Dimethyl fumarate

This article covers a compound of fumaric acid. For the compound of formic acid, which is also abbreviated to DMF and used as a solvent, see dimethylformamide .

Structural formula
General
Surname	Dimethyl fumarate
other names	Dimethyl fumarate trans -Ethenedicarboxylic acid dimethyl ester ( E ) Dimethyl -2-butenedioate
Molecular formula	C 6 H 8 O 4
Brief description	white, crystalline, odorless powder
External identifiers / databases
CAS number 624-49-7 EC number 210-849-0 ECHA InfoCard 100,009,863 PubChem 637568 DrugBank DB08908 Wikidata Q418123
properties
Molar mass	144.13 g mol −1
Physical state	firmly
density	1.03 g cm −3
Melting point	102 ° C
boiling point	193 ° C
solubility	little in water (1.6 g l −1 at 20 ° C)
Refractive index	1.4062 (111 ° C)
safety instructions
GHS labeling of hazardous substances Caution H and P phrases H: 312-317-315-319-335-411 P: 273-280-302 + 352-305 + 351 + 338
Toxicological data	1,250 mg kg −1 ( LD 50 ,  rabbit ,  transdermal ) 2,240 mg kg −1 ( LD 50 ,  rat ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . Refractive index: Na-D line , 20 ° C

Fumaric acid dimethyl ester , also dimethyl fumarate , is the diester of fumaric acid with the alcohol methanol . This and other fumaric acid esters are used as medicinal substances for the treatment of multiple sclerosis and psoriasis . Dimethyl fumarate is said to have immunomodulatory and antioxidant properties.

In a non-medical use, dimethyl fumarate is used as a biocide for the treatment of clothing, shoes and furniture against mold infestation . Since May 1, 2009, however, the EU as a whole has been banned from using it as a biocide due to the increased number of allergic reactions .

properties

Dimethyl fumarate is a white, almost odorless, crystalline powder that is soluble in acetone, slightly soluble in ether, sparingly soluble in ethanol and practically insoluble in water (1.6 g · l ⁻¹ at 20 ° C). A suspension of 10 g of the ester in one liter of water shows weakly acidic properties with a pH value of 4-6 . In water and in the human organism , dimethyl fumarate hydrolyzes rapidly to form monomethyl fumarate; the half-life is about 10 minutes.

Mechanism of action

The immunomodulatory and antioxidant effects of dimethyl fumarate appear to be mediated by interaction with the intracellular thiol system. Downstream, the anti-inflammatory protein HO-1 is induced and pro-inflammatory mediators such as tumor necrosis factor and interleukin-8 are influenced . In addition, dimethyl fumarate appears to have an antioxidant effect on nerve cells and heart muscle cells in particular.

In multiple sclerosis (MS), dimethyl fumarate is used to activate the Nrf2 signaling pathway in order to have an immunomodulatory and anti-inflammatory effect. In addition, antioxidant genes are upregulated. The " N uclear Factor (erythroid-derived 2) - R elated F actor 2 " (Nrf2) is a transcription factor that when activated the transcription of genes that encode effective, inter alia, anti-inflammatory and antioxidant gene products. The Nrf2 signaling pathway is the main defense system in cells, with which they react to inflammation and oxidative stress in order to avert their harmful effects. In MS, the Nrf2 pathway appears to have increased activity, which is evident in active MS lesions. However, the endogenous defense system seems to be unable to fend off oxidative stress in MS lesions. Strengthening the immune system through drugs is therefore considered an approach to MS therapy. So far, dimethyl fumarate is the only active ingredient against MS that has been tested in clinical studies and is believed to activate the Nrf2 signaling pathway, although - as of October 2014 - not all aspects of long-term use are known.

Medical use

multiple sclerosis

Dimethyl fumarate has the potential to favorably affect some chronic inflammatory immune-mediated diseases. In 2006, German neurologists and dermatologists accidentally noticed that two patients who suffered from multiple sclerosis (MS) and psoriasis at the same time showed a significantly more stable course of MS under oral dimethyl fumarate therapy for psoriasis.

Two clinical phase 3 studies (DEFINE and CONFIRM study) showed in 2012 that orally ingested dimethyl fumarate (referred to as oral BG-12 ) significantly reduced the relapse rate in multiple sclerosis (53% reduction in relapse rate vs. placebo; 38% reduction in risk disability progression vs. placebo) and was as effective as glatiramer .

Dimethyl fumarate is approved under the trade name Tecfidera , manufacturer Biogen in the USA and in Europe for the oral treatment of relapsing-remitting MS .

The European Medicines Agency (EMA) resp. In November 2013, the CHMP classified Tecfidera as a “ new active substance” , which protects the fumaric acid drug from copycat versions for ten years.

Biogen (then still Biogen Idec) received the Galenus von Pergamon Prize (Prix Galien) in the Primary Care category for Tecfidera ^® in 2014 .

Side effects

According to the manufacturer, around 340,000 patients worldwide receive Tecfidera ^® (as of July 2018). Since its inception, the Disease-Related Competence Network Multiple Sclerosis (KKNMS) has recommended determining the number of leukocytes and lymphocytes in the blood every six to eight weeks in the first year of treatment in order to avoid progressive multifocal leukoencephalopathy (PML). If leukopenia below 3000 / µl and lymphopenia below 500 / µl are found, the medication should be discontinued. The reason for the renewed urgent recommendation is the death of an MS patient who received dimethyl fumarate for 4.5 years and who contracted lymphopenia for 3.5 years without risk factors such as prior therapy with natalizumab , fingolimod , immunosuppressants or an HIV infection templates.

psoriasis

A mixture of dimethyl fumarate and monoethyl fumarate (ethyl hydrogen fumarate) has been used in Germany for the treatment of psoriasis since the 1990s (trade name Fumaderm ), after the biochemist Walter Schweckendiek tested dimethyl fumarate for the first time in 1959. Fumaric acid monomethyl ester is probably biologically active. In 2011, the Working Group of the Scientific Medical Societies in Germany (AWMF) judged in its S3 guideline for the treatment of psoriasis vulgaris that fumaric acid esters are suitable for long-term therapy, but noted that there have so far been more observations than documented clinical studies on the effectiveness and safety of fumaric acid ester therapy . In view of the fact that psoriasis is an autoimmune disease, i.e. an inflammatory, systemic disease, systemic treatment clearly plays the greater role. Cosmetic (topical) treatment cannot be a satisfactory solution for a systemic disease. Fumaric acid dimethyl ester has an immunomodulatory effect (anti-inflammatory) and is the antipsoriatic drug with the longest experience in use (namely since 1959). As the inflammation goes down, the dandruff also goes down.

Although the substance shows few undesirable interactions with other drugs , the guideline recommends not to use any other basic therapeutic agents together with fumaric acid esters and advises to be particularly careful with simultaneous treatment with preparations that can impair kidney function.

Fumaric acid esters are the most frequently used systemically acting substances in Germany for the treatment of psoriasis. A new, only dimethyl fumarate based formulation with controlled release of the active ingredient (FP187) is in the late clinical development stage for psoriasis.

Further indications

Other chronic skin and autoimmune diseases, such as Necrobiosis Lipoidica , granuloma annulare , sarcoidosis and Crohn's disease , talking on dimethyl fumarate on.

Early benefit assessment according to § 35a SGB V

In its early benefit assessment in 2014, IQWiG came to the conclusion that an additional benefit of the active ingredient in the treatment of adults with relapsing-remitting multiple sclerosis (RRMS) had not been proven due to a lack of suitable study data. The Federal Joint Committee agreed with this assessment.

In another early benefit assessment, IQWiG 2018 examined whether dimethyl fumarate offers adults with moderate to severe psoriasis vulgaris who require systemic drug therapy an added benefit compared to the ACT. Individuals who did not respond adequately to other systemic therapies or who had a contraindication or intolerance to such therapies were considered separately. An additional benefit of dimethyl fumarate has therefore not been proven for either them or the other patients. The Federal Joint Committee agreed with the result of the assessment.

safety instructions

Dimethyl fumarate is not only a potent contact allergen , but is also well absorbed through the skin . It was found to be moderately toxic in animal experiments with rabbits and rats ( LD ₅₀ 2,240 mg · kg ⁻¹ in oral rats, but already 1,250 mg · kg ⁻¹ in rabbits dermally). The eyes, respiratory tract and skin are acutely irritated in humans; a strong skin-sensitizing effect was also observed. The most common unwanted immediate symptoms are brief flushing and diarrhea . With chronic admission, for example in psoriasis treatment, around half of the patients experience changes in the white blood count in the form of lymphopenia , around 11% develop leukopenia , and around 3% of those treated develop more severe forms of lymphopenia that occur during treatment can also recur or be permanent. Worsening kidney function and liver values ​​are also observed. Regular checks of kidney, liver and blood count parameters are therefore necessary; if necessary, the dose must be reduced or the drug discontinued.

Non-medical use

Dimethyl fumarate is a biocide that is effective against mold . It can be used, for example, to protect leather furniture or shoes . Due to the frequent triggering of allergic reactions, however, the use of dimethyl fumarate has been banned for products manufactured in the European Union since 1998 and for imported products since May 1, 2009.

Individual evidence

1. ↑ ^{a b c d e f g h} Entry on dimethyl fumarate in the GESTIS substance database of the IFA , accessed on January 8, 2020(JavaScript required) .
2. ↑ David R. Lide (Ed.): CRC Handbook of Chemistry and Physics . 90th edition. (Internet version: 2010), CRC Press / Taylor and Francis, Boca Raton, FL, Physical Constants of Organic Compounds, pp. 3-198.
3. ↑ ^{a b c} American Industrial Hygiene Association Journal. Vol. 30, p. 470, 1969.
4. ↑ ^{a b c} Entry on dimethyl fumarate in the ChemIDplus database of the United States National Library of Medicine (NLM) .
5. ↑ Green light for fumaric acid and teriflunomide for the treatment of relapsing multiple sclerosis . ( Memento from March 10, 2016 in the Internet Archive ) dmsg.de, March 22, 2013; Retrieved September 26, 2013.
6. ↑ ^{a b c} M. Meissner, EM Valesky a. a .: Dimethyl fumarate - only an anti-psoriatic medication? In: Journal of the German Dermatological Society . Volume 10, number 11, 2012, pp. 793-801, doi: 10.1111 / j.1610-0387.2012.07996.x . PMID 22897153 (Review).
7. ↑ Consumer protection: Commission bans biocide that causes severe allergies. ( Memento of June 16, 2009 in the Internet Archive ) European Commission , April 30, 2009.
8. ↑ Consumer protection: EU bans dimethyl fumarate (DMF) in consumer goods such as sofas, shoes and plush toys. European Commission , April 30, 2009.
9. ^ Ulrich Schwabe, Dieter Paffrath: Drug Ordinance Report 2005: Current data, costs, trends and comments. Springer, 2006, ISBN 978-3-540-28368-3 , p. 588.
10. ↑ Martin Rostami Yazdi: Pharmacokinetics and pharmacodynamics of fumaric acid esters . 2008, dissertation, Mathematical and Natural Science Faculty of the University of Kiel, urn : nbn: de: gbv: 8-diss-27682
11. ↑ JC Lehmann, JJ Listopad u. a .: Dimethylfumarate induces immunosuppression via glutathione depletion and subsequent induction of heme oxygenase 1. In: Journal of Investigative Dermatology . Volume 127, Number 4, April 2007, pp. 835-845, doi: 10.1038 / sj.jid.5700686 . PMID 17235328 .
12. ↑ RH Scannevin, S. Chollate et al. a .: Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2) -like 2 pathway. In: The Journal of pharmacology and experimental therapeutics. Volume 341, Number 1, April 2012, pp. 274-284, doi: 10.1124 / jpet.111.190132 . PMID 22267202 .
13. ↑ H. Ashrafian, G. Czibik et al. a .: Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway. In: Cell metabolism. Volume 15, number 3, March 2012, pp. 361-371, doi: 10.1016 / j.cmet.2012.01.017 . PMID 22405071 . PMC 3314920 (free full text).
14. ↑ Tecfidera ^® specialist information , tecfidera.de; Retrieved February 7, 2014.
15. ↑ R. Gold, L. Kappos et al. a .: Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. In: The New England Journal of Medicine . Volume 367, number 12, September 2012, pp. 1098-1107, doi: 10.1056 / NEJMoa1114287 . PMID 22992073 .
16. ↑ RJ Fox, DH Miller et al. a .: Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. In: The New England Journal of Medicine . Volume 367, number 12, September 2012, pp. 1087-1097, doi: 10.1056 / NEJMoa1206328 . PMID 22992072 .
17. ↑ AH Ropper: The "poison chair" treatment for multiple sclerosis. In: The New England Journal of Medicine . Volume 367, number 12, September 2012, pp. 1149-1150, doi: 10.1056 / NEJMe1209169 . PMID 22992079 .
18. ↑ FDA approves new multiple sclerosis treatment: Tecfidera , FDA press release of March 27, 2013, accessed February 6, 2014.
19. ↑ TECFIDERA® (Dimethyl Fumarate) Approved in the European Union as a First-Line Oral Treatment for Multiple Sclerosis , press release from BiogenIdec of February 4, 2014, accessed on March 26, 2015.
20. ↑ (AkdÄ) Tecfidera® (dimethyl fumarate) , information from the drug commission of the German medical profession from May 15, 2014, accessed on May 15, 2014.
21. ↑ CHMP has updated its previous opinion and agreed that dimethyl fumarate in Tecfidera is qualified as a new active substance , Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) November 18-21, 2013, accessed on February 6, 2014.
22. ↑ Galenus von Pergamon Prize 2014 Awards for innovations and ideas . Press release from Springer Medizin, accessed on November 7, 2014.
23. ↑ Biogen Highlights at ECTRIMS 2018 Data on Its Industry-Leading Multiple Sclerosis Portfolio and a Range of Initiatives Aimed at Transforming Patient Care. Accessed April 16, 2019 . 
24. ↑ Information on Tecfidera ^® (PDF) Medicines Commission of the German Medical Association (AkdÄ); accessed on March 26, 2015.
25. ↑ Lisa Meier: KKNMS: Close-knit blood count controls under dimethyl fumarate indispensable. Disease-related Competence Network Multiple Sclerosis, press release from October 24, 2014 from Informationsdienst Wissenschaft (idw-online.de), accessed on January 18, 2020.
26. ↑ Rote-Hand-Brief on Tecfidera ^® (dimethyl fumarate): Suspected case of progressive multifocal leukoencephalopathy (PML) , AkdÄ Drug Safety Mail 2014-34 of December 4, 2014; accessed on March 26, 2015.
27. ^ F. von Bruchhausen, R. Braun, Siegfried Ebel: Hager's manual of pharmaceutical practice. Volume 4: Substances A – K. Springer, 1999, ISBN 978-3-540-62644-2 , p. 468.
28. ↑ ^{a b} A. Nast: S3 guidelines for the therapy of psoriasis vulgaris Archived from the original on February 28, 2013. In: AWMF Online . August.
29. ↑ PsoBest: Long-term study on the efficacy, tolerability and safety of biological and conventional systemic therapy for psoriasis and psoriatic arthritis in routine care: inclusion numbers .
30. ^ Efficacy and Safety Trial of FP187 in Moderate to Severe Plaque Psoriasis . Clinicaltrials.gov. Retrieved December 13, 2012.
31. ^ Forward Pharma Newsroom . Forward Pharma. Archived from the original on September 21, 2013. Retrieved on December 13, 2012.
32. ↑ A14-14 Dimethyl fumarate - benefit assessment according to Section 35a SGB V (dossier assessment) , accessed on July 8, 2019.
33. ↑ A14-33 Addendum to Commission A14-14 (dimethyl fumarate) , accessed on July 8, 2019.
34. ↑ Resolution of the Federal Joint Committee of October 16, 2014 on an amendment to the Drugs Directive (AM-RL): Annex XII - Resolutions on the benefit assessment of drugs with new active ingredients according to Section 35a SGB V - Dimethyl fumarate , accessed on July 8, 2019.
35. ↑ A17-49 Dimethyl fumarate (psoriasis) - benefit assessment according to Section 35a SGB V , accessed on October 29, 2018.
36. ↑ Resolution of the Federal Joint Committee of March 16, 2018 on an amendment to the Drugs Directive (AM-RL): Annex XII - Resolutions on the benefit assessment of drugs with new active ingredients according to § 35a SGB V - Dimethyl fumarate (new area of ​​application: plaque psoriasis) , accessed October 29, 2018.
37. ↑ Initial instructions for use for specialist groups on Fumaderm® and Fumaderm®.
38. ↑ Regulations on dimethyl fumarate . ( Memento of February 4, 2012 in the Internet Archive ) Federal Ministry of Labor, Social Affairs and Consumer Protection ; Retrieved January 3, 2012.

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