Dimethyl fumarate is a derivative of fumaric acid used in the systemic treatment of psoriasis vulgaris (Gebu 2011; 45: 121-132). Until recently, fumarates were only available as magistral preparations, and in Germany also as a proprietary product, Fumaderm®. As reported in our German sister publication Arznei-Telegramm (AT 2014; 45: 28-29), the manufacturer has managed to get dimethyl fumarate, one of the components of Fumaderm® (which also contains monoethyl fumarate) classified by the European Medicines Agency as a New Chemical Entity (NCE) in the Tecfidera® preparation. The trials performed by the manufacturer have obtained it a market authorisation for Tecfidera® and market exclusivity for this drug for the next ten years. Based on this ‘dossier protection’ of an agent that has for many years been used as a magistral preparation for the treatment of psoriasis vulgaris, the manufacturer has raised its cost tenfold, resulting in extra costs of over € 1000 a month (see the table). This method of obtaining a patent is a rarity and can be added to the list of profit-maximising tips for manufacturers published in Gebu 2012; 46: 148-150. In fact, Germany’s own registration authority does not regard Tecfidera® as an NCE. Serious side-effects have been found when the drug is used for the treatment of psoriasis vulgaris, such as progressive multifocal leuko-encephalopathy (PML) (Gebu 2014; 48: 3).
In response to questions by Dutch parliamentarians in November 2014 about the cost of dimethyl fumarate, the Minister of Health, Welfare and Sports (VWS) stated that Tecfidera® was a special case, in view of the availability of an alternative in the form of the magistral preparation, which is still covered by Dutch basic healthcare insurance.5 European drugs legislation allows pharmacists to prepare the drug magistrally, which means that no manufacturing authorisation or marketing authorisation is required, provided it concerns a drug that is prepared by the pharmacist at the pharmacy, on a doctor’s prescription. This means that doctors are allowed to prescribe dimethyl fumarate using the generic name, and pharmacists are allowed to supply a magistral prepation.5
The results of the two randomised double-blind trials of dimethyl fumarate to treat patients with multiple sclerosis that have been published so far showed that, over the study period of approximately two years, the agent produced a statistically significant reduction of the number of exacerbations in patients with relapsing-remitting multiple sclerosis, compared to placebo. A remarkable reduction of the number of exacerbations was seen in the placebo group, largely corresponding to the findings in the dimethyl fumarate group (1.0 vs. 1.1 in the first study), which raises the question whether the exacerbation rate in the year preceding the trial may have been overestimated. No conclusions can be drawn from the open arm of the first trial, using glatiramer, since the comparison with placebo or dimethyl fumarate was not a primary endpoint. In view of the risk of leukopenia, it is more practical to instruct patients to consult a doctor with any serious infections than to have routine comprehensive blood tests. Drop-out rates in these trials were considerable, and no randomised double-blind trials into the agent’s long-term efficacy have been published in peer-reviewed journals. The nature and number of the side-effects implies a considerable risk of deblinding in the trials. We conclude that it is not possible to establish the correct place of dimethyl fumarate in the treatment of multiple sclerosis on the basis of these trials.
Gebu 2008; 42: 51-58 presented a review of the treatment of multiple sclerosis, which concluded that the severity of exacerbations of relapsing-remitting multiple sclerosis may be somewhat reduced by active treatment with other immunomodulants, such as interferon beta 1a (Avonex®, Rebif®) or beta 1b (Betaferon®) or glatiramer than with placebo, but that this favourable finding should be weighed against the disadvantages of this therapy, such as side-effects, discomforts and high cost. The long-term efficacy of this therapy remains insufficiently proven, so the question is when and for which patients relapsing-remitting multiple sclerosis should be treated with immunomodulants, and when the therapy should be terminated. It seems better to save patients with a mild form of multiple sclerosis (admittedly hard to predict) the disadvantages of medication by not treating the first manifestation of relapsing-remitting multiple sclerosis with immunomodulants, the more so since there is no proof that early treatment is better than late treatment.
Unfortunately, the introduction of dimethyl fumarate has not changed the above conclusion from 2008, whereas the new drug considerably raises the costs of health care (see the table).
1. Productinformatie dimethylfumaraat (Tecfidera®), via: www.ema-europa.eu, human medicines, EPAR’s.
2. CG-rapport dimethylfumaraat (Tecfidera®), via: www.zinl.nl/publicaties/Geneesmiddelenbeoordelingen.
3. Fox RJ, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012; 367: 1087-1097.
4. Gold R, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012; 367: 1098-1107.
5. Beantwoording Kamervragen over de vergoeding van een geneesmiddel zonder de meerwaarde ervan te beoordelen (1).pdf.
*The literature refers to the Dutch tekst