Resolution of extravascular hemolysis with oral iptacopan monotherapy in a patient with treatment experienced paroxysmal nocturnal hemoglobinuria (PNH).

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematologic disorder characterized by a loss of glycosyl-phosphatidyl-inositol-linked (GPI) proteins on various hematopoietic cells. Some GPI proteins are involved in the regulation of the complement system, and their absence renders erythrocytes susceptible to complement-mediated lysis. Current standard of care in PNH is to block the complement system at the level of C5 using ravulizumab or eculizumab; however, some patients with PNH may develop extravascular hemolysis (EVH) during treatment with C5 inhibitors. The proximal complement inhibitor iptacopan has recently been shown to be efficacious in patients with PNH. This article reports on a 43-year-old female patient with PNH who was successfully treated with iptacopan. The patient had received ravulizumab for several years and developed a clinically relevant EVH. After obtaining informed consent, the patient received oral iptacopan 200 mg twice daily and ravulizumab was discontinued. Over the next few weeks hemoglobin levels and reticulocyte counts normalized. The patient reported mild flushes with erythema, chills, and mild muscle pain, all of which resolved during follow-up. No breakthrough hemolysis occurred, and no severe adverse events were recorded.

Eculizumab treatment in paediatric patients diagnosed with aHUS after haematopoietic stem cell transplantation: a HSCT-TMA case series from Japanese aHUS post-marketing surveillance.

Haematopoietic stem-cell transplantation (HSCT)-associated thrombotic microangiopathy (HSCT-TMA) is a serious complication with high mortality. Accumulating evidence suggests that complement dysregulation is potentially involved in the development of HSCT-TMA. We retrospectively analysed the clinical characteristics and outcomes of thirteen paediatric patients who were diagnosed with atypical haemolytic uremic syndrome and treated with eculizumab to manage HSCT-TMA during post-marketing surveillance in Japan. The median time from HSCT to TMA was 31 days (Interquartile range, IQR;21-58) and the median doses of eculizumab was three (IQR;2-5). Seven patients (54%) were alive at the last follow-up while six died due to complications related to HSCT. Six of seven survivors initiated eculizumab after insufficient response to plasma therapy. Following eculizumab treatment, median platelet counts and LDH levels in all survivors significantly improved and renal function improved in 4/7 patients. All survivors possessed potential risk factors of complement overactivation. During the follow-up period after eculizumab discontinuation (median;111.5 days, IQR;95-555), no TMA recurrence was observed. In this analysis, eculizumab showed benefit in over half of this paediatric patient population. Ongoing clinical studies are expected to optimize the treatment regimen of terminal complement pathway inhibitor, and it may become a therapeutic option for paediatric HSCT-TMA in the future.

Real-world safety profile of eculizumab in patients with paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, or generalized myasthenia gravis: an integrated analysis of post-marketing surveillance in Japan.

Eculizumab is a C5 inhibitor approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and anti-acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR + gMG) in Japan. We report integrated safety data from post-marketing surveillance in these three indications, focusing on commonly occurring adverse events (AEs) and infection-related AEs. Of 1219 patients registered, 1055 (PNH: 780; aHUS: 192; AChR + gMG: 83) had available safety data. Total eculizumab exposure was 3977.361 patient-years. AEs were reported in 74.03% of patients. AEs with an incidence of  ≥ 1.0 per 100 patient-years included hemolysis, headache, nasopharyngitis, renal impairment, anemia, pneumonia, upper respiratory tract inflammation, influenza, condition aggravated, and infection. The incidence of infection-related AEs was 21.30 per 100 patient-years, the most frequent types (≥ 1.0 per 100 patient-years) being nasopharyngitis, pneumonia, influenza, and infection. Meningococcal infections were reported in four patients (0.10 per 100 patient-years). Two patients died from meningococcal sepsis, with a mortality rate of 0.05 per 100 patient-years. This is the largest safety dataset on eculizumab in Japan derived from more than 10 years of clinical experience. No new safety signals were observed and the safety profile of eculizumab was consistent with that in previous clinical trials and international real-world safety analyses.

Ravulizumab pharmacokinetics and pharmacodynamics in patients with generalized myasthenia gravis.

INTRODUCTION: The terminal complement C5 inhibitor ravulizumab has a long elimination half-life, allowing maintenance dosing every 8 weeks. In the 26-week, double-blind, randomized, placebo-controlled period (RCP) of the CHAMPION MG study, ravulizumab provided rapid and sustained efficacy and was well tolerated in adults with anti-acetylcholine receptor antibody-positive (AChR Ab+) generalized myasthenia gravis (gMG). This analysis evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and potential immunogenicity of ravulizumab in adults with AChR Ab+ gMG. METHODS: Data were analyzed from 86 patients who received ravulizumab in the CHAMPION MG RCP. Ravulizumab dosing was weight-based: initial loading dose of 2400/2700/3000 mg on Day 1 and maintenance doses of 3000/3300/3600 mg on Day 15 and then every 8 weeks. PK parameters were estimated from serum ravulizumab concentrations determined pre- and post-dose; PD effects of ravulizumab on serum free C5 concentrations were measured; and immunogenicity was assessed using anti-drug antibody and neutralizing-antibody assays. RESULTS: Target serum ravulizumab concentrations (> 175 µg/mL) were achieved immediately after the first ravulizumab dose (within 30 min of infusion completion) and maintained throughout the 26-week treatment period irrespective of patient body weight. Following the final maintenance dose, mean Cmax was 1548 µg/mL and Ctrough 587 µg/mL; no meaningful differences were noted among body-weight categories. Inhibition of serum free C5 was immediate, complete (< 0.5 µg/mL), and sustained throughout treatment in all patients. No treatment-emergent anti-drug antibodies were observed. CONCLUSIONS: PK/PD evidence supports the use of ravulizumab every 8 weeks for immediate, complete, and sustained inhibition of terminal complement C5 in adults with AChR Ab+ gMG. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03920293 (April 18, 2019).

Eculizumab precision-dosing algorithm for thrombotic microangiopathy in children and young adults undergoing HSCT.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal posttransplant complication of hematopoietic stem cell transplantation. We recently reported that survival for TA-TMA has been improved by early intervention with eculizumab, a complement C5 inhibitor, guided by pharmacokinetic/pharmacodynamic (PK/PD) model-informed precision dosing. However, patients with gastrointestinal bleeding showed poor survival, even when treated with more frequent doses. Our objective was to develop separate models in bleeding and nonbleeding patients with TA-TMA and to propose precision dosing algorithms. Eculizumab PK/PD was analyzed in 19 bleeding and 38 nonbleeding patients (0.5-29.9 years of age). A complement activation biomarker (sC5b-9) and body weight were identified as significant determinants of eculizumab clearance regardless of bleeding. Eculizumab clearance after the first dose was higher in bleeding than in nonbleeding patients (83.8 vs 61.3 mL/h per 70 kg; P = .07). The high clearance was maintained over treatment doses in bleeding patients, whereas nonbleeding patients showed a time-dependent decrease in clearance. sC5b-9 levels were highest before the first dose and decreased over time, regardless of bleeding complications. A Monte Carlo Simulation analysis showed that the current dosing protocols recommended for atypical hemolytic uremic syndrome had <15% probability of attaining the target concentration of >100 µg/mL eculizumab in nonbleeding patients. We identified an intensified loading protocol to reach 80% target attainment. Our data clearly showed the need for individualized dosing for patients with significant bleeding and for ongoing dose adjustments to optimize outcomes. The developed models will be incorporated into a clinical decision guideline for precision dosing to improve outcomes in children and young adults with TA-TMA.

Terminal Complement Inhibitor Ravulizumab in Generalized Myasthenia Gravis.

BACKGROUND: Generalized myasthenia gravis (gMG) is a rare, chronic, and debilitating autoimmune disease. Activation of the complement system by autoantibodies against the postsynaptic acetylcholine receptor (AChR) leads to destruction of the postsynaptic membrane and disruption of neuromuscular transmission. This trial evaluated ravulizumab, a long-acting inhibitor of terminal complement protein C5, as a treatment for gMG. METHODS: In this randomized, double-blind, placebo-controlled, multinational trial, we randomly assigned (1:1) patients with anti-AChR antibody-positive gMG to intravenous ravulizumab or placebo for 26 weeks. Patients received a loading dose on day 1, followed by maintenance doses on day 15 and every 8 weeks thereafter. The primary end point and first secondary end point (change from baseline to week 26 in patient-reported Myasthenia Gravis­Activities of Daily Living [MG-ADL] scale and clinician-reported Quantitative Myasthenia Gravis [QMG] total scores, respectively) were compared between the ravulizumab- and placebo-treated groups. RESULTS: In total, 175 patients were enrolled. Ravulizumab significantly increased the magnitude of mean changes from baseline to week 26 versus placebo in MG-ADL (−3.1 vs. −1.4; P<0.001) and QMG (−2.8 vs. −0.8; P<0.001) total scores. Improvements in both measures occurred within 1 week of ravulizumab initiation and were sustained through week 26. QMG total scores improved by 5 points or more in a significantly greater proportion of ravulizumab-treated patients than of those receiving placebo (30.0% vs. 11.3%; P=0.005). No notable differences in adverse events were observed. CONCLUSIONS: Ravulizumab demonstrated rapid and sustained improvements in both patient- and clinician-reported outcomes and had a side effect and adverse-event profile that did not limit treatment in adults with anti-AChR antibody-positive gMG. (Funded by Alexion, AstraZeneca Rare Disease; ClinicalTrials.gov number, NCT03920293; EudraCT number, 2018-003243-39.)

Efficacy and Safety of Eculizumab for Paroxysmal Nocturnal Hemoglobinuria: A Systematic Review and Meta-Analysis.

BACKGROUND: Eculizumab is indicated for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). This study aimed to evaluate the efficacy and safety of eculizumab in patients with PNH. METHODS: PubMed, EMBASE, The Cochrane Library, and ClinicalTrials.gov were searched for prospective interventional studies treating PNH with eculizumab. The primary outcome was the change in lactate dehydrogenase (LDH) levels, whereas secondary outcomes included the change in hemoglobin (Hb) levels, transfusion rates, and adverse drug events. RESULTS: Patients (n=235) from 6 studies were included in this meta-analysis. LDH and Hb levels and transfusion rates decreased significantly at 12, 26 weeks, 12, 15, and >15 months. The most frequent adverse events included nasopharyngitis (effect size [ES]: 0.53; 95% confidence intervals [CI]: 0.47 to 0.60; P=0.00), headache (ES: 0.47; 95% CI: 0.25 to 0.69; P=0.00), upper respiratory tract infection (ES: 0.37; 95% CI: 0.27 to 0.46; P=0.00), nausea (ES: 0.31; 95% CI: 0.24 to 0.38; P=0.00), fatigue, diarrhea, cough, pyrexia, abdominal pain, pain in extremities, and contusion. CONCLUSION: Eculizumab is an effective and well-tolerated treatment for patients with PNH. It is effective at decreasing LDH levels and transfusion rates while increasing Hb levels. Further studies are needed to explore the safety of eculizumab.

Zilucoplan: An Investigational Complement C5 Inhibitor for the Treatment of Acetylcholine Receptor Autoantibody-Positive Generalized Myasthenia Gravis.

INTRODUCTION: Generalized myasthenia gravis (gMG) is an autoimmune disorder in which pathogenic autoantibodies damage the neuromuscular junction, causing disabling or life-threatening muscle weakness. Most treatments nonspecifically inhibit aspects of the immune system, do not directly address the causal mechanisms of tissue damage, and often have side-effect profiles that negatively impact patients. Understanding of the central pathogenic role of the complement cascade in gMG is advancing, and a new complement-targeting treatment is under investigation. AREAS COVERED: We provide an overview of gMG etiology, the complement cascade, current treatments, and the investigational gMG therapy zilucoplan. Zilucoplan is a small, subcutaneously administered, macrocyclic peptide that inhibits cleavage of complement component C5 and the subsequent formation of the membrane attack complex. EXPERT OPINION: In a randomized, double-blind, placebo-controlled, phase 2 clinical trial, zilucoplan demonstrated clinically meaningful complement inhibition in patients with acetylcholine receptor-positive gMG. Zilucoplan, a first-of-its-kind cyclic peptide targeting C5, appears to be a therapeutic option for the treatment of gMG based on available pharmacokinetic/pharmacodynamic data and phase 1 and 2 efficacy, safety, and tolerability data with limited long-term follow-up. Zilucoplan use earlier in the treatment paradigm would be suitable in this population should phase 3 efficacy and safety data be equally favorable.

Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease characterized by chronic complement-mediated hemolysis. C5 inhibition controls intravascular hemolysis in untreated PNH but cannot address extravascular hemolysis. Pegcetacoplan, a pegylated peptide targeting proximal complement protein C3, potentially inhibits both intravascular and extravascular hemolysis. METHODS: We conducted a phase 3 open-label, controlled trial to assess the efficacy and safety of pegcetacoplan as compared with eculizumab in adults with PNH and hemoglobin levels lower than 10.5 g per deciliter despite eculizumab therapy. After a 4-week run-in phase in which all patients received pegcetacoplan plus eculizumab, we randomly assigned patients to subcutaneous pegcetacoplan monotherapy (41 patients) or intravenous eculizumab (39 patients). The primary end point was the mean change in hemoglobin level from baseline to week 16. Additional clinical and hematologic markers of hemolysis and safety were assessed. RESULTS: Pegcetacoplan was superior to eculizumab with respect to the change in hemoglobin level from baseline to week 16, with an adjusted (least squares) mean difference of 3.84 g per deciliter (P<0.001). A total of 35 patients (85%) receiving pegcetacoplan as compared with 6 patients (15%) receiving eculizumab no longer required transfusions. Noninferiority of pegcetacoplan to eculizumab was shown for the change in absolute reticulocyte count but not for the change in lactate dehydrogenase level. Functional Assessment of Chronic Illness Therapy-Fatigue scores improved from baseline in the pegcetacoplan group. The most common adverse events that occurred during treatment in the pegcetacoplan and eculizumab groups were injection site reactions (37% vs. 3%), diarrhea (22% vs. 3%), breakthrough hemolysis (10% vs. 23%), headache (7% vs. 23%), and fatigue (5% vs. 15%). There were no cases of meningitis in either group. CONCLUSIONS: Pegcetacoplan was superior to eculizumab in improving hemoglobin and clinical and hematologic outcomes in patients with PNH by providing broad hemolysis control, including control of intravascular and extravascular hemolysis. (Funded by Apellis Pharmaceuticals; PEGASUS ClinicalTrials.gov, NCT03500549.).

Characterizing New-Onset Exudation in the Randomized Phase 2 FILLY Trial of Complement Inhibitor Pegcetacoplan for Geographic Atrophy.

OBJECTIVES: To evaluate clinical characteristics of eyes in which investigator-determined new-onset exudative age-related macular degeneration (eAMD) developed during the FILLY trial. DESIGN: Post hoc analysis of the phase 2 study of intravitreal pegcetacoplan in geographic atrophy (GA). SUBJECTS: Patients with GA secondary to age-related macular degeneration (AMD), n = 246. INTERVENTION: Either 15 mg intravitreal pegcetacoplan or sham given monthly or every other month for 12 months followed by a 6-month off-treatment period. MAIN OUTCOME MEASURES: Time of new eAMD onset in the study eye, history of eAMD in the fellow eye, presence of double-layer sign (DLS) on structural OCT in the study eye, changes in retinal anatomic features by structural OCT and fluorescein angiography (FA), and changes in visual acuity. RESULTS: Exudation was reported in 26 study eyes across treatment groups over 18 months. Mean time to eAMD diagnosis was 256 days (range, 31-555 days). Overall, a higher proportion of patients with a baseline history of eAMD in the fellow eye (P = 0.016) and a DLS in the study eye (P = 0.0001) demonstrated eAMD. Among study eyes in which eAMD developed, 18 of 26 (69%) had history of fellow-eye eAMD and 19 of 26 (73.1%) had DLS at baseline, compared with 76 of 217 study eyes (35%; P = 0.0007) and 70 of 215 study eyes (32.5%; P < 0.0001), respectively, in which eAMD did not develop. All 21 patients with structural OCT imaging at the time of eAMD diagnosis demonstrated subretinal fluid, intraretinal cysts, or both consistent with exudation. Among 17 patients who underwent FA at eAMD diagnosis, 10 showed detectable macular neovascularization (MNV), all occult lesions. Development of eAMD did not have an appreciable impact on visual acuity, and all patients responded to anti-vascular endothelial growth factor (VEGF) therapy. CONCLUSIONS: Intravitreal pegcetacoplan slowed the rate of GA growth and was associated with an unexpected dose-dependent increased incidence of eAMD with no temporal clustering of onset. Exudative AMD seemed to be associated with baseline eAMD in the contralateral eye and a DLS, suggestive of nonexudative MNV, in the study eye. The safety profile of pegcetacoplan was acceptable to proceed to phase 3 studies without adjustments to enrollment criteria.

Therapeutic Lessons to be Learned From the Role of Complement Regulators as Double-Edged Sword in Health and Disease.

The complement system is an important part of the innate immune system, providing a strong defense against pathogens and removing apoptotic cells and immune complexes. Due to its strength, it is important that healthy human cells are protected against damage induced by the complement system. To be protected from complement, each cell type relies on a specific combination of both soluble and membrane-bound regulators. Their importance is indicated by the amount of pathologies associated with abnormalities in these complement regulators. Here, we will discuss the current knowledge on complement regulatory protein polymorphisms and expression levels together with their link to disease. These diseases often result in red blood cell destruction or occur in the eye, kidney or brain, which are tissues known for aberrant complement activity or regulation. In addition, complement regulators have also been associated with different types of cancer, although their mechanisms here have not been elucidated yet. In most of these pathologies, treatments are limited and do not prevent the complement system from attacking host cells, but rather fight the consequences of the complement-mediated damage, using for example blood transfusions in anemic patients. Currently only few drugs targeting the complement system are used in the clinic. With further demand for therapeutics rising linked to the wide range of complement-mediated disease we should broaden our horizon towards treatments that can actually protect the host cells against complement. Here, we will discuss the latest insights on how complement regulators can benefit therapeutics. Such therapeutics are currently being developed extensively, and can be categorized into full-length complement regulators, engineered complement system regulators and antibodies targeting complement regulators. In conclusion, this review provides an overview of the complement regulatory proteins and their links to disease, together with their potential in the development of novel therapeutics.

Beneficial effects of eculizumab regardless of prior transfusions or bone marrow disease: Results of the International Paroxysmal Nocturnal Hemoglobinuria Registry.

OBJECTIVES: To evaluate the effects of eculizumab on transfusions and thrombotic events (TEs) in patients with and without prior history of transfusion in the International Paroxysmal Nocturnal Hemoglobinuria (PNH) Registry. METHODS: Registry patients enrolled on or before January 1, 2018, initiated on eculizumab no more than 12 months prior to enrollment, having known transfusion status for the 12 months before eculizumab initiation, and ≥12 months of Registry follow-up after eculizumab initiation, were included. RESULTS: Eculizumab treatment was associated with a 50% reduction in transfusions in patients with a transfusion history (10.6 units/patient-year before eculizumab vs 5.4 after; P < .0001), with greater reduction observed in those with no history of bone marrow disease vs those with bone marrow disease. Mean lactate dehydrogenase levels decreased from a mean of 6.7 to 1.4 times the upper limit of normal (ULN) in patients with transfusion history and from 5.1 to 1.2 times ULN in those with no transfusion history. TE and major adverse vascular event rates also decreased by 70% in patients with and without history of transfusion. CONCLUSIONS: The benefit of eculizumab therapy does not appear to be limited to any group defined by transfusion history or bone marrow disease history.

Complement Inhibitor Therapy for Myasthenia Gravis.

Complement activation as a driver of pathology in myasthenia gravis (MG) has been appreciated for decades. The terminal complement component [membrane attack complex (MAC)] is found at the neuromuscular junctions of patients with MG. Animals with experimental autoimmune MG are dependent predominantly on an active complement system to develop weakness. Mice deficient in intrinsic complement regulatory proteins demonstrate a significant increase in the destruction of the neuromuscular junction. As subtypes of MG have been better defined, it has been appreciated that acetylcholine receptor antibody-positive disease is driven by complement activation. Preclinical assessments have confirmed that complement inhibition would be a viable therapeutic approach. Eculizumab, an antibody directed toward the C5 component of complement, was demonstrated to be effective in a Phase 3 trial with subsequent approval by the Federal Drug Administration of the United States and other worldwide regulatory agencies for its use in acetylcholine receptor antibody-positive MG. Second- and third-generation complement inhibitors are in development and approaching pivotal efficacy evaluations. This review will summarize the history and present the state of knowledge of this new therapeutic modality.

Retrospective Analysis of Eculizumab in Patients with Acetylcholine Receptor Antibody-Negative Myasthenia Gravis: A Case Series.

BACKGROUND: The role of the complement cascade in acetylcholine receptor antibody-negative (AChR-) myasthenia gravis (MG) is unclear. OBJECTIVE: To assess the efficacy and tolerability of eculizumab (terminal complement inhibitor) in patients with AChR-MG. METHODS: Retrospective chart review of data from six patients treated for 12 months with eculizumab for treatment-refractory, AChR-(by radioimmunoassay) generalized MG (gMG). The eculizumab dose was 900 mg/week for 4 weeks then 1200 mg every 2 weeks. Outcome measures were Myasthenia Gravis-Activities of Daily Living (MG-ADL) scores, number of exacerbations, and qualitative physical assessments based on selected items of the Quantitative Myasthenia Gravis evaluation (ptosis, double vision, eye closure, duration of ability to stretch out limbs). RESULTS: All patients were female (mean age, 50.8 years). In the 12 months before eculizumab initiation, all measures were relatively stable. After its initiation, clinically meaningful reductions (≥2 points) in total MG-ADL scores were observed before or at 5 months and were maintained to Month 12 in all patients; mean (standard deviation [SD]) scores were 11.3 (0.9) and 5.0 (0.9), respectively. There was also a reduction in the mean (SD) number of exacerbations per patient, from 2.8 (1.2) to 0.3 (0.5) in the 12 months before and after eculizumab initiation, respectively. Physical assessment ratings were improved in all patients. Adverse events were reported in four patients, but all were mild and none were treatment-related. CONCLUSIONS: This small retrospective analysis provides preliminary evidence for the efficacy of eculizumab in treatment-refractory gMG that was AChR-according to radioimmunoassay. Larger, more robust studies are warranted to evaluate this further.

Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab.

Overactivated complement is a high-risk feature in hematopoietic stem cell transplant (HSCT) recipients with transplant-associated thrombotic microangiopathy (TA-TMA), and untreated patients have dismal outcomes. We present our experience with 64 pediatric HSCT recipients who had high-risk TA-TMA (hrTA-TMA) and multiorgan injury treated with the complement blocker eculizumab. We demonstrate significant improvement to 66% in 1-year post-HSCT survival in treated patients from our previously reported untreated cohort with same hrTA-TMA features that had 1-year post-HSCT survival of 16.7%. Responding patients benefited from a brief but intensive course of eculizumab using pharmacokinetic/pharmacodynamic-guided dosing, requiring a median of 11 doses of eculizumab (interquartile range [IQR] 7-20). Treatment was discontinued because TA-TMA resolved at a median of 66 days (IQR 41-110). Subjects with higher complement activation measured by elevated blood sC5b-9 at the start of treatment were less likely to respond (odds ratio, 0.15; P = .0014) and required more doses of eculizumab (r = 0.43; P = .0004). Patients with intestinal bleeding had the fastest eculizumab clearance, required the highest number of eculizumab doses (20 vs 9; P = .0015), and had lower 1-year survival (44% vs 78%; P = .01). Over 70% of survivors had proteinuria on long-term follow-up. The best glomerular filtration rate (GFR) recovery in survivors was a median 20% lower (IQR, 7.3%-40.3%) than their pre-HSCT GFR. In summary, complement blockade with eculizumab is an effective therapeutic strategy for hrTA-TMA, but some patients with severe disease lacked a complete response, prompting us to propose early intervention and search for additional targetable endothelial injury pathways.

Efficacy and Safety of Eculizumab in the Treatment of Transplant-Associated Thrombotic Microangiopathy: A Systematic Review and Meta-Analysis.

Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a dangerous and life-threatening complication in patients undergoing hematopoietic stem cell transplantation (HSCT). Eculizumab has been used in the treatment of TA-TMA, and several studies have confirmed the benefit of Eculizumab in patients with TA-TMA. However, the results remain controversial. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of Eculizumab for TA-TMA. Materials and Methods: We searched PubMed and Embase for studies on the efficacy and safety of Eculizumab in TA-TMA patients. Efficacy outcomes consisted of overall response rate (ORR), complete response rate (CRR), and survival rate at the last follow-up (SR). Safety outcomes were adverse events (AEs), including infection, sepsis, impaired liver function, infusion reactions, and death. Results: A total of 116 patients from six studies were subjected to meta-analysis. The pooled estimates of ORR, CRR, and SR for TA-TMA patients were 71% (95% CI: 58-82%), 32% (95% CI: 11-56%), and 52% (95% CI: 40-65%), respectively. Only one patient presented with a severe rash, and infection was the most common AEs. The main causes of death were infection and GvHD. Conclusion: Current evidence suggests that Eculizumab improves SR and ORR in patients with TA-TMA and that Eculizumab is well tolerated. However, the number of studies is limited, and the findings are based mainly on data from observational studies. Higher quality randomized controlled trials and more extensive prospective cohort studies are needed.

C1 esterase inhibitor in pediatric cardiac surgery with cardiopulmonary bypass plays a vital role in activation of the complement system.

Our prospective study was therefore designed to determine which part of the systemic inflammatory response after cardiac operations resulted from Cardiopulmonary bypass (CPB) in neonates and infants. After approval by the human ethical committee of the Gunma Children's Medical Center (GCMC) and informed consent of the parents, 40 consecutive term congenital heart disease patients aged until 1 year who underwent long CPB time (> 3 h) at surgery were included in the prospective study between January 2012 and December 2014. C1 esterase inhibitor (C1-inh) drug (@Berinert) was generously provided by CSL Behring (King of Prussia, PA). The C1-inh (20 IU/kg) was given intravenously 60 min after CPB. Blood samples for complement factors were obtained before and 48 h after administration of C1-inh. Six patients did not survive and their data were not included. Of 34 patients included, median age was 6.5 months, median body weight was 6050 g, and 16 (47%) were female. According to the Mann-Whitney U test, there were no differences between the two groups concerning demographic and intraoperative data, postoperative chemical data. C1q concentration was only significant lower in patients with C1-inh non-treated group than in patients with C1-inh treated group. But, the consumption of C1q, C3, C4, CH50, and C1-inh in patients with C1-inhibitor non-treated group was observed early postoperatively. There is a significant difference in the values before and after C1-inh treatment between the two groups. The lower value in the C1-inh-treated group is explained by the activation of the classical pathway through the replenishment of complements by C1-inh treatment. This study proposes the administration of C1-inh is an effective therapy to reduce the activation and improve the clinical capillary leak syndrome.

Fusobacterium nucleatum bacteremia with pneumopathy in a patient receiving eculizumab: A case report.

Fusobacterium nucleatum is a common oral commensal bacterium capable of severe invasive infections. We report a case of a diffuse bilateral pneumopathy with F. nucleatum-positive blood culture successfully treated by common antibiotics in a patient receiving eculizumab for a drug-induced thrombotic microangiopathy (TMA). It is the first described case of a severe F. nucleatum-associated infection in a patient undergoing terminal complement inhibitor therapy. We suggest providing preventive dental care before eculizumab initiation.

Long-term efficacy and safety of eculizumab in Japanese patients with generalized myasthenia gravis: A subgroup analysis of the REGAIN open-label extension study.

The terminal complement inhibitor eculizumab was shown to improve myasthenia gravis-related symptoms in the 26-week, phase 3, randomized, double-blind, placebo-controlled REGAIN study (NCT01997229). In this 52-week sub-analysis of the open-label extension of REGAIN (NCT02301624), eculizumab's efficacy and safety were assessed in 11 Japanese and 88 Caucasian patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. For patients who had received placebo during REGAIN, treatment with open-label eculizumab resulted in generally similar outcomes in the Japanese and Caucasian populations. Rapid improvements were maintained for 52 weeks, assessed by change in score from open-label extension baseline to week 52 (mean [standard error]) using the following scales (in Japanese and Caucasian patients, respectively): Myasthenia Gravis Activities of Daily Living (-2.4 [1.34] and - 3.3 [0.65]); Quantitative Myasthenia Gravis (-2.9 [1.98] and - 4.3 [0.79]); Myasthenia Gravis Composite (-4.5 [2.63] and - 4.9 [1.19]); and Myasthenia Gravis Quality of Life 15-item questionnaire (-8.6 [5.68] and - 6.5 [1.93]). Overall, the safety of eculizumab was consistent with its known safety profile. In this interim sub-analysis, the efficacy and safety of eculizumab in Japanese and Caucasian patients were generally similar, and consistent with the overall REGAIN population.