Inhibitor Eculizumab Research Articles

Clinical efficacy and safety of switching from eculizumab to ravulizumab in adult patients with aHUS– real-world data

BackgroundThe complement factor 5 (C5)-inhibitor eculizumab has been established as standard-of-care for the treatment of atypical hemolytic uremic syndrome (aHUS). In 2021, the long-acting C5-inhibitor ravulizumab was approved, extending intervals of intravenous treatment from two to eight weeks resulting in improvement of quality of life for patients and lowering direct and indirect therapy associated costs.MethodsThis multicenter, retrospective data analysis of 32 adult patients with aHUS (including 10 kidney transplant recipients) treated with eculizumab for at least three months and switched to ravulizumab aims to evaluate the safety and efficacy of switching medication in the real-world setting. Hematologic parameters, kidney function, concurrent therapy and aHUS associated events were evaluated three months before and until up to 12 months after switching to ravulizumab.ResultsMean age (range) at ravulizumab initiation was 41 years (19–78 years) and 59% of the patients were female. Genetic analysis was available for all patients with 72% showing a pathogenic variant. Median time (range) on eculizumab before switching was 20 months (3–120 months). No new events of TMA or worsening of renal function were reported during up to 12 months of follow-up during ravulizumab treatment.ConclusionsThis is the largest, non-industry derived, multi-center retrospective analysis of adult patients with aHUS switching C5-inhibitor treatment from eculizumab to ravulizumab in the real-world setting. Switching to ravulizumab was safe and efficient resulting in sustained hematological stability and preservation of renal function.

Plain language summary: treatment of paroxysmal nocturnal hemoglobinuria with pegcetacoplan for 48 weeks (PEGASUS study)

What is this summary about? Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, serious blood disease, characterized by uncontrolled activation of the complement system that causes hemolysis (destruction of red blood cells). The complement component 5 (C5) inhibitor eculizumab was the first approved treatment for PNH. The PEGASUS trial compared eculizumab with pegcetacoplan, a new complement component 3 (C3) inhibitor. Because C3 is activated before C5, blocking C3 would also block C5; thus, a C3 inhibitor might prevent hemolysis more completely than a C5 inhibitor in patients with PNH. During the first 16 weeks of PEGASUS, patients received either pegcetacoplan or eculizumab; results were published separately. This summary describes results of the following 32 weeks of PEGASUS, during which all patients received pegcetacoplan to evaluate if pegcetacoplan continued to be effective and safe for up to 48 weeks. What were the results? Pegcetacoplan continued to be effective in participants who received it throughout the study and improved symptoms in participants who switched from eculizumab. The most common adverse events (side effects) were skin irritation at the injection site, hemolysis, nasopharyngitis (runny nose and sore throat), and diarrhea. Adverse events were serious and related to pegcetacoplan in 4 of 77 (5%) patients; all patients recovered from these events. What do the results mean? Pegcetacoplan improved symptoms and was well tolerated for up to 48 weeks by most patients in PEGASUS, suggesting that adult patients with PNH may benefit from long-term pegcetacoplan treatment.

In vitro characterization of rare anti-αIIbβ3 isoantibodies produced by patients with Glanzmann thrombasthenia that severely block fibrinogen binding and generate procoagulant platelets via complement activation

BackgroundGlanzmann thrombasthenia (GT) is a rare bleeding disorder caused by inherited defects of the platelet αIIbβ3 integrin. Platelet transfusions can be followed by an immune response that can block integrin function by interfering with fibrinogen binding. ObjectivesIn this study, we aimed to determine the prevalence of such isoantibodies and better characterize their pathogenic properties. MethodsTwelve patients with GT were evaluated for anti-αIIbβ3 isoantibodies. Sera from patients with GT with or without anti-αIIbβ3 isoantibodies were then used to study their in vitro effect on platelets from healthy donors. We used several approaches (IgG purification, immunofluorescence staining, and inhibition of signaling pathways) to characterize the pathogenic properties of the anti-αIIbβ3 isoantibodies. ResultsOnly 2 samples were able to severely block integrin function. We observed that these 2 sera caused a reduction in platelet size similar to that observed when platelets become procoagulant. Mixing healthy donor platelets with patients’ sera or purified IgGs led to microvesiculation, phosphatidylserine exposure, and induction of calcium influx. This was associated with an increase in procoagulant platelets. Pore formation and calcium entry were associated with complement activation, leading to the constitution of a membrane attack complex (MAC) with enhanced complement protein C5b-9 formation. This process was inhibited by the complement 5 inhibitor eculizumab and reduced by polyvalent human immunoglobulins. ConclusionOur data suggest that complement activation induced by rare blocking anti-αIIbβ3 isoantibodies may lead to the formation of a MAC with subsequent pore formation, resulting in calcium influx and procoagulant platelet phenotype.

PB1934: REAL-WORLD OUTCOMES OF ECULIZUMAB TREATMENT IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINUREA: A SYSTEMATIC LITERATURE REVIEW AND EVIDENCE SYNTHESIS

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, hematologic disorder characterized by uncontrolled terminal complement activation, thrombotic events (TEs) and increased morbidity and mortality. The complement component 5 (C5) inhibitor eculizumab has been the standard of care for treating patients with PNH since approval by the US Food and Drug Administration and European Medicines Agency in 2007. Although randomized controlled trials have demonstrated the clinical efficacy and safety of eculizumab, there is a paucity of real-world effectiveness data. Aims: To describe the real-world effectiveness of eculizumab treatment in patients with PNH. Methods: A systematic literature review (SLR) and grey literature search was conducted to identify published observational studies that reported outcomes of eculizumab treatment in patients (aged ≥18 years) with PNH. The search was performed using MEDLINE, Embase and the Cochrane Library from database inception to July 2021. Outcomes of interest included lactate dehydrogenase (LDH) levels, transfusion requirement, units of red blood cells (RBCs) transfused, TEs and mortality. A feasibility assessment for meta-analyses was also performed. Results: The search identified 2,622 unique records, of which 28 were eligible for inclusion (patient sample range: 6–1,807). Of the included studies, 15 (53.6%) utilized a prospective, observational study design and, aside from seven multinational studies, data from 11 unique countries were reported. Meta-analyses were not feasible owing to the considerable heterogeneity in study populations, assessment time points, outcome reporting and definitions. The median age of patients at assessment ranged from 23–56 years and the proportion of male patients was 32–83%. Median PNH disease duration ranged from 2.1–11.0 years (5 studies). Duration of follow-up varied from 11 weeks to 10 years (12 studies). LDH levels following eculizumab treatment were reported in 10 studies and all demonstrated a reduction from baseline levels. The mean (standard error; SE) change in LDH ranged from –338.0 (87.3; mean [SE] baseline LDH = 581.0 [94.9] U/L; n = 11) to –3,101.0 (569.9; mean [SE] baseline LDH = 3,552.0 [584.6] U/L; n = 12) U/L. Amongst studies that had non-zero baseline values, the reduction in transfusion dependence following eculizumab treatment ranged from 15.0% (baseline proportion, 23.0%; n = 231) to 80.0% (baseline proportion, 100.0%; n = 5). The mean (SE) reduction in units of RBCs transfused following eculizumab treatment was reported in six studies and ranged from 1.5 (1.1; n = 6) to 14.3 (1.4; n = 75). TEs following eculizumab treatment were described in 11 studies and ranged from 0.0% (baseline TEs, 0.0–33.3%; n = 5–105) to 9.0% (baseline TEs, 40.9%; n = 22). All-cause mortality among eculizumab-treated patients was reported in six studies and ranged from 0.0% (n = 17–105) to 7.3% (n = 123). These deaths were not related to eculizumab. Summary/Conclusion: This SLR synthesized real-world outcomes associated with complement C5 inhibition in patients with PNH and demonstrated consistent effectiveness of eculizumab beyond the clinical trial setting. Although the heterogeneity of study populations precluded meta-analyses of outcomes data, consistent improvements in key clinical parameters were widely reported, including reductions in LDH levels, TEs, transfusion dependence and mortality outcomes. This analysis further reinforces the benefits of complement C5 inhibition in patients with PNH.

Eculizumab Pharmacokinetics and Pharmacodynamics in Patients With Neuromyelitis Optica Spectrum Disorder.

Objective: To investigate the pharmacokinetics and pharmacodynamics of the approved 900/1,200 mg dosing regimen for the terminal complement component 5 (C5) inhibitor eculizumab in patients with neuromyelitis optica spectrum disorder (NMOSD).Methods: Data were analyzed from 95 patients with aquaporin-4-IgG-positive NMOSD who received eculizumab during the PREVENT study (ClinicalTrials.gov: NCT01892345). Relationships were explored between eculizumab exposure and free complement C5 concentrations, terminal complement activity, and clinical outcomes.Results: Pharmacokinetic data were well-described by a two-compartment model with first-order elimination, and time-variant body-weight and plasmapheresis/plasma exchange effects. Steady-state serum eculizumab concentrations were achieved by Week 4 and were sustained, with serum trough eculizumab concentrations maintained above the 116 μg/ml threshold for complete complement inhibition throughout 168 weeks of treatment in all post-baseline samples from 89% of patients. Complete inhibition of terminal complement was achieved at Day 1 peak and pre-dosing trough eculizumab concentration in nearly all post-baseline samples assessed (free C5 <0.5 μg/ml in all post-baseline samples from 96% of patients; in vitro hemolysis <20% in all post-baseline samples from 93% of patients). Kaplan–Meier survival analysis of time to first relapse showed separation of eculizumab-treated patients from those receiving placebo, but no separation based on eculizumab exposure quartile, indicating an optimized dose regimen with maximized efficacy.Conclusions: The approved eculizumab dosing regimen (900/1,200 mg) for adults with aquaporin-4-IgG-positive NMOSD is confirmed by rigorous quantitative model-based analysis of exposure–response. The data demonstrate that eculizumab's mechanism of action translates into clinical effect by achieving rapid, complete, and sustained terminal complement inhibition.

Eculizumab Pharmacokinetics and Pharmacodynamics in Patients With Generalized Myasthenia Gravis.

Objective: To investigate the pharmacokinetics, pharmacodynamics, and exposure–response of the approved 900/1,200 mg dosing regimen for the terminal complement component 5 (C5) inhibitor eculizumab in patients with generalized myasthenia gravis (gMG).Methods: The analysis used data from 62 patients aged ≥ 18 years with anti-acetylcholine receptor (AChR) antibody-positive refractory gMG who received eculizumab during the REGAIN study (ClinicalTrials.gov: NCT01997229). One- and two-compartment population-pharmacokinetic models were evaluated, and the impact of covariates on pharmacokinetic parameters was assessed. Relationships between eculizumab exposure and free C5 concentration, in vitro hemolytic activity, clinical response, and tolerability were characterized.Results: Steady-state serum eculizumab concentrations were achieved by Week 4 and were sustained throughout the 26-week treatment period. The eculizumab pharmacokinetic data were well-described by a two-compartment model with first-order elimination, including effects of body weight on pharmacokinetic parameters and plasma-exchange events on clearance. Complete inhibition of terminal complement was achieved in nearly all patients at the time of trough and peak eculizumab concentrations at all post-dose timepoints assessed (free C5 < 0.5 μg/ml in 92% of patients; in vitro hemolysis < 20% in 87% of patients). Serum eculizumab concentrations of ≥116 μg/ml achieved free C5 concentrations of < 0.5 μg/ml. Clinical efficacy and tolerability were consistent across the eculizumab exposure range.Conclusions: Rigorous, quantitative, model-based exposure–response analysis of serum eculizumab concentration and response data demonstrated that the approved eculizumab dosing (900/1,200 mg) for adults with anti-AChR antibody-positive refractory gMG rapidly achieved complete inhibition of terminal complement activation and provided sustained clinical efficacy across the eculizumab exposure range.

Eculizumab: A Review in Neuromyelitis Optica Spectrum Disorder.

The terminal complement protein (C5) inhibitor eculizumab (Soliris®) is the first agent to be specifically approved in the EU, USA, Canada and Japan for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults who are aquaporin-4 water channel autoantibody (AQP4-IgG) seropositive and (in the EU only) for those with a relapsing course of disease. In the phase III PREVENT trial, eculizumab significantly reduced the risk of adjudicated relapse relative to placebo in patients with AQP4-IgG-seropositive NMOSD, approximately a quarter of whom did not receive concomitant immunosuppressive therapies. The beneficial effect of eculizumab was seen across all patient subgroups analysed and was accompanied by improvements in neurological and functional disability assessments, as well as generic health-related quality of life measures; it was sustained through 4 years of treatment, according to combined data from the PREVENT trial and an interim analysis of its ongoing open-label extension study. The safety profile of eculizumab in AQP4-IgG-seropositive NMOSD was consistent with that seen for the drug in other approved indications. Thus, eculizumab provides an effective, generally well tolerated and approved treatment option for this rare, disabling and potentially life-threatening condition.Video abstract Video (MP4 241640 KB)Supplementary InformationThe online version contains supplementary material available at 10.1007/s40265-020-01297-w.

Thrombotic Microangiopathy in Inverted Formin 2-Mediated Renal Disease.

The demonstration of impaired C regulation in the thrombotic microangiopathy (TMA) atypical hemolytic uremic syndrome (aHUS) resulted in the successful introduction of the C inhibitor eculizumab into clinical practice. C abnormalities account for approximately 50% of aHUS cases; however, mutations in the non-C gene diacylglycerol kinase-ε have been described recently in individuals not responsive to eculizumab. We report here a family in which the proposita presented with aHUS but did not respond to eculizumab. Her mother had previously presented with a post-renal transplant TMA. Both the proposita and her mother also had Charcot-Marie-Tooth disease. Using whole-exome sequencing, we identified a mutation in the inverted formin 2 gene (INF2) in the mutational hotspot for FSGS. Subsequent analysis of the Newcastle aHUS cohort identified another family with a functionally-significant mutation in INF2 In this family, renal transplantation was associated with post-transplant TMA. All individuals with INF2 mutations presenting with a TMA also had aHUS risk haplotypes, potentially accounting for the genetic pleiotropy. Identifying individuals with TMAs who may not respond to eculizumab will avoid prolonged exposure of such individuals to the infectious complications of terminal pathway C blockade.

Complement activation in kidney transplantation: from risk stratification to therapeutic strategies.

One of the most important advances in transplantation medicine has been the recognition that anti-human leucocyte antigen (HLA) antibodies are destructive. Various studies over the past decade have indicated that the alloimmune response, mediated by anti-HLA antibodies, plays a key role in the failure of kidney allografts 1,2; this concept has been extended to heart, lung and composite tissue transplants 3. Although anti-HLA antibodies are considered to be harmful, there is a wide spectrum of graft injury related to these antibodies, ranging from no recognizable damage to florid rejection. The presence or absence and characteristics of donor-specific anti-HLA antibodies (DSA) are therefore crucial to determine patient outcomes following transplantation. Activation of the complement cascade is known to be a key component of antibody-mediated rejection (ABMR), and deposition of C4d is often used as a marker for complement activation 4–6. It is the ability of anti-HLA antibodies to bind complement that determines the cytotoxic potential of these antibodies 5. Therefore, we hypothesized that the presence of DSA and their ability to bind and activate complement would play a key role in solid organ transplant. A total of 1016 consecutive kidney transplant recipients were enrolled into this population-based study 7. All patients were screened for the presence of circulating DSA at the time of transplantation and at 1 year after transplantation, in patients with no immunological event or at the time of rejection using the Luminex assay. The complement-binding capacity of any detected DSA was also analysed. Of the 1016 patients, 1 year post-transplantation, 700 patients (69%) were devoid of circulating DSA and 316 patients (31%) had circulating DSA, 77 of whom (24%) were C1q-positive, i.e. had complement-binding DSA. The patients with complement-binding DSA (representing 7% of the overall population) had the poorest outcome, with a risk of graft loss 11-fold higher than patients with non-complement-binding DSA (C1q-negative) 7. Assessment of allograft biopsies (n = 1016) demonstrated that DSA, both complement (C1q-positive)- and non-complement (C1q-negative)-binding, were capable of inducing injury to the graft. Histologically, the incidence of microvascular inflammation, C4d deposition, early transplant glomerulopathy and interstitial inflammation tubulitis were significantly higher in allografts from patients with DSA (P < 0·05), particularly in those patients with C1q-positive, complement-binding DSA (P < 0·05) 7. These results were confirmed further by molecular microscopy with higher ABMR score, higher endothelial cell injury response and higher numbers of natural killer cells and interferon (IFN)-γ-inducible transcripts observed in patients with C1q-positive, complement-binding DSA. In order to translate our findings into clinical practice, we developed a risk prediction model at 1 year post-transplantation based on all histological and immunological parameters, defined by the current classical diagnosis tools. When C1q-positive, complement-binding DSA were added to the model we observed an increase in the performance and discrimination capacity, and reclassification of patients at lower or higher risk of graft loss 8. Compared with a traditional approach to predicting graft loss, we demonstrate that a new approach, which integrates the capacity of DSA to bind complement, identifies patients at high risk of graft loss and increases our risk stratification performance in kidney transplant recipients. An improved understanding of DSA mechanism of action, better patient identification and construction of risk models will pave the way to specific and personalized treatment for patients undergoing solid organ transplantation. As promising therapeutic agents targeting complement [e.g. a C5 inhibitor (eculizumab) or a C1 inhibitor] are used increasingly in patients undergoing transplantation, this study may serve as a basis for future clinical trials.