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|October 01, 2013 8:01 a.m.|
|Newly Published Phase III Exploratory Analysis Suggests Investigational Oral Laquinimod for Multiple Sclerosis May Reduce Brain Damage Caused by Neurodegeneration|
"This Phase III sub-study was pre-planned to explore the ability of laquinimod to act on mechanisms leading to irreversible brain tissue damage," said Professor
The results showed that when compared with placebo, patients treated with laquinimod experienced decreased rates in brain tissue damage shown by various MRI markers. Specifically, patients receiving laquinimod showed decreased rates of white matter (WM), grey matter (GM) and thalamic atrophy; developed fewer permanent black holes (PBH); and accumulated less damage in normal appearing brain tissue (NABT), WM and GM, when compared to patients receiving placebo.
“These analyses reinforce our faith in the potential of laquinimod and we are proud to announce that we plan to initiate a clinical trial of the drug in PPMS to gather even more evidence of this novel mechanism of action,” said Dr.
A third Phase III laquinimod trial, CONCERTO, is evaluating two doses of the investigational product (0.6mg and 1.2mg) in approximately 1,800 patients for up to 24 months. The primary outcome measure is the time to confirmed disability progression as measured by the EDSS. The study will also examine the impact of laquinimod on endpoints such as percent change in brain volume, as well as other clinical and MRI markers of disease activity.
ABOUT THE ALLEGRO STUDY
ALLEGRO was a two-year multi-national, multi-center randomized, double blind, placebo-controlled study designed to evaluate the efficacy, safety and tolerability of laquinimod in MS patients. The study was conducted at 139 sites in 24 countries and enrolled 1,106 MS patients. Patients were randomized to receive a once-daily oral dose of 0.6 mg laquinimod or matching placebo. The primary outcome measure was the number of confirmed relapses; secondary measures included confirmed disability progression and changes in MRI active lesions.
In the ALLEGRO study, laquinimod showed a statistically significant 23 percent reduction in annualized relapse rate (p=0.0024), the primary endpoint, along with a significant 36 percent reduction in the risk of confirmed disability progression, as measured by Expanded Disability Status Scale (EDSS) (p=0.0122). Treatment with laquinimod was also associated with a significant reduction in brain tissue loss, as measured by a 32.8 percent reduction in progression of brain atrophy (p<0.0001).
In these MRI analyses, white matter (WM), grey matter (GM) and thalamic fractions were derived at baseline, and months 12 and 24. Also assessed were evolution of gadolinium enhancing and/or new T2 lesions into permanent black holes (PBH); magnetization transfer ratio (MTR) of normal-appearing brain tissue (NABT), WM, GM and T2 lesions as assessed by magnetization transfer (MT) MRI; and changes in n-acetylaspartate/creatinine (NAA/Cr) levels.
Eighty percent of laquinimod and 77 percent of placebo patients completed the two-year study. Patients who completed the ALLEGRO study were offered to join an open-label extension phase, in which they are being treated with laquinimod 0.6 mg daily.
The safety and tolerability profile of laqunimod observed in the ALLEGRO and BRAVO studies was favorable. The overall frequencies of adverse events, including incidence of infections, were similar to those observed in the placebo group. The most commonly reported adverse events were headaches, nasopharyngitis and back pain. The incidence of liver enzyme elevation was higher in laquinimod treated patients; however, these elevations were transient, asymptomatic and reversible.
Laquinimod is an oral, investigational, CNS-active immunomodulator with a novel mechanism of action being developed for the treatment of relapsing-remitting MS (RRMS). The global Phase III clinical development program evaluating oral laquinimod in MS includes two pivotal studies, ALLEGRO and BRAVO. A third Phase III laquinimod trial, CONCERTO, is evaluating two doses of the investigational product (0.6mg and 1.2mg) in approximately 1,800 patients for up to 24 months. The primary outcome measure is the time to confirmed disability progression as measured by the EDSS.
In addition to the MS clinical studies, laquinimod is currently in Phase II of development for Crohn's disease and lupus nephritis. Because of the neuroprotective findings, Teva is evaluating further studies to determine the effectiveness of laquinimod in treating patients with primary progressive multiple sclerosis, Huntington’s disease and Alzheimer’s disease.
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