Susan Jeffrey

April 26, 2012

April 26, 2012 (New Orleans, Louisiana) — Full 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 glatiramer acetate (Copaxone, Teva Pharmaceuticals) in a reference group.

Results of the Comparator and an Oral Fumarate in RRMS (CONFIRM) trial 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 (BID) dose and by 51% for the thrice-daily (TID) dose vs placebo at 2 years. Treatment also reduced T1 lesions, T2 lesions, and the risk for relapse, as well as the 12-week confirmed disability progression, although this latter finding was not statistically significant.

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, presented full results here at the American Academy of Neurology 64th Annual Meeting. Topline results were released October 26, 2011, and reported by Medscape Medical News at that time.

Dr. Robert J. Fox

CONFIRM is the second of 2 phase 3 trials of BG-12, both funded by Biogen Idec. The other, called the Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS (DEFINE) trial, was presented last fall at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

"The results are quite consistent with what was seen in the previous phase 3 trial, the DEFINE trial, and suggest that this drug has quite robust efficacy, and an acceptable safety and tolerability profile," Dr. Fox concluded.

In a statement, the company confirmed that data from CONFIRM and DEFINE were included in regulatory applications that were submitted as part of a New Drug Application (NDA) to the Food and Drug Administration (FDA) in the United States and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) earlier this year.

"The EMA has validated Biogen Idec's MAA and is reviewing the BG-12 data package," the statement notes. "Biogen Idec is awaiting formal acceptance of its NDA for review by the FDA."

Anti-Inflammatory Mechanism

BG-12 is believed to have dual anti-inflammatory and neuroprotective effects via the Nrf2 pathway, although other pathways are also under investigation. In a phase 2b trial, it reduced inflammatory activity in patients with relapsing-remitting MS. BG-12 received fast-track designation from the FDA in 2008.

CONFIRM was a 2-year trial comparing 2 dose regimens of BG-12 (240 mg BID and 240 mg TID), as well as a reference comparator of open-label glatiramer acetate at a dosage of 20 mg a day given subcutaneously. Both BG-12 groups and the glatiramer acetate group were evaluated against a placebo group, not each other.

A total of 1430 patients were included; patients were eligible if they had relapsing-remitting MS, with a requirement of disease activity before the trial of 1 or more gadolinium-enhancing lesions on magnetic resonance imaging (MRI) within 6 weeks of randomization. Patients with progressive forms of MS were excluded, as were those previously treated with glatiramer acetate.

The primary endpoint was the annualized relapse rate over 2 years. Secondary outcomes included new or newly enlarging T2-hyperintense lesions, new nonenhancing T1-hypointense lesions, the proportion of patients relapsing over 2 years, and disability progression measured by using the Expanded Disability Status Scale.

About 30% of patients discontinued the study drug over the course of the trial, Dr. Fox noted. "In the BG-12-treated arms, about 10% discontinued because of adverse events, which is a little bit higher than the 6% rate seen in the placebo group." Approximately 80% of patients completed the trial, either receiving their original randomized therapy or receiving an alternative treatment.

For the primary endpoint, AAR was significantly reduced relative to placebo in both BG-12 groups, with a 44% reduction for the BID and 51% for the TID dosage (P < .0001 for both comparisons vs placebo). The reduction with glatiramer acetate was 29% (P = .0128 vs placebo), he noted, "which is quite similar to what was seen with that therapy in its previous clinical trial."

Table 1. CONFIRM: Primary Endpoint

Endpoint Placebo BG-12 BID BG-12 TID Glatiramer Acetate
Annualized relapse rate 0.401 0.224 0.198 0.286


Significant reductions were also seen in secondary MRI endpoints, including new or newly enhancing T2 and nonenhancing T1 lesions.

Table 2. Secondary Imaging Endpoints: Percentage Reduction With Treatment vs Placebo

Endpoint BG-12 BID P Value BG-12 TID P Value Glatiramer Acetate P Value
New or enlarging T2 lesions (% reduction) 71 <.0001 73 .0001 54 .0001
New nonenhancing T1 lesions (% reduction) 57 <.0001 65 <.0001 41 .0021


Another secondary endpoint was the proportion of patients who relapsed, according to a Kaplan-Meier analysis. "As you can see here, the 2 BG-12-treated arms had a 34% to 45% reduction in risk of relapse over the 2 years, and glatiramer acetate with a 29%" reduction, Dr. Fox noted.

The treatment curves diverged early in year 1, he added, "and there was a consistent impact over the entire 2-year period of the trial."

In terms of disability, risk for sustained progression of disability decreased 21% in the BG-12 BID group and 24% in the TID group, but neither reduction reached statistical significance.

"I will point out that this trial was powered for annualized relapse rate reduction and not powered for disability," Dr. Fox noted. "In addition, the disability rate of 16.9% over the 2 years in the placebo group was somewhat lower than is typically seen in phase 3 clinical trials."

The glatiramer acetate group had a 7% reduction in disability, also not statistically significant, he added.

A preplanned sensitivity analysis for disability progression examined 24-week confirmed disability and showed risk reductions of 33% to 38% with the 2 BG-12 doses, with glatiramer acetate between these marks; these findings were also not statistically significant.

Full imaging results were presented here in a separate presentation by David Miller, MD, from the University College London Institute of Neurology, United Kingdom.

"In summary, BG-12 at both doses had a potent anti-inflammatory effect, and substantially, significantly, reduced the volume of new T2, T1, and gadolinium-enhancing lesions," Dr. Miller said. "This was seen at the earliest stage of follow-up and was sustained throughout the trial."

There was a trend as well for decreased atrophy at 2 years compared with baseline measures, he noted.

"Taking this data, along with the robust clinical efficacy and safety data from the trial, suggests that this is a potentially promising new oral treatment for active relapsing-remitting multiple sclerosis," he concluded.

Safety and Tolerability

Flushing and gastrointestinal (GI) events such as diarrhea were common adverse events that were reported more often in the BG-12 groups than the placebo group. The incidence of the flushing and GI events decreased substantially after the first month of BG-12 treatment, he noted.

Adverse events reported more frequently with glatiramer acetate were injection-related reactions, "not surprisingly," Dr. Fox added.

The incidence of serious infections was low and similar across the groups. "There were no opportunistic infections reported in any treatment arm, and importantly there were no malignancies reported in patients receiving BG-12," he noted. There was 1 malignancy in the placebo group and 4 with glatiramer acetate.

In the DEFINE trial, 2 cases of cancer developed in each treatment group, including placebo recipients. "Just as an aside, because there's been a bit of chatter about cancers with BG-12-treated patients in the open-label extension studies," he said. "We don't think BG-12 prevents cancer, so there would be some cancers expected when following 1700 patients over time. There is not any increased risk of cancer in the open-label extension with BG-12."

For serious adverse events occurring in more than 1 patient in any group, MS relapses were the most common, seen in all the groups, and a "smattering" of other adverse events, he noted, "but no obvious trends."

Table 3. CONFIRM: Adverse Events

Endpoint Placebo BG-12 BID BG-12 TID Glatiramer Acetate
Adverse events (%) 92 94 92 87
Serious adverse events (%) 22 17 16 17
Discontinuations due to adverse events (%) 10 12 12 10

Table 4. CONFIRM: Adverse Events With Increased Incidence in BG-12 Groups

Event Placebo BG-12 BID BG-12 TID Glatiramer Acetate
Flushing (%) 4 31 24 2
GI events (%) 8 13 15 4
Nausea (%) 8 11 15 4
Upper abdominal pain (%) 5 10 10 1


Full safety data will be presented in a separate paper April 26 by J. Theodore Phillips, MD, PhD, program director of the Multiple Sclerosis Program at the Baylor Institute for Immunology Research, clinical professor of neurology at the University of Texas Southwestern Medical Center in Dallas.

Questions Remain

Asked for comment on the findings by Medscape Medical News, Mark Freedman, MD, professor of medicine (neurology) at the University of Ottawa and director of the Multiple Sclerosis Research Unit, Ontario, Canada, said he had a few questions about the compound itself. "Is it really that different than the generic cheap drug that's available in Germany?" he said. If it's not different, then it's not clear what the cost would be here, he noted, "just because it's being manufactured differently than a generic product. So that's a basic question that needs to be answered."

Although the drug seems safe, the flushing it produces could be a tolerability issue, he noted. "There's no question that people get reactions to it, this niacin-like reaction that doesn't necessarily translate into comfort. I think there's going to be a problem with patients taking it for that reason, and the fact that it has to be multi-dosed, at least twice a day."

Still, the 2-year data look "very good," Dr. Freedman noted, "but we're talking about a very low-risk population. The patients didn't have a lot of attacks, they didn't have a lot of progression, and I think that's just the nature of the beast today. We have very low activity-based patients, so seeing a difference in low numbers can translate into big percents when they're relative, so you have to accept that for what it is."

Finally, unlike the DEFINE findings, there was no confirmation in CONFIRM of an effect on disability progression, he said.

"They have some tantalizing technological data on MRI which is always the case, and there was this indication, at least for the first study, that it takes a while for it to kick in," he noted. This may again be a function of low disease activity, but in other studies, the curves begin to separate fairly quickly, while it took about 6 months with BG-12.

"So is it going to be more advantageous, less advantageous than the other orals it's going to compete with? I don't know. Those issues need to be decided."

The CONFIRM and DEFINE studies were funded by Biogen Idec. Dr. Fox discloses he is a paid advisor to Biogen Idec for projects not related to BG-12 clinical development. Dr. Freedman reports he has received grants for clinical research from Bayer HealthCare Pharmaceuticals and Genzyme Corporation and has served as an advisor or consultant for Bayer HealthCare Pharmaceuticals, Biogen Idec Inc, EMD Serono Inc, Novartis Pharmaceuticals, sanofi-aventis, and Teva Neuroscience Inc. He is also an uncompensated member of the editorial advisory board of Medscape Neurology.

American Academy of Neurology 64th Annual Meeting: Abstract #S01.003, S11.001. Presented April 24, 2012. Abstract #S41.005. Presented April 26, 2012.


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