Dimethyl fumarate
Names | |
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Preferred IUPAC name
Dimethyl (2E)-but-2-enedioate | |
Other names
trans-1,2-Ethylenedicarboxylic acid dimethyl ester
(E)-2-Butenedioic acid dimethyl ester | |
Identifiers | |
3D model (
JSmol ) |
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ChEBI | |
ChEMBL | |
ChemSpider | |
DrugBank | |
ECHA InfoCard
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100.009.863 |
EC Number |
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IUPHAR/BPS |
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KEGG | |
PubChem CID
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UNII | |
CompTox Dashboard (EPA)
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Properties | |
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 | |
By mouth | |
Legal status | |
Hazards | |
GHS labelling: | |
Warning | |
H312, H315, H317, H319, H335 | |
P261, P264, P271, P272, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P322, P332+P313, P333+P313, P337+P313, P362, P363, P403+P233, P405, P501 | |
Related compounds | |
Related
diesters |
Diethyl fumarate, dimethyl maleate, dimethyl malonate, dimethyl adipate |
Related compounds
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Fumaric acid Methyl acrylate |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Dimethyl fumarate (DMF) is the methyl
Dimethyl fumarate has also been applied as a
Medical uses
In Germany, dimethyl fumarate is marketed for the treatment of psoriasis and is available as an oral formulation mixed with related compounds (Fumaderm);[9] in the UK, it is available as a pure oral formulation (Skilarence).[2] It is also available in the US as an oral formulation (Tecfidera) to treat adults with relapsing multiple sclerosis.[4]
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 dimethyl fumarate 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.[14]
History
The first medical use of fumaric acid was described in 1959 by Walter Schweckendiek, a German chemist,[15] and was a topical formulation for psoriasis. The Swiss company Fumapharm eventually brought Fumaderm, an oral formulation of dimethyl fumarate (along with some monoesters) to market for psoriasis in Germany in 1994.[16][17][18]
Based on the efficacy and safety of this formulation, and evidence that dimethyl fumarate was the main active component, an oral formulation of dimethyl fumarate was developed by Almirall.[19] This oral formulation, under the brand name Skilarence, was approved by the European Medicines Agency (EMA) in June 2017, for the treatment of moderate-to-severe plaque psoriasis in adults.[6][2]
Initial clinical research on the use of dimethyl fumarate for the treatment of multiple sclerosis was conducted by Fumapharm in collaboration with
Biogen continued developing its oral formulation of dimethyl fumarate 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.[21] Biogen priced the drug at $54,000 per year in the US.[16] It was approved in Europe in 2014.[3] 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.[22]
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.[20]
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.[23][24][25]
Pharmacology
Dimethyl fumarate is metabolized to monomethyl fumarate (MMF) prior to entering systemic distribution.[4][26] Dimethyl fumarate has been described a prodrug.[27]
Dimethyl fumarate 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.[28][29][30]
The precise mechanism of action of dimethyl fumarate is not clear. Dimethyl fumarate and monomethyl fumarate can activate the
Dimethyl fumarate and monomethyl fumarate have 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 dimethyl fumarate and monomethyl fumarate, as cell-permeable metabolites, can epigenetically regulate the expression of micro-RNA-21 via the metabolic-epigenetic interplay in developing immune cells.[32]
The main activity of dimethyl fumarate and monomethyl fumarate 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.[26]
The primary route of elimination is via exhalation of CO2, with small amounts excreted through urine or faeces.[26]
There is no evidence for dimethyl fumarate 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.[26]
Synthesis and reactions
Several methods exist for the laboratory synthesis of dimethyl fumarate, with reported methods including
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.[36][16]
The compound undergoes electrohydrodimerization.[37]
Adverse effects
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.[38]
For multiple sclerosis, adverse effects include flushing and gastrointestinal events, such as diarrhoea, nausea and upper abdominal pain.
There is no information on how dimethyl fumarate affects the fetus during pregnancy; in animal tests there was fetal harm at clinically relevant doses.[4]
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
The sensitizing risk was brought to public attention by the "poison chair" incident, where Chinese manufacturer Linkwise produced two-seater sofas with dimethyl fumarate sachets inside to inhibit mould while they were in storage or transport.
In the European Union, the use of dimethyl fumarate in consumer product manufacturing has been forbidden since 1998, and in 2009 the importation of consumer products containing dimethyl fumarate was also forbidden.[12] EU Commission Decision 2009/251 of 17 March 2009 required member states to ensure that consumer products containing dimethyl fumarate were not placed or made available on the market from 1 May 2009. This definitely outlawed any marketing of consumer products containing dimethyl fumarate in the European Union.[46] The ban on dimethyl fumarate as laid down in Decision 2009/251 establishes a maximum dimethyl fumarate concentration in products of 0.1 ppm. The decision dictated that consumer products containing more than 0.1 ppm dimethyl fumarate should be withdrawn from the market and recalled from consumers.
Research
In 2021, dimethyl fumarate was evaluated as a treatment for COVID-19 as part of the RECOVERY Trial in the UK.[47] The results of the trial found that dimethyl fumarate did not significantly improve clinical outcomes in hospitalized COVID-19 patients.[48]
References
- ^ a b "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 19 July 2018.
- ^ a b c "Skilarence 120 mg Gastro-resistant Tablets - Summary of Product Characteristics". Electronic Medicines Compendium. May 2018. Retrieved 19 July 2018.
- ^ a b "Tecfidera 120mg and 240mg gastro-resistant hard capsules - Summary of Product Characteristics". Electronic Medicines Compendium. February 2018. Retrieved 19 July 2018.
- ^ a b c d e f g "Tecfidera- dimethyl fumarate kit Tecfidera- dimethyl fumarate capsule". DailyMed. Retrieved 13 February 2021.
- ^ "Tecfidera EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 25 May 2022.
- ^ a b c "Skilarence EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 25 May 2022.
- ^ a b "Dimethyl fumarate Accord EPAR". European Medicines Agency. 12 October 2022. Retrieved 22 February 2023.
- ^ 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.
- ^ S2CID 7431706.
- ^ "Agency EM. Skilarence [Updated]". 17 September 2018. Archived from the original on 20 June 2018. Retrieved 26 February 2019.
- ^ 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.
- ^ a b "Consumers: EU to ban dimethylfumarate (DMF) in consumer products, such as sofas and shoes" (Press release). European Commission. Retrieved 29 November 2012.
- ^ "Office of Generic Drugs 2020 Annual Report". U.S. Food and Drug Administration (FDA). Retrieved 12 February 2021.
- ^ PMID 25900414.
- ^ Immunomodulatory Effects of Drugs for Treatment of Immune-Related Diseases
- ^ a b c d Lowe, Derek (2 April 2013). "Tecfidera's Price". In the Pipeline. Archived from the original on 11 November 2020. Retrieved 19 July 2018.
- ISBN 9780128032015.
- ^ 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.
- ^ Blair HA. Dimethyl Fumarate: A Review in Moderate to Severe Plaque Psoriasis. Drugs. 2017.
- ^ a b c Vinluan, Frank (17 January 2017). "Xconomy: Biogen to Pay $1.25B to Settle Forward Pharma Patent Suit on MS Drug". Xconomy.
- ^ "FDA approves new multiple sclerosis treatment: Tecfidera". FDA. 27 March 2013. Retrieved 5 April 2013.
- PMID 28845815.
- ^ "Biogen loses patent dispute with Mylan, putting its top drug's future in doubt". BioPharma Dive. Retrieved 19 June 2020.
- ^ "BRIEF-Biogen Says To Appeal Court Decision Regarding Patent Related To Tecfidera". Reuters. 18 June 2020. Retrieved 19 June 2020.
- Barron's. Retrieved 19 June 2020.
- ^ a b c d e "Skilarence Summary of Product Characteristics" (PDF). May 2018. Archived from the original (PDF) on 18 June 2018. Retrieved 26 February 2019.
- ^ Goldhill, Jon (15 September 2015). "Disappointing Phase 2 psoriasis data reported for the monomethyl fumarate prodrug, XP23829". Advances in drug discovery.
- ^ "Vumerity (Previously BIIB098 and ALKS 8700)". Multiple Sclerosis News Today. 1 November 2019. Retrieved 21 February 2020.
- ^ "Biogen and Alkermes Announce FDA Approval of Vumerity (diroximel fumarate) for Multiple Sclerosis". Biogen. Retrieved 21 February 2020.
- ^ "Drug Approval Package: Vumerity". U.S. Food and Drug Administration (FDA). 21 April 2020. Retrieved 1 February 2021.
- PMID 27078105.
- PMID 30698680.
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- ^ Hamilton, Mike (13 September 2012). "Just how much profit is there in a new drug?". Biotech Translated.
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- ^ 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.
- ^ "FDA Drug Safety Communication: FDA warns about case of rare brain infection PML with MS drug Tecfidera (dimethyl fumarate)". fda.gov. Retrieved 2 December 2014.
- ^ S2CID 45134115.
- ^ a b c "Myrkkytuoli-ihottumien syy selvisi". YLE Uutiset (in Finnish). YLE. 24 April 2008. Retrieved 10 June 2008.
- ^ "Clifton woman's toxic sofa claim". The Nottingham Post. Local World. 2 April 2009.[permanent dead link]
- ^ a b BBC – Consumer – TV and radio – itchy sofas Archived 22 February 2008 at the Wayback Machine
- ^ BBC: Judge rejects 'toxic sofa' claims in burns injury cases, 18 March 2010
- ^ "BBC: 3 reports on dimethyl fumarate in furniture". April 2010.
- ^ "2009/251/EC: Commission Decision of 17 March 2009".
- ^ "RECOVERY trial closes recruitment to colchicine treatment for patients hospitalised with COVID-19". Nuffield Department of Population Health, University of Oxford. 5 March 2021.
- PMID 38296965.