The U.S. Food and Drug Administration has approved high-dose glatiramer acetate (40 mg/day) with a new three times per weekly dose schedule.
The approval was based on the results of the placebo-controlled GALA trial of glatiramer acetate 40 mg tiw in 1,404 patients with relapsing-remitting MS (Khan et al. Ann Neurol 2013;73:705-713). At 12 months, the mean annualized relapse rate was 0.331 with GA versus 0.505, a significant 34% reduction. Treatment was also associated with a 44.8% reduction in gadolinium-enhancing T1 lesions, and a 34.7% reduction in new/enlarging T2 lesions.
A number of previous studies raised questions about the optimal dosing schedule of glatiramer acetate. In the FORTE study, 40 mg/day was no more effective than the standard dose of 20 mg/day (Comi et al. Ann Neurol 2011;69:75-82). At one year, the mean ARR was 0.35 and 0.33 for the 40-mg and 20-mg groups, respectively.
An open-label study reported that a regimen of glatiramer acetate 20 mg administered every other day compared favourably with once-daily dosing (Flechter et al. Clin Neuropharmacol 2002;25:11-15). Moreover, a two-year prospective study comparing glatiramer acetate 20 mg OD versus 20 mg twice-weekly showed no difference between the two dosing schedules with respect to ARR, EDSS, proportion of patients relapse-free and number of T1 and T2 lesions (Caon et al. AAN 2010; abstract S11.002). Twice-weekly dosing had the advantage of a lower incidence of lipoatrophy, injection site reactions and immediate post-injection systemic reactions, as expected with less frequent injections.
Thus, while the new dosing of glatiramer acetate 40 mg may be administered three times per week without an apparent loss of efficacy, there is evidence to suggest that a tiw dosing schedule could also be used with the standard 20-mg dose and with the advantage of better tolerability. However, it should be noted that 20-mg tiw dosing is not currently approved by regulators. The relative benefits of different doses and schedules of glatiramer acetate would need to be evaluated in head-to-head studies.
Dr. François Grand’Maison: Progressively fewer MS patients are being initially treated with injectables, given the increasing number of alternatives and the tendency to treat patients more aggressively from onset. MS is a bad disease and withholding the more effective drugs for fear of inducing relatively rare or manageable complications must be carefully weighed against the often-irreversible progression of disease. Time is brain. Canadian neurologists are appropriately resisting the disposition of provincial regulators to mandate escalation procedures whereby treatment is initiated with the least effective drugs and gradually augmented as the patient deteriorates. Nevertheless, there are situations where injectables are appropriate and thrice-weekly glatiramer acetate injections are definitely preferable to daily injections.