Dimethyl fumarate: Oral option for MS
Tecfidera (dimethyl fumarate—Biogen Idec)
Dimethyl fumarate (Tecfidera—Biogen Idec), a new oral drug for relapsing–remitting multiple sclerosis (MS), was approved by FDA in late March. Much anticipated because of its possible superiority over currently available medications, the drug joins fingolimod (Gilenya—Novartis) and teriflunomide (Aubagio—Sanofi) as the only MS treatments currently in oral form.
In two clinical trials—DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in Relapsing–Remitting MS) and CONFIRM (Comparator and an Oral Fumarate in Relapsing–Remitting MS)—dimethyl fumarate reduced MS relapse rates by approximately 50% over placebo and reduced the progression of disability by about 30%. The drug was significantly more effective in reducing relapses and slowing the progression of MS than commonly prescribed injectable agents glatiramer acetate (Copaxone—Teva), interferon beta-1a (Rebif—EMD Serono and Avonex—Biogen), and interferon beta-1b (Betaseron—Extavia).
Dimethyl fumarate is a simple molecule derived from naturally occurring fumaric acid. The agent is known to activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, which is involved in cellular response to oxidative stress, but its mechanism of action in interrupting the pathogenic processes of MS is unknown.
Efficacy and safety data
The efficacy and safety of dimethyl fumarate were demonstrated in two Phase III clinical trials involving more than 2,600 patients. Both trials compared dimethyl fumarate taken either two or three times daily with placebo in patients with relapsing–remitting MS. The starting dose was 120 mg two or three times daily for the first 7 days, followed by 240 mg two or three times daily over 2 years.
The primary DEFINE trial endpoint was the proportion of patients relapsing at 2 years, along with the number of new or newly enlarging T2 hyperintense lesions, new T1 hypointense lesions, and Gd+ lesions; annualized relapse rate; and time to confirmed disability progression. The CONFIRM trial included those endpoints as well as a reference comparator of glatiramer acetate, 20-mg subcutaneous daily injection.
In both trials, dimethyl fumarate had a statistically significant effect on all endpoints, and 240 mg taken three times daily showed no additional benefit over the twice-daily dose. Results also showed favorable safety and tolerability profiles.
In addition to potentially neuroprotective actions mediated through Nrf2 activation, dimethyl fumarate may decrease a patient’s white blood cell count and increase the risk of infection. In the placebo-controlled trials, white blood cell counts decreased by approximately 30% during the first year of treatment and then remained stable. Study participants taking the drug showed no increased risk of serious infections or malignancies.
Flushing and gastrointestinal problems were the most common adverse reactions, especially at the start of therapy (see sidebar). These may decrease over time.
Dimethyl fumarate (Tecfidera)
Manufacturer: Biogen Idec
Drug class: Nrf2 activator
Indication: Treatment of patients with relapsing–remitting forms of multiple sclerosis
Dosage: Starting oral dose is 120 mg twice daily for 7 days, after which the dose increases to 240 mg twice daily.
Of note: Because the drug may decrease white blood cell counts, FDA recommends a complete blood cell count within 6 months before starting therapy to identify patients with preexisting low white blood cell counts. Patients who have serious infections should not take the drug until the infection has been resolved.
- Adverse effects include flushing (warmth, redness, itching, and/or burning sensation) and gastrointestinal reactions (nausea, vomiting, diarrhea, stomach pain, indigestion).
- Other warnings and precautions: Because no adequate and well-controlled studies exist on use during pregnancy and because adverse effects were noted in pregnancy and lactation in studies on animals, pregnant women should not take dimethyl fumarate unless the potential benefits justify the potential risk to the fetus. Encourage patients to enroll in the Tecfidera Pregnancy Registry (800-456-2255) if they become pregnant while taking the drug.
Review the Medication Guide with patients. Educate patients on proper administration, which includes taking the capsules twice daily, not crushing or chewing the capsules, and not sprinkling the capsule contents on food. Inform patients of potential adverse affects such as flushing and gastrointestinal symptoms.