Safety and Efficacy of the Terminal Complement Inhibitor Eculizumab in Japanese Patients with Paroxysmal Nocturnal Hemoglobinuria: AEGIS Phase II Clinical Study Results

In patients with paroxysmal nocturnal hemoglobinuria (PNH), lack of the GPI-anchored terminal complement inhibitor CD59 on hematopoietic stem cells and subsequently matured blood cells results in chronic intravascular hemolysis and thrombosis. The patients also show kidney disease and pulmonary hypertension in addition to disabling fatigue, abdominal pain and impaired quality of life. Eculizumab is a humanized MoAb against a terminal complement molecule C5, and has been evaluated in 2 phase III studies in North America, Western Europe and Australia. Eculizumab significantly reduced hemolysis, anemia, transfusion requirements, and thrombotic events, and improved fatigue, renal impairment and quality of life. We conducted an open-label single-arm phase II study (AEGIS) to evaluate the safety and efficacy of eculizumab in Japanese patients with PNH relative to the two phase III eculizumab studies previously reported. The AEGIS study criteria included patients with significant thrombocytopenia (platelet counts ≥ 30x109/L) and/or minimal transfusion requirements (1 or more transfusion episodes in the preceding 2 years). Eculizumab was dosed as follows: 600mg weekly for 4 weeks; 900mg one week later; and then 900mg every other week for a total of 12 weeks of therapy. Patients received meningococcal vaccine 2 weeks prior to treatment. Eculizumab was administered to 29 Japanese patients at 9 institutions. The median patient age was 47 years (range 26–70 years), median platelet count was 150x109/L (range 28–291x109/L), 45% had a history of aplastic anemia or MDS, and 48% were taking corticosteroids. Eculizumab serum levels were sufficient to completely block complement. Twenty seven out of 29 patients completed the study. Intravascular hemolysis, the primary efficacy endpoint of the trial, was rapidly and significantly reduced with eculizumab treatment. Lactate dehydrogenase (LDH) decreased 86% from a median of 1,814 U/L at baseline to a median of 244 U/L at 12 weeks of treatment ( P