Experimental Medications Tecfidera™ (dimethyl fumarate)

Company: Biogen Idec

Tecfidera™ (dimethyl fumarate or DMF, formerly known as BG-12) is an oral fumaric acid ester, related to a medication called Fumaderm® which was previously shown to be effective in patients with psoriasis, and 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. 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. Tecfidera is initially being studied in RRMS.

Tecfidera has had positive outcomes in two Phase III trials and is under FDA review for approval, likely in the first half of 2013. The Phase III DEFINE study, which compared two doses of Tecfidera against placebo in 1,200 patients, was completed in February 2011. Results from the DEFINE trial were reported in a platform presentation16 at the 2011 Joint European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS]. DEFINE was a multicenter, double-blind trial of Tecfidera 240 mg 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. Secondary clinical endpoints included annualized relapse rate (ARR) and confirmed disability progression. Tecfidera reduced disability progression by 34 to 38 percent.

The Phase III CONFIRM study, completed in September 2011, tested two dose levels against Copaxone and placebo in 1,232 patients. The primary measure was a reduction in relapse rate. Results of the CONFIRM trial were presented at the AAN Annual Meeting in 201217. CONFIRM was also a multicenter, double-blind trial comparing the same two doses of Tecfidera with placebo and daily subcutaneous injection of Copaxone for two years. The study met its primary endpoint with reduction in relapse rates of 44 to 51 percent for Tecfidera compared to placebo while Copaxone reduced the relapse rate by 29 percent compared to placebo. There was no statistically significant difference in the remaining clinical endpoint of confirmed disability progression, possibly due to the unexpectedly low rate of progression in the placebo group.

The incidence of serious adverse events and events leading to drug discontinuation was similar in all groups (Tecfidera, Copaxone, and placebo groups) in both trials. Flushing and gastrointestinal adverse effects (nausea, abdominal pain, and diarrhea) were more common with Tecfidera than with placebo, and there were neither opportunistic infections nor treatment-related deaths in either Phase III trial. The flushing and gastrointestinal symptoms seem to diminish with prolonged use of Tecfidera, decreasing in frequency after the first month to two months on this medication.

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 as well as its long-term efficacy on clinical outcomes, MRI scans, and quality-of-life. The study will continue through 2013, although initial data were presented in Fall 201218. No new safety concerns were identified, and no deaths were thought to be related to the medication. There were 14 malignancies observed in this patient population, though it was not apparent that these were directly caused by Tecfidera. This set of data will be reviewed by the FDA as part of their decision process to approve the drug; a decision is expected in spring of 2013.

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 to 100 people (who continue to have evidence of disease activity despite receiving consistent treatment for at least one year). Efficacy endpoints (determining the effectiveness) will also be assessed in a subset of participants. The study concluded in early 2012 and study results are expected in 2013.

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