Tecfidera™ (dimethyl fumarate)
FDA-Approved Medications: Administered Orally
- Oral medication; 240 mg pill taken twice daily (taking Tecfidera only once daily has not been demonstrated to be effective in MS)
- Tecfidera is approved for relapsing forms of MS
The United States Food and Drug Administration (FDA) announced in March 2013 that it had approved Tecfidera (dimethyl fumarate or DMF, formerly known as BG-12) as a first-line therapy for the long-term treatment of relapsing forms of multiple sclerosis (MS). Tecfidera is an oral fumaric acid ester, related to a medication called Fumaderm®. This latter medication was previously shown to be effective in patients with psoriasis and was used for this indication in Germany for many years. The mechanism of action in MS is still under investigation; however, Tecfidera may have a distinct dual mechanism of action.
First, it is an immunomodulator with anti-inflammatory properties. This induces anti-inflammatory cytokines (small proteins that may stimulate or inhibit the function of other cells) and appears to suppress damaging macrophage cell activity. Macrophages are a type of white blood cell that can damage both myelin in the central nervous system and the nerves themselves.
Second, Tecfidera may also have neuroprotective effects. This is due to its activation of a substance that is critical for resistance to cellular damage (from what is termed “oxidative stress”) as well as for normal immune function.
Completed Studies with Tecfidera
Two large Phase III trials were conducted with Tecfidera; both showed positive outcomes. The Phase III DEFINE study, which compared two doses of Tecfidera against placebo in 1,200 patients, was completed in February 2011. The Phase III CONFIRM study, which enrolled 1,232 patients, tested two dose levels against placebo, and also compared Copaxone against the same placebo group; the study was completed in September 2011.
In the DEFINE study, 240 mg of Tecfidera was given either twice or three times daily versus placebo for two years. The study met its primary endpoint with a 49-to 50-percent reduction in the proportion of patients who relapsed during the study period. In addition, each of the two doses reduced the risk of sustained disability progression (for at least 12 weeks) by 34-to-38 percent.
The CONFIRM study compared the same two dosing frequencies of Tecfidera with placebo for two years and also compared the same placebo group to a group receiving daily subcutaneous injections of Copaxone. (Please note that the study was not designed to compare the effectiveness of Tecfidera to Copaxone.) The study met its primary endpoint with a reduction in relapse rates of 44 to 51 percent for Tecfidera compared to placebo. No statistically significant difference was observed in the remaining clinical endpoint of confirmed disability progression, possibly due to the unexpectedly low rate of progression in the placebo group. In both studies, compared to placebo, individuals given Tecfidera had significantly reduced disease activity as shown on magnetic resonance imaging (MRI) scans.
A continuation study of 1,736 patients who participated in the DEFINE and CONFIRM studies, called ENDORSE, is evaluating the long-term safety profile of Tecfidera and efficacy on clinical outcomes, MRI scans, and quality-of-life. The study continues as of 2015.41
In 2014, PML occurred in one patient in the ENDORSE study who had taken Tecfidera for four years. Because of this event, the FDA revised its label for Tecfidera with new precautions and recommendations.
The label points out that the patient who developed PML had experienced prolonged lymphopenia while taking Tecfidera. Lymphopenia is a reduction in circulating lymphocytes, which are white blood cells aimed at fighting disease and infection. In general, the label now explains that Tecfidera may decrease lymphocyte counts, and states that 2 percent of patients experienced low lymphocyte counts for at least six months.
The revised labeling includes instructions that lymphocyte counts should also be obtained after six months of treatment, and every six-to-12 months thereafter. Neurologists should consider if Tecfidera should be discontinued if lymphocytes remain low.
Other medical safety issues continue to be followed through the ENDORSE study. Although malignancies have been observed in this patient population, at an incidence of less than 1 percent, it was not apparent that these were directly caused by Tecfidera. Additional data from ENDORSE is anticipated at national meetings in 2015.
Side Effects and Adverse Events
In studies, flushing and gastro-intestinal (GI) events – such as diarrhea, nausea and vomiting, and abdominal pain – were the most commonly reported side effects. Flushing and gastrointestinal events occurred in approximately 30-to-40 percent of patients and occurred more often at the beginning of treatment, decreasing in frequency after the first one to two months on this medication.
A small study presented at the 2014 American Academy of Neurology meeting evaluated four individuals who took the oral asthma medication montelukast, 10 mg once daily (while continuing treatment with Tecfidera)42. The study found that GI symptoms decreased within 72 hours and the improvement persisted for 30 days on montelukast. Symptom severity, as measured by the Gastrointestinal Symptom Rating Scale (GSRS), decreased by 81 percent.
Other adverse events, which were mild or moderate in severity, included upper respiratory infection, pruritus (chronic itching), and erythema (skin redness or rash). The only serious adverse events (aside from MS relapses) to occur in two or more patients taking Tecfidera during these large studies were gastroenteritis (an inflammation of the lining of the intestines) and gastritis (an inflammation of the stomach lining).
During the first six months of therapy in the DEFINE study, liver enzymes were elevated in 6 percent of individuals taking Tecfidera, compared to 3 percent of the placebo group. No cases of liver failure were reported in either study. Excess protein in the urine (proteinuria) was observed slightly more often in the treated groups versus the placebo group of the DEFINE study. No cases of kidney failure were reported in either study.
Pregnancy outcomes are known for 25 of the 35 pregnancies exposed to Tecfidera. To date, pregnancy data indicate no increased risk of fetal abnormalities or adverse pregnancy outcomes associated with exposure to Tecfidera during the first trimester. Further data regarding pregnancies will be collected through a pregnancy registry. As with DMTs discussed previously, the recommendations of the FDA are for women on DMTs, including Tecfidera, to take preventative measures to avoid pregnancy.
The Phase II EXPLORE trial is evaluating oral Tecfidera as a combination therapy with an injectable medication. It will determine the safety and tolerability of Tecfidera when administered in combination with interferons or Copaxone, in 100 people who continue to have evidence of disease activity despite receiving consistent treatment for at least one year. Efficacy endpoints that will determine the effectiveness will also be assessed in a subset of participants. Although the study concluded in 2012, the results have not been published as of early 2015.