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Second BG-12 Trial Positive in MS

October 26, 2011

Second BG-12 Trial Positive in MS

Medscape Medical News

Susan Jeffrey

October 26, 2011

Top-line results of a second phase 3 trial of oral BG-12 (dimethyl fumarate, Biogen Idec) in relapsing-remitting multiple sclerosis (MS) show that the drug significantly reduced annualized relapse rates vs placebo and compared favorably to a reference group treated with glatiramer acetate (Copaxone, Teva Pharmaceuticals).

Results of the Comparator and an Oral Fumarate in RRMS (CONFIRM) trial, released today by Biogen Idec, showed that the still-investigational oral drug met the study’s primary endpoint, significantly reducing the annualized relapse rate by 44% for the twice-daily dose (P < .0001) and by 51% for the 3-times daily dose (P < .0001) vs placebo at 2 years.

A reference group of patients receiving glatiramer acetate, a treatment already approved for MS, showed that drug reduced the relapse rate by 29% (P < .02) at 2 years, again vs placebo.

Principal investigator of the CONFIRM trial, Robert J. Fox, MD, neurologist and medical director of the Mellen Center for MS at the Cleveland Clinic, Ohio, said he was pleased with the results.

“We need therapies for the relapsing stage of MS that are effective, and tolerated, and have an acceptable route of administration for patients like orals, and I think this drug fits that very well,” Dr. Fox told Medscape Medical News.

“These results confirm what was seen in the previous trial, the DEFINE trial, and show a robust reduction in clinical relapses and MRI measures of disease activity,” he said. “It has a very reasonable safety profile, so it seems like this is going to be a very useful therapy in our armamentarium for relapsing MS.”

In fact, he feels it may even be a candidate for use as a first-line agent. “Given what we see with the efficacy, and a very favorable safety profile that to me measures up as well [as] or better than our current therapies, I don’t see any reason that this couldn’t be considered a first-line therapy for MS.”

The results come hard on the heels of full disclosure of data from the Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS (DEFINE) trial, another phase 3 trial of BG-12, released at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS), and reported byMedscape Medical News at that time. Top-line results from the study were released in April.

“We conclude that these results may provide a therapeutic option for patients with relapsing MS, with robust efficacy, a good tolerability, and excellent safety profile for this oral drug,” DEFINE principal investigator Ralf Gold, MD, professor and chair, Department of Neurology, St. Josef-Hospital/Ruhr-University, Bochum, Germany, concluded at the meeting, which was held in Amsterdam.

Both studies were funded by Biogen Idec.

DEFINE and CONFIRM

BG-12 is believed to have dual anti-inflammatory and neuroprotective effects via the Nrf2 pathway. In a phase 2b trial, it reduced inflammatory activity in patients with relapsing-remitting MS. BG-12 received fast track designation from the US Food and Drug Administration in 2008.

The CONFIRM clinical trial was a phase 3, global, randomized, double-blind, placebo-controlled, dose-comparison study to determine the efficacy and safety of BG-12. It enrolled 1430 people with relapsing MS.

The study looked at 2 dose regimens of BG-12 (240 mg twice a day [BID] and 240 mg 3 times a day [TID]), as well as a reference comparator of glatiramer acetate at a dose of 20 mg daily given subcutaneously. Both BG-12 and glatiramer acetate groups were evaluated vs placebo.

In addition to significantly reducing the primary endpoint of acute relapse rates at 2 years, BG-12 met all secondary relapse and magnetic resonance imaging endpoints for both dose regimens, the company notes. Results for the BG-12 and glatiramer acetate treatment groups at 2 years compared with placebo included:

  • BG-12 reduced the number of new or newly enlarging T2-hyperintense lesions by 71% for BID (P < .0001) and by 73% for TID (P < .0001) vs placebo; there was a 54% reduction for glatiramer acetate vs placebo (P< .0001).
  • BG-12 reduced new T1-hypointense lesions by 57% for BID (P < .0001) and by 65% for TID (P < .0001) vs placebo; the reduction was 41% with glatiramer acetate vs placebo (P < .003).
  • BG-12 reduced the proportion of patients who relapsed by 34% for BID (P < .003) and by 45% for TID (P < .0001) vs placebo; the reduction was 29% with glatiramer acetate vs placebo (P < .01).

Initial results showed that BG-12 reduced 12-week confirmed disability progression, as measured by the Expanded Disability Status Scale, by 21% for BID and 24% for TID at 2 years compared with placebo vs 7% with glatiramer acetate.

Although these latter effects of disability were not statistically significant, they may be attributable to the unexpectedly low rate of disease progression in the placebo group, which was approximately half of what has been seen in clinical trials of approved and experimental MS therapies, including the rate seen in DEFINE, Doug Williams, PhD, Biogen Idec’s executive vice president of research and development said during a conference call this morning.

“Further analyses of this endpoint are underway,” he added. They still plan nevertheless to file for a claim on reduction of disability based on these data in combination with DEFINE, company executives noted.

Dr. Fox acknowledged that the lack of effect on disability was a disappointing aspect of the trial. “Certainly we need to look further at the data to understand why that is,” he said. “Clearly the trend was in the right direction but the statistical significance was not met.”

The entry criteria were the same for CONFIRM and DEFINE in terms of recruiting patients with active disease; the only difference was that in CONFIRM, patients could not have been treated previously with glatiramer acetate, which was allowed in DEFINE.

In CONFIRM, both dose regimens of BG-12 showed favorable safety and tolerability profiles, which were similar to those seen in DEFINE, the company notes.

Overall, the incidence of adverse events, serious adverse events including serious infections, and discontinuations resulting from adverse events were similar across all study groups, including placebo. The incidence of hepatic and renal events was also comparable among all study groups.

As in DEFINE, the most common adverse events with BG-12 were flushing and gastrointestinal events. There were no malignancies in the BG-12 groups, the company notes.

“We now have strong positive results for BG-12 in two robust pivotal clinical trials with more than 2,600 patients,” said Doug Williams, PhD, Biogen Idec’s executive vice president of research and development said in a statement. “We are gratified by these strong efficacy and safety results, which, when combined with BG-12′s oral route of administration, position it as a potentially important MS therapy. We are working aggressively to prepare our regulatory submissions with the goal of making BG-12 available to MS patients as quickly as possible.”

The company plans to present detailed data from CONFIRM at an upcoming medical meeting, he noted, “and our filing is on track for the first half of next year.”

In the CONFIRM and DEFINE results, there were some differences between doses on some of the endpoints, Dr. Williams acknowledged.

“I think our conclusion looking across both studies is that both TID and BID provide approximately comparable results,” he said. “We don’t really see that there’s a huge or meaningful difference between the doses based on the aggregate data that we’ve seen, so we think that BID dosing for this drug will be appropriate.”

The DEFINE study was supported by Biogen Idec Inc. Dr. Fox has received consultant fees from Avanir, Biogen Idec, EMD Serono, and Novartis and has received research support from Biogen Idec. Dr. Gold discloses having received honoraria from Bayer Health Care, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience research support from Bayer Health Care, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience. Several of the authors are employees of the company.

Susan Jeffrey is the news editor for Medscape Neurology & Neurosurgery. Susan has been writing principally for physician audiences for nearly 20 years. Most recently, she was news editor for thekidney.org and also wrote for theheart.org; both of these Web sites have been acquired by WebMD. Prior to that, she spent 10 years covering neurology topics for a Canadian newspaper for physicians. She can be contacted at SJeffrey@webmd.net.