BG-12 Reduces Relapses, Disease Activity in MS

Susan Jeffrey

September 19, 2012

September 19, 2012 — Full results of two phase 3 trials evaluating the effect of oral BG-12 (dimethyl fumarate, Biogen Idec) in patients with multiple sclerosis (MS) show the investigational agent reduced relapse rates, disease activity on imaging, and, in 1 trial, progression of disability.

Findings from the Determination of the Efficacy and safety of oral Fumarate IN rElapsing-remitting MS (DEFINE) trial, and the Comparator and an Oral Fumarate in RRMS (CONFIRM) trial, are published in the September 20 issue of the New England Journal of Medicine. Both trials were funded by Biogen Idec.

DEFINE was presented in 2011 at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS), and CONFIRM earlier this year at the American Academy of Neurology 64th Annual Meeting, and reported by Medscape Medical News.

Data from these trials were included in regulatory applications submitted to the US Food and Drug Administration and the European Medicines Agency earlier this year.

DEFINE

Dr. Ralf Gold

In DEFINE, researchers with principal investigator Ralf Gold, MD, professor and chair, Department of Neurology, St. Josef-Hospital/Ruhr-University, Bochum, Germany, randomized 1237 patients with relapsing-remitting MS to receive 1 of 2 doses of oral BG-12 (240 mg twice daily, or 240 mg thrice daily) or placebo. Of these, 1234 patients received at least 1 dose of BG-12, and 952 patients (78% in the placebo group and 77% of each treatment group) completed the study.

The primary endpoint was the proportion of patients with a relapse by 2 years. Investigators report that the estimated proportion of patients with relapse was significantly lower in both BG-12 groups vs placebo.

Table 1. DEFINE: Primary Endpoint

Outcome

Placebo

BG-12 BID

P

BG-12 TID

P

Patients with relapse (%)

46

27

< .001

26

< .001

BID = twice daily; TID = thrice daily.

Annualized relapse rate at 2 years was 0.17 in the twice-daily group, 0.19 in the thrice daily group, and 0.36 with placebo, for relative risk reductions of 53% and 48% respectively that were significant for both comparisons (P < .001).

The proportion of patients with confirmed progression of disability was 16% for the twice-daily group, 18% in the thrice-daily group, and 27% with placebo, for significant relative risk reductions of 38% (P = .005) for the twice-daily dose and 34% (P = .01) for the thrice-daily dose vs placebo.

Gadolinium-enhancing lesions were also reduced significantly, as were new or enlarging T2-weighted hypertense lesions.

Adverse events associated with treatment included flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain, abdominal pain, and vomiting. Decreased lymphocyte counts and elevated liver transaminase levels were also observed with treatment.

"In patients with relapsing-remitting multiple sclerosis, both BG-12 regimens, as compared with placebo, significantly reduced the proportion of patients who had a relapse, the annualized relapse rate, the rate of disability progression, and the number of lesions on MRI," Dr. Gold and colleagues conclude.

CONFIRM

Dr. Robert J. Fox

CONFIRM was also a phase 3 randomized trial, comparing the same 2 doses of BG-12 with placebo; an active agent, glatiramer acetate (Copaxone, Teva Pharmaceuticals) was included as a reference comparator. All treatments were compared with placebo, not each other, and were not designed to test for superiority or noninferiority of BG-12 vs glatiramer acetate, the authors note.

The principal investigator of the CONFIRM trial was Robert J. Fox, MD, neurologist and medical director of the Mellen Center for MS at the Cleveland Clinic in Ohio. In this trial, unlike in DEFINE, the primary endpoint was the annualized relapse rate (ARR) over 2 years.

The researchers found a significant reduction in both treatment arms vs placebo with significant relative reductions of 44% with the twice-daily and 51% with the thrice-daily doses. The relative reduction with glatiramer acetate was 29% vs placebo, also significant reduction

Table 2. CONFIRM: Primary Endpoint

Endpoint

Placebo

BG-12 BID

P

BG-12 TID

P

GA

P

ARR

0.40

0.22

< .001

0.20

< .001

0.29

.01

BID = twice daily; GA = glatiramer acetate; TID = thrice daily.

Also unlike DEFINE, reductions in disability progression did not reach statistical significance, with a 21% reduction vs placebo with BG-12 twice-daily, 24% with thrice-daily BG-12, and 7% with glatiramer acetate. The authors speculate that 1 potential contributor to this difference in findings is that in CONFIRM, the proportion of patients with disability progression in the placebo group was 17%, compared to 27% in DEFINE.

However, all 3 treatment arms significantly reduced the numbers of new or enlarging T2-weighted hyperintense lesions and new T1-weighted hypointense lesions.

In post hoc comparisons of BG-12 vs glatiramer acetate, differences were not significant, with the exception of ARR with the thrice-daily BG-12 dose, new or enlarging T2-weighted hypertense lesions with both BG-12 doses, and new T1-weighted hypointense lesions with the thrice-daily dose of BG-12.

Again, adverse events occurring with a higher incidence with treatment than placebo included flushing and gastrointestinal events with BG-12, and injection-related events with glatiramer acetate, they report. No malignant neoplasms or opportunistic infections were seen with BG-12, but lymphocyte counts did decrease with treatment.

"In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo," the authors conclude.

"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 told Medscape Medical News when these results were presented in April.

'Poison Chair' Treatment

In an editorial accompanying the publications, Allan H. Ropper, MD, from Brigham and Women's Hospital in Boston, harks back to early experience with this new treatment, as the cause of "the very curious incident of the poison chair," where hundreds of people in several European cities "appeared at clinics with eczematous burns that had no apparent cause," Dr. Ropper writes.

The cause, proposed by a Finnish physician, was dimethyl fumarate, used as a fungicide and desiccant in the shipping of sofas. The agent had also been found to treat psoriasis, was reformulated as Fumaderm and evaluated in the clinical trials in the 1990s, he notes.

"On the basis of an encounter between a German dermatologist and a neurologist over 2 patients with psoriasis whose multiple sclerosis stabilized after treatment with oral fumarate, the drug, which has immunosuppressant and neuroprotectant properties, was studied in multiple sclerosis," Dr. Ropper writes. "In this issue of the Journal, reports of 2 phase 3 trials introduce it as yet another oral medication for the disease on a background of its long use for psoriasis."

The appeal of oral agents is patient preference, he notes, but the choice of the oral drugs coming to the fore now will likely be dominated by issues of safety. "The 2-decade safety record of fumarate in psoriasis lessens concern about the long-term risks, because neoplasms and infections have not emerged as problems."

None of the other oral agents, with the exception of teriflunomide (Aubagio, Genzyme/Sanofi), an active metabolite of leflunomide, approved in 1998 for rheumatoid arthritis, has more than a few years of surveillance. Teriflunomide was just approved last week for the treatment of MS.

Still, Dr. Ropper writes, physicians will want more data on the long-term safety and efficacy of these drugs over the long disease course in MS.

"Even fumarate will need to prove that its efficacy is durable by reducing disability over the many decades that encompass the representative course of multiple sclerosis," he notes. "By that time, there will certainly be many newer drugs. In addition, we do not know if there will be synergistic effects of the new drugs on the risk of PML [progressive multifocal encephalopathy] and other infections if they are combined, or used serially, with other immunosuppressive agents."

Clinicians will need to have "longer and perhaps more scripted discussions" with their patients starting MS treatment, he concludes.

"The question of switching from an existing medication to an oral agent in a patient with relapses, or even in a patient with few relapses but for whom a new drug is more convenient, is a difficult and unresolved one. It is not clear at the moment how to advise patients about the new oral drugs, but the overall benefit-to-risk assessment, as of this month, may favor fumarate," he writes. "And beware — if treatment for multiple sclerosis becomes too trouble-free, there could be a loosening of standards for diagnosis and for the initiation of treatment."

The trials were funded by Biogen Idec. Dr. Fox reports receiving consulting fees from Avanir Pharmaceuticals, Biogen Idec, EMD Serono, Novartis and Questcor. Disclosures for DEFINE authors and Dr. Ropper at available at www.nejm.org .

N Engl J Med. 2012;367:1098-1107, 1087-1097, 1149-1150. DEFINE, CONFIRM, Editorial

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