Two randomized, double-blind clinical trials of oral laquinimod in relapsing–remitting multiple sclerosis (MS) have been completed. The BRAVO study failed to meet its primary end point, a significant decrease in annualized relapse rate (ARR), until a prespecified readjustment was carried out because of an imbalance in baseline characteristics. The ALLEGRO study, however, satisfied this end point.
Despite the adjustments, the effect of laquinimod on a reduction in ARR was only 21.3%, its effect on decrease in Expanded Disability Status Scale (EDSS) was 33.5%, and its effect on decrease in brain volume loss was 27.5%. No significant decrease in ARR or disability progression was found comparing placebo to interferon b-1a. Comparisons between interferon and laquinimod have not yet been published.
A post hoc analysis of the combined studies yielded results similar to those of the individual studies. Although it is dangerous to do a cross-study comparison, the laquinimod results compared unfavorably to those of other phase 3 trials in effect on ARR reduction, or decrease in Gad+ or new T2 lesions. The major positive findings were the effects of laquinimod in reducing sustained EDSS progression and loss of brain volume. This result raises the possibility that laquinimod may have a mechanism of action other than as an anti-inflammatory agent.
In considering any drug in MS, assessment of progression can be difficult. Progression may occur slowly and may be secondary to clinical or MRI relapses. Even sustained progression is difficult to assess and may reverse itself after study completion.
It is of interest that comparing decrease in three-month EDSS progression in all completed phase III oral trials (ie, of five drugs), a mean clustering of decrease in sustained three-month disease progression was found in a fairly narrow range between 30% and 34%. Measurements of brain-volume loss can also be confounded by the degree and timing of inflammation. If inflammation occurs later in a study, there can be an impression that brain-volume loss is lessened due to an increase in brain volume seen with inflammation (ie, pseudohypertrophy).
—Stuart Cook, MD
Professor of Neurosciences
University of Medicine and Dentistry of New Jersey