Table 1 Summary of anticomplement therapy used in clinical trials Clinical situation Principle of anticomplement therapy Paroxysmal nocturnal hemoglobinuria C5 inhibition Paroxysmal nocturnal hemoglobinuria Replacement of deﬁcient complement inhibitor molcule Glomerulonephritis C5 inhibition AMI treated with thrombolysis Augmentation of complement inhibitory molecules AMI treated with thrombolysis C5 inhibition AMI treated with angioplasty C5 inhibition AMI treated with CABG surgery Augmentation of complement inhibitory molecules Cardiac surgery requiring CPB Augmentation of complement inhibitory molecules Cardiac surgery requiring CPB Inhibition of the complement system at many levels Cardiac surgery requiring CPB C5 inhibition Anticomplement therapy Treatment Eculizumab (monoclonal antibody) Recombinant soluble CD59 Eculizumab C1 inhibitor Pexelizumab (monoclonal antibody) Pexelizumab (monoclonal antibody) C1 inhibitor TP10 (recombinant soluble complement receptor 1) Heparin Pexelizumab (monoclonal antibody) Abbreviations: CABG, coronary artery bypass graft; AMI, acute myocardial infarction; CPB, cardiopulmonary bypass; CD, cluster of differentiation. (Hillmen et al 1995; Socie et al 1996). Patients usually have acute severe hemolytic episodes with a chronic mild hemolysis in the background (Hill et al 2007). Despite the extensive hemolysis, the major cause of morbidity and mortality in PNH is venous thrombosis, which occurs in about 50% of patients and is responsible for one-third of deaths in PNH (Hillmen et al 1995; Socie et al 1996). The cause of PNH patients’ predilection to thrombosis is currently unknown (Hill et al 2007). While venous thrombosis is the major cause of morbidity and mortality in PNH, many patients also develop pancytopenia due to aplastic anemia (Hill et al 2007). The median survival of patients with PNH from the time of diagnosis is about 10–15 years. However, approxi- mately 15% of patients experience spontaneous regression of PNH with no residual sequelae (Hillmen et al 1995). Therapy Standard therapy for PNH includes supportive care with red blood cell (RBC) transfusions and treatment of thrombotic complications (Hill et al 2007). The only deﬁnitive cure for PNH currently is allogeneic bone marrow transplantation (BMT), with indications for this similar to the indications for BMT in aplastic anemia. In the past several years, studies have been conducted on the humanized monoclonal antibody eculizumab (Alexion Pharmaceuticals, Soliris, Cheshire, Connecticut, USA), which is directed against human C5 (Thomas et al 1996). In 2004, a pilot study using 11 patients with PNH was conducted in which the patients received infusions of eculizumab over Biologics:Targets & Therapy 2008:2(4) a period of 12 weeks (Hillmen et al 2004). In this small study, mean lactate dehydrogenase (LDH) levels decreased signiﬁcantly over the course of the study; the percentage of PNH erythrocytes increased signiﬁcantly; transfusion rates declined; and the occurrence of hemoglobinuria subsided dramatically. All of the patients from this study chose to participate in a 52-week extension of the study, in which they received eculizumab infusions every 12–14 days (Hill et al 2005a). The ﬁndings from the initial pilot study all held up during the follow-up study, with the addition of quality-of- life measurements being signiﬁcantly improved. It was also shown through this study that long-term eculizumab therapy is safe and well tolerated. In a study of two patients treated with eculizumab, intravascular hemolysis decreased, and symptoms associated with smooth muscle dystonia, such as abdominal pain, dysphagia, and erectile dysfunction, were also signiﬁcantly reduced (Hill et al 2005b). All of this work provided the impetus for a future study involving larger numbers of patients in a double-blind, randomized, placebo-controlled phase III trial, termed the Transfusion Reduction Efﬁcacy and Safety Clinical Investi- gation, a Randomized, Multicenter, Double-Blind, Placebo- Controlled, Using Eculizumab in Paroxysmal Nocturnal Hemoglobinuria (TRIUMPH) study (Hillmen et al 2006). Eighty-seven patients were given either 600 mg eculizumab or placebo on a weekly basis for 4 weeks, then a 900 mg dose one week later, then 900 mg every other week up to 26 weeks. The primary end points were the hemoglobin level and how many units of blood the patients needed during 675