C5 Complement Inhibitor Research Articles

Low efficacy of vaccination against serogroup B meningococci in patients with atypical hemolytic uremic syndrome.

Background: The C5 complement inhibitor eculizumab is first-line treatment in atypical hemolytic uremic syndrome (aHUS) going along with a highly increased risk of meningococcal infections. Serogroup B meningococci (MenB) are the most frequently encountered cause for meningococcal infections in Europe. Efficacy of the protein-based MenB-vaccine Bexsero in aHUS has not been determined and testing is only possible in patients off-treatment with eculizumab as a human complement source is required.Methods: Patients with aHUS were vaccinated with two doses of the protein-based MenB-vaccine Bexsero. Serum bactericidal antibody (SBA) titers against factor H binding protein (fHbp) of MenB were determined in 14 patients with aHUS off-treatment with eculizumab.Results: Only 50% of patients showed protective human serum bactericidal antibody (hSBA) titers (≥1:4) against MenB following two vaccinations. Bactericidal antibody titers were relatively low (≤1:8) in three of seven patients with protective titers. While 71% of patients were on immunosuppressive treatment for either thrombotic microangiopathy or renal transplantation at either first or second vaccination, all four patients not receiving any immunosuppressive treatment showed protective bactericidal antibody response. Time between second vaccination and titer measurement was not significantly different between patients with protective titers compared with those with non-protective titers, while time between first and second vaccination was significantly longer in patients with protective titers going along with a tendency for reduction in immunosuppressive treatment.Conclusions: Efficacy of vaccination against MenB is insufficient in patients with aHUS. Response to vaccination seems to be hampered by immunosuppression. Therefore, implementation of adequate antibiotic prophylaxis seems pivotal.

Breakthrough Hemolysis in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with Ravulizumab: Results of a 52-Week Extension from Two Phase 3 Studies

Breakthrough Hemolysis in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with Ravulizumab: Results of a 52-Week Extension from Two Phase 3 Studies

One-Year Efficacy and Safety from a Phase 3 Trial of Ravulizumab in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria Receiving Prior Eculizumab Treatment

One-Year Efficacy and Safety from a Phase 3 Trial of Ravulizumab in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria Receiving Prior Eculizumab Treatment

S864 A PHASE 2 OPEN-LABEL PROOF OF CONCEPT STUDY OF THE ORAL, SMALL MOLECULE FACTOR D INHIBITOR, ACH-4471, IN UNTREATED PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)

Background: Ravulizumab, a novel C5 complement inhibitor, was approved by FDA for treating paroxysmal nocturnal hemoglobinuria (PNH) and is under review in EMEA and Japan. In the largest phase 3 study in complement inhibitor-naive PNH patients (pts) conducted to date, qw8 ravulizumab was noninferior to qw2 eculizumab for all primary and secondary endpoints after 26 wks. To evaluate long-term efficacy and safety, all pts had the option of continuing to receive ravulizumab in an extension study. Aims: To characterize the durability of efficacy responses to ravulizumab through 52 wks and to evaluate the efficacy profile of ravulizumab after switching from eculizumab in adult PNH pts naive to eculizumab therapy (NCT02946463). Methods: This phase 3, randomized, active-controlled, open-label study was conducted in 123 centers in 25 countries. Pts were randomly assigned to receive eculizumab (n = 121) or ravulizumab (n = 125) for 26 wks, after which pts in the ravulizumab arm continued ravulizumab maintenance therapy (R-R arm), while pts in the eculizumab arm were then switched to ravulizumab (E-R arm). Results of the co-primary [lactate dehydrogenase normalization (LDH-N), transfusion avoidance] and key secondary endpoints [breakthrough hemolysis (BTH) and LDH levels] are provided descriptively. Plasma free C5 levels were obtained through 52 wks. Results: During the first 26 wks, 74% of pts in the R-R arm avoided transfusion, compared to 77% avoiding transfusion in wks 27–52. More than 90% (n = 83) of pts who avoided transfusion during the initial 26 wk period maintained this response through 52 wks, and 38% (n = 12) who required transfusion in the 0–26 wk period avoided it in wks 27–52. In the E-R arm, 66% (26 wks) vs 67% (52 wks) avoided transfusion; 87% (n = 69) who avoided transfusion for 26 wks maintained this response through 52 wks. Additionally, 28% (n = 11) who required transfusion during the 26 wks while on eculizumab avoided it through 52 wks once switched to ravulizumab. In the R-R arm, LDH-N occurred in 48% of pts (n = 60) at 26 wks and in 44% of pts (n = 54) at 52 wks. Similarly, in the E-R arm, at 26 wks, LDH-N was 42%, and was 40% at 52 wks. At the end of 26 wks, pts on ravulizumab had a 77% (SEM = 1.4) mean reduction in LDH from baseline and this was maintained through 52 wks (77%, SEM = 1.2). All pts (n = 119) in the ravulizumab treatment group continued to maintain free C5 <0.5 μg/mL at all time points through 52 wks (Figure). In pts initially randomized to eculizumab, the switch to ravulizumab showed improved free C5 control, and no patients had free C5 >0.5 μg/ml after the switch. Of the 125 pts initially on ravulizumab, 5 pts (4%) had BTH in the first 26 wks vs 4 pts (3%) during wks 27–52. In the E-R arm, 13 pts (11%) experienced BTH during the first 26 wks vs 2 pts (2%) in wks 27–52 after the switch to ravulizumab. During wks 27–52, none of the BTH events in both arms were associated with free C5 >0.5 μg/ml, the threshold associated with complete inhibition of hemolysis. These results demonstrate maintenance of complete free C5 control in pts receiving ravulizumab. Ravulizumab was well tolerated and the most common treatment-related adverse events decreased in frequency with increased treatment duration.Summary/Conclusion: Ravulizumab demonstrated consistent and durable efficacy over 52 wks of treatment. Importantly, all pts who had suboptimal free C5 control receiving eculizumab achieved complete free C5 inhibition after the switch to ravulizumab. Complete suppression of free C5 level was associated with a decreased incidence of BTH.

Diagnosis and management of PNH: Review and recommendations from a Belgian expert panel.

Despite its considerable morbidity and mortality, paroxysmal nocturnal haemoglobinuria (PNH) is still underdiagnosed. Patients with PNH can suffer from cardiovascular, gastrointestinal, neurological or haematological symptoms and refer to several specialists. The aim of this paper is to review the diagnosis and the management of PNH patients, with the primary focus on identifying high-risk groups. Additionally, the implementation and prognostic value of the defined high-risk groups will be commented on and the management of PNH patients is discussed from a Belgian perspective. Finally, based on the available data, recommendations are provided. Eculizumab is a potent C5 complement inhibitor and reduces intravascular haemolysis and thrombosis in PNH patients and improves their quality of life. As thrombosis is the main cause of death in PNH patients, identifying high-risk PNH patients in need of therapy is essential. Currently, novel complement inhibitors are in development and the first data seem promising. Another challenge in PNH is to identify new markers to assess the thrombotic risk to achieve a better risk-based prophylactic anti-thrombotic management. Finally, because of the low prevalence of the disease, PNH patients should be included in the prospective PNH registry, which will offer new insights on the natural course of the disease and the impact of treatment of PNH.

Failure of first meningococcal vaccination in patients with atypical haemolytic uraemic syndrome treated with eculizumab

The C5 complement inhibitor eculizumab is a first-line treatment in atypical haemolytic uraemic syndrome (aHUS). Therapy with eculizumab is associated with a highly increased risk for meningococcal infection. Therefore, vaccination is highly recommended before beginning treatment. Efficacy of quadrivalent meningococcal vaccines (MenACWY) in patients treated with the C5 complement inhibitor eculizumab in aHUS has not yet been determined. Patients with aHUS received one dose of a MenACWY conjugate vaccine before eculizumab treatment commenced. Bactericidal titres against meningococcal serogroups A, C, W and Y were determined using baby rabbit complement in 25 patients. Full immune response to meningococcal vaccination was detected in five patients (20%), while seven patients (28%) showed no immune response in any of the tested serogroups. The remaining 13 patients showed incomplete immune response with proof of protective antibody titres for one to three serogroups without perceptible preference for any serogroup. Bactericidal titres after re-vaccination were available for 17 patients. Nine patients with incomplete immune response after first vaccinations showed protective antibody titres for all serogroups after re-vaccination. Kidney function had improved in >50% of patients at the time of re-vaccination compared with the time of first vaccination and immunosuppressive therapy was only applied to re-vaccinated patients following kidney transplantation. Immunogenicity of first quadrivalent meninongococcal vaccination is insufficient in patients with aHUS. Booster response is promising, but incomplete. Therefore, establishing antibiotic prophylaxes seems pivotal.

Treating C3 glomerulopathy with eculizumab

BackgroundC3 glomerulopathy (C3G) is a rare, but severe glomerular disease with grim prognosis. The complex pathogenesis is just unfolding, and involves acquired as well as inherited dysregulation of the alternative pathway of the complement cascade. Currently, there is no established therapy. Treatment with the C5 complement inhibitor eculizumab may be a therapeutic option. However, due to rarity of the disease, parameters predicting treatment response remain largely unknown.MethodsSeven patients with C3G (five with C3 glomerulonephritis and two with dense deposit disease) were treated with eculizumab. Subjects underwent biopsy before enrollment. The histopathology, clinical data, and response to eculizumab treatment were analyzed. The key parameters to determine outcome were changes of serum creatinine and urinary protein over time.ResultsAfter treatment with eculizumab, four subjects showed significantly improved or stable renal function and urinary protein. A positive response occurred between 2 weeks and 6 months after therapy initiation. One subject (with allograft recurrent C3 glomerulonephritis) initially showed a positive response, but relapsed when eculizumab was discontinued, and did not respond after re-initiation of treatment. Two subjects showed impaired renal function and increasing urinary protein despite therapy with eculizumab.ConclusionsEculizumab may be a therapeutic option for a subset of C3G patients. The response to eculizumab is heterogeneous, and early as well as continuous treatment may be necessary to prevent disease progression. These findings emphasize the need for studies identifying genetic and functional complement abnormalities that may help to guide eculizumab treatment and predict response.

Targeted Delivery of Neutralizing Anti-C5 Antibody to Renal Endothelium Prevents Complement-Dependent Tissue Damage.

Complement activation is largely implicated in the pathogenesis of several clinical conditions and its therapeutic neutralization has proven effective in preventing tissue and organ damage. A problem that still needs to be solved in the therapeutic control of complement-mediated diseases is how to avoid side effects associated with chronic neutralization of the complement system, in particular, the increased risk of infections. We addressed this issue developing a strategy based on the preferential delivery of a C5 complement inhibitor to the organ involved in the pathologic process. To this end, we generated Ergidina, a neutralizing recombinant anti-C5 human antibody coupled with a cyclic-RGD peptide, with a distinctive homing property for ischemic endothelial cells and effective in controlling tissue damage in a rat model of renal ischemia/reperfusion injury (IRI). As a result of its preferential localization on renal endothelium, the molecule induced complete inhibition of complement activation at tissue level, and local protection from complement-mediated tissue damage without affecting circulating C5. The ex vivo binding of Ergidina to surgically removed kidney exposed to cold ischemia supports its therapeutic use to prevent posttransplant IRI leading to delay of graft function. Moreover, the finding that the ex vivo binding of Ergidina was not restricted to the kidney, but was also seen on ischemic heart, suggests that this RGD-targeted anti-C5 antibody may represent a useful tool to treat organs prior to transplantation. Based on this evidence, we propose preliminary data showing that Ergidina is a novel targeted drug to prevent complement activation on the endothelium of ischemic kidney.

Management of pregnancy and delivery in patients with paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hemolytic anemia, which generally affects women of childbearing age. PNH hemolysis increases the risk of complications such as thrombosis during pregnancy and the postpartum period. Management of a pregnant woman with PNH remains a challenge due to the high incidence of thrombotic complications and the difficulty of differentiating a PNH crisis from the complications of pregnancy. PNH is associated with an increased rate of premature labor and fetal loss. Eculizumab, a C5 complement inhibitor, is a potential therapeutic option for such patients. This review presents the current strategies for the management of pregnant women with PNH, the cases experienced in our hospital, and the recently proposed remedy guide regarding the management of pregnancy in cases with PNH by the Pregnancy Working Group of The Japan PNH Interest group.

Eculizumab in Typical Hemolytic Uremic Syndrome (HUS) With Neurological Involvement

In typical hemolytic uremic syndrome (HUS) approximately 25% of patients show central nervous system (CNS) involvement often leading to serious long-term disabilities. We used the C5-complement inhibitor Eculizumab as rescue therapy.From 2011 to 2014, 11 children (median age 22 months, range 11–175) with enterohemorrhagic Escherichia coli-positive HUS requiring dialysis who had seizures (11/11) and/or were in a stupor or coma (10/11) were treated with Eculizumab. Two patients enrolled on the Safety and Efficacy Study of Eculizumab in Shiga-Toxin Producing E coli Hemolytic-Uremic Syndrome (STEC-HUS) each received 6 doses of Eculizumab, 3 patients 2 doses, and 6 patients 1 dose. Laboratory diagnostics of blood samples and magnetic resonance imaging (MRI) were performed as per center practice. Data were analyzed retrospectively.Cranial MRI was abnormal in 8 of 10 patients with findings in the basal ganglia and/or white matter. A 2-year-old boy with severe cardiac involvement and status epilepticus needed repeated cardio-pulmonary resuscitation and extracorporeal membrane oxygenation. He died 8 days after start of Eculizumab treatment. Two patients with hemorrhagic colitis and repeated seizures required artificial ventilation for 6 and 16 days, respectively. At the time of discharge, 1 patient showed severe neurological impairment and 1 mild neurological impairment. The 8 surviving patients experienced no further seizures after the first dose of Eculizumab. Three patients showed mild neurological impairment at discharge, whilst the remaining 5 showed no impairment. The platelets normalized 4 days (median) after the first dose of Eculizumab (range 0–20 days). The mean duration of dialysis after the first dose of Eculizumab was 14.1 ± 6.1 days.In children with typical HUS and CNS involvement early use of Eculizumab appears to improve neurological outcome. In severe HUS cases which progress rapidly with multiple organ involvement, late treatment with Eculizumab seems to show less benefit. We speculate that prophylactic Eculizumab therapy before development of neurological symptoms could be advantageous.

A Novel C5 Complement Inhibitor Protects Against Sepsis-Induced Activation of Complement, Coagulation and Inflammation and Provides Survival Benefit in E. coli Sepsis

Bacterial sepsis triggers robust early activation of the complement system that leads to the formation of the C5b-9 terminal complex (TCC) and potent proinflammatory anaphylatoxins, C3a and C5a, which significantly contribute to organ failure and death. Complement inhibition at C3 level provides organ protection in low bacteremia experimental sepsis but may impair the clearance of the bacteria. Here we used a baboon model of E. coli sepsis and in vitro whole-blood assays to test the protective effects of a novel C5 inhibitor (RA101295, a 2036 Da cyclic peptide). In vitro whole blood assays were performed to study the effects of RA101295 on sepsis-induced complement activation, inflammation, oxidative stress and phagocytosis of the bacteria. Lepirudin-anticoagulated blood was incubated with 5x107 cfu/ml E. coli or 500 µg/ml lipopolysaccharide (LPS) for 30-240 min in the presence/absence of the inhibitor. Results showed that RA101295 strongly inhibited E. coli and LPS–dependent C5b-9 and C5a generation. Similarly, RA101295 inhibited the E. coliand LPS induced oxidative burst in neutrophils and monocytes by 40-50% with minimal decrease (<15%) on their phagocytic function.Next, we used a baboon model of E. coli sepsis to investigate the in vivo effects of RA101295. E. coli challenge (1-2x1010 cfu/kg; LD100) in baboons strongly induced the generation of soluble C5b-9 complexes. Treatment with RA101295 C5 inhibitor (four subcutaneous 10 mg/kg doses at 8-12 hrs intervals) fully inhibited complement activation. RA101295 inhibitor remarkably improved the clinical parameters of all treated animals. Two of three baboons survived the lethal dose; while the survival time of the third animal was increased by 300%. Animals treated with complement inhibitor displayed better heart and lung performance and had lower febrile response than non-treated septic baboons.RA101295 treatment of E. coli sepsis led to significantly lower consumptive coagulopathy as reflected by the APTT/PT, fibrinogen consumption and fibrin/fibrinogen degradation products. These data highlight the tight crosstalk between the coagulation and complement systems and suggest that the observed protective effects are due in part to dampening of sepsis-induced coagulopathy. The treatment during the bacteremic stage had no negative effects on bacterial clearance. Similar to the in vitro data, these results suggest that C5 inhibition with this peptide does not increase the risk of secondary infections and reoccurrence of sepsis, probably because is not interfering with the generation of C3b opsonin. Histologic analysis of organs confirmed that treatment with RA101295 provided substantial organ protection. In contrast to the non-treated group, RA101295 treated animals showed no obvious signs of thrombosis and capillary leak in the lungs; no follicular necrosis in the spleen and no tubular necrosis and glomerular thrombosis in the kidneys.Overall, our data demonstrate that RA101295 strongly inhibits LPS and E. coli induced complement activation and TCC without affecting the bacterial clearance. These results suggest that complement inhibition at C5 level represents a promising therapeutic target in the fight against sepsis-induced MOF. DisclosuresKeshari:Oklahoma Medical Research Foundation: Employment. Silasi-Mansat:Oklahoma Medical Research Foundation: Employment. Popescu:Oklahoma Medical Research Foundation: Employment. Chaaban:Oklahoma University Health Sciences Center: Employment. Lupu:Oklahoma Medical Research Foundation: Employment. DeMarco:Ra Pharmaceuticals: Employment. Lupu:American Heart Association: Membership on an entity’s Board of Directors or advisory committees; Merck: Research Funding; NIH: Research Funding; Oklahoma Medical Research Foundation: Employment.

Management Of Pregnancy In Paroxysmal Nocturnal Hemoglobinuria (PNH): A Report Of 10 Cases From The Working Group On Pregnancy Of The Japan PNH Study Group

BackgroundParoxysmal nocturnal hemoglobinuria (PNH) often affects young adults, including women of childbearing age. Because PNH hemolysis increases the risk of complications such as thrombosis during pregnancy and the postpartum period, proper management should be provided for pregnant patients with PNH. Eculizumab, a C5 complement inhibitor, could be a therapeutic option for such patients. Aim/methodsJapan PNH Study Group aimed to survey the current status of management of pregnant PNH patients and to propose a consensus recommendation for such a challenging situation in the treatment of PNH. Clinical data were collected from 10 pregnant PNH patients from 7 institutes and analyzed. We had consensus meetings 5 times since January 2012. ResultsSummary of patients' characteristics are shown in Table. Age of the patients at the time of conception ranged from 29 to 40 years old (median 30). Plasma levels of LDH at the baseline assessment were 200-2300 IU/L (median 1900). PNH clone sizes in granulocytes were 1.6-96.0% (median 81). Prophylactic anticoagulation with heparin was employed in all patients except one who showed little hemolysis due to a small size of PNH clone. Four patients received eculizumab during pregnancy with favorable efficacy. Complications including preeclampsia, hemolytic episodes and deep venous thrombosis were manageable. Newborn babies were all healthy. A negligible amount of eculizumab was detected in cord blood of three babies.TableSummary of patients' characteristicsUPNAge (Yrs)Delivery methodEculizumab useComplicationOutcome of babyAnti-coagulationA-134VaginalAll periodBreakthrough hemolysisHealthyUFHB-129VaginalFrom 19 wksNoHealthyUFHC-130C-sectionFrom 27 wksPreeclampsiaPremature, but healthyLWMHD-137C-sectionAll periodNoHealthyLWMHE-130VaginalNoNoHealthyNoE-2-130VaginalNoNoHealthyUFHE-2-234VaginalNoNoHealthyUFHF-130C-sectionNoHemolytic attackHealthyLWMHF-241C-sectionNoDVTHealthyUFHG-130C-sectionNoNoHealthyUFH DiscussionRecently successful pregnancy outcomes have been reported in patients with PNH on eculizumab therapy during pregnancy, and we also experienced additional 4 cases. As eculizumab inhibits intravascular hemolysis itself, it can be expected to lower the risk of complications during pregnancy and postpartum period in women with PNH. Eculizumab is a hybrid of IgG4 and IgG2, and the latter is known to be less prone to cross the placenta. In fact eculizumab concentrations in the cord blood was much lower than therapeutic levels. Importance of anticoagulation therapy has been emphasized for the management of pregnancy with PNH. Theoretically, if intravascular hemolysis is completely inhibited by eculizumab, the risk of thromboembolic complication would become as low as that in non-PNH pregnancies. It is not clear whether the use of anticoagulant is mandatory for the pregnant patients who are receiving eculizumab, although the use of anticoagulant should not be hesitated. ConclusionEculizumab could be safely and effectively used in pregnant patients with PNH. Taking these findings into account, we propose the following protocol for the management of a pregnancy with PNH, as shown in Figure. [Display omitted] The patients are classified into 4 categories based on eculizumab use and the history of venous thromboembolisms or anticoagulant use. Disclosures:Usuki:Alexion Pharmaceuticals: Speakers Bureau. Urabe:Alexion Pharmaceuticals: Speakers Bureau. Kawaguchi:Alexion Pharmaceuticals: Honoraria. Miura:Alexion Pharmaceuticals: Research Funding. Morita:Alexion Pharmaceuticals: Research Funding. Nishiwaki:Alexion Pharmaceuticals: Research Funding. Ninomiya:Alexion Pharmaceuticals: Honoraria. Gotoh:Alexion Pharmaceuticals: Honoraria. Shichishima:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nishimura:Alexion Pharma: Research Funding, Speakers Bureau. Kanakura:Alexion Pharmaceuticals: Research Funding, Speakers Bureau.

Effects of C5 complement inhibitor pexelizumab on outcome in high-risk coronary artery bypass grafting: Combined results from the PRIMO-CABG I and II trials

The previous Pexelizumab for Reduction of Infarction and Mortality in Coronary Artery Bypass Graft Surgery I (PRIMO-CABG I) trial (n = 3099) indicated that C5 complement inhibition with pexelizumab might reduce myocardial infarction (MI) and postoperative mortality. PRIMO-CABG II was designed to investigate the safety and efficacy of terminal complement inhibition in reducing perioperative MI and mortality in patients undergoing CABG surgery who have 2 or more predefined preoperative risk factors. PRIMO-CABG II, a randomized, double-blind, placebo-controlled trial, enrolled 4254 patients undergoing CABG with or without valve surgery at 249 hospitals in North America and Western Europe from June 2004 to July 2005. The patients were randomly assigned to receive intravenous pexelizumab or placebo. The primary composite endpoint was the incidence of death or MI within 30 days of randomization. The PRIMO-CABG II trial did not meet its prespecified primary endpoint of death or MI at 30 days, the secondary endpoints of death at 30 days, or the development of new or worsening congestive heart failure (relative risk 0.91, 0.82, and 1.01, respectively; P > .05). However, in a combined analysis of both pivotal trials, PRIMO-CABG I and II (n = 7353), death at 30 days was significantly reduced for the greatest risk subset (n = 2156, pexelizumab 5.7% vs placebo 8.1%, P = .024). Furthermore, this mortality reduction persisted throughout the 180-day follow-up period (pexelizumab 11.1% vs placebo 14.4%, P = .036). Pexelizumab was associated with a nonsignificant 6.7% reduction in the primary composite endpoint of death or MI at postoperative day 30 in CABG patients enrolled in the PRIMO-CABG II trial, despite the suggestion of a more favorable treatment effect in the previous PRIMO-CABG I trial. However, an exploratory analysis of the combined PRIMO I and II data set using an established predictive risk model showed a mortality benefit for high-risk surgical patients.

Novel complement inhibitor limits severity of experimentally myasthenia gravis

Complement mediated injury of the neuromuscular junction is considered a primary disease mechanism in human myasthenia gravis and animal models of experimentally acquired myasthenia gravis (EAMG). We utilized active and passive models of EAMG to investigate the efficacy of a novel C5 complement inhibitor rEV576, recombinantly produced protein derived from tick saliva, in moderating disease severity. Standardized disease severity assessment, serum complement hemolytic activity, serum cytotoxicity, acetylcholine receptor (AChR) antibody concentration, IgG subclassification, and C9 deposition at the neuromuscular junction were used to assess the effect of complement inhibition on EAMG induced by administration of AChR antibody or immunization with purified AChR. Administration of rEV576 in passive transfer EAMG limited disease severity as evidenced by 100% survival rate and a low disease severity score. In active EAMG, rats with severe and mild EAMG were protected from worsening of disease and had limited weight loss. Serum complement activity (CH(50)) in severe and mild EAMG was reduced to undetectable levels during treatment, and C9 deposition at the neuromuscular junction was reduced. Treatment with rEV576 resulted in reduction of toxicity of serum from severe and mild EAMG rats. Levels of total AChR IgG, and IgG(2a) antibodies were similar, but unexpectedly, the concentration of complement fixing IgG(1) antibodies was lower in a group of rEV576-treated animals, suggesting an effect of rEV576 on cellular immunity. Inhibition of complement significantly reduced weakness in two models of EAMG. C5 inhibition could prove to be of significant therapeutic value in human myasthenia gravis.

C5 complement inhibition contributes to increased proliferative activity and antigen specific recall response in experimentally acquired myasthenia gravis (EAMG)

Background: Myasthenia gravis (MG) is an autoimmune disorder caused by the production of autoantibodies against the acethylcholine receptor (AChR). Antibodies bind to the AChR and activate the complement system leading to the destruction of neuromuscular junction (NMJ). Experimentally acquired MG (EAMG) rats were used to investigate the therapeutic role of C5 complement inhibitor, rEV576.Methods: Severity of disease was measured by grip strength and weight loss of the animal; serum cytokines and toxicity; cells proliferative activity and antigen specific recall responses were analyzed in vitro.Results: Treatment with C5 complement inhibitor for 10 days attenuated the outcome of EAMG. Administration of rEV576 resulted in reduction of serum toxicity and increased IFN‐γ production. Splenic cell suspensions isolated from EAMG + rEV576 had higher proliferation ability in the presence of specific antigen (AChR) or mitogen (Con A). ELISPOT recall responses to the specific AChR showed that the frequency of splenic T‐cells secreting IFN‐γ is increased in rEV576 treated EAMG rats.Conclusions: Inhibition of complement activity attenuated the outcome of EAMG. EAMG rats treated with rEV576 showed increased cell activity suggesting an effect of complement deficiency on cellular immunity. The data demonstrate that complement inhibition may have significant therapeutic value in human MG.

Pexelizumab Reduces Death and Myocardial Infarction in Higher Risk Cardiac Surgical Patients

Morbidity and mortality after coronary artery bypass graft surgery are directly related to specific preoperative risk factors. We assessed the influence of preoperative risk factors on the effect of pexelizumab, a C5 complement inhibitor, to reduce postoperative morbidity and mortality in this post hoc analysis of the Pexelizumab for Reduction in Myocardial Infarction and MOrtality in Coronary Artery Bypass Graft surgery (PRIMO-CABG) trial, a phase III double-blind, placebo-controlled study of 3,099 patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. The composite endpoint of death or myocardial infarction or both through postoperative day 30 was examined in subpopulations of patients with pre-specified risk factors, which included diabetes mellitus, prior coronary artery bypass graft, urgent intervention, female sex, history of neurologic event, history of congestive heart failure, and two or more previous myocardial infarctions or a recent myocardial infarction. Stratified post hoc analyses were also performed on patients presenting with two or more and three or more of those risk factors. Pexelizumab significantly reduced the incidence of the composite endpoint of death or myocardial infarction through postoperative day 30 by 28% in patients with two or more risk factors (p = 0.004) and 44% in patients with three or more risk factors (p < 0.001). The C5 complement inhibitor, pexelizumab, reduced morbidity and mortality among high-risk patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.

Effect of pexelizumab on mortality in patients with acute myocardial infarction or undergoing coronary artery bypass surgery: A systematic overview

Recent trials evaluating the C5 complement inhibitor, pexelizumab, have shown that modulation of inflammation during ischemia/reperfusion in patients with acute myocardial infarction (MI) or undergoing coronary artery bypass graft (CABG) surgery may improve clinical outcomes. We performed a systematic overview of individual patient data from all completed randomized controlled trials of pexelizumab to evaluate the effect on all-cause mortality at 30 and 180 days after treatment. We used a random effects model and included all 5916 patients randomized in 4 clinical trials. Patients received placebo, pexelizumab bolus only or pexelizumab bolus followed by a 24-hour infusion. A significant reduction in mortality at 30 days was observed in patients treated with bolus plus infusion (n = 2476) compared with placebo (n = 2492) (2.9% vs 4.2%; relative risk [RR], 0.70; 95% confidence interval [CI], 0.52-0.95; P = .02), with no interaction according to disease state of CABG or acute MI (P for interaction .33). A trend toward a reduction in mortality was observed in patients who received bolus plus infusion or bolus only (n = 3429) compared with placebo (n = 2476) (3.5% vs 4.2%; RR, 0.85; 95% CI, 0.66-1.0975; P = .215), but not in patients who received bolus only (n = 937) compared with placebo (n = 937) (5.2% vs 5.4%; RR, 0.96; 95% CI, 0.66-1.41; P = .918). The mortality benefit with bolus plus infusion compared with placebo persisted through 180 days (P = .05). Pexelizumab reduced 30-day mortality in this systematic evaluation. Bolus plus infusion dose is being studied in ongoing trials in acute MI and CABG populations.

Inhibition of complement activation by pexelizumab reduces death in patients undergoing combined aortic valve replacement and coronary artery bypass surgery

We sought to evaluate the effects of pexelizumab, a C5 complement inhibitor, on death and myocardial infarction in patients undergoing combined aortic valve replacement and coronary artery bypass grafting surgery. The Pexelizumab for Reduction in Myocardial Infarction and Mortality in Coronary Artery Bypass Graft surgery trial, a phase III prospective, randomized, double-blind, placebo-controlled study, enrolled 3099 patients at 205 centers. The primary end point was the composite of death, myocardial infarction, or both at postoperative day 30 in patients undergoing coronary artery bypass grafting without valve surgery. Postoperative myocardial infarction was defined as a creatine kinase MB fraction value of 100 ng/mL or greater, Q-wave myocardial infarction with a creatine kinase MB fraction value of 70 ng/mL or greater, or new Q-wave evidence of myocardial infarction by postoperative day 30. Because patients undergoing coronary artery bypass grafting with a valve procedure were not included in the primary population, separate analysis of death and myocardial infarction was conducted in 218 patients undergoing combined aortic valve replacement and coronary artery bypass grafting surgery. Of the 353 patients randomized to any valve procedure, 106 (61%) underwent combined aortic valve replacement and coronary artery bypass grafting in the pexelizumab treatment group compared with 112 (63%) patients in the placebo group. Coronary artery bypass grafting was performed with 1 or more internal thoracic artery grafts in 139 (64%) patients and with 1 or more saphenous vein grafts in 179 (82%) patients. There were 4 (3.8%) deaths in the pexelizumab group versus 11 (9.9%) in the placebo group by postoperative day 30 and 6 (5.7%) deaths in the active group versus 16 (14.4%) in the placebo group by postoperative day 180 (P =.107 and P =.043, respectively, Fisher exact test). The incidence of myocardial infarction 30 days after surgical intervention was identical in the 2 groups, but the study was not designed to detect differences in this cohort of patients. Inhibition of complement activation by pexelizumab resulted in a decreased mortality at 180 days among 218 patients who underwent combined aortic valve replacement and coronary artery bypass grafting surgery. Additional studies are warranted to confirm this decrease in mortality with pexelizumab in combined aortic valve replacement and coronary artery bypass grafting procedures.

C5 complement inhibition attenuates shock and acute lung injury in an experimental model of ruptured abdominal aortic aneurysm

Ruptured abdominal aortic aneurysm (RAAA) is associated with a systemic inflammatory response syndrome and multiple organ dysfunction. The potential role of a novel C5 complement inhibitor in attenuation of pathological complement activation and tissue injury was explored in a model of RAAA. Anaesthetized rats were randomized to sham (control) or shock and clamp (SC) groups. Animals in the SC group underwent 1 h of haemorrhagic shock (mean arterial pressure 50 mmHg or less), 45 min of supramesenteric aortic clamping and 2 h of reperfusion. They were randomized to receive an intravenous bolus of a functionally blocking anti-C5 monoclonal antibody (C5 inhibitor), at a dose of 20 mg/kg, or saline. Lung injury was assessed by permeability to 125I-labelled albumin, tissue myeloperoxidase (MPO) activity, and semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) for mRNAs encoding tumour necrosis factor (TNF) alpha and interleukin (IL) 6. The lung permeability index was significantly increased in the SC compared with the sham group (P = 0.032); this was prevented by the C5 inhibitor (P = 0.015). Lung MPO activity was significantly increased in the SC compared with the sham group (P < 0.001), and this increase was attenuated by treatment with the C5 inhibitor (P < 0.001). Semiquantitative RT-PCR in SC group demonstrated downregulation of TNF-alpha mRNA (P = 0.050) and upregulation of IL-6 mRNA (P < 0.001), which were both prevented by the C5 inhibitor (P = 0.014 and P < 0.001 respectively). These results indicated that C5 complement inhibition can reduce shock and acute lung injury in an experimental model of RAAA.

Pexelizumab – a C5 complement inhibitor for use in both acute myocardial infarction and cardiac surgery with cardiopulmonary bypass

Myocardial injury and dysfunction in acute infarction and during cardiac surgery with cardiopulmonary bypass (CPB) are associated with an undesirable systemic inflammatory response, in which the complement cascade plays a major role. In animal models C5 inhibition has been found to significantly reduce myocardial infarct size and decrease cellular necrosis and apoptosis. Pexelizumab (Alexion Pharmaceuticals, Inc., Cheshire, CT, USA) is a humanised, monoclonal, single-chain antibody fragment that inhibits C5, thereby blocking its cleavage into active forms. Prospective, randomised, double-blind, placebo-controlled trials using pexelizumab during percutaneous coronary intervention following acute myocardial infarction (AMI), or in patients undergoing coronary artery bypass graft (CABG) with CPB, have demonstrated a reduction in morbidity and mortality. Thus, pexelizumab represents a promising therapeutic option with sustained benefit both in AMI and during CABG with CPB.