Safety and Efficacy of the Terminal Complement Inhibitor Eculizumab in Japanese Patients with Paroxysmal Nocturnal Hemoglobinuria: AEGIS Phase II Clinical Study Results.
Authors: Kanakura Yuzuru , Ohyashiki Kazuma , Shichishima Tsutomu , Okamoto Shinichiro , Ando Kiyoshi , Ninomiya Haruhiko , Kawaguchi Tatsuya , Nakao Shinji , Nakakuma Hideki , Nishimura Jun-Ichi , Kinoshita Taroh , Bedrosian Camille , Valentine Marye Ellen , Ozawa Keiya , Omine Mitsuhiro 
Published: October 2019

Abstract
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<0.001; normal range 103–223 U/L). Control of hemolysis resulted in improvement in anemia; hemoglobin levels increased from baseline (p=0.002 respectively). Transfusion requirements decreased 71% from a mean (SE) of 5.2 (±1.04) PRBC units/patient during the 12-week pre-treatment period to 1.5 (±0.67) units/patient during 12 weeks of eculizumab treatment (P<0.001 for the prespecified median change). Transfusion independence was achieved in 67% (14/21) of patients who were transfusion-dependent prior to treatment (P<0.001). Fatigue levels, as measured by the FACIT-Fatigue instrument, significantly improved within one week of eculizumab treatment, with a median increase of 5.0 points at 12 weeks (P<0.001). A change of 3 or more points is considered clinically meaningful. A post hoc analysis was performed to evaluate the effect of eculizumab on chronic kidney disease (CKD), measured as an improvement or worsening in CKD stage during treatment according to the KDOQI CKD published guidelines. Eculizumab improved CKD in 41% (12/29) of patients, while 55% (16/29) maintained stable kidney function, and only 3.4% (1/29) showed worsening (P<0.001). There were five reported thrombotic events in patients prior to eculizumab and no reported events in treated patients to-date. The drug was safe and well tolerated in all patients. The most frequent adverse events (AEs) were headache (52%), nasopharyngitis (41%), and nausea (21%). Most AEs were mild to moderate in severity and not considered related to eculizumab. No serious AEs were reported as probably related to drug. In summary, this trial demonstrates that eculizumab is safe and well tolerated in Japanese patients with PNH and provides beneficial effects in PNH similar to those observed in previous phase III trials.
Table 1: Efficacy of Eculizumab
Baseline 12 weeks Treatment Change From Baseline P-Valuea aOverall mixed model analysis bBaseline represents the number of units transfused during the 12 week period prior to treatment. One PRBC unit is prepared from 200 ml of donor peripheral blood. cA change of ≥ 3 is considered clinically meaningful LDH, U, L Median (mean ± SE) 1,814 (1,845 ±115) 244 (399 ± 99) P < 0.001 Transfusions (PRBC Units/Patient)bmedian (mean ± SE) 2.0 (5.2 ±1.04) 0.0 (1.5 ± 0.67) P < 0.001 Hemoglobin (g/dL) Median (mean ± SE) 7.5 (7.3±0.3) 9.0 (8.9 ± 0.4) P =0.002 FACIT-fatigue scorec Median (mean ± SE) 41.0 (38.5 ±1.9) 43.0 (42.6± 1.5) +5.0 (4.1 ±2.3) P < 0.001