Dimethyl fumarate finally coming of age
Fumaric acid esters (FAEs) have a long history as a systemic treatment for psoriasis, but their somewhat unusual development did not follow the evidence-based standards that are applied in drug development today. In 1959, the German chemist Schweckendiek was the first to demonstrate that psoriasis severity decreases through the oral administration of FAEs by performing experiments on himself. Without proper preceding pharmacological evaluations, FAE therapy was empirically further developed in the following decades with a favourable risk–benefit profile. However, treatment with FAEs remained restricted to prescription on a small scale in Germany, Switzerland and the Netherlands. It was not until 1994 that the use of FAEs became more widespread following a randomized, placebo-controlled evaluation of Fumaderm, a FAE-formulation consisting of dimethyl fumarate (DMF) and three monoethyl fumarate salts. The choice for the Fumaderm-components remains unclear, but DMF alone is now considered the most active component. Fumaderm is currently the most frequently prescribed systemic treatment for psoriasis in Germany after registration in 1994 for the treatment of severe psoriasis and in 2008 for moderately severe psoriasis. However, outside Germany the use of FAEs is still unlicensed and limited, and the level of evidence to support the efficacy and safety of FAEs in psoriasis treatment remains low. In this issue of the BJD, Mrowietz and colleagues describe findings from the BRIDGE trial, a phase III, multicentre, randomized, placebo-controlled, noninferiority trial that evaluated a novel FAE-formulation containing only DMF (LAS41008).8 The investigators randomized 704 adult patients with moderate- to-severe chronic plaque psoriasis in a 2 : 2 : 1 ratio to receive LAS41008, Fumaderm, or placebo for 16 weeks of treatment. LAS41008 was statistically significantly superior to placebo in the induction of a ≥ 75% reduction in Psoriasis Area and Severity Index (PASI-75), 38% vs. 15%, respectively. Compared with Fumaderm (PASI-75 40%), the DMF-formulation was noninferior. Adverse events were similar among the LAS41008 and Fumaderm treatment groups; both treatments were well tolerated. This trial is relevant, considering the demand for high-quality evidence on the use of FAEs in psoriasis treatment. The BRIDGE trial is the largest randomized, placebo-controlled study to date that has evaluated FAEs in psoriasis by using accepted efficacy outcomes and adhering to reporting guidelines now considered standard. Overall, the findings from the BRIDGE trial are in line with previous smaller trials and observational studies that demonstrated beneficial effects of DMF in reducing psoriasis severity. A clear limitation in this study is the relatively short treatment duration of 16 weeks, when taken into consideration that FAEs typically have a long onset until full clinical efficacy. Thus, the short treatment duration may explain the relatively low efficacy outcomes found in this trial. In conclusion, the BRIDGE trial provides high-quality evidence to support the use of DMF alone as FAE treatment for psoriasis. Future studies may benefit from longer treatment duration assessments and head-to-head comparisons with other systemic treatments, most notably methotrexate. In time, hopefully, this will pave the way for a wider registration and an increased availability of DMF as a treatment for psoriasis.