SAN DIEGO – Full results of the second phase III trial of dimethyl fumarate in patients with relapsing-remitting multiple sclerosis show that the investigational drug significantly reduces annualized relapse rates and MRI lesions over the course of 2 years
The results of the study, called CONFIRM (Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis), are in line with those of an earlier phase III study called DEFINE. But unlike the earlier trial, CONFIRM did not demonstrate a statistically significant benefit for disease progression based on the Expanded Disability Status Scale (EDSS).
Dr. Theodore Phillips
Even so, the two studies indicate that dimethyl fumarate, also known as BG-12, "has a future as an oral therapeutic option for patients with relapsing MS," said Dr. Theodore Phillips, an MS researcher at the Baylor Institute for Immunology Research and clinical professor in the neurology department at the University of Texas Southwestern Medical Center, both in Dallas.
The drug is under review by the Food and Drug Administration. "Hopefully, we won’t have to wait for a decision much past the first quarter of 2013," Dr. Phillips said at the Fourth Cooperative Meeting on Multiple Sclerosis.
"People are very excited about BG-12 because it’s a much better tolerated oral, we think, than fingolimod (Gilenya)," which it will compete against, Dr. Lael Stone, an MS specialist at the Cleveland Clinic, said about the study.
"The question [will] be, ‘Is it as good as promised?’ " she said.
The trial randomized 359 patients to BG-12 240 mg twice daily, 345 patients to BG-12 240 mg three times daily, 350 to subcutaneous glatiramer acetate (GA) 20 mg daily, and 363 to placebo.
About 70% of the subjects were women, with approximately 1.4 relapses in the prior year and a mean EDSS score of about 2.6. The average age in the trial was about 37 years.
The annualized relapse rate was 0.401 in the placebo group, 0.224 in the BG-12 twice-daily group (44% reduction versus placebo), 0.198 in the BG-12 three-times-daily group (51% reduction), and 0.286 in the GA group (29% reduction). These rates correspond to hazard ratios for relapse of 0.66, 0.55, and 0.71, respectively. The results were statistically significant.
About 17% of placebo, 13% of BG-12, and 15.6% of GA patients experienced disease progression in the trial. The differences did not reach significance, perhaps because progression rates overall were low, unlike the earlier trial, where 27% of placebo patients progressed, Dr. Phillips said.
About 140 patients in each arm were included in the MRI analysis. The placebo arm had an adjusted mean of 17.4 new or newly enlarging T2 hyperintense lesions and 7 new T1 hypointense lesions. Both BG-12 arms had a mean of about 5 new or newly enlarging T2 lesions and just under 3 T1 lesions. The GA group had a mean of 8 T2 lesions and 4.1 T1 lesions. The differences versus placebo were significant.
Flushing and gastrointestinal complaints were the most common side effects of BG-12, but they decreased after the first month of the trial. Mean lymphocyte counts fell during the first 6-12 months, but remained within normal limits throughout the study.
No opportunistic infections or malignancies were reported in the BG-12 groups. The twice-daily arm had two cellulitis cases, whereas the three-times-daily arm had one. No cellulitis was reported in the placebo and GA arms.
The meeting was sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
The CONFIRM trial was funded by the maker of BG-12, Biogen Idec. Dr. Phillips reported financial relationships with Biogen, Avanir, Genzyme, Novartis, Teva, and Roche. Dr. Stone said she had no disclosures.