Randomized, Double-Blind, Placebo-Controlled, Crossover, Multicenter, Phase II Study of Eculizumab in Patients with Refractory Generalized Myasthenia Gravis (gMG) (S35.004)

Abstract

Objective: Phase 2 study to establish safety and efficacy of eculizumab in severe and refractory generalized myasthenia gravis (gMG) patients. Background Complement activation at the neuromuscular junction may be the primary cause of acetylcholine receptor loss and failure of neuromuscular transmission seen in myasthenia gravis. Eculizumab a humanized monoclonal antibody blocks the formation of terminal complement complex by selectively preventing the enzymatic cleavage of C5. Design/Methods: This clinical study was a randomized, double-blind, placebo-controlled, cross-over study in 14 patients who had moderate to severe muscle weakness despite treatment with immunosuppressants. Results: 6/7 patients treated in the first period with Eculizumab for 16 weeks (86%) achieved the primary endpoint of a 3 point reduction in QMG score. During the first 16 weeks, mean change from baseline in QMG score in eculizumab was greater than placebo (-7.43 vs . -2.71, p=0.11, respectively). Exploratory analysis of the first treatment period demonstrated that 4/7 of patients treated with eculizumab obtained an eight-point improvement in total QMG score vs . 1/7 in placebo. Examining both period visits, overall change in mean QMG total score was significantly different between Eculizumab and Placebo (-7.92 vs . - 3.67; paired t-test P =0.0144). Assessing data at all visits, overall change in mean QMG total score was significantly different between Eculizumab and Placebo (-6.43 vs . -3.18; repeated measures mixed model P Conclusions: These data highlight the central role of uncontrolled complement activation in severe and refractory gMG. The 14-patient pilot study achieved nominal significance in the primary endpoint and also achieved its objective of demonstrating a significant clinical benefit of eculizumab in improving QMG score relative to placebo. Eculizumab was safe and well tolerated in all treated gMG patients. Supported by: Alexion Pharmaceuticals. Disclosure: Dr. Howard holds stock and/or stock options in Alexion Pharmaceuticals, Cytokinetics, Inc. & GSK Pharmaceuticals which sponsored research in which Dr. Howard was involved as an investigator.Dr. Howard holds stock and/or stock options in Pfizer Inc, General Electric, Johnson & Johnson. Dr. Barohn has received personal compensation for activities with Talecris Biotherapeutics, Genzyme Corporation and Speakers Bureau. Dr. Barohn has received research support from Alexion Pharmaceuticals. Dr. Freimer has nothing to disclose. Dr. Juel has nothing to disclose. Dr. Mozaffar has nothing to disclose. Dr. Mellion has nothing to disclose. Dr. Benatar has received personal compensation for activities with Cytokinetics as a participant on an advisory board. Dr. Benatar has received personal compensation in an editorial capacity for Journal Watch Neurology. Dr. Benatar has received research support from Alexion Pharmaceuticals and Orphazyme. Dr. Farrugia has received research support from Alexion Pharmaceuticals. Dr. Kissel has nothing to disclose. The MG Study Group has nothing to disclose.