This phase II trial was followed up with a larger phase III, randomized, double-blind, placebo-controlled, multicenter study of 3099 patients undergoing nonemergent CABG surgery with or without valve surgery (Verrier et al 2004). In this study, termed the Pexelizumab for Reduction in Infarction and MOrtality in Coronary Artery Bypass Graft surgery (PRIMO-CABG) trial, patients were randomized into two groups, one receiving an intravenous bolus of pexelizumab plus a subsequent 24-hour infusion and the other receiving placebo. The primary endpoint in this trial was the composite of death or MI within 30 days of surgery. This large, extensive study did not show any signiﬁcant difference between the two groups with regard to the incidence of death or MI at 30 days, with the event rate being 9.8% (134/1373) in patients who received pexelizumab and 11.8% (161/1359) in patients who received placebo (p = 0.07). In a substudy of the PRIMO-CABG trial, it was shown that pexelizumab reduced the incidence of death or MI by POD 30 by 28% in patients with two or more risk factors, including DM, prior CABG surgery, urgent intervention, female sex, history of a neurological event, CHF, two or more previous MIs, or a recent MI (Haverich et al 2006). In separate follow-up analysis, a subgroup of patients with aortic cross-clamp times 90 min showed reduced perioperative myocardial injury (Smith et al 2006). Of this speciﬁc subset of patients, those with two or more serious cardiovascular risk factors had a reduced incidence of death or MI through POD 30 and a signiﬁcantly reduced incidence of mortality 180 days after surgery. In one final substudy analysis of patients in the PRIMO-CABG trial, pexelizumab reduced mortality at 180 days in patients who underwent aortic valve replacement (AVR) at the time of CABG surgery (Carrier et al 2006). However, both mortality and the incidence of MI at 30 days were not signiﬁcantly different between those who had an AVR with their CABG surgery and those who did not. In a broad meta-analysis of the four large trials with pexelizumab described above (COMMA, COMPLY, Phase II CABG study, and PRIMO-CABG), using data from 5916 patients who either had an AMI treated with PCI or thrombolytic therapy or who underwent CABG surgery, it was shown that pexelizumab reduced 30-day mortality when given as a bolus followed by subsequent infusion (Mahaffey et al 2006). The angioplasty, thrombolytic, and CABG surgery trials involving anticomplement therapy did not provide as much beneﬁt to patients as had been hoped for. We can only speculate about why the in vitro and animal studies Biologics:Targets & Therapy 2008:2(4) Anticomplement therapy did not translate to successful therapeutic results in human trials; however, advances in the complement science and in understanding of thrombotic disorders will provide the real answers. Future directions In addition to the clinical applications described in the previous section, there are two other main clinical conditions with potential therapeutic roles for complement regulatory proteins. Sepsis There are several studies reporting an increase in complement activation products (C5a, C3a, C5b-9) in animal models of sepsis, as well as in patients with sepsis and multiorgan system failure (Ward 2008). For example, in the setting of experimental sepsis in mice or rats induced by cecal ligation and puncture, there is an upregulation of C5a receptor (C5aR) in solid organs and on the surface of neutrophils (Riedemann et al 2002; Ward 2008). Despite an increase in the concentration of C5a, the normal functions of neutrophils, including chemotaxis, phagocytosis, and oxidative burst, are impaired during sepsis (Huber-Lang et al 2002b). These abnormalities in neutrophil function are probably due to a paralysis of C5a signaling (Ward 2008). Using anti-C5a antibody or anti-C5aR cyclic peptide can reverse neutrophil paralysis and, more importantly, can increase survival in animals with severe sepsis (Huber-Lang et al 2001, 2002a). To date, no trials using anti-C5a antibody or anti-C5aR agents have been performed in patients with sepsis. Age-related macular degeneration Age-related macular degeneration (AMD) is a leading cause of blindness among older individuals in developed countries. In 1998, a genome-wide screening study in a family with AMD identiﬁed the long arm of chromosome 1 (1q25–q31) as the locus for the responsible gene (Klein et al 1998). In 2005, three independent studies using different methods identiﬁed an asso- ciation between a polymorphism in factor H (Tyr402His) and AMD in the general population (Edwards et al 2005; Haines et al 2005; Klein et al 2005). Later on, associations between AMD and additional polymorphisms in the factor H gene, as well as polymorphisms in other complement proteins, were detected (Gold et al 2006; Hughes et al 2006; Li et al 2006; Maller et al 2006; Dinu et al 2007). Functional and anatomical studies conducted on factor H-deficient mice revealed a signiﬁcant reduction in visual acuity and abnormalities in electroretinography of factor H-deﬁcient mice as compared to 681