At that time, the control patients crossed over and the entire population continued single-agent pegcetacoplan therapy for a 32-week open-label period. The primary endpoint of the study was the change in hemoglobin from baseline level to week 16. Subsequently, they were randomized to either pegcetacoplan 1,080 mg twice weekly (n = 41) or their current dose regimen of eculizumab (n = 39). During the 4-week run-in period, all patients received pegcetacoplan 1,080 mg twice weekly in addition to the eculizumab standard dose. Pegcetacoplan monotherapy was assessed in the randomized, open-label, controlled, phase III PEGASUS trial that included PNH patients who had been on eculizumab treatment for ≥ 6 months but still showed hemoglobin levels < 10.5 g/dL. The investigational compound pegcetacoplan is a subcutaneously administered C3 inhibitor that has the potential to control both intra- and extravascular hemolysis in PNH. PEGASUS: pegcetacoplan induces hemoglobin increase Strategies that are being investigated in the setting of proximal complement inhibition include agents directed against C3 as well as factors D and B that are involved in the formation of the alternative pathway C3 convertase. Therefore, novel anti-complement treatment approaches focus on some of these mechanisms. Factors contributing to residual anemia include underlying bone marrow dysfunction, residual intravascular hemolysis, and the emergence of C3-mediated extravascular hemolysis, which is not improved by C5 inhibitors such as eculizumab. Many continue to experience some degree of anemia, in some cases requiring regular red blood cell transfusions. However, only one third of PNH patients was shown to achieve complete normalization of hemoglobin levels with eculizumab treatment. Eculizumab is administered intravenously this agent targets the component 5 (C5) of the complement cascade, thereby preventing intravascular hemolysis. Treatment options for hemolytic PNH remained limited until the monoclonal antibody eculizumab became available. PNH is associated with a high burden of disease and impaired health-related quality of life. The absence of these proteins leads to uncontrolled activation of the terminal complement pathway and complement-mediated lysis of erythrocytes. The disease results from an acquired loss-of-function mutation of the PIGA gene involved in the synthesis of the glycosylphosphatidylinositol-anchored complement inhibitors CD55 and CD59. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, potentially life-threatening clonal hematopoietic stem cell disorder characterized by hemolytic anemia, bone marrow failure, thrombosis, and peripheral blood cytopenia.
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