FDA approves third oral agent for MS

Dimethyl fumarate (Tecfidera, Biogen Idec) oral delayed-release capsules, formerly called BG-12, was approved by the FDA on March 27, 2013 for the treatment of relapsing forms of multiple sclerosis (MS). It is the third oral drug to be recently approved for the treatment of these types of MS.

Efficacy

Dimethyl fumarate and its metabolite monomethyl fumarate have been shown to activate an antioxidant response pathway (Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans. It is thought that the Nrf2 pathway is involved in cellular defense against oxidative stress.

The CONFIRM study was a phase 3 comparison between dimethyl fumarate and placebo of 1417 patients with relapsing-remitting MS for 2 years. Dimethyl fumarate 240 mg given orally two or three times a day reduced the annual relapse rate (ARR) by 44% and 51%, respectively, versus placebo. Additionally, new or enlarged CNS lesions were significantly reduced with dimethyl fumarate.  Glatirimer acetate was included as an active comparator in the study and showed an ARR of 29%.  Neither dimethyl fumarate nor glatiramer acetate slowed the progression of disability compared to placebo.

Another phase 3 study comparing dimethyl fumarate with placebo (DEFINE) enrolled 1234 patients with relapsing-remitting MS and compared two dosages with placebo for 2 years.  Dimethyl fumarate showed a significant reduction of 53% in ARR as well as a significant reduction in new CNS lesions and lesion progression. In this study, unlike CONFIRM, dimethyl fumarate did show a decrease in disability progression versus placebo.

The efficacy of dimethyl fumarate appears to be similar to fingolimod and slightly better than teriflunomide for reducing ARR.

Safety

Dimethyl fumarate most commonly causes flushing (40% of patients) and gastrointestinal (GI) effects (diarrhea, nausea, vomiting), but these effects tend to lessen with time and can be reduced by administering with food. Dimethyl fumarate can also lower white blood counts, and the manufacturer recommends checking a complete blood count within 6 months prior to starting the medication, and repeating at least annually while on therapy.

While no evidence exists that its effects on white counts is related to any increased risk of opportunistic infections, mean lymphocyte counts decreased by about 30% during the first year of treatment, but stabilizes thereafter in studies. A handful of cases of progressive multifocal leukopenia (PML) have been reported following use of other products containing dimethyl fumarate that were used to treat psoriasis. To date, no cases of PML have been reported with dimethyl fumarate used for the treatment of MS. Compared with fingolimod and teriflunomide, dimethyl fumarate appears to have better safety data, though no direct head-to-head comparisons have been made.

No appreciable drug-drug interactions have been reported with dimethyl fumarate, especially since it is not metabolized by CYP enzymes. Food reduces flushing, but otherwise has not been associated with pharmacokinetic effects of dimethyl fumarate.

Dosing

The starting dose for dimethyl fumarate is 120 mg twice a day for 7 days, followed by a maintenance dose of 240 mg twice a day. Dimethyl fumarate should be swallowed whole and may be taken with or without food, though taking it with food might reduce flushing. 

No dosage adjustments are required for renal or hepatic dysfunction. Patients should be counseled to keep dimethyl fumarate in its original container as it is sensitive to light; unused capsules need to be discarded after 90 days of opening. Dimethyl fumarate is available in 7-day starter packs of 120 mg, 23-day bottles and 30-day bottles of 240 mg.

References

Tecfidera (dimethyl fumarate) product information.  Cambridge, MA: Biogen Idec Inc; 2013.  Accessed: July 2, 2013.

Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in Multiple Sclerosis: the CONFIRM study. NEJM 2012;367:1087-97.  DOI: 10.1056/NEJMoa1206328

Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing Multiple Sclerosis: the DEFINE study. NEJM 2012;367:1098-1107.  DOI: 10.1056/NEJMoa1114287

Kevin W. Chamberlin, PharmD, is assistant clinical professor and assistant department head, pharmacy practice, University of Connecticut School of Pharmacy, Storrs, Conn.