Fumaric Acid Esters: The Psoriasis Treatment Becoming a European Standard
"From Patient Discovery to European Approval: How Fumaric Acid Esters are Revolutionizing Psoriasis and Multiple Sclerosis Treatment."
The story of fumaric acid esters in medicine is extraordinary. Originating from a patient's insight, developed by Swiss pharmacists, clinically tested by German dermatologists, and initially approved only in Germany, Fumaderm® achieved a market share of up to 60% among conventional systemic therapies. This medication holds a distinctive position in the world of dermatology.
However, the history of fumaric acid esters is marked by unusual circumstances. The composition of Fumaderm®, including dimethyl fumarate and three ethyl hydrogen fumarate salts, was never scientifically justified. To this day, the rationale behind this specific mixture remains unknown. Furthermore, the approval of Fumaderm® in 1994 was primarily based on data from a single double-blind, randomized, placebo-controlled study conducted by Peter Altmeyer in Bochum, involving only 100 patients over 16 weeks.
Despite these unusual beginnings, Fumaderm®'s success grew, becoming a leading systemic treatment for psoriasis. This success did not go unnoticed by dermatologists in other European countries. While the Netherlands had long been producing similar formulations in hospital pharmacies, the UK and Ireland had special arrangements allowing certain centers to prescribe imported Fumaderm®. Even in these countries, it became a frequently used systemic therapy for psoriasis.
Current Evidence and Availability
Fumaric acid esters (FAEs) are licensed for moderate-to-severe psoriasis in Germany but remain unlicensed in most other countries. A Cochrane review included six randomized controlled trials involving 544 participants to assess their efficacy and safety. Despite extensive German experience, information about patient demographics and baseline characteristics that may influence real-world response remains limited.
Treatment Use and Tolerability
A systematic review reported that FAEs can be a safe and effective option for adults with moderate-to-severe psoriasis. Gastrointestinal side effects may occur when treatment begins, and the review suggested that slow dose titration may reduce them. FAEs are also considered alongside systemic treatments such as methotrexate, TNF inhibitors, and IL-17 inhibitors, reflecting the range of therapies used when psoriasis requires systemic management.
From Empirical Use to Standardized Therapy
FAEs were introduced as a systemic psoriasis treatment in 1959 and were developed empirically in Germany between 1970 and 1990. The historical account also places this development in Germany, Switzerland, and the Netherlands. The compounds include monoethyl fumarate and dimethyl fumarate, derived from fumaric acid, while later work emphasized dimethyl fumarate and its active metabolite, monomethyl fumarate.
From Fumaderm® to Tecfidera®: Overcoming Regulatory Hurdles
The irrational mixture of fumaric acid esters in Fumaderm® hindered its approval outside of Germany. Consequently, the Swiss company Fumapharm AG developed FAG-201, a new drug containing only the active ingredient dimethyl fumarate (DMF). This was intended for the European and international markets. Following an initial Phase II study of FAG-201 in psoriasis patients in Poland, Fumapharm partnered with the US firm Biogen.
- Key Development: BG-12, containing only Dimethyl Fumarate (DMF), showed fewer gastrointestinal side effects.
- Psoriasis Focus Shift: Biogen acquired Fumapharm in 2006, halting the psoriasis program and focusing BG-12 on multiple sclerosis.
- Regulatory Approval: The FDA and EMA approved BG-12 (Tecfidera®) for multiple sclerosis treatment.
Evidence Remains Developing
Current evidence supports continued interest in fumaric acid esters for psoriasis, but the available material does not establish a single definitive view of their role across all settings. Research attention includes efficacy, safety, dosing, and how patients respond in routine practice. Further well-designed studies may help clarify where FAEs fit among contemporary systemic treatments.
Important Limitations
FAE treatment may be limited by tolerability concerns, particularly gastrointestinal side effects at initiation. Their regulatory status also differs substantially between countries, which can restrict access or lead to off-label use. These limitations mean that their benefits and risks need to be considered in the context of individual treatment choices.
FAEs Compared With Other Systemic Options
A direct comparison reported that risankizumab appeared more effective, safer, and better tolerated than fumaric acid esters, and suggested that it should be discussed collaboratively as a first-line option for moderate-to-severe plaque psoriasis. Comparisons involving FAEs and methotrexate are also relevant because both are systemic therapies used in this setting. However, comparative guides note that direct head-to-head trials across all relevant treatments remain limited.
Skilarence®: A New Hope for Psoriasis Patients
Almirall, a Spanish company, developed a DMF-only medication with the galenic properties of Fumaderm®, taking advantage of a temporary EMA allowance for hybrid generics. This paved the way for European approval of DMF therapy for psoriasis. A European comparative study between LAS41008, the new DMF development drug, and Fumaderm® showed no differences in efficacy, tolerability, and adverse drug reactions. This study was the basis for the EMA's positive opinion on April 21, 2017, and the EU approval on June 27, 2017, of LAS41008 under the brand name Skilarence®.
A Qualified Place in Care
Taken together, fumaric acid esters appear to have an established but geographically uneven role in psoriasis treatment. Their use is supported by clinical experience and systematic review evidence, while tolerability and limited comparative evidence remain important considerations. Their place in therapy is therefore best understood as dependent on treatment setting, patient circumstances, and available alternatives.
Questions for Future Research
Future work may need to clarify how fumaric acid esters compare with newer systemic therapies in routine clinical practice. Research could also improve understanding of which patients are most likely to respond and how treatment initiation can be made more tolerable. Until stronger comparative evidence is available, projections about their future role should remain cautious.
Psoriasis Within Systemic Care
Psoriasis is described as a recurring skin condition associated with keratinocyte hyperproliferation and immune dysregulation. Because management frequently requires systemic therapy, FAEs are considered alongside methotrexate, TNF inhibitors, and IL-17 inhibitors. This broader treatment landscape places FAEs within a complex set of systemic options rather than treating them as an isolated intervention.
Treatment Decisions in Practice
For patients, the practical value of fumaric acid esters depends not only on efficacy but also on tolerability, access, and the treatment options available in their country. Differences in licensing can mean that patients in different countries are offered different psoriasis treatments. Shared decisions may therefore need to account for both clinical considerations and the realities of local care.
Skilarence®'s dosing and titration schedule are identical to those of Fumaderm®, and it is available in 30 mg and 120 mg DMF tablets. The pharmacological properties also match those of Fumaderm® due to the identical galenic formulation. A key advantage of Skilarence® is the updated monitoring recommendations, which align with clinical practice and guidelines, improving safety. For Skilarence®, monitoring can be done every 3 months if Lymphocytes is above 1000/Microliter. if it goes below this a monthly test must be taken. If Lymphocyte is below 700/Microliter, therapy must stop.
The approval of Skilarence®, containing only DMF, makes approvals outside Europe feasible. However, to further benefit patients, regulatory bodies like the EMA should reconsider their stance on DMF. The EMA should have a clear position for Europe.