The Pharmacokinetics of Fumaric Acid Esters Reveal Their In Vivo Effects

Mrowietz, Ulrich; Morrison, Peter J; Suhrkamp, Ina; Kumanova, Margaret; Clement, Bernd

doi:10.1016/j.tips.2017.11.002

Cited by 81 publications

(92 citation statements)

References 49 publications

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“…Fumaderm was initially licensed for the treatment of severe psoriasis in adult patients and afterwards, in 2008, the label was expanded to include patients with moderate psoriasis. Fumaderm is a combination of different FAEs: dimethyl fumarate (DMF) plus calcium, magnesium and zinc salts of monoethyl fumarate (MEF) . DMF is considered to be the main active ingredient accounting for the clinical effects in psoriasis .…”

Section: Introductionmentioning

confidence: 99%

“…FAEs are the most frequently used systemic treatment in Germany with more than 220 000 patient‐years of experience . Until recently, FAEs were only licensed in Germany for the treatment of psoriasis but were imported to many other European countries . In 2017, the European Medicines Agency (EMA) approved Skilarence ® , a new oral formulation of DMF (Almirall S.A.), for the treatment of adults with moderate‐to‐severe chronic plaque psoriasis in need of systemic medical therapy.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Clinical use of dimethyl fumarate in moderate‐to‐severe plaque‐type psoriasis: a European expert consensus

Mrowietz¹,

Barker

Boehncke

et al. 2018

Acad Dermatol Venereol

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118

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Fumaric acid esters (FAEs) are a group of small molecules that were first investigated for the treatment of psoriasis in 1959. The first fumarate‐based drug – Fumaderm® – was approved in Germany in 1994 for severe psoriasis and then in 2008, the label was expanded to include moderate psoriasis. Fumaderm is a combination of different FAEs: dimethyl fumarate (DMF), which is regarded as the main active component, plus calcium, magnesium and zinc salts of monoethyl fumarate (MEF). FAEs are the most frequently used first‐line systemic psoriasis treatment in Germany, with an overall treatment experience comprising more than 220 000 patient‐years. FAEs have demonstrated good, sustained clinical efficacy with an acceptable safety profile for the long‐term treatment of patients with moderate‐to‐severe psoriasis. Indeed, the European S3‐Guideline on the systemic treatment of Psoriasis vulgaris recommends FAEs for induction and long‐term treatment. Until recently, FAEs were only licensed (for the psoriasis indication) in Germany, but were imported to many other European countries, such as The Netherlands, UK, Ireland, Austria and Italy, for the treatment of psoriasis. In 2017, the European Medicines Agency (EMA) approved Skilarence®, a new oral formulation of DMF, for the treatment of adult patients with moderate‐to‐severe chronic plaque psoriasis in need of systemic therapy. Skilarence only contains DMF and is the first FAE for the treatment of psoriasis that has been approved by the EMA. This approval has given rise to a new oral treatment option for patients with moderate‐to‐severe plaque psoriasis across Europe. Here, we report the results of an expert meeting which was convened to deliver clinician‐agreed consensus and real‐world guidance on the clinical use of DMF in moderate‐to‐severe chronic plaque psoriasis. Guidance on appropriate patient selection, DMF dosage considerations, monitoring and side‐effect management is offered based upon available evidence and collective real‐world clinical experience.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clinical use of dimethyl fumarate in moderate‐to‐severe plaque‐type psoriasis: a European expert consensus

Mrowietz¹,

Barker

Boehncke

et al. 2018

Acad Dermatol Venereol

Self Cite

118

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“…Methotrexate is the most frequently prescribed systemic agent for psoriasis treatment in many European countries and has received renewed interest due to novel data on its clinical and immunological effects . FAEs have been an approved treatment for plaque psoriasis in Germany since 1994 (Fumaderm ® ), but, due to their attractive long‐term potential and unique mode of action, they are also being used as an unlicensed treatment in several European countries . Recently, a dimethyl fumarate‐only product (LAS41008) was approved by the European Commission based on a comparator trial with Fumaderm, and it is indicated as a first‐line induction and long‐term maintenance treatment for moderate‐to‐severe psoriasis…”

mentioning

confidence: 99%

A 24‐week multicentre, randomized, open‐label, parallel‐group study comparing the efficacy and safety of ixekizumab vs. fumaric acid esters and methotrexate in patients with moderate‐to‐severe plaque psoriasis naive to systemic treatment

et al. 2019

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Summary Background Interleukin‐17 antagonists have received a first‐line label for moderate‐to‐severe plaque psoriasis. Objectives We conducted the first head‐to‐head trial between the two most commonly used first‐line therapies in Germany, fumaric acid esters (FAEs) and methotrexate, and the interleukin‐17A antagonist, ixekizumab. Methods Systemic‐naive patients were randomized in this parallel‐group, active‐comparator, open‐label, rater‐blinded trial (each group n = 54). The primary outcome was the proportion of patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at 24 weeks. Key secondary outcomes included 24‐week PASI 90 and 100, static Physician's Global Assessment (sPGA) score of 0 or 1, and Dermatology Life Quality Index (DLQI) score of 0 or 1. Safety events at week 24 were analysed using Fisher's exact test. Missing data were imputed using nonresponder imputation. The trial was registered at ClinicalTrials.gov (NCT02634801) and EudraCT (2015‐002649‐69). Results At week 24, more ixekizumab‐treated patients achieved PASI 75 [91% vs. 22% FAEs (P < 0·001) and 70% methotrexate (P = 0·014)], PASI 90 [80% vs. 9% FAEs (P < 0·001) and 39% methotrexate (P < 0·001)] and PASI 100 [41% vs. 4% FAEs (P < 0·001) and 13% methotrexate (P = 0·0041)], as well as sPGA (0,1) and DLQI (0,1). Conclusions Ixekizumab was superior in inducing PASI 75/90/100, sPGA (0,1) and DLQI (0,1) responses at week 24 compared with methotrexate and FAEs. Safety profiles for all treatments were consistent with prior studies.

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“…Most of its activity appears to be mediated via metabolic conversion to MMF. DMF in fact is a prodrug that, upon oral administration, is rapidly hydrolysed to MMF, the principal active molecule that elicits most of the anti-psoriatic effects [29]. …”

Section: Discussionmentioning

confidence: 99%

Dimethyl fumarate (DMF) vs. monoethyl fumarate (MEF) salts for the treatment of plaque psoriasis: a review of clinical data

et al. 2018

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Fumarates (fumaric acid esters, FAEs) are orally administered systemic agents used for the treatment of psoriasis and multiple sclerosis. In 1994, a proprietary combination of FAEs was licensed for psoriasis by the German Drug Administration for use within Germany. Since then, fumarates have been established as one of the most commonly used treatments for moderate-to-severe psoriasis in Germany and other countries. The licensed FAE formulation contains dimethyl fumarate (DMF), as well as calcium, zinc, and magnesium salts of monoethyl fumarate (MEF). While the clinical efficacy of this FAE mixture is well established, the combination of esters on which it is based, and its dosing regimen, was determined empirically. Since the mid-1990s, the modes of action and contribution of the different FAEs to their overall therapeutic effect in psoriasis, as well as their adverse event profile, have been investigated in more detail. In this article, the available clinical data for DMF are reviewed and compared with data for the other FAEs. The current evidence substantiates that DMF is the main active compound, via its metabolic transformation to monomethyl fumarate (MMF). A recent phase III randomized and placebo-controlled trial including more than 700 patients demonstrated therapeutic equivalence when comparing the licensed FAE combination with DMF alone, in terms of psoriasis clearance according to the Psoriasis Area and Severity Index (PASI) and Physician’s Global Assessment (PGA). Thus, DMF as monotherapy for the treatment of psoriasis is as efficacious as in combination with MEF, making the addition of such fumarate derivatives unnecessary.

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The Pharmacokinetics of Fumaric Acid Esters Reveal Their In Vivo Effects

Cited by 81 publications

References 49 publications

Clinical use of dimethyl fumarate in moderate‐to‐severe plaque‐type psoriasis: a European expert consensus

Clinical use of dimethyl fumarate in moderate‐to‐severe plaque‐type psoriasis: a European expert consensus

A 24‐week multicentre, randomized, open‐label, parallel‐group study comparing the efficacy and safety of ixekizumab vs. fumaric acid esters and methotrexate in patients with moderate‐to‐severe plaque psoriasis naive to systemic treatment

Dimethyl fumarate (DMF) vs. monoethyl fumarate (MEF) salts for the treatment of plaque psoriasis: a review of clinical data

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