Last updated: 5 May 2013

Dimethyl fumarate

Summary

Trade name:

TECFIDERA [[5317]]

A mixture of dimethyl fumarate and salts of monoethylfumarate is marketed in Germany as Fumaderm [[380]]

Class:

Immunomodulator [[392]]

Neuroprotector (?) [[341]]

Target:

Cytokine secretion [[341]]

CD62E [[341]]

Inflammation [[341]]

Nrf2 transcriptional pathway [[341]]

Status for MS:

Results from Phase III trials have been published (September 2012) and reported in Biogen Idec press releases (October 2011 and April 2011) [[583]] [[1793]] [[3222]] [[3221]]

Approved by the US Food and Drug Administration as a first-line treatment for relapsing forms of MS (27 March 2013) [[5512]]

Administration:

Oral [[583]]

Commercial:

Jointly developed by Biogen Idec and Fumapharm [[585]]

Biogen Idec acquired the company Fumapharm, which has two products, Fumaderm (approved for treating psoriasis in Germany) and BG-12, in 2006 [[585]]

Clinical trials have been sponsored by Biogen Idec [[583]]

Marketing applications from Biogen Idec have been accepted by US and EU regulatory authorities for review (May 2012) [[1792]]

Review time for the New Drug Application has been extended 3 months by the US Food and Drug Administration (meaning a ruling would be made by the end of March 2013), because the agency needs more time to review the application; no additional studies are requested (18 October 2012) [[3767]] [[3781]]

Dosing regimen (480 mg per day) has been granted patent protection by the US Patent and Trademark Office (19 March 2013) [[5317]]

Recommended to receive marketing authorization as a first-line therapy for RRMS by the Committee for Medicinal Products for Human Use of the European Medicines Agency (22 March 2013) [[5367]]

Approved by the US Food and Drug Administration as a first-line treatment for relapsing forms of MS (27 March 2013) [[5512]]

Names

Name:

Dimethyl fumarate

Trade name:

TECFIDERA [[5317]]

A mixture of dimethyl fumarate and salts of monoethylfumarate is marketed in Germany as Fumaderm [[380]]

Synonyms:

2-Butenedioic acid, dimethyl ester, (E)- [[465]]

4-02-00-02205 (Beilstein Handbook Reference) [[465]]

AI3-07872 [[465]]

AZL O 211089 [[465]]

Allomaleic acid dimethyl ester [[465]]

BG 00012 [[465]]

BG-12 [[341]]

BG 12 [Fumarate] [[465]]

BG 12 compound [[465]]

BG-00012 [[465]]

BG00012 [[465]]

BRN 0774590 [[465]]

Boletic acid dimethyl ester [[465]]

Dimethyl fumarate [[465]]

Dimethyl trans-ethylenedicarboxylate [[465]]

Dimethylester kyseliny fumarove [[465]]

Dimethylester kyseliny fumarove [Czech] [[465]]

Dimethylfumarate [[465]]

DMF [[341]]

EINECS 210-849-0 [[465]]

Ethylene, 1,2-bis(methoxycarbonyl)-, trans- [[465]]

FAG 201 [[465]]

FAG201[[465]]

Fumaderm [[465]]

Fumaric acid, dimethyl ester [[465]]

HSDB 7725 [[465]]

Methyl fumarate [[465]]

NSC 167432 [[465]]

NSC 25942 [[465]]

TL 353 [[465]]

UNII-FO2303MNI2 [[465]]

trans-1,2-Ethylenedicarboxylic acid dimethyl ester [[465]]

trans-Butenedioic acid dimethyl ester [[465]]

Systematic name:

2-Butenedioic acid (2E)-, 1,4-dimethyl ester [[465]]

2-Butenedioic acid (2E)-, dimethyl ester [[465]]

2-Butenedioic acid (E)-, dimethyl ester [[465]]

2-Butenedioic acid, dimethyl ester, (E)- [[465]]

Dimethyl fumarate [[465]]

Fumaric acid, dimethyl ester (8CI) [[465]]

Physiology

Class:

Immunomodulator [[392]]

Neuroprotector (?) [[341]]

Target:

Cytokine secretion [[341]]

CD62E [[341]]

Inflammation [[341]]

Nrf2 transcriptional pathway [[341]]

Properties:

After ingestion, is rapidly hydrolyzed to its primary metabolite, monomethylfumarate, which is in turn further metabolized in the citric acid cycle [[341]]

Half-life of dimethyl fumarate is 12 minutes [[341]]

Half-life of metabolite monomethylfumarate is 36 hours [[341]]

Mechanisms/Effects

Human:

Exact mechanism unknown [[341]]

Shifts T-helper response from Th1 to Th2 in cultured human cells [[341]]

Inhibits expression of tumor-necrosis-factor-induced CD62E, a protein that mediates cell adhesion to the vascular lining and is responsible for accumulation of leukocytes at sites of inflammation, in human endothelial cells [[341]][[398]]

Animal:

In experimental autoimmune encephalomyelitis models, activates the nuclear factor E2-related factor 2 (Nrf2) transcriptional pathway, which functions to modulate oxidative stress and has neuroprotective effects [[341]]

Inhibits maturation of dendritic cells and Th1 and Th17 cell differentiation by suppressing signaling by NF-kB and extracellular signal-regulated kinase 1 and 2, as shown by studies of mouse cells [[2252]]

Appears to reduce oxidative stress without changing the activity of neuronal networks, as shown by examination of the effects of immunomodulatory concentrations of drug on mouse cells [[2411]]

Regulatory and Commercial Status

Status for MS:

Results from Phase III trials have been published (September 2012) and reported in Biogen Idec press releases (October 2011 and April 2011) [[583]] [[1793]] [[3222]] [[3221]]

Approved by the US Food and Drug Administration as a first-line treatment for relapsing forms of MS (27 March 2013) [[5512]]

Highest status achieved (for any condition):

Approved [[5512]]

Other uses:

Esters of fumaric acid, which include dimethylfumarate, have been used to treat psoriasis in European countries for more than 30 years [[380]]

Fumaderm, which contains dimethyl fumarate and salts of monoethylfumarate, was approved in 1994 in Germany for the treatment of psoriasis [[380]]

Administration:

Oral [[583]]

Negative effects:

Abdominal pain [[370]]

Diarrhea [[5512]]

Fatigue [[370]]

Flushing [[370]]

Hot flush [[370]]

Headache [[370]]

Nausea [[5512]]

Commercial:

Jointly developed by Biogen Idec and Fumapharm [[585]]

Biogen Idec acquired the company Fumapharm, which has two products, Fumaderm (approved for treating psoriasis in Germany) and BG-12, in 2006 [[585]]

Clinical trials have been sponsored by Biogen Idec [[583]]

Marketing applications from Biogen Idec have been accepted by US and EU regulatory authorities for review (May 2012) [[1792]]

Dosing regimen (480 mg per day) has been granted patent protection by the US Patent and Trademark Office (19 March 2013) [[5317]]

Recommended to receive marketing authorization as a first-line therapy for RRMS by the Committee for Medicinal Products for Human Use of the European Medicines Agency (22 March 2013) [[5367]]

Approved by the US Food and Drug Administration as a first-line treatment for relapsing forms of MS (27 March 2013) [[5512]]

Key Clinical Trials

Placebo-controlled Trials:

Trial name:

COmparator and aN oral Fumarate In RRMS (CONFIRM) (publ September 2012, press releases April 2012 and October 2012, meeting report March 2013) [[1793]] [[3222]] [[3590]] [[5513]]

Phase:

Phase III trial [[1793]] [[3222]]

Study Design:

Company-sponsored, global, randomized, double-blind, placebo-controlled, dose-comparison study to determine the safety and efficacy of oral BG-12 (240 mg given either twice a day or three times a day) or glatiramer acetate (20 mg subcutaneous injection each day) in reducing the annualized relapse rate (ARR) (primary endpoint) and the proportion of patients who relapse at two years and the number of T2-hyperintense lesions (secondary endpoints); study was not designed to test whether BG-12 is superior or noninferior to glatiramer acetate [[1793]] [[3222]]

Disease Stage:

RRMS [[1793]] [[3222]]

Enrollment/Number of Patients:

1430 [[1793]] [[3222]]

Duration:

2 years [[1793]] [[3222]]

Status/Outcome:

BG-12 reduced the ARR by 44% (twice a day dose; ARR=0.22) or 51% (three times a day dose; ARR=0.20) and glatiramer acetate reduced this rate by 29% (ARR=0.29) as compared to placebo (ARR=0.40); BG-12 reduced the proportion of patients who relapsed at two years by 34% (twice a day dose) or 45% (three times a day dose) and glatiramer acetate reduced this rate by 29% as compared to placebo; BG-12 also had a significant effect on brain lesions [[1793]] [[3222]]; pooled analysis from >2,300 patients in the CONFIRM and DEFINE studies indicated that both doses decreased the ARR by 49%; the drug decreased the proportion of patients who relapsed by 43% (twice a day dose) and 47% (three times a day dose) and reduced the risk of 12-week confirmed disability progression by 32% (twice a day dose) and 30% (three times a day dose) (press release, 12 October 2012) [[3590]]; secondary analysis showed that the twice a day dose led to a reduction in relapse rate within 10 weeks [[5513]]

Trial name:

Determination of the Efficacy and safety of oral Fumarate IN rElapsing-remitting MS (DEFINE) (publ September 2012, press releases October 2011 and October 2012, meeting report March 2013) [[583]] [[3221]] [[3590]] [[5513]]

Phase:

Phase III trial [[583]] [[3221]]

Study Design:

Global, randomized, double-blind, placebo-controlled, dose-comparison trial to determine the safety and efficacy of BG-12 (240 mg, 2 or 3 times per day) at reducing the proportion of relapsing patients at two years (primary endpoint) and at reducing the annualized relapse rate (ARR), the risk of disability progression, and the number of lesions as measured by brain MRI (secondary endpoints) [[583]] [[3221]]

Disease Stage:

RRMS [[583]] [[3221]]

Enrollment/Number of Patients:

1237, with 952 completing the study [[583]] [[3221]]

Duration:

2 years [[583]] [[3221]]

Status/Outcome:

Drug reduced the risk of relapse by 49% (2 times per day dose; 27% of these patients, versus 46% in the placebo group, had at least one relapse by 2 years) or 50% (3 times per day; 26% had at least one relapse by 2 years), the ARR by 53% (2 times a day; ARR=0.17 versus 0.36 for the placebo group) or 48% (3 times per day; ARR=0.19), and the risk of disability progression by 38% (2 times per day) or 34% (3 times per day), as well as reducing the mean number of several types of brain lesions [[583]] [[3221]]; pooled analysis from >2,300 patients in the CONFIRM and DEFINE studies indicated that both doses decreased the ARR by 49%; the drug decreased the proportion of patients who relapsed by 43% (twice a day dose) and 47% (three times a day dose) and reduced the risk of 12-week confirmed disability progression by 32% (twice a day dose) and 30% (three times a day dose) (press release, 12 October 2012) [[3590]]; secondary analysis showed that the twice a day dose led to a reduction in relapse rate within 10 weeks [[5513]]

Trial name:

Kappos et al., Lancet, Oct 2008 trial [[370]]

Phase:

Phase IIb trial [[370]]

Study Design:

Multicenter, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of BG00012 (120 mg, 1 time per day; 120 mg, 3 times per day; or 240 mg, 3 times per day) at reducing the number of new gadolinium enhancing lesions (primary endpoint) and at reducing other types of brain lesions and the annualized relapse rate (secondary endpoints) [[370]]

Disease Stage:

RRMS [[370]]

Enrollment/Number of Patients:

257 [[370]]

Duration:

24 weeks, with a 24 week extension period [[370]]

Status/Outcome:

240 mg drug (3 times a day) reduced the mean total number of new gadolinium enhancing lesions by 69% from week 12 to 24 as compared to placebo and reduced the annualized relapse rate by 32% [[370]]; additional analysis showed that the 240 mg, 3 times a day dose reduced the number of new gadolinium-enhanced lesions in a range of patient subgroups (which were based on demographics and baseline disease characteristics), and the reduction varied depending on the subgroup [[2193]]

Trial name:

Schimrigk et al., Eur. J. Neurol., Jun 2006 trial [[385]]

Phase:

Pilot study [[385]]

Study Design:

Exploratory, prospective, baseline-controlled, open-label study to examine the effects of Fumaderm (which contains dimethyl fumarate and and salts of monoethylfumarate) [6 weeks baseline, 18 weeks treatment (target dose of 720 mg per day), 4 weeks washout, 48 weeks treatment (target dose of 360 mg per day)] on number and volume of gadolinium enhancing lesions (primary outcome) [[385]]

Disease Stage:

RRMS [[385]]

Enrollment/Number of Patients:

10, with 3 withdrawing [[385]]

Duration:

76 weeks [[385]]

Status/Outcome:

Drug was associated with reductions from baseline in the number and volume of gadolinium enhancing lesions [[385]]

Head-to-Head Trials:

Other Trials:

Trial name:

ENDORSE (press release, 12 October 2012) [[3590]]

Phase:

Phase III extension study [[3590]]

Study Design:

Industry-sponsored, dose-blind, multicenter extension study to evaluate the long-term safety and efficacy of dimethyl fumarate (240 mg, two times a day or three times a day); patients from the 2-year DEFINE or CONFIRM trials who had received dimethyl fumarate continued on the same dose, whereas those who had received placebo or glatiramer acetate (CONFIRM trial) were randomized to the twice a day or three times a day dimethyl fumarate doses [[3590]]

Disease Stage:

RRMS [[3590]]

Enrollment/Number of Patients:

1736 [[3590]]

Duration:

>1 year [[3590]]

Status/Outcome:

Overall safety profile was similar to those from the DEFINE and CONFIRM trials as of October 2012 [[3590]]

References

ChemIDplus Advanced

United States National Library of Medicine

Accessed on 4 Jan 2012 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

Note: Compound name must be entered under "Substance Identification" and then "Names and Synonyms" selected to view synonyms.

Development of oral immunomodulatory agents in the management of multiple sclerosis.

Nicholas R, Giannetti P, Alsanousi A, Friede T, Muraro PA

Drug Des Devel Ther. 2011; 5:255-74. Epub 2011 May 10. PMID: 21625416. Abstract

Oral BG-12 (dimethyl fumarate) significantly reduced multiple sclerosis (MS) relapses and disability progression in DEFINE Phase 3 clinical trial

Biogen Idec, 21 Oct 2011

Accessed on 4 Jan 2012 from http://www.biogenidec.com/press_release_details.aspx?ID=5981&ReqId=1619878.

Dimethylfumarate inhibits tumor-necrosis-factor-induced CD62E expression in an NF-kappa B-dependent manner.

Loewe R, Pillinger M, de Martin R, Mrowietz U, Gröger M, Holnthoner W, Wolff K, Wiegrebe W, Jirovsky D, Petzelbauer P

J Invest Dermatol. 2001 Dec; 117(6):1363-8. PMID: 11886496. Abstract

Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study.

Schimrigk S, Brune N, Hellwig K, Lukas C, Bellenberg B, Rieks M, Hoffmann V, Pöhlau D, Przuntek H

Eur J Neurol. 2006 Jun; 13(6):604-10. PMID: 16796584. Abstract

Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study.

Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Yang M, et al.

Lancet. 2008 Oct 25; 372(9648):1463-72. PMID: 18970976. Abstract

Use of fumaric acid esters in psoriasis.

Roll A, Reich K, Boer A

Indian J Dermatol Venereol Leprol. 2007 Mar-Apr; 73(2):133-7. PMID: 17456929. Abstract

Biogen Idec to acquire Fumapharm AG; Consolidates ownership of oral compound BG-12 being studied for multiple sclerosis

Biogen Idec, 31 May 2006

Accessed on 4 Jan 2012 from http://www.biogenidec.com/PRESS_RELEASE_DETAILS.aspx?ID=5981&ReqId=862060.

BG 12: BG 00012, BG 12/Oral Fumarate, FAG-201, second-generation fumarate derivative--Fumapharm/Biogen Idec.

Drugs R D. 2005; 6(4):229-30. PMID: 15991882. Abstract

US and EU regulatory authorities accept oral BG-12 marketing applications for review

Biogen Idec, 9 May 2012

Accessed on 16 May 2012 from http://www.biogenidec.com/PRESS_RELEASE_DETAILS.aspx?ID=5981&ReqId=1694087.

Positive results from Phase 3 CONFIRM clinical trial show efficacy and safety of oral BG-12 in multiple sclerosis

Biogen Idec, 24 Apr 2012

Accessed on 16 May 2012 from http://www.biogenidec.com/PRESS_RELEASE_DETAILS.aspx?ID=5981&ReqId=1686377.

Effect of BG-12 on contrast-enhanced lesions in patients with relapsing--remitting multiple sclerosis: subgroup analyses from the phase 2b study.

Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Eraksoy M, et al.

Mult Scler. 2012 Mar; 18(3):314-21. Epub 2011 Aug 30. PMID: 21878455. Abstract

Dimethyl fumarate inhibits dendritic cell maturation via nuclear factor kcyB (NF-kcyB) and Extracellular Signal-regulated kinase 1 and 2 (ERK1/2) and Mitogen Stress activated kinase 1 (MSK1) signaling.

Peng H, Guerau-de-Arellano M, Mehta VB, Yang Y, Huss DJ, Papenfuss TL, Lovett-Racke AE, Racke MK

J Biol Chem. 2012 Jun 25. PMID: 22733812. Abstract

Effects of dimethyl fumarate on neuroprotection and immunomodulation.

Albrecht P, Bouchachia I, Zimmermann C, Hofstetter HH, Kovacs Z, Henke N, Lisak D, Issberner A, Lewerenz J, Maher P, et al.

J Neuroinflammation. 2012 Jul 7; 9(1):163. Epub 2012 Jul 07. PMID: 22769044. Abstract

Editors' Pick

Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis.

Fox RJ, Miller DH, Phillips TJ, Hutchinson M, Havrdova E, Kita M, Yang M, Raghupathi K, Novas M, Sweetser MT, et al.

N Engl J Med. 2012 Sep 20; 367(12):1087-97. Epub 1969 Dec 31. PMID: 22992072. Abstract

Editors' Pick

Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis.

Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, et al.

N Engl J Med. 2012 Sep 20; 367(12):1098-107. Epub 1969 Dec 31. PMID: 22992073. Abstract

New data from Phase 3 studies provide additional evidence supporting treatment effect for oral BG-12 (dimethyl fumarate) in multiple sclerosis

Biogen Idec, 12 Oct 2012

Accessed on 16 Oct 2012 from http://www.biogenidec.com/PRESS_RELEASE_DETAILS.aspx?ID=5981&ReqId=1744697.

Biogen Idec receives notification of PDUFA date extension

Biogen Idec, 18 Oct 2012

Accessed on 1 Nov 2012 from http://www.biogenidec.com/PRESS_RELEASE_DETAILS.aspx?ID=5981&ReqId=1747042.

Biogen slips as FDA extends review of MS drug

CBSNews.com, 19 Oct 2012

Accessed on 1 Nov 2012 from http://www.cbsnews.com/8301-505245_162-57536324/biogen-slips-as-fda-extends-review-of-ms-drug/.

US patent office grants patent claiming dosing regimen for TECFIDERA™ (dimethyl fumarate)

19 Mar 2013

Accessed on 21 Mar 2013 from http://www.biogenidec.com/PRESS_RELEASE_DETAILS.aspx?ID=5981&ReqId=1798029.

CHMP issues positive opinion for TECFIDERA™ (dimethyl fumarate) as a first-line treatment for multiple sclerosis in the European Union

Biogen Idec, 22 Mar 2013

Accessed on 25 Mar 2013 from http://www.biogenidec.com/PRESS_RELEASE_DETAILS.aspx?ID=5981&ReqId=1799179.

Biogen Idec's TECFIDERA™ (dimethyl fumarate) approved in US as a first-line oral treatment for multiple sclerosis

Biogen Idec, 27 Mar 2013

Accessed on 5 Apr 2013 from http://www.biogenidec.com/PRESS_RELEASE_DETAILS.aspx?ID=5981&ReqId=1801165.

MS research gears up for new drugs

Gever J, MedPage Today, 26 Mar 2013

Accessed on 5 Apr 2013 from http://www.medpagetoday.com/clinical-context/MultipleSclerosis/38102.

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Dimethyl fumarate

Mechanisms/Effects