Tecfidera® (dimethyl fumarate)

FDA-Approved Medications: New Data on Previously Approved Medications

Company: Biogen

• Starting dose: 120 mg twice a day, orally for seven days; ongoing dose: 240 mg twice a day, orally
• Approved in 2013 for RMS

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The FDA’s 2013 approval of Tecfidera® (dimethyl fumarate) for use in RMS followed completion of two randomized, double-blind, placebo-controlled trials in which the medication reduced the annualized relapse rate (ARR) by 44 percent to 53 percent relative to placebo. Tecfidera also had a favorable impact on disability progression and MRI measures of MS activity, compared to placebo, in those studies.²⁸

The exact means by which Tecfidera, or dimethyl fumarate, exerts its therapeutic effects in MS is not known. The agent has been shown to activate a pathway involved in the cellular response to oxidative stress, which is induced by inflammation. However, it is unclear whether this pathway activation plays a role in Tecfidera’s impact on the MS disease process.²⁸

In 2017, the prescribing information for Tecfidera was amended to include direction to obtain a complete blood cell count and to measure liver enzymes and other values before initiating the medication. Additionally, warnings were added to the prescribing information noting that progressive multifocal leukoencephalopathy (PML), a rare but serious brain infection, and liver injury, have occurred in people taking Tecfidera.²⁸

Data from the ongoing ENDORSE extension study suggest that Tecfidera helps preserve function over time in RMS. ENDORSE is a long-term study that follows people who were newly diagnosed with RMS and had participated in a Phase III study of Tecfidera versus placebo. In the first study, participants received either Tecfidera 240 mg twice daily or placebo for two years. They then had the opportunity to enter ENDORSE. Those who had received Tecfidera in the earlier study continued on that medication, while those who had received placebo were switched to Tecfidera.

Adjusted mean ARRs in the placebo-to-Tecfidera group fell from 0.25 during the two-year placebo period to 0.09 in seven years of Tecfidera treatment, representing a 64-percent decrease. Additionally, between 90 and 93 percent of patients in both groups maintained Expanded Disability Status Scale (EDSS) scores of 3.5 or less, suggesting that Tecfidera helps patients maintain function long-term.¹¹

A Swedish MS registry identified two very different paths for its 2,010 participants who reported taking Tecfidera. One-quarter discontinued the drug within the first year, and almost half stopped the medicine eventually. Of those who discontinued treatment, 53 percent cited adverse effects as their reason for stopping, while 29 percent cited lack of effect. However, the 918 patients who took Tecfidera continuously for two years or longer showed significant improvements in mean scores of several tests used to measure physical, psychological, and cognitive function in MS. The EDSS, Multiple Sclerosis Severity Scale, Symbol Digit Modalities Test, Multiple Sclerosis Impact Scale, and Visual Analog Scale were among the tests used.²⁹

Another recent study, this one from Italy, looked at risk factors for the development of lymphopenia among people using Tecfidera. Lymphopenia, a common side effect of disease-modifying therapies, is marked by a shortage of lymphocytes, a type of white blood cell that helps the body fight infection. Data from the Italian researchers suggest that older age and treatment duration may be risk factors for Tecifdera-induced lymphopenia.

A total of 147 individuals with RMS were divided into two groups — those with lymphopenia and those with normal lymphocyte counts — and then were divided again into four groups based on the age at which they started Tecfidera. Patients aged 50 years or older were found to have developed lymphopenia an average 15.5 months after starting Tecfidera. As patient age decreased, the interval between Tecfidera initiation and lymphopenia diagnosis increased, suggesting an age-related correlation. The researchers hypothesized that gradual deterioration of the immune system with aging might increase an older patient’s risk of Tecfidera-induced lymphopenia, and that low baseline lymphocyte counts and longer treatment with Tecfidera might further increase that risk.³⁰

Tecfidera® (delayed-release dimethyl fumarate) altered the gut microbiome in relapsing-remitting MS (RRMS) patients who took the oral disease modifying therapy (DMT) over 12 weeks.³¹ The gut microbiome is a mix of bacteria and other microbes found in the gastrointestinal (GI) tract. In recent years, the gut microbiome has been recognized as a key component of the body’s immune system. In particular, research suggests that the composition of the microbiome, in terms of the presence and number of various microbes, may affect the course of MS.

In a study of 36 patients with RMS, 17 types of microbes were significantly altered in MS patients compared with 165 healthy controls. Notably, people with MS had lower levels of Faecalibacterium compared to the healthy controls. A total of 27 of the study participants received Tecfidera, while nine received an injectable DMT. At two weeks, subjects receiving Tecfidera reported a worsening of GI symptoms compared to baseline, but this impact on symptoms was not seen at 12 weeks. Meanwhile, at 12 weeks, the Tecfidera patients had an increased abundance of Faecalibacterium. Similar changes were not seen in the participants receiving an injectable DMT. Researchers continue to investigate the role of the gut microbiome in MS. As that effort continues, this study comparing patients taking different DMTs adds to the understanding of the interaction between MS medications and the composition of the microbiome. As the investigators note, “It could therefore be speculated that direct effects on the gut microbiome are part of the therapeutic actions” of Tecfidera.

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