trans-1,2-Ethylenedicarboxylic acid dimethyl ester
(E)-2-Butenedioic acid dimethyl ester
3D model (JSmol)
|Molar mass||g·mol−1 144.126|
|Appearance||White crystalline solid|
|Melting point||103.5 °C (218.3 °F; 376.6 K)|
|Boiling point||193 °C (379 °F; 466 K)|
|GHS signal word||Warning|
|H312, H315, H317, H319, H335|
|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|
|Diethyl fumarate, dimethyl maleate, dimethyl malonate, dimethyl adipate|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|what is ?)(|
Dimethyl fumarate (DMF) is the methyl ester of fumaric acid and is named after the earth smoke plant (Fumaria officionalis). DMF combined with three other fumaric acid esters (FAEs) is solely licensed in Germany as an oral therapy for psoriasis (trade name Fumaderm®). Since 2013, it has been used to treat adults with relapsing multiple sclerosis (trade name Tecfidera®). In 2017, a new oral formulation of DMF (trade name Skilarence®) was approved by the European Medicines Agency (EMA) for use in Europe as a treatment for moderate-to-severe plaque psoriasis. DMF is thought to have immunomodulatory properties without causing significant immunosuppression.
DMF has also been applied as a biocide in furniture or shoes to prevent growths of mould 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. Nevertheless, these measures have had no bearing on DMF’s use in medical settings, in which the medical authorities have granted its usage for psoriasis and multiple sclerosis due to the clinical evidence supported by different clinical trials and real world evidence (or daily clinical practice).
It is also used in oral formulations to treat adults with relapsing multiple sclerosis. For the treatment of psoriasis, DMF is dosed in 30 mg and 120 mg tablets, and the maximum daily dose is 720 mg. Meanwhile, for multiple sclerosis, the doses are 120 mg and 240 mg of DMF, with a maximum daily dose of 480 mg.
Fumaric acid´s first medical use was described in 1959 by Walter Schweckendiek, a German chemist, 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, where it has become the most frequently used first-line systemic psoriasis treatment.
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. 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.
Some people using the topical formulation as a cream for psoriasis also had MS and their MS improved; this led to clinical studies for that purpose. Fumapharm was one of the laboratories involved and Biogen Idec collaborated with them on the research and then acquired Fumapharm in 2006. Another company, 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.
Meanwhile, 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. Biogen priced the drug at $54,000 per year in the US. It was approved in Europe in 2014. In the UK NICE issued a 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.
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.
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. Through these reactions, it is metabolised to monomethyl fumarate (MMF) prior to entering systemic distribution. DMF has been described a prodrug.
The precise mechanism of action of dimethyl fumarate is unknown. DMF and MMF activate the transcription factor (erythroid-derived 2)-like 2 (Nrf2) pathway and MMF has been identified as a nicotinic acid receptor agonist in vitro. 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).
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.
The primary route of elimination is via exhalation of CO2, with small amounts excreted through urine or faeces.
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.
Several methods exist for the laboratory synthesis of dimethyl fumarate, with reported methods including alkene isomerization of dimethyl maleate, and Fischer esterification of fumaric acid.
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.
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.
For multiple sclerosis, adverse effects include flushing and gastrointestinal events, such as diarrhoea, nausea and upper abdominal pain. The drug label includes warnings about the risk of anaphylaxis and angio-oedema, PML, lymphopenia and liver damage.
There is no information on how DMF affects the fetus during pregnancy; in animal tests there was fetal harm at clinically relevant doses.
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. There are only a handful of equally potent sensitisers.
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 Finland where the chairs were sold from 2006 to 2007, 60 users sustained serious rashes. The cause was identified as dimethyl fumarate-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. In the United Kingdom, sofas sold by Argos, Land of Leather and Walmsley Furnishing containing the chemical caused over a hundred injuries. 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. The danger came to public attention in 2008 when the BBC Watchdog programme alerted consumers to the sofas.
In the European Union, the use of dimethyl fumarate for consumer products has been forbidden since 1998, and in January 2009 it was proposed that the import of consumer products containing dimethyl fumarate is also forbidden.
EU Commission Decision 2009/251 of 17 March 2009 required Member States to ensure that consumer products containing the biocide 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. The ban on dimethyl fumarate as laid down in Decision 2009/251 establishes a maximum concentration of dimethyl fumarate in products of 0.1 ppm. The Decision dictated that consumer products containing more than 0.1 ppm of dimethyl fumarate should be withdrawn from the market and recalled from consumers.
- "Background document to the opinions on the Annex XV dossier proposing restrictions on Dimethylfumarate (DMFu)" (PDF). European Chemicals Agency. 16 March 2011. p. 9.
- 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.
- Mrowietz, Ulrich; Altmeyer, Peter; Bieber, Thomas; et al. (2007). "Treatment of psoriasis with fumaric acid esters (Fumaderm®)". JDDG. 5 (8): 716–7. doi:10.1111/j.1610-0387.2007.06346.x. PMID 17659047.
- "Dimethyl fumarate label" (PDF). FDA. December 2017. Retrieved 19 July 2018. For label updates see FDA index page for NDA 204063
- "Agency EM. Skilarence® [Updated]".
- 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.
- "Consumers: EU to ban dimethylfumarate (DMF) in consumer products, such as sofas and shoes" (Press release). European Commission. Retrieved 29 November 2012.
- "Skilarence 120 mg Gastro-resistant Tablets - Summary of Product Characteristics". Electronic Medicines Compendium. May 2018. Retrieved 19 July 2018.
- Immunomodulatory Effects of Drugs for Treatment of Immune-Related Diseases
- Lowe, Derek (2 April 2013). "Tecfidera's Price". In the Pipeline.
- 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.
- 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.
- 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. Mar 27, 2013. Retrieved 2013-04-05.
- "Tecfidera 120mg and 240mg gastro-resistant hard capsules - Summary of Product Characteristics". Electronic Medicines Compendium. February 2018. Retrieved 19 July 2018.
- 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.
- 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.
- 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.
- 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.
- "Skilarence® Summary of Product Characteristics" (PDF). Almirall, May 2018 [Updated]. Check date values in:
- Goldhill, Jon (September 15, 2015). "Disappointing Phase 2 psoriasis data reported for the monomethyl fumarate prodrug, XP23829". Advances in drug discovery.
- 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
- Isomerization of dimethyl maleate to dimethyl fumarate: An undergraduate experiment utilizing high performance liquid chromatography David B. Ledlie, Thomas J. Wenzel, and Susan M. Hendrickson Journal of Chemical Education 1989 66 (9), 781 doi:10.1021/ed066p781
- Isomerization of dimethyl maleate to dimethyl fumarate: An undergraduate experiment illustrating amine-catalyzed alkene isomerization, stereochemical principles, sublimation, and product identification by spectroscopic methods Craig B. Fryhle, Carol M. Rybak, and Kenneth E. Pulley Journal of Chemical Education 1991 68 (12), 1050 doi:10.1021/ed068p1050
- Hamilton, Mike (13 September 2012). "Just how much profit is there in a new drug?". Biotech Translated.
- 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.
- 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.
- "Myrkkytuoli-ihottumien syy selvisi". YLE Uutiset (in Finnish). YLE. 2008-04-24. Retrieved 2008-06-10.
- "Clifton woman's toxic sofa claim". The Nottingham Post. Local World. 2 Apr 2009.
- BBC - Consumer - TV and radio - itchy sofas Archived February 22, 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".
- fishersci.ca: Dimethyl fumarate Material Safety Data Sheet (MSDS)