US and EU regulatory authorities have accepted Biogen Idec’s marketing applications for the review of BG-12 (dimethyl fumarate), an investigational oral therapeutic candidate for the treatment of multiple sclerosis. BG-12 is the only currently known investigational compound for the treatment of MS that has experimentally demonstrated activation of the Nrf-2 pathway. In 2011, Biogen Idec announced positive data from DEFINE and CONFIRM, two global, placebo-controlled Phase III clinical trials that evaluated 240mg of BG-12, administered either twice a day or three times a day, for two years. BG-12 is currently being evaluated in a long-term extension study, ENDORSE. Here, Practical Neurology talks about the development with Gilmore O’Neill, MD, Vice President of Medical Research at Biogen Idec.
What should neurologists take away from the DEFINE and CONFIRM studies?
The strong efficacy and safety results seen in DEFINE and CONFIRM, coupled with its oral route of administration, position BG-12 as a potential new therapeutic option for MS. Results of these studies show that BG-12, administered twice or three times daily, demonstrated efficacy across a number of critical endpoints vs. placebo at two years, as well as favorable safety and tolerability profiles.
To dive deeper, twice-daily treatment with BG-12 resulted in:
• Significant reductions in annualized relapse rate: 53 percent in DEFINE, 44 percent in CONFIRM.
• Significant reductions in the proportion of patients who relapsed: 49 percent in DEFINE, 34 percent in CONFIRM
• Significant reductions in MS lesions as measured by MRI
• Reduced risk of disease progression: 38 percent in DEFINE, 21 percent in CONFIRM (not significant).
While the reduction in disability progression in CONFIRM was not significant, the results may be confounded to the unexpectedly low rate of disease progression in the placebo group.
In both studies, adverse events (AEs), serious adverse events, and discontinuations due to AEs were similar in the BG-12 treatment arms and placebo arm. In addition, there was no increased risk of serious infections or malignancies.
Can you explain what makes BG-12’s mechanism of action so distinct and how it might benefit patients?
BG-12 is the only compound in clinical trials for the treatment of MS known to activate the Nrf-2 pathway, a central mechanism of cellular defense. Early stage research suggests that BG-12 has the potential to reduce the activity and impact of inflammatory cells on the CNS and induce direct cytoprotective responses in CNS cells. These effects may enhance the CNS cells’ ability to mitigate the toxic inflammatory and oxidative stress, which play a role in MS pathophysiology.
While the drug had a favorable safety and tolerability profile, both fumaric acid and malic acid have some potential to cause kidney problems. Did study participants have their kidney function monitored? Might there be any recommendations that future patients have their kidney function monitored?
BG-12 is different from other products containing fumaric acids and is supported by separate and independent clinical data. Serum creatinine was closely monitored during the BG-12 clinical trials in MS. There was no clinically relevant difference in serum creatinine levels in the studies between placebo and BG-12 treated patients. This information has been submitted as part of the BG-12 regulatory filings. However, we cannot speculate on regulatory actions/decisions or if additional monitoring will be required.
What’s next and when do you expect to release the product? How much do you expect the drug to cost?
On May 9, 2012, Biogen Idec announced that US and EU regulatory authorities have accepted the company’s marketing applications for the review of BG-12 for the treatment of MS. The FDA accepted our New Drug Application (NDA) and granted a standard review timeline (10 months). In addition, the EMA validated our Marketing Authorisation Application (MAA) for review of BG-12 in the European Union. This review can take more than a year.
Biogen Idec also recently submitted regulatory applications in Canada and Switzerland, and our goal is to submit applications in additional markets in the near future. We expect an early 2013 launch for BG-12 in the US. At this point, we cannot speculate on pricing or reimbursement.
Another Biogen MS candidate, daclizumab, was moved to a Phase III trial in 2010. In phase II studies, daclizumab reduced annual relapse rate by approximately 50 percent compared to placebo. Are you seeing similar encouraging results in the Phase III trial? When do you hope to have final results?
The ongoing Phase 3 DECIDE study is investigating the safety and efficacy of daclizumab high-yield process (DAC HYP) monotherapy against an active comparator of interferon beta 1-a. DECIDE is currently underway and anticipates enrolling approximately 1,800 patients. It is too early to speculate on the results of the study. We anticipate that DECIDE will be completed in 2014.