Laquinimod for MS
Laquinimod (manufacturer: Teva Pharma and Active Biotech) is an immunomodulatory drug that is thought to induce a shift in the immune system from a proinflammatory to an anti-inflammatory profile, resulting in decreased leukocyte (a type of white blood cell that is a key part of the immune response) infiltration into the CNS. Laquinimod may also have neuroprotective effects, by triggering the production of brain-derived neurotrophic factor, a type of protein that supports the survival and growth of neurons.
How far along is laquinimod in the development process?
Two Phase 2 and two Phase 3 (BRAVO and ALLEGRO) studies of laquinimod in people with MS have been completed. The European Medications Agency is currently reviewing an application for use of laquinimod in relapsing-remitting MS (RRMS). Due to the failure of laquinimod to show a significant effect in the primary efficacy outcome in the Phase 3 BRAVO study, Teva Pharma placed its submission to the FDA on hold. There are currently no new Phase 3 studies in progress.
What evidence do we have that laquinimod works in MS?
The effectiveness of laquinomod in people with MS has been tested in two Phase 2 and two Phase 3 (BRAVO and ALLEGRO) studies. In the first Phase 2 study, a randomized, placebo-controlled study conducted in 209 people with RRMS, laquinimod resulted in a 44% decrease in gadolinium (Gd)-enhancing brain lesions over 24 weeks of treatment compared with placebo. However, in another analysis of results, this decrease was smaller and did not reach significance. In a 36-week Phase 2b randomized, placebo-controlled study conducted in 306 people with RRMS, laquinimod resulted in significant decreases in the cumulative numbers of Gd-enhancing lesions (40% decrease) and T2 lesions compared with placebo.
Results from the 2-year Phase 3 ALLEGRO and BRAVO randomized, placebo-controlled studies including a combined 2,400 people with RRMS were recently reported, but have not been published. In ALLEGRO, laquinimod resulted in significant decreases in the annual rate of relapse (23% reduction) and percentage of patients with progression of disability (36% reduction) compared with placebo. The BRAVO study, which, in addition to comparing laquinimod with placebo, provided a less formal comparison with interferon beta-1a. Laquinimod failed to result in a significant difference with placebo in reduction of annual rate of relapse, the primary efficacy outcome for the study. However, differences in baseline magnetic resonance imaging (MRI) lesion characteristics between the laquinimod and placebo groups may have accounted for the failure to reach statistical significance. When this imbalance was corrected, the annual rate of relapse was significantly lower in the laquinimod group compared with the placebo group. Additionally, laquinimod resulted in a significantly lower risk of progression of disability and lower brain volume loss compared with placebo.