Laquinimod Trial Misses Primary Endpoint in MS

Susan Jeffrey

August 01, 2011

August 1, 2011 — Topline phase 3 results from the BRAVO trial of oral laquinimod showed the study did not meet its primary endpoint in reducing annualized relapse rates in patients with relapsing-remitting multiple sclerosis.

Teva Pharmaceutical Industries Ltd. and Active Biotech issued a statement outlining the results earlier today. BRAVO is the second of 2 pivotal phase 3 trials of the still-investigational agent; positive results for the other phase 3 investigation, ALLEGRO, were reported in April at the American Academy of Neurology annual meeting.

BRAVO was a 2-year, multicenter, randomized, double-blind, parallel-group, placebo-controlled study comparing the safety, efficacy, and tolerability of a once-daily, oral, 0.6-mg dose of laquinimod with those of placebo and to provide what the companies call "a descriptive comparison of the risk-benefit profiles of laquinimod and interferon beta-1a (Avonex)," the companies' release notes.

The primary outcome was the efficacy of 0.6 mg of laquinimod daily as measured by the relapse rate vs placebo. Secondary outcome measures included effect on the accumulation of disability and brain atrophy, the release notes. Enrollment was completed in June 2009; more than 1331 patients were recruited at 153 sites worldwide, including in the United States, Europe, Russia, Israel, and South Africa.

Although the primary endpoint was not met vs placebo (P = .075), the release notes, randomization in BRAVO was "adequately performed" and showed dissimilarity in 2 baseline characteristics on magnetic resonance imaging. "According to a standard and pre-specified sensitivity analysis included within the original statistical analysis plan, when this imbalance was corrected laquinimod demonstrated a significant reduction in the annualized relapse rate (21.3%, P = .026), in the risk of disability progression as measured by Expanded Disability Status Scale (EDSS) (33.5%, P = .044) and in brain volume loss (27.5%, P < .0001).

"The BRAVO findings support the direct effect of laquinimod within the central nervous system and are in line with the results of the first laquinimod phase 3 trial, ALLEGRO," the companies write. As in ALLEGRO, the BRAVO study showed laquinimod had a favorable safety and tolerability profile compared with placebo.

Compared with placebo, treatment with interferon 1-alfa reduced annualized relapse rates; "however, a reduction in brain tissue loss was not demonstrated and a reduction in the progression of disability did not yield a supportive p value."

The BRAVO study was not designed to provide direct statistical comparisons of efficacy endpoints between the 2 active arms, they note.

In ALLEGRO, annualized relapse rates were reduced by 23% with treatment, somewhat less than was expected, Giancarlo Comi, MD, director of the Department of Neurology and Institute of Experimental Neurology at the Scientific Institute and University Vita-Salute San Raffaele in Milan, Italy, said at the American Academy of Neurology meeting earlier this year.

However, disability was reduced by 36%, a large effect similar to that seen in recent trials with newer agents. In addition, brain atrophy was reduced by 38%.

"Here we have for the first time a drug that has a quite clear different modality of action on the disease compared to all previous drugs," Dr. Comi said. All these drugs affect inflammation, albeit through different pathways, but it has always been the impact on inflammation that determined the effect on disability, he noted.

Other agents reduced new lesions by up to 90%, relapses by about 50% — "usually about half of the effect on the lesions" — and then were associated with disability scores that were not affected at all or were affected by about 30%; these latter effects on disability have been achieved by drugs such as natalizumab, fingolimod, or cladribine, with strong reductions of inflammatory activity, he said.

"In this trial, what I think was surprising was that the effect on disability is larger than the effect on relapses," Dr. Comi said. Severe relapses leading to hospitalization were reduced by 38%, he noted. "So you have to ask yourself, what is better at the end of 2 years — to have a better physical condition or an attack less?"

"We are encouraged by the overall outcomes achieved in the laquinimod phase 3 clinical development program, and plan to submit applications to regulatory authorities in the [United States] and [European Union]," said Professor Yitzhak Peterburg, Teva's Group Vice President, Global Branded Products, in the release. "Teva remains committed to the clinical development of laquinimod and is confident that the drug could provide a unique option for the treatment of multiple sclerosis."

"Data from the ALLEGRO and BRAVO studies demonstrated that laquinimod reduced disability and brain tissue loss, 2 of the most important goals in the treatment of relapsing forms of multiple sclerosis," said Professor Per Soelberg Sorensen, MD, head of MS Research Unit, Copenhagen University Hospital, Rigshospitalet, Denmark, Co-principal investigator of the BRAVO study. "These effects, coupled with a favorable safety profile and a once-daily dosing regimen create a promising potential treatment for the disease."

Additional analyses of the BRAVO study data are ongoing, and results will be submitted for presentation at a scientific congress later in the year.

In addition to the multiple sclerosis clinical studies, laquinimod is in phase 2 development for Crohn's disease and lupus, as well as other autoimmune diseases.

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