For many years the only drugs licensed for the treatment of multiple sclerosis (MS) were administered by injection (interferon beta, glatiramer and ▼natalizumab). Recently, three oral drugs have become available. We have previously reviewed the use of ▼fingolimod for highly active relapsing-remitting MS1 and ▼teriflunomide for the management of relapsing-remitting MS in adults.2 Here, we review the evidence for ▼dimethyl fumarate (Tecfidera—Biogen Idec Ltd) for the treatment of adults with relapsing-remitting MS.
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Multiple sclerosis (MS) is an inflammatory disorder of the brain and spinal cord resulting in damage to myelin and axons. Initially, inflammation is temporary and is followed by some form of remyelination. In the early stages patients may recover from episodes of neurological dysfunction. Around 80% of patients present with an acute episode (clinically isolated syndrome) with further episodes occurring sporadically (usually fewer than 1.5 episodes/year). Over time persistent symptoms accumulate with only partial recovery from each episode. Eventually, around 65% of patients develop secondary progressive MS and in 20% of cases the illness is progressive from onset.3
What is dimethyl fumarate?
Dimethyl fumarate is the principal fumaric acid ester contained in Fumadermi, which is used in Germany for the treatment of psoriasis.4 Although the exact mechanism of action of dimethyl fumarate in MS is not fully understood, it is thought to involve the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcriptional pathway, which is responsible for mediating cellular response to oxidative stress.5 The summary of product characteristics (SPC) states that dimethyl fumarate demonstrated anti-inflammatory and immunomodulatory properties in preclinical and clinical studies.6
Dimethyl fumarate was launched in the UK in February 2014 for the treatment of adult patients with relapsing-remitting MS.7 The licensed dose is 120mg twice daily, increased to 240mg twice daily after 7 days. Treatment should be initiated under supervision of a physician experienced in the treatment of MS.6
The licensing submission included two randomised double-blind placebo-controlled phase III studies (DEFINE and CONFIRM),8,9 one of which (CONFIRM)9 used open-label (rater-blinded) glatiramer acetate as a reference comparator. Both trials included adults aged 18–55 years with relapsing-remitting MS, a baseline score of 0–5 on the Expanded Disability Status Scaleii (EDSS), and evidence of disease activity demonstrated by at least one gadolinium-enhancing lesion seen on an MRI scan obtained within 6 weeks prior to randomisation, or at least one clinically documented relapse within the 12 months prior to randomisation. The DEFINE study excluded patients who had been treated with interferon alpha, interferon beta or glatiramer acetate within 3 months of randomisation; the criteria for the CONFIRM study were similar but excluded patients with any previous use of glatiramer acetate. Those who had experienced a relapse or had been treated with a corticosteroid within 50 days of randomisation, and those not stabilised after a relapse, were excluded from both studies. Approximately 40% of patients in the DEFINE study and 29% of patients in the CONFIRM study had received previous treatment with an “approved medication” for MS.
All efficacy analyses were performed using the modified intention-to-treat population, including all patients who underwent randomisation and received at least one dose of study drug. The primary outcome measures were the proportion of patients with a relapse at 2 years (DEFINE) and the annualised relapse rate at 2 years (CONFIRM). Relapses were defined as new or recurrent neurological symptoms, not associated with fever or infection, that lasted for at least 24 hours and that were accompanied by new objective neurological findings. The risk of confirmed disability progression, defined as at least a 1-point increase on the EDSS in patients with a baseline score of ≥1 or at least a 1.5-point increase in patients with a baseline score of 0, sustained for 12 weeks, was evaluated in both studies as a secondary endpoint.8,9 Although the studies investigated two different dose regimens for dimethyl fumarate, only the results for the dose currently licensed in the UK (240mg twice daily) are presented here.
In the DEFINE study, participants were randomised to double-blind treatment with dimethyl fumarate 240mg twice daily (n=410), dimethyl fumarate 240mg three times daily (n=416) or placebo (n=408).8 The proportion of patients with a relapse at 2 years was 27% with twice daily dimethyl fumarate and 46% with placebo (hazard ratio [HR] 0.51, 95% CI 0.40 to 0.66; p<0.001). This is equivalent to a number-needed-to-treat of five to prevent one additional patient relapsing within 2 years. The annualised relapse rate (secondary endpoint) was also lower for dimethyl fumarate twice daily (0.17 vs. 0.36 for placebo; rate ratio 0.47, 95% CI 0.37 to 0.61; p<0.001), and there was a lower rate of confirmed progression of disability sustained for 12 weeks (16% vs. 27%; HR 0.62, 95% CI 0.44 to 0.87; p=0.005).8
In the CONFIRM study, participants were randomised to treatment with dimethyl fumarate 240mg twice daily (n=359), dimethyl fumarate 240mg three times daily (n=345), open-label glatiramer acetate 20mg daily (n=350) or placebo (n=363) for 96 weeks.9 The annualised relapse rate at 2 years was lower with dimethyl fumarate twice daily compared with placebo (0.22 vs. 0.40, p<0.001; relative risk reduction [RRR] 44%, 95% CI 26% to 58%; p<0.001) and also with glatiramer acetate compared with placebo (0.29 vs 0.40, p<0.01; RRR 29%, 95% CI 7% to 45%; p<0.05).9 The estimated proportion of patients who relapsed by 2 years (secondary endpoint) was 29% for dimethyl fumarate twice daily (HR 0.66, 95% CI 0.51 to 0.86; p≤0.01 vs. placebo), 32% for glatiramer acetate (HR 0.71, 95% CI 0.55 to 0.92; p≤0.01 vs. placebo) and 41% for placebo. Confirmed progression of disability sustained for 12 weeks occurred in similar proportions in each group, with no statistically significant difference for either dimethyl fumarate (13%) or glatiramer acetate (16%) compared with placebo (17%).
Limitations of the data
Although both studies demonstrated a statistically significant effect compared with placebo for their primary endpoints, the absolute reduction in relapse rate (<0.2 relapses per year in both studies) was small. Despite subgroup analyses suggesting a similar efficacy in patients with high disease activity compared with the overall study population,10 the studies were not powered to detect differences in outcomes for this specific group of patients.
While the results of the primary and secondary outcomes in the CONFIRM study were similar for the two active treatments, the study was not designed or powered to demonstrate statistical superiority or non-inferiority of dimethyl fumarate compared with glatiramer acetate.9 There are no published studies comparing dimethyl fumarate with any other disease-modifying therapy in the treatment of MS.
The European Medicines Agency (EMA) advises that the most relevant parameter in MS is the accumulation of disability.11 Dimethyl fumarate was shown to reduce the proportion of patients with confirmed accumulation of disability sustained for at least 12 weeks (secondary endpoint) compared with placebo in only one of the studies,8 but there was no statistically significant difference in the 6-month assessment of disability in either study.10 The effects of dimethyl fumarate on disability progression are therefore uncertain.12 The European Public Assessment Report notes that the effect on disability progression was not considered robust enough to support a claim for a disease-modifying drug.10
There are no safety or efficacy data beyond a treatment duration of 2 years,13 which is a relatively short time considering the chronic nature of the disease.
Comparison with other therapies
A systematic review funded by the company (Biogen Idec US) included 27 randomised controlled trials (number of participants ranging from 31 to 2,244) evaluating disease-modifying therapies in adults with MS (≥80% with relapsing-remitting disease).14 Mixed treatment comparisons suggested that for annualised relapse rate, dimethyl fumarate was superior to placebo (rate ratio 0.53, 95% CI 0.45 to 0.62), interferons (rate ratio 0.76, 95% CI 0.64 to 0.90), glatiramer acetate (rate ratio 0.80, 95% CI 0.67 to 0.95), and teriflunomide (rate ratio 0.78, 95% CI 0.61 to 0.98), and similar to fingolimod (rate ratio 1.19, 95% CI 0.97 to 1.46). Natalizumab was superior to dimethyl fumarate (rate ratio 1.54, 95% CI 1.23 to 1.92). However, this analysis was associated with a number of limitations, including heterogeneity between the studies, variability in outcome definitions, and a reliance on indirect comparisons (due to the lack of head-to-head studies), and the results should therefore be interpreted with caution.
The most common adverse reactions associated with dimethyl fumarate seen in the placebo-controlled studies included flushing (34% vs. 4% placebo), gastrointestinal events (e.g. diarrhoea [14% vs. 10%], nausea [12% vs. 9%] and abdominal pain [9% vs. 4%]), which were mainly of mild to moderate severity.6 These reactions tend to occur early in the course of treatment, but may continue to occur intermittently.6 In the Phase III studies, the incidence of adverse effects leading to discontinuation was similar for dimethyl fumarate and placebo (16% vs. 13% in DEFINE; 12% vs. 10% in CONFIRM).8,9
Dimethyl fumarate has been associated with elevated hepatic transaminases, primarily during the first 6 months of treatment. The incidence of proteinuria was higher with dimethyl fumarate than placebo (9% vs. 7%, respectively), and this is considered by the EMA to be an important identified risk (derived from post-marketing experience with the product Fumaderm).10 Renal tubular injury and hepatic injury are important potential risks identified from animal data and the SPC recommends assessment of hepatic function (e.g. ALT and AST) and renal function (e.g. creatinine, urea and urinalysis) at baseline, after 3 and 6 months of treatment, and then every 6–12 months as clinically indicated.6
Dimethyl fumarate may decrease lymphocyte counts, with average reductions of 30% seen in placebo-controlled studies, but the mean counts remained within normal limits, and there was no evidence of an increased incidence of infections. The SPC states that the results of a complete blood count performed within the previous 6 months should be available before starting therapy, and further assessments are then recommended after 6 months of treatment and then every 6–12 months and as clinically indicated.6 The EMA's Committee for Medicinal Products for Human Use (CHMP) has requested that a specific study be conducted to assess the effects of dimethyl fumarate on the immune response to vaccination and on lymphocyte subsets and immunoglobulin levels.10
Progressive multifocal leukoencephalopathy (PML) has been reported in patients taking Fumaderm. Because the mechanism of action of dimethyl fumarate in patients with MS is not completely understood, the CHMP has recommended that serious and opportunistic infection is considered an important potential risk.
The number of malignancies reported during the clinical trials was low and of a similar rate to placebo; however, further long-term data, included in the Risk Management Plan, are required to investigate this potential risk.10 Further studies are required to establish the long-term safety profile of the drug.
Cautions and contraindications
Dimethyl fumarate is contraindicated in patients with hypersensitivity to the active substance or any of the excipients. It is not recommended during pregnancy unless clearly needed and if the potential benefit justifies the potential risk to the foetus. Women of childbearing potential should use effective contraception before and during treatment.6 A registry has been established to monitor pregnancy outcomes in women exposed to dimethyl fumarate during pregnancy.10
Live vaccines should not be given to patients treated with dimethyl fumarate unless the potential risk of clinical infection from vaccination is outweighed by the risk to the individual of not vaccinating. Concomitant use with nephrotoxic drugs may increase the potential of renal adverse reactions, and simultaneous use of other fumaric acid derivatives (including topical formulations) should be avoided.6
The Scottish Medicines Consortium has accepted dimethyl fumarate for the treatment of adult patients with relapsing-remitting MS, taking account of a Patient Access Scheme that improves its cost-effectiveness.13 The National Institute for Health and Care Excellence (NICE) has not yet published final guidance on dimethyl fumarate; the Final Appraisal Determination issued in July 2014, recommends it as an option for treating adults with relapsing-remitting MS provided that they do not have highly active or rapidly evolving severe disease.12
The list price of dimethyl fumarate is £17,849 per patient per year. In comparison the list prices are £6,701 for glatiramer acetate, £7,259–£10,572 for interferon beta (depending on the product used) and £13,529 for teriflunomide.2,15 Dimethyl fumarate is available at a discounted price through an agreed patient access scheme in Scotland, and the manufacturer has agreed a patient access scheme with the Department of Health in England, which is being taken into account by NICE as part of the appraisal process. The size of the discount is commercial in confidence and no details have been made public.12,13
▼Dimethyl fumarate is the third oral agent to be approved for use in the treatment of relapsing-remitting multiple sclerosis (MS). It has been shown to result in an absolute reduction in the annualised relapse rate of about 0.2 relapses per year when compared with placebo. Its effects on progression of disability are, however, uncertain and the results for this outcome were not considered robust enough by the European regulator to support a claim for a disease-modifying drug. Although one study used glatiramer acetate as a reference comparator, it was not designed to compare the efficacy of the two active treatments. In the absence of head-to-head studies, the relative efficacy and tolerability of dimethyl fumarate compared with other therapies remains to be established.
The most common adverse effects include flushing and gastrointestinal upset (nausea, abdominal pain and diarrhoea) of mild to moderate severity. However, a 30% mean reduction in lymphocyte count is routinely observed and regular monitoring of complete blood cell count is recommended. Hepatic and renal function should also be monitored regularly for the first 6 months and then as clinically indicated. There are a lack of data on long-term safety and post-marketing surveillance will be essential.
The lack of head-to-head data prevent direct comparison between drugs licensed for the management of MS and we believe that a properly designed comparative study is needed. In the absence of such data, an independent multiple technology assessment might help to define the clinical- and cost-effectiveness, and place in therapy of these newer agents. In the meantime, we recommend that dimethyl fumarate should be reserved for patients who are not able to tolerate first-line treatment with interferon beta or glatiramer and should only be prescribed under the direct supervision of clinicians experienced in the management of MS.