Long-term efficacy and safety of eculizumab in Japanese patients with PNH: AEGIS trial

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, progressive hematopoietic stem cell disorder characterized by chronic complement-mediated hemolysis leading to life-threatening complications and early mortality. Eculizumab, a humanized anti-C5 monoclonal antibody, inhibits terminal complement activation, reduces hemolysis, decreases the risk of thrombosis, and improves renal function and quality of life in PNH patients. The long-term efficacy and safety of eculizumab in Japanese patients were assessed in a 2-year extension to a 12-week, open-label study (AEGIS). Eculizumab treatment led to an immediate and sustained reduction in intravascular hemolysis (P < 0.001) and red blood cell transfusions (P = 0.0016) compared with baseline levels. There were no reports of thromboembolism during eculizumab treatment. The majority of patients had stable (56 %) or improved (41 %) renal function and an improved quality of life (P = 0.015), with sustained reductions in fatigue and dyspnea. Eculizumab was well tolerated; no deaths or serious hemolytic events were reported, and the rate of infections declined over time. There were no significant differences in the response to eculizumab in patients with or without bone marrow dysfunction. These results demonstrate that eculizumab is an effective, well-tolerated long-term treatment for Japanese PNH patients and leads to continued amelioration of some hemolytic complications.

Efficacy and safety of eculizumab in children and adolescents with paroxysmal nocturnal hemoglobinuria

“…Hematologic parameters stabilized and other manifestations of PNH were significantly reduced. These findings are similar to those in adults and support the use of eculizumab in children with PNH .…”

“…Eculizumab inhibits cleavage of C5 into C5a and C5b, which prevents both the release of the anaphylatoxin C5a and the formation of the membrane attack complex, which induces red blood cell (RBC) lysis. Several clinical trials of eculizumab in adults with PNH showed dramatic reduction in hemolysis and decreases in transfusion requirements and episodes of hemoglobinuria, as well as improvement in quality of life (QOL) [24][25][26][27][28][29][30][31][32]. Eculizumab was found to be safe with sustained responses up to 8 years, and protective against complications of PNH such as thrombosis, renal dysfunction, and pulmonary hypertension, and improved overall survival rate from 67% to 96% at 5 years.…”

Improvement of Renal Function by Long-Term Sustained Eculizumab Treatment in a Patient with Paroxysmal Nocturnal Hemoglobinuria

“…Improvement of renal function in PNH by administration of eculizumab is time-dependent, as reported by Hillmen et al [5] and Kanakura et al [6]. Improvement of renal function is less common in the advanced stages 3–5 of CKD than stages 1-2 of CKD, even with long-term administration of eculizumab, whereas patients with stages 3–5 did not worsen during treatment with eculizumab [4].…”

“…Improvement in renal function was more commonly seen in patients with baseline stages 1-2 CKD, although improvement was also observed in patients with stages 3–5 CKD [4]. Long-term observation of Japanese PNH patients in a two-year extension to the 12-week AEGIS study also showed that the majority of patients exhibited stable (56%) or improved (41%) renal function [6]. …”

Terapeutisk komplementhemming – fra eksperimentell til klinisk medisin

“…Transfusjonsbehovet gikk ned ved eculizumabbehandling. Det er gjort ikke-placebokontrollerte studier på sikkerhet og effekt (15,16). Dessuten foreligger det studier med overlevelse som endepunkt med sammenlikning mot historiske kontrollpersoner, der bruk av eculizumab var assosiert med redusert dødelighet (17).…”