Tecfidera: Clinical Trials
Tecifera (previously known as BG-12), was approved by the FDA in March 2013 for relapsing-remitting forms of MS. An oral fumarate derivative, Tecfidera has been shown to activate the Nrf2 transcriptional pathway—the first compound to do so. This pathway is thought to defend against oxidative-stress induced neuronal death, protect the blood-brain barrier, and support maintenance of myelin integrity in the central nervous system—all key elements to treating MS. According to Dr. Tim Vollmer, Medical Director of the MS Center, in addition to its use as an individual therapy, the activation of this pathway may also make BG-12 a candidate for combination therapy.
Phase III Studies
In April 2012, Biogen Idec announced that detailed positive results from CONFIRM, the second of two Phase III trials, will be presented at the 64th Annual Meeting of the American Academy of Neurology (AAN). The study enrolled 1,430 patients at 175 sites in North America, Europe and other parts of the world, and tested 240 mg of BG-12, which was given either twice or three times a day to RRMS patients, and compared to placebo. Glatiramer acetate (Copaxone) was given and tracked as a comparison. The goal was to assess the efficacy of the oral therapy compared to currently used injectable therapies, in this case Copaxone.
The study reached its primary endpoint—i.e. goal—by reducing the annual relapse rates by 44% in those who received BG-12 twice a day, and 51% in those who received it three times a day—compared to placebo over two years. In study participants on Copaxone, relapse rate was reduced by 29% compared to placebo.
Secondary endpoints were met as well. There was a reduction of 34% in the proportion of patients who relapsed (twice-daily BG-12), and 45% (three times a day) at the end of two years. Those on Copaxone demonstrated a 29% reduction. BG-12 reduced new or newly enlarging T2-hyperintense lesions as seen on MRIs by 71% in those on the twice daily dose and 73% for those on three-times-a-day dose. A 54% reduction was seen in Copaxone recipients. The number of non-enhancing T1-hypointense lesions was also reduced by 57% and 65% for those on BG-12, and 41% for those on Copaxone. There was also a reduction in the odds of developing gadolinium-enhancing (Gd+) lesions by 74% and 65% for BG-12 recipients, and 61% for those on Copaxone.
At two years compared to placebo, the risk of 12-week confirmed disability progression, as measured by the Expanded Disability Status Scale (EDSS), was reduced by 21% and 24% in study participants on BG-12. For those on Copaxone, the risk was reduced by 7%.
Data from DEFINE, the first of the two Phase III studies, had similar results. The study involved 1,234 patients at 160 different sites in North America, Europe and other parts of the world. Patients were dosed with placebo, BG-12 twice a day, or BG-12 three times a day. At two years, those taking BG-12 twice a day reduced the proportion of patients who relapsed by 49% and those taking it three times a day reduced the risk of relapse by 50%, compared with placebo. The risk of confirmed 12-week disability progression was reduced by 38% with people taking BG-12 twice a day and by approximately 34% with people taking it three times a day. The overall incidence of adverse and serious adverse events was similar among the placebo group and both BG-12 treatment groups.
Both doses of BG-12 also met all of the secondary study endpoints, providing a statistically significant reduction in annualized relapse rate, in the number of new or newly enlarging lesions, and in the rate of disability progression as measured by the Expanded Disability Severity Scale (EDSS) at two years.
BG-12 has a favorable safety and tolerability profile. In CONFIRM, there was no evidence of suppression of the immune system and no increase in infections. Study participants on BG-12 experienced “hot flashes”, otherwise known as flushing, which tended to resolve after the first month, and some mild gastro-intestinal side effects of dyspepsia and diarrhea. The overall incidence of infection, adverse events and serious adverse events was similar among the placebo group and both BG-12 treatment groups. The safety profile was consistent with what was seen in the published Phase II study.
DATA TABLE: Click here to review the DEFINE and CONFIRM data side by side.
Phase II Studies
The Phase II study concluded in 2006 and was published in October 2008. The study involved 257 participants with RRMS in 10 European countries. For six months, patients received a 120 mg, 360 mg, or 720 mg dose per day of BG-12, or a placebo. Those receiving the 720 mg dose had much less disease activity compared with those receiving placebo as measured by MRI changes. Those receiving a lower dose did not differ from those receiving placebo.
Between weeks 12 and 24, study participants who received the 720 mg dose (240 mg three times a day) demonstrated a 69% reduction in new active gadolinium-enhancing lesions compared to placebo; cumulatively, a 44% reduction in new active lesions was demonstrated versus placebo. The data also showed a 53% reduction in T1-hypointense lesions (“black holes”), which are generally thought to represent areas of axonal damage. Additionally, participants who received the 720 mg dose demonstrated 48% reduction in new or newly enlarging T2-hyperintense lesions, and 63% of BG-12 patients showed no new T2 lesions. T2 lesions are generally considered to be markers of overall disease activity.
Clinically, the group receiving the higher dose of BG-12 had fewer relapses than the group receiving placebo. The Phase II trial, however, was not designed to be definitive in measuring clinical outcomes. Clinical relapse and disability progression were the focus of the two Phase III trials.