrf2) pathway and MMF has been identified as a nicotinic acid receptor agonist in vitro.[2] In mice that lack Nrf2 expression, however, DMF is still able to modulate the immune system, which indicates that Nrf2 is not required for its immunomodulatory action.[21] For psoriasis, the mechanism of action is believed to be due to the interaction of MMF and the intracellular reduced glutathione of cells directly involved in the pathogenesis of psoriasis. The interaction with glutathione leads to the inhibition of nuclear translocation and the transcriptional activity of the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB).[16]

More recently, DMF and MMF has been shown to reduce the expression of micro-RNA-21, which is essential for the production of pathogenic cells in multiple sclerosis and psoriasis. This can be achieved because DMF and MMF, as cell-permeable metabolites, can epigenetically regulate the expression of micro-RNA-21 via the metabolic-epigenetic interplay in developing immune cells.[22]

The main activity of DMF and MMF is considered to be immunomodulatory, resulting in a shift in T helper cells (Th) from the Th1 and Th17 profile to a Th2 phenotype. Inflammatory cytokine production is reduced by the induction of proapoptotic events, inhibition of keratinocyte proliferation, reduced expression of adhesion molecules and diminished inflammatory infiltrate within psoriatic plaques.[16]

The primary route of elimination is via exhalation of CO2, with small amounts excreted through urine or faeces.[16]

There is no evidence for DMF interaction with cytochrome P450 and the most common efflux and uptake transporters, and therefore no interactions are expected with medicinal products metabolised or transported by these systems.[16]

History

The first medical use of fumaric acid, as a topical formulation for psoriasis, was described in 1959 by Walter Schweckendiek, a German chemist,[23] and was a topical formulation for psoriasis. The Swiss company Fumapharm eventually brought Fumaderm, an oral formulation of DMF (along with some monoesters) to market for psoriasis in Germany in 1994.[24][25][26]

Based on the efficacy and safety of this formulation, and evidence that DMF was the main active component, an oral formulation of DMF was developed by Almirall.[27] This oral formulation, under the brand name Skilarence, was approved in Europe by the EMA in June 2017 for the treatment of moderate-to-severe plaque psoriasis in adults.[9]

Initial clinical research on the use of DMF for the treatment of multiple sclerosis was conducted by Fumapharm in collaboration with Biogen Idec; Fumapharm was subsequently acquired by Biogen Idec in 2006.[24][28] Aditech Pharma in Sweden had also been researching oral formulations of DMF for MS and in 2010, the Danish company Forward Pharma acquired Aditech's patents.[28]

Biogen continued developing its oral formulation of DMF from Fumapharm under the code name BG-12; it was approved, under the trade name Tecfidera, for the treatment of adults with relapsing forms of MS in March 2013.[29] Biogen priced the drug at $54,000 per year in the US.[24] It was approved in Europe in 2014.[30] In the UK NICE issued guidance recommending the drug as cost-effective, but only for patients who do not have highly active or rapidly evolving severe relapsing–remitting multiple sclerosis and only if Biogen agreed to provide it at a discount.[31]

Forward and Biogen entered into patent litigation in many jurisdictions; in 2017 the companies settled the litigation, with Biogen paying Forward $1.25 billion, with the potential for up to 10% of royalties depending on what happened with the patents in various jurisdictions.[28]

In June 2020, In a case between Biogen and Mylan, the U.S. District Court in West Virginia declared invalid Biogen’s so-called “514” patent protecting Tecfidera from generic competition. The ruling gave Mylan the right to launch its own version of Tecfidera within days, although Biogen planned to file an appeal.[32][33][34]

Society and culture

Synthesis

Several methods exist for the laboratory synthesis of DMF, with reported methods including alkene isomerization of dimethyl maleate,[35][36][37] and Fischer esterification of fumaric acid.[35]

Dimethyl fumarate is an old compound used in industrial chemistry and can be purchased by the ton; as of 2012, one could purchase it for $1 to $50 per metric ton, with a two-ton minimum purchase.[38][24]

The compound undergoes electrohydrodimerization.[39]

Consumer products

There have been cases of severe contact dermatitis which was likely related to a dimethyl fumarate contact allergy of newly acquired sofas and chairs. Dimethyl fumarate has been found to be an allergic sensitizer at very low concentrations, producing eczema by contact allergy that is difficult to treat. Concentrations as low as 1 ppm (parts-per-million) may produce allergic reactions in the most severe cases.[40] There are only a handful of equally potent sensitisers.[41]

The sensitizing risk was brought to public attention by the "poison chair" incident, where Chinese manufacturer Linkwise produced two-seater sofas with DMF sachets inside to inhibit mould while they were in storage or transport.[42] In Finland where the chairs were sold from 2006 to 2007, 60 users sustained serious rashes.[41] The cause was identified as DMF-induced allergic reaction by Tapio Rantanen from Finland and his original article became the cover story in the July 2008 issue of the British Journal of Dermatology.[40] In the United Kingdom, sofas sold by Argos, Land of Leather and Walmsley Furnishing containing the chemical caused over a hundred injuries.[41] Argos withdrew the sofas from stores and contacted buyers to collect those that had been sold — with Land of Leather withdrawing the sofas without notifying buyers and Walmsley saying they had removed the sachets from sofas they sold after the danger came to light.[43][44] The danger came to public attention in 2008 when the BBC Watchdog programme alerted consumers to the sofas.[43][45]

In the European Union, the use of DMF in consumer product manufacturing has been forbidden since 1998, and in 2009 the importation of consumer products containing DMF was also forbidden.[7] EU Commission Decision 2009/251 of 17 March 2009 required member states to ensure that consumer products containing DMF were not placed or made available on the market from 1 May 2009. This definitely outlawed any marketing of consumer products containing DMF in the European Union.[46] The ban on DMF as laid down in Decision 2009/251 establishes a maximum DMF concentration in products of 0.1 ppm. The decision dictated that consumer products containing more than 0.1 ppm DMF should be withdrawn from the market and recalled from consumers.

See also

References

  1. 1 2 "Background document to the opinions on the Annex XV dossier proposing restrictions on Dimethylfumarate (DMFu)" (PDF). European Chemicals Agency. 16 March 2011. p. 9. Archived from the original (PDF) on 22 February 2021. Retrieved 15 May 2021.
  2. 1 2 3 4 5 6 7 8 "Tecfidera- dimethyl fumarate kit Tecfidera- dimethyl fumarate capsule". DailyMed. Archived from the original on 4 May 2021. Retrieved 13 February 2021.
  3. 1 2 Mrowietz, Ulrich; Altmeyer, Peter; Bieber, Thomas; et al. (2007). "Treatment of psoriasis with fumaric acid esters (Fumaderm)". Journal der Deutschen Dermatologischen Gesellschaft. 5 (8): 716–7. doi:10.1111/j.1610-0387.2007.06346.x. PMID 17659047. S2CID 7431706.
  4. ↑ "Agency EM. Skilarence [Updated]". Archived from the original on 2018-06-20. Retrieved 2022-03-14.
  5. ↑ Linker RA, Haghikia A. Dimethyl fumarate in multiple sclerosis: latest developments, evidence and place in therapy. Ther Adv Chronic Dis. 2016;7(4):198-207.
  6. ↑ McEntee, Joanne. "Fumaderm: what is the evidence for its efficacy and safety". North West Medicines Information Centre. Archived from the original on 5 May 2013. Retrieved 29 November 2012.
  7. 1 2 3 "Consumers: EU to ban dimethylfumarate (DMF) in consumer products, such as sofas and shoes" (Press release). European Commission. Archived (PDF) from the original on 31 August 2013. Retrieved 29 November 2012.
  8. ↑ "Office of Generic Drugs 2020 Annual Report". U.S. Food and Drug Administration (FDA). Archived from the original on 12 February 2021. Retrieved 12 February 2021.
  9. 1 2 3 "Skilarence 120 mg Gastro-resistant Tablets - Summary of Product Characteristics". Electronic Medicines Compendium. May 2018. Archived from the original on 19 July 2018. Retrieved 19 July 2018.
  10. 1 2 Xu, Zhu; Zhang, Feng; Sun, FangLi; Gu, KeFeng; Dong, Shuai; He, Dian (2015-04-22). "Dimethyl fumarate for multiple sclerosis". The Cochrane Database of Systematic Reviews (4): CD011076. doi:10.1002/14651858.CD011076.pub2. ISSN 1469-493X. PMID 25900414.
  11. ↑ Gieselbach RJ, Muller-Hansma AH, Wijburg MT, et al. Progressive multifocal leukoencephalopathy in patients treated with fumaric acid esters: a review of 19 cases. J Neurol. 2017;264(6):1155-1164.
  12. ↑ "FDA Drug Safety Communication: FDA warns about case of rare brain infection PML with MS drug Tecfidera (dimethyl fumarate)". fda.gov. Archived from the original on 30 November 2014. Retrieved 2 December 2014.
  13. ↑ Boyland, E; Chasseaud, LF (1967). "Enzyme-catalysed conjugations of glutathione with unsaturated compounds". The Biochemical Journal. 104 (1): 95–102. doi:10.1042/bj1040095. PMC 1270549. PMID 6035529.
  14. ↑ Kubal, Gina; Meyer, David J.; Norman, Richard E.; Sadler, Peter J. (1995). "Investigations of Glutathione Conjugation in Vitro by 1H NMR Spectroscopy. Uncatalyzed and Glutathione Transferase-Catalyzed Reactions". Chemical Research in Toxicology. 8 (5): 780–91. doi:10.1021/tx00047a019. PMID 7548762.
  15. ↑ Schmidt, Thomas J.; Ak, Muharrem; Mrowietz, Ulrich (2007). "Reactivity of dimethyl fumarate and methylhydrogen fumarate towards glutathione and N-acetyl-l-cysteine—Preparation of S-substituted thiosuccinic acid esters". Bioorganic & Medicinal Chemistry. 15 (1): 333–42. doi:10.1016/j.bmc.2006.09.053. PMID 17049250.
  16. 1 2 3 4 5 "Skilarence Summary of Product Characteristics" (PDF). Almirall, May 2018 [Updated]. Archived (PDF) from the original on 2018-06-18. Retrieved 2021-05-15. {{cite web}}: Check date values in: |date= (help)
  17. ↑ Goldhill, Jon (September 15, 2015). "Disappointing Phase 2 psoriasis data reported for the monomethyl fumarate prodrug, XP23829". Advances in drug discovery. Archived from the original on May 15, 2020. Retrieved May 15, 2021.
  18. ↑ "Vumerity (Previously BIIB098 and ALKS 8700)". Multiple Sclerosis News Today. 1 November 2019. Archived from the original on 7 March 2020. Retrieved 21 February 2020.
  19. ↑ "Biogen and Alkermes Announce FDA Approval of Vumerity (diroximel fumarate) for Multiple Sclerosis". Biogen. Archived from the original on 2020-02-21. Retrieved 2020-02-21.
  20. ↑ "Drug Approval Package: Vumerity". U.S. Food and Drug Administration (FDA). 21 April 2020. Archived from the original on 6 February 2021. Retrieved 1 February 2021.
  21. ↑ Schulze-Topphoff, U; Varrin-Doyer, M; Pekarek, K; Spencer, CM; Shetty, A; Sagan, SA; Cree, BA; Sobel, RA; Wipke, BT; Steinman, L; Scannevin, RH; Zamvil, SS (26 April 2016). "Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2". Proceedings of the National Academy of Sciences of the United States of America. 113 (17): 4777–82. Bibcode:2016PNAS..113.4777S. doi:10.1073/pnas.1603907113. PMC 4855599. PMID 27078105.
  22. ↑ Ntranos, Achilles; Ntranos, Vasilis; Bonnefil, Valentina; Liu, Jia; Kim-Schulze, Seunghee; He, Ye; Zhu, Yunjiao; Brandstadter, Rachel; Watson, Corey T; Sharp, Andrew J; Katz Sand, Ilana; Casaccia, Patrizia (March 2019). "Fumarates target the metabolic-epigenetic interplay of brain-homing T cells in multiple sclerosis". Brain. 142 (3): 647–661. doi:10.1093/brain/awy344. PMC 6821213. PMID 30698680.
  23. ↑ "Immunomodulatory Effects of Drugs for Treatment of Immune-Related Diseases". Archived from the original on 2020-05-16. Retrieved 2021-05-15.
  24. 1 2 3 4 Lowe, Derek (2 April 2013). "Tecfidera's Price". In the Pipeline. Archived from the original on 11 November 2020. Retrieved 15 May 2021.
  25. ↑ Ettmayer, P; Schnitzer, R; Bergner, A; Nar, H (2017). "Chapter 2.02: Hit and Lead Generation Strategies". In Chackalamannil, Samuel; Rotella, David; Ward, Simon; Martinez, Ana; Gil, Carmen (eds.). Comprehensive Medicinal Chemistry III: Volume 2: Drug Discovery Technologies. Elsevier. p. 58. ISBN 9780128032015. Archived from the original on 2020-05-18. Retrieved 2021-05-15.
  26. ↑ Lijnen R, Otters E, Balak D, et al. Long-term safety and effectiveness of high-dose dimethylfumarate in the treatment of moderate to severe psoriasis: a prospective single-blinded follow-up study. J Dermatolog Treat. 2016;27(1):31-36.
  27. ↑ Blair HA. Dimethyl Fumarate: A Review in Moderate to Severe Plaque Psoriasis. Drugs. 2017.
  28. 1 2 3 Vinluan, Frank (17 January 2017). "Xconomy: Biogen to Pay $1.25B to Settle Forward Pharma Patent Suit on MS Drug". Xconomy. Archived from the original on 24 November 2020. Retrieved 15 May 2021.
  29. ↑ "FDA approves new multiple sclerosis treatment: Tecfidera". FDA. Mar 27, 2013. Archived from the original on 2013-03-29. Retrieved 2013-04-05.
  30. ↑ "Tecfidera 120mg and 240mg gastro-resistant hard capsules - Summary of Product Characteristics". Electronic Medicines Compendium. February 2018. Archived from the original on 19 July 2018. Retrieved 19 July 2018.
  31. ↑ Burke, MJ; Richardson, J; George, E; Adler, AI (November 2014). "Dimethyl fumarate for relapsing-remitting multiple sclerosis". The Lancet. Neurology. 13 (11): 1077–1078. doi:10.1016/S1474-4422(14)70159-0. PMID 28845815. open access
  32. ↑ "Biogen loses patent dispute with Mylan, putting its top drug's future in doubt". BioPharma Dive. Archived from the original on 2020-06-20. Retrieved 2020-06-19.
  33. ↑ "BRIEF-Biogen Says To Appeal Court Decision Regarding Patent Related To Tecfidera". Reuters. 2020-06-18. Archived from the original on 2020-06-20. Retrieved 2020-06-19.
  34. ↑ Alpert, Bill. "Biogen Stock Is Slumping After Judge Rules Against Its Biggest Drug". www.barrons.com. Archived from the original on 2020-06-18. Retrieved 2020-06-19.
  35. 1 2 Two Approaches to the Synthesis of Dimethyl Fumarate That Demonstrate Fundamental Principles of Organic Chemistry Brian E. Love and Lisa J. Bennett Journal of Chemical Education 2017 94 (10), 1543-1546 doi:10.1021/acs.jchemed.6b00818
  36. ↑ Ledlie, David B.; Wenzel, Thomas J.; Hendrickson, Susan M. (1989). "Isomerization of dimethyl maleate to dimethyl fumarate: An undergraduate experiment utilizing high performance liquid chromatography". Journal of Chemical Education. 66 (9): 781. Bibcode:1989JChEd..66..781L. doi:10.1021/ed066p781.
  37. ↑ Fryhle, Craig B.; Rybak, Carol M.; Pulley, Kenneth E. (1991). "Isomerization of dimethyl maleate to dimethyl fumarate: An undergraduate experiment illustrating amine-catalyzed alkene isomerization, stereochemical principles, sublimation, and product identification by spectroscopic methods". Journal of Chemical Education. 68 (12): 1050. Bibcode:1991JChEd..68.1050F. doi:10.1021/ed068p1050.
  38. ↑ Hamilton, Mike (13 September 2012). "Just how much profit is there in a new drug?". Biotech Translated. Archived from the original on 28 February 2021. Retrieved 15 May 2021.
  39. ↑ D. A. White (1981). "Electrohydrodimerization of an Activated Alkene: Tetraethyl 1,2,3,4-Butanetetracarboxylate". Organic Syntheses. 60: 58. doi:10.15227/orgsyn.060.0058.
  40. 1 2 Rantanen, T. (2008). "The cause of the Chinese sofa/chair dermatitis epidemic is likely to be contact allergy to dimethylfumarate, a novel potent contact sensitizer". British Journal of Dermatology. 159 (1): 218–21. doi:10.1111/j.1365-2133.2008.08622.x. PMID 18503603. S2CID 45134115.
  41. 1 2 3 "Myrkkytuoli-ihottumien syy selvisi". YLE Uutiset (in suomi). YLE. 2008-04-24. Archived from the original on 2013-01-06. Retrieved 2008-06-10.
  42. ↑ "Clifton woman's toxic sofa claim". The Nottingham Post. Local World. 2 Apr 2009.
  43. 1 2 BBC - Consumer - TV and radio - itchy sofas Archived February 22, 2008, at the Wayback Machine
  44. ↑ "BBC: Judge rejects 'toxic sofa' claims in burns injury cases, 18 March 2010". Archived from the original on 28 August 2021. Retrieved 15 May 2021.
  45. ↑ "BBC: 3 reports on dimethyl fumarate in furniture". April 2010. Archived from the original on 2021-08-28. Retrieved 2021-05-15.
  46. ↑ "2009/251/EC: Commission Decision of 17 March 2009". Archived from the original on 19 September 2020. Retrieved 15 May 2021.
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