NEW ORLEANS—Laquinimod, an oral, CNS-active therapy for multiple sclerosis (MS), significantly slows disability progression and brain atrophy, compared with placebo, according to research presented at the 64th Annual Meeting of the American Academy of Neurology. The drug’s safety profile suggests that “it may have an important role in the long-term management of MS,” said Timothy Vollmer, MD, Professor of Neurology and Director of Clinical Research at the University of Colorado School of Medicine in Aurora.
Laquinimod reduced the probability of three-month sustained disability by 34% with a hazard ratio of 0.658 and a highly significant P value. “From an exploratory standpoint, if you extend this definition to a six-month sustained disability progression, you get an even larger effect of 46%, again with a significant P value and a hazard ratio of 0.54,” said Dr. Vollmer.
After 24 months, laquinimod reduced the rate of cerebral atrophy by 30%, compared with placebo. “This effect was actually visible at month 12 and was already statistically significant,” observed Dr. Vollmer.
“This effect on disability seems somewhat out of proportion to what we would expect, based on the reduction of the inflammatory phase of the disease,” he continued. After 24 months, patients on laquinimod had a 21% lower annualized relapse rate than patients on placebo. At months 12 and 24, the researchers observed a 30% reduction in the number of gadolinium-enhancing lesions and a 24% reduction in new T2 lesions. These three results were highly statistically significant, but their effects were “modest,” said Dr. Vollmer.
Pooled Analyses of Two Trials
Dr. Vollmer and his colleagues performed pooled analyses of data from the Safety and Efficacy of Orally Administered Laquinimod Versus Placebo for Treatment of Relapsing Remitting Multiple Sclerosis (ALLEGRO) and Laquinimod Double Blind Placebo Controlled Study in RRMS Patients With a Rater Blinded Reference Arm of Interferon b-1a (BRAVO) phase III trials to assess the effect of laquinimod on relapse, disability, and brain atrophy in patients with MS. The ALLEGRO trial was a randomized, double-blinded, placebo-controlled study comparing 0.6 mg of laquinimod to placebo in patients with relapsing MS. The BRAVO trial was a randomized study that compared the same dose of laquinimod and placebo, but included an open-label comparator arm that was analyzed using a rater-blinded method. The two trials had similar study designs and shared the same primary outcome, secondary outcome, and exploratory end point.
The two patient data sets included almost 2,000 patients, approximately 50% of whom were randomized to laquinimod. About 21% of patients in the placebo arm ultimately were excluded from analysis, and 19% of patients in the laquinimod arm were excluded from analysis, mostly because of withdrawal of consent or failure to reconsent. Approximately 6.4% of the laquinimod group withdrew because of adverse events (primarily gastrointestinal side effects and abdominal pain), compared with 4.7% of the placebo group. About 80% of patients in both groups completed the protocol.
Trials Show Laquinimod’sPositive Safety Profile
Laquinimod was well tolerated among patients in the ALLEGRO and BRAVO trials. Approximately 9% of laquinimod and placebo patients reported experiencing serious adverse events. Six patients receiving laquinimod experienced appendicitis, the most commonly reported serious adverse event, compared with one patient on placebo. Three patients on laquinimod experienced malignant breast neoplasms, compared with one patient on placebo.
Overall, nearly 82% of patients receiving laquinimod experienced adverse events, compared with 76% of patients receiving placebo. Compared with control patients, those receiving laquinimod experienced higher rates of headache (15.1% vs 18.2%), back pain (8.2% vs 13.6%), arthralgia (6.0% vs 7.2%), increased liver enzymes (2.7% vs 5.9%), urinary tract infection (4.2% vs 5.7%), cough (3.1% vs 5.2%), and abdominal pain (2.6% vs 5.0%).
“Laquinimod’s toxicity-related liver function was very mild—0.7% of patients on laquinimod had elevated liver transaminase, compared with 0.4% of placebo,” Dr. Vollmer noted. “In all cases, they were mild elevations and resolved despite patients staying on therapy,” he added.