Study in 14 Patients Shows Clinically Meaningful Trend in Disease Severity Score
Eculizumab Achieves Strong Disease Improvement Signal and Important Secondary Endpoints
The Phase 2 eculizumab 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. In the first treatment period of this cross-over study, which enrolled only 14 patients with severe and refractory gMG, 86% (6/7) of eculizumab-treated patients compared to 57% (4/7) of placebo-treated patients achieved a three-point reduction in their QMG score after 16 weeks of treatment, the primary endpoint of the study. This improvement was achieved more rapidly for eculizumab compared to placebo (p= 0.078). In the lead secondary endpoint, the study achieved its objective of demonstrating a significant clinical benefit of eculizumab in improving QMG score relative to placebo: the overall change in mean QMG total score from baseline to the last visit of the study was significantly improved more than 4 points with eculizumab compared to placebo (-7.92 vs -3.67, respectively; p=0.0144). Examining whether there would be even further differential at higher thresholds of disease improvement, an exploratory analysis of the first treatment period demonstrated that 57% of patients (4/7) treated with eculizumab obtained an eight-point improvement in total QMG score as compared to 14% (1/7) of patients receiving placebo.
"These data highlight the central role of uncontrolled complement activation in severe, refractory generalized myasthenia gravis," said
Severe and refractory gMG is an ultra-rare, debilitating, neurological disorder caused by uncontrolled complement activation due to autoantibodies directed at the neuromuscular junction (NMJ).1 Eculizumab is a first-in-class terminal complement inhibitor. There is no known cure for myasthenia gravis.2 Common treatments include medications (anticholinesterase agents, corticosteroids, immunosuppressive agents or cytotoxic therapy), thymectomy (surgical removal of the thymus gland) and plasma exchange.2,3
About the Study
Patients were randomly assigned to receive eculizumab in the first treatment period (16 weeks) followed by placebo in the second treatment period (16 weeks), or the reverse treatment sequence, placebo followed by eculizumab, respectively. The first treatment period for all patients was followed by a 5-week washout period.
Following treatment with eculizumab in the first treatment period, QMG scores in eculizumab treated patients did not return to baseline levels at the start of the second treatment period, highlighting the presence of a prolonged carry-over effect of eculizumab treatment on the reduction in total QMG scores. Changes in QMG score with eculizumab, compared to placebo, observed only in the first treatment period, were similar to those reported above for the entire study period (-6.67 vs -3.48, respectively; p=0.058).
Eculizumab appeared well-tolerated in the study with the three most common adverse events being nausea, back pain and headache. One patient in the eculizumab to placebo treatment group experienced two serious adverse events following termination of eculizumab: a myasthenia gravis exacerbation during the washout period, and a myasthenia gravis crisis during the subsequent placebo period.
"This study demonstrates that eculizumab provided a strong clinical signal for meaningful disease improvement in these investigational study patients with severe and refractory generalized myasthenia gravis, an ultra-rare disorder," said
About Myasthenia Gravis
Myasthenia Gravis is a rare, debilitating, neurological disorder caused by uncontrolled complement activation. The uncontrolled complement activation, resulting from auto-antibodies that recognize a specific target in the nerve-muscle junction, causes tissue damage and interference with signaling between nerve and muscle fibers.1,4 Patients with myasthenia gravis initially experience weakness in their ocular (eye) muscles, and the disease typically progresses to the more severe and generalized form to include head, spinal, limb and respiratory muscles. Symptoms can include drooping eyelid, blurred vision, slurred speech, difficulty chewing or swallowing, weakness in the arms and legs and difficulty breathing.
About Eculizumab (Soliris®)
Soliris is a first-in-class terminal complement inhibitor developed from the laboratory through regulatory approval and commercialization by Alexion. Soliris has been approved in the U.S.,
Important Safety Information
Soliris is generally well tolerated in patients with PNH. The most frequent adverse events observed in clinical studies of patients with PNH were headache, nasopharyngitis (runny nose), back pain and nausea. Treatment with Soliris should not alter anticoagulant management because the effect of withdrawal of anticoagulant therapy during Soliris treatment has not been established.
The U.S. product label for Soliris also includes a boxed warning: "Soliris increases the risk of meningococcal infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Vaccinate patients with a meningococcal vaccine at least two weeks prior to receiving the first dose of Soliris; revaccinate according to current medical guidelines for vaccine use. Monitor patients for early signs of meningococcal infections, evaluate immediately if infection is suspected, and treat with antibiotics if necessary." During PNH clinical studies, two out of 196 vaccinated PNH patients treated with Soliris experienced a serious meningococcal infection. Prior to beginning Soliris therapy, all patients and their prescribing physicians are encouraged to enroll in the PNH Registry, which is part of a special risk-management program that involves initial and continuing education and long-term monitoring for detection of new safety findings.
About Alexion
Safe Harbor Statement
This news release contains forward-looking statements, including statements related to anticipated clinical development, regulatory and commercial milestones and potential health and medical benefits of Soliris® (eculizumab) for the potential treatment of patients with severe and refractory generalized myasthenia gravis. Forward-looking statements are subject to factors that may cause Alexion's results and plans to differ from those expected, including for example, decisions of regulatory authorities regarding marketing approval or material limitations on the marketing of Soliris for its current or potential new indications, and a variety of other risks set forth from time to time in Alexion's filings with the
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References
1. Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future. J Clin Invest 2006 Nov;116(11):2843-54.
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4. Tüzün E, Huda R,
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