Alexion Pharmaceuticals has announced that Eculizumab ( Soliris ) in a small group of 14 patients with severe and refractory generalized myasthenia gravis, an ultra-rare and debilitating form of generalized myasthenia gravis ( gMG ), showed a strong disease improvement signal. The exploratory 14-patient study aimed to identify a clinically meaningful benefit of Eculizumab in improving Quantitative Myasthenia Gravis disease severity score ( QMG score ) relative to placebo.
The primary endpoint showed a clinically meaningful trend, and important secondary endpoints were achieved with statistical significance.
Data from the Phase 2 study were presented tat the annual Scientific Session of the Myasthenia Gravis Foundation of America ( MGFA ) in San Francisco.

The 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.

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.

Soliris is a terminal complement inhibitor. Soliris has been approved in the United States, European Union, Japan and other territories as the first treatment for patients with paroxysmal nocturnal hemoglobinuria ( PNH ), a debilitating, ultra-rare and life-threatening blood disorder defined by chronic uncontrolled complement activation which causes hemolysis, leading to blood clots, organ failure, and shortened survival.
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, 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.

Source: Alexion, 2011

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