Rationale For Advancing Laquinimod For Progressive MS: Evidence From Large Clinical Trials In RRMS (S4.001)

OBJECTIVE: To assess laquinimod’s potential to treat progressive forms of MS (PMS) based on RRMS clinical trial data. BACKGROUND: Currently there is no effective treatment for PMS (i.e., PPMS or SPMS), and all tested disease-modifying therapies currently used in RRMS have failed to show efficacy. Based on its neuroprotective preclinical profile and the clinical effect of slowing disability progression, and reducing brain volume loss and black hole evolution, the large clinical trial data set from RRMS cohorts was further analyzed for the effects of laquinimod on various aspects of the disease that may contribute to its effect on slowing of disability progression. DESIGN/METHODS: In post hoc analyses, laquinimod effect versus placebo on confirmed disability progression (CDP) was evaluated in patient subgroups based on relapse rate during the study, baseline Expanded Disability Status Scale (EDSS) scores, and Multiple Sclerosis Functional Composite (MSFC) z-score quartiles. The correlation between relapse rate and EDSS worsening with laquinimod was assessed using the Sormani meta-analysis. RESULTS: In pooled ALLEGRO/BRAVO data (laquinimod n=984, placebo n=1006), compared with placebo, laquinimod reduced CDP by 38.9% (P=.036) in patients who were relapse-free throughout the studies, by 34.6% (P=.12) in patients with baseline EDSS scores 蠅4, and by 38.6% (P=.023) in the 25% quartile of MSFC z-score (denoting patients with the least favorable changes in MSFC). Per the Sormani model, the predicted reduction in 3-month CDP with laquinimod, given the observed effect on relapse rate, should be only 5% (RR=0.95; 95% CI: 0.87, 1.00), whereas the observed reduction in 3-month CDP using the relative risk was 29% (RR=0.71; 95% CI: 0.56, 0.91; P=.007). This pronounced dissociation indicates the effect of laquinimod on disability is disproportionally large relative to its effect on relapses. CONCLUSIONS: Several analyses of laquinimod effects noted in RRMS clinical studies suggest it may benefit people with PMS. Study Supported by: Teva Pharmaceutical Industries, Petach Tiqva, Israel. Disclosure: Dr. Comi has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals Inc., Novartis, Merck Serono, Biogen Idec, Bayer Pharmaceuticals Corp., Teva Neuroscience, and Actellion. Dr. Sormani has received personal compensation for activities with Allozyne, Merck Serono, Teva Neuroscience, Synthon, Actelion and Biogen Idec. Dr. Giovannoni has received personal compensation for activities with Biogen Idec, Merck Serono, Vertex Pharmaceuticals, Bayer Schering, Pfizer Inc., Teva Neuroscience, and Sanofi-Aventis Pharmaceuticals Inc. Dr. Giovannoni has received research support from Biogen Idec, Merck Serono, Novartis, and Ironwood. Dr. Ladkani has received personal compensation for activities with Teva Neuroscience. Dr. Ladkani holds stock and/or stock options in Teva Neuroscience which sponsored research in which Dr. Ladkani was involved as an investigator. Dr. Sasson has received personal compensation for activities with Teva Neuroscience. Dr. Gorfine has received personal compensation for activities with Teva Neuroscience. Dr. Knappertz has received personal compensation for activities with Teva Neuroscience as an employee.