Treating relapsing multiple sclerosis with dimethyl fumarate
Common signs and symptoms of MS include episodes of fatigue, numbness, visual disturbances, spasticity, stiffness, bowel and bladder abnormalities, and cognition disturbances followed by periods of remission.2 As the disease progresses, patients slowly develop an increasing decline in their ability to ambulate. Treatment is initiated to reduce the progression to secondary progressive MS and disability.2 Two landmark clinical trials led to the approval of dimethyl fumarate in the management of relapsing MS.3,4 The Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS (DEFINE) study evaluated the efficacy of dimethyl fumarate administered orally twice a day and three times a day compared with placebo.3 The proportion of patients having a relapse at 2 years was evaluated as the primary outcome. Among the placebo, twice-daily dimethyl fumarate, and thrice-daily dimethyl fumarate study groups, the proportion of patients experiencing a relapse at 2 years was 46%, 27%, and 26%, respectively.
The difference between the placebo group and both dimethyl fumarate groups was statistically significant (P < 0.001).3 Secondary endpoints of annualized relapse rates, progression of disability, and MRI findings were also consistently lower in the dimethyl fumarate treatment groups as compared with placebo.3 The Comparator and an Oral Fumarate in Relapsing-Remitting MS (CONFIRM) study design was similar to the DEFINE study, with the addition of an active treatment comparator group.4
Subjects were randomly assigned to one of four study groups: placebo, dimethyl fumarate 240 mg orally twice daily, dimethyl fumarate 240 mg orally three times daily, or glatiramer acetate 20 mg subcutaneously daily. The primary endpoint of annual relapse rate at 2 years was significantly lower in the twice-daily and thrice-daily dimethyl fumarate groups (0.22 and 0.20, respectively) as compared with placebo, with a relapse rate of 0.4 (P < 0.001).
Two-year relapse rates of both dimethyl fumarate groups were lower but similar to the 2-year relapse rate for glatiramer acetate.4 Although the CONFIRM study was not designed to evaluate noninferiority or superiority of dimethyl fumarate compared with glatiramer, a post-hoc analysis was performed to determine relative benefit differences between the active agents. Statistically significant differences in favor of dimethyl fumarate were noted in the following analyses:
The results of the CONFIRM study closely mirrored those of the DEFINE study, with the only inconsistency being in the proportion of patients with disability progression. There were no statistical differences between the disability progression of patients in the placebo group compared with patients in the treatment groups in the CONFIRM trial; however, there was a statistically significant difference between the placebo and treatment groups in the DEFINE trial.3,4 A proposed explanation for this difference could be due to the higher percentage of patients in the placebo group with disability progression in the DEFINE study as compared with the CONFIRM study (27% versus 17%, respectively).3,4
Dimethyl fumarate (Tecfidera) received FDA approval for the treatment of relapsing forms of MS on March 27, 2013.5 Since its initial approval, changes to the prescribing information were made in 2014, 2016, and 2017.