Mediation of the Effect of Laquinimod on Disability Progression in Relapsing-Remitting Multiple Sclerosis (RRMS) (P3.195)

OBJECTIVE: To explore whether laquinimod9s effect on disability progression is mediated through its effect on relapses and new T2 lesions. BACKGROUND: Laquinimod treatment is associated with significant reduction of disability progression in RRMS relative to placebo. However, whether effects on relapses and MRI parameters contribute to the effect on disability progression has not yet been elucidated. DESIGN/METHODS: Pooled individual patient data from the ALLEGRO and BRAVO studies were used for this analysis. Treatment response to laquinimod vs. placebo on 6-month confirmed disability progression, defined as an increase of EDSS 蠅1 point from baseline for patients with baseline EDSS ≤5, or increase of EDSS 蠅0.5 for patients with baseline EDSS >5, was assessed by a baseline-adjusted logistic regression model with number of relapses and number of new T2 lesions during the first year of the study independently added to the model. A Freedman’s (1992) proportion of treatment effect explained by each potential surrogate was used to interpret the results. RESULTS: The initial logistic model yielded reductions of 44% (OR=0.56, P =.005; 95% CI [0.40; 0.78]) in the odds for disability progression confirmed for 6 months with laquinimod vs. placebo. This result is consistent with the 46% reduction previously reported using survival analysis (HR=0.54, P =.0001; 95% CI [0.392; 0.739]). Treatment response when adjusting for relapses or new T2 lesions activity during the first year was only mildly changed (to a 40% reduction) or remained similar (46% reduction) to the response achieved in the initial model. Proportion of treatment response on disability progression explained by relapses during the first year was 11%. CONCLUSIONS: The observed treatment effect of laquinimod in reducing disability progression is not strongly mediated through its effects on either relapses or new T2 lesions activity. This finding supports laquinimod’s novel mechanism of action, i.e., affecting irreversible tissue damage independently from acute inflammatory activity. 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. 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. Vollmer has received personal compensation for activities with Cleveland Clinic, Novartis, Mandell Center for Multiple Sclerosis, Teva Neuroscience, Questcor Pharmaceuticals, Biogen Idec, Xenoport, University of Florida PeerView, and Krog & Partners. Dr. Vollmer has received research support from Biogen Idec, Teva Neuroscience, Genzyme Corp., Ono Pharmaceuticals, Elan Pharmaceuticals, Novartis, Avanir Pharmaceuticals, and Janssen Pharmaceutica. Dr. Sormani has received personal compensation for activities with Allozyne, Merck Serono, Teva Neuroscience, Synthon, Actelion and Biogen Idec. Dr. Sidi has received personal compensation for activities with Teva Neuroscience. Dr. Knappertz has received personal compensation for activities with Teva Neuroscience as an employee.