The changing fortunes of dimethyl fumarate

From an inauspicious start to life as a fungicide and desiccant used in the shipping of sofas and shoes, where concerns over prolonged exposure to skin resulting in contact dermatitis were raised, the use of dimethyl fumarate (also known as BG-12) as a medicine began as an oral therapy for psoriasis(1) and for other unlicensed indications such as sarcoidosis in combination with other fumaric esters.

That dimethyl fumarate might have a promising effect on the lymphocytes was already known 40 years ago. In 1975, phytohaemaglutinin (PHA)-stimulated cultivated human lymphocytes were noted to respond to exposure to fumaric acid monoethylester (FAME). Lymphocytic incorporation of thymidine, uridine, alanine and leucine into RNA and DNA was inhibited by FAME at a rate six-times higher than the inhibitory effect on protein synthesis.(2)

Dimethyl fumarate was found to be the most active of the esters and has now been investigated as a novel therapy for multiple sclerosis (MS). On 21 March 2013, the European Medicines Agency recommended granting marketing authorisation for dimethyl fumarate for relapsing-remitting multiple sclerosis.(3) The majority of patients diagnosed with MS will be in a relapsing-remitting phase at the point of diagnosis, and so would be eligible for treatment with dimethyl fumarate within the licensed indication, pending any national restrictions that might be applied.

Dimethyl fumarate has been shown to have anti-inflammatory and cytoprotective properties. These actions are thought to be mediated via activation of the nuclear 1 factor erythroid-2-related factor-2 (Nrf-2) transcriptional pathway. This pathway(4) controls phase-2 detoxifying gene expression, and is crucial for oxidative stress response and immune homeostasis. This anti-oxidant response pathway appears to be the primary cellular defence against the cytotoxic effects of oxidative stress. Dimethyl fumarate therefore activates a pathway that defends against oxidative stress-induced neuronal death in astroglial and microglial cells.

It also protects the blood–brain barrier and supports myelin integrity. Furthermore, dimethyl fumarate may modulate dendritic cell differentiation and modulate immune cell responses, and suppress pro-inflammatory cytokine production (for example, interleukin-12) and peripheral T-cell numbers (CD4+ and CD8+ cells).

Two seminal phase III trials of dimethyl fumarate have been published: CONFIRM and DEFINE. The CONFIRM trial recruited 1417 patients with clinically definite multiple sclerosis and at least two relapsed in the previous two years or one in the preceding year.(5) The four study arms were: placebo; BG-12 240mg twice daily; BG-12 240mg three-times daily; and glatiramer acetate 20mg s/c daily (as a reference comparator) for 96 weeks. Discontinuation rates were high, but highest in the placebo group (36%: 30% BG-12 twice daily: 28% BG-12 three-times daily: 25% glatiramer).

The primary endpoint was the annualised relapse rate and the study was not powered to determine non-inferiority or superiority of dimethyl fumarate over glatiramer acetate. Reported in 2012, the results of CONFIRM were promising. As expected, the annualised relapse rate was significantly lower in each of the treatment groups. Each active treatment positively diminished magnetic resonance imaging (MRI) evidence of disease.

Significant reductions in the size and quantity of T1-weighted gadolinium-enhancing MRI hyper-intense lesions versus placebo were observed. However, disability progression was not altered significantly by any of the active study arms. Dimethyl fumarate treatment also resulted in a lower number of hypo-intense lesions on T1-weighted MRI, which are characterised by greater neuronal loss than iso- or hyper-intense lesions. This suggests that dimethyl fumarate may be able to reduce axonal loss in addition to various phase II neuroprotective findings.

The DEFINE study, co-published with CONFIRM, recruited 1234 patients of whom 952 completed the study (78% of the placebo group, 77% of each of the BG-12 arms).(6) Each patient had clinically definite MS, an Expanded Disability Status Scale score of 0–5, and at least one relapse in the last year or MRI evidence of a gadolinium-enhancing lesion within the previous six weeks. Three study arms were employed: placebo: BG-12 240mg twice daily: BG-12 240mg three times daily over two years. Relapse rates in the BG-12 arms were significantly lower than with placebo; 27%: 28%: 46% (placebo arm). In contrast to the CONFIRM study, DEFINE was able to show an impact on the progression of disability.

Patients with progression of disability sustained for 12 weeks were 16%: 18%: 27% (placebo group). The mean number of gadolinium-enhancing lesions was also less, with significant odds ratio versus placebo p-values of <0.001 for both BG-12 arms. Adverse events were similar to CONFIRM with flushing and gastrointestinal events being most common, though DEFINE found higher levels of proteinuria and pruritis. Serious adverse events were sporadic and no pattern emerged, other than for MS relapse, which was higher in the placebo group.

Dimethyl fumarate noted adverse events include flushing, gastrointestinal events (diarrhoea, nausea, upper abdominal pain), upper respiratory tract infections and erythema. The incident for flushing in particular was noted to be around 35% and 28% of patients treated with 240mg twice daily: 240mg thrice daily respectively versus 6% in the placebo arm (CONFIRM trial). It is interesting to note than the rate was lower in the more intense treatment arm, which could be due to a withdrawal effect. The other side effects noted have a higher incidence in the more intense treatment arm. Events were mostly of mild or moderate severity and were more acute in the first month of treatment, decreasing thereafter.

Adverse events not reported in CONFIRM but reported in previous psoriasis trials include increased cholesterol, triglycerides, serum potassium and serum creatinine. Proteinuria has previously been found in 11% of patients treated with fumaric acid esters for three years.(2) In CONFIRM and DEFINE, proteinuria was noted in between 8% and 12% of patients over two years of therapy. Monitoring of the lipid profile, electrolytes and renal function may be warranted in dimethyl fumarate-treated individuals pending the reporting of further extension studies.

In 2013, two case reports were published linking PML with treatment with fumaric acid or compounded mixed fumarate esters.(7,8) Both patients had a profound lymphopenia, which is a known risk factor for the development of PML. Biogen Idec, the manufacturers the BG-12 formulation of dimethyl fumarate (Tecfidera), point out in their response that there has been no increased risk of opportunistic infections reported in the BG-12 data to date, and there have been no PML cases linked to treatment with BG-12.(9)

The bioavailability of fumaric acid is low, where the absorption of its esters in the small intestine is almost complete. Dimethyl fumarate is rapidly hydrolysed by esterases to monomethylfumarate (MMF), which is considered to be the active metabolite.(1) The plasma half-life of dimethyl fumarate is measured at 12 minutes, but the MMF metabolite has a far longer half-life of 36 hours. Peak concentrations of MMF in humans from single-dose administration occur at approximately 5–6 hours and protein binding is approximately 50%. Metabolism appears to be independent of the cytochrome P450 system, nor is dimethyl fumarate or MMF though to be an inducer or inhibitor of these enzymes. Excretion appears to be mainly pulmonary excretion (by breathing out) with minimal amounts lost in the urine or faeces.

A trial of Asian patients with relapsing-remitting MS with a similar design to DEFINE is underway (NCT01838668).(10) Interestingly, there is only one active arm of 240mg twice daily. The study is based in Japan, presumably because most Asian cases of MS are recorded in Japan. Results are expected in 2019. An extension study for 240mg twice daily and 240mg three times daily monotherapy in relapsing-remitting MS are also underway with results expected in 2016. Another study in healthy volunteers designed to assess potential interventions to address flushing and gastrointestinal events to BG-12 is recently completed (NCT01568112).(11) This study may be of benefit in increasing the tolerability of dimethyl fumarate and thereby the number of patients who feel they wish to continue with treatment.

There are no dimethyl fumarate combination therapy studies registered at the present time.

As with all the new oral MS drugs, patient satisfaction is likely to be high with dimethyl fumarate owing to the ease of administration. Additionally, the active ingredient, dimethyl fumarate, in Tecfidera is noted to have a pleasing ‘fruit-like’ taste. With general treatment acceptability and a lack of serious side effects, but perhaps a lower potency than some of the newer agents in reducing disease progression, dimethyl fumarate may be an option for first-line treatment. With such a unique mode of action, it will be interesting to see if eventually dimethyl fumarate becomes a therapy to combine with other MS therapies. We await further data with anticipation.