Eculizumab Treatment Research Articles

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.

P839: PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA TREATED WITH PEGCETACOPLAN SHOW IMPROVEMENTS IN D-DIMER NORMALIZATION AND DECREASE IN INCIDENCE OF THROMBOSIS

Background: Thrombosis is the main life-threatening complication of paroxysmal nocturnal hemoglobinuria (PNH), a rare acquired hematologic disease. Pegcetacoplan (PEG) is a C3 complement-inhibitor approved by the FDA/EMA for treatment of adults with PNH. Aims: This post hoc analysis examined incidence of thrombosis, anti-thrombotic therapy (ATT), and D-dimer normalization in adult patients with PNH treated with PEG in the Phase 3 PEGASUS (NCT03500549) and PRINCE (NCT04085601) studies. Methods: PEGASUS enrolled adult patients with PNH with prior suboptimal response to eculizumab (ECU) despite stable ECU treatment (≥3 months) and hemoglobin (Hb) levels <10.5 g/dL at screening. For the randomized controlled period (RCP), patients were randomized 1:1 to ECU (n=39) or PEG (n=41; 1080 mg subcutaneously [sc] 2x weekly) for 16 weeks. Thereafter, ECU patients were switched to PEG monotherapy and PEG RCP patients remained on PEG during the open-label period (OLP, n=77) through Week 48. PRINCE compared PEG treatment (n=35; 1080 mg sc 2x weekly) in complement-inhibitor-naïve patients to patients receiving control treatment (CTRL; excluding complement-inhibitors i.e., ECU/ravulizumab; n=18). CTRL patients had the option to escape to the PEG group if Hb levels decreased ≥2 g/dL from baseline (n=11). Safety analyses in all trials included monitoring of thrombotic events. D-dimer normalization, defined as D-dimer level less than the upper limit of normal (0.5 µg/mL) was examined at baseline, Week 8, and the end of the study period (PEGASUS: 16 weeks [RCP] and 48 weeks [OLP], PRINCE: 26 weeks). Results: Prior to study entry, 31% (n=25) of PEGASUS patients (6 of these while on ECU therapy) and 9% (n=5) of PRINCE patients experienced at least one type of thrombosis. During the PEGASUS OLP, 2 of 77 patients experienced a thrombotic event, one in the setting of non-Hodgkin’s lymphoma and one during sepsis; neither event was deemed related to PEG. No patients in the PEGASUS RCP or PRINCE trial experienced a thrombotic event. Pooled analysis of completed clinical trials of PEG including PEGASUS and PRINCE indicated there were 2 cases of thrombosis in 164 patients comprising 130 patient-years (1.54 events per 100 patient-years), compared to 1.77 events per 100 patient-years for patients on ECU treatment before entry into PEGASUS. In PEGASUS, 34% (n=27) of patients were on ATT prior to study entry. During the PEGASUS RCP, concomitant ATT was observed in 37% (PEG, n=15) and 33% (ECU, n=13) of patients, and during the PEGASUS-OLP in 23% (n=18) of patients (PEG monotherapy). In PRINCE, concomitant ATT decreased from 21% (n=11) prior to the study to 7% (PEG, n=3) and 0% (CTRL, n=0) during the study. In PEGASUS, D-dimer normalization in the PEG arm increased from 73% (baseline, n=30) to 89% (Week 8, n=33) and was largely sustained at Week 16 and Week 48 (Table 1). D-dimer normalization in the ECU arm increased once ECU patients switched to PEG monotherapy, from 76% (Week 16, n=29) to 89% (Week 48, n=17) (Table 1). In PRINCE, D-dimer normalization in the PEG arm increased from 51% (baseline, n=18) to 67% (Week 8, n=18) and increased further to 68% (n=19) at Week 26 (Table 1). Image:Summary/Conclusion: Overall, these results demonstrate that PEG treatment can increase D-dimer normalization and reduces incidence of thrombotic events in patients with PNH who are complement-inhibitor naïve or remained anemic after ECU treatment, suggesting that PEG treatment is as effective as ECU in these outcomes.

P813: EFFICACY, TREATMENT ADMINISTRATION SATISFACTION AND SAFETY OF SUBCUTANEOUS RAVULIZUMAB THROUGH 1 YEAR IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA WHO RECEIVED PRIOR INTRAVENOUS ECULIZUMAB

Background: The efficacy of ravulizumab (intravenous [IV] formulation; administered every 8 weeks) for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) has been demonstrated in several randomized trials (NCT02946463, NCT03056040, NCT03406507). In study 303 (NCT03748823), subcutaneous (SC) ravulizumab, administered weekly via an on-body delivery system, showed pharmacokinetic non-inferiority to IV ravulizumab in adult patients with PNH who were clinically stable on prior IV eculizumab treatment. Here, we report results from the first 1 year of SC treatment, starting at day 15 for patients who continued SC ravulizumab during the extension period (SC/SC) and day 71 for patients who switched from IV ravulizumab to SC ravulizumab (IV/SC). Aims: To evaluate the efficacy, treatment administration satisfaction and safety of SC ravulizumab through the first 1 year (day 351) of treatment in adult patients with PNH previously treated with eculizumab. Methods: Patients (≥ 18 years) with clinically stable PNH (lactate dehydrogenase [LDH] levels ≤ 1.5 × upper limit of normal [246 U/L]) and ≥ 3 months prior eculizumab treatment were enrolled in the study, which consisted of a screening period (day -1 to day -30), a 10-week randomized treatment period and an extension period of up to 172 weeks. During the randomized treatment period, patients were assigned (2:1 ratio) to receive either SC ravulizumab or IV ravulizumab; all patients received SC ravulizumab during the extension period. Efficacy endpoints included: change in LDH from baseline; incidence of breakthrough hemolysis; transfusion avoidance; and stabilized hemoglobin (avoidance of a ≥ 2 g/dL decrease in hemoglobin in the absence of transfusion). Treatment administration satisfaction was assessed via the Treatment Administration Satisfaction Questionnaire (TASQ), which has been validated in a PNH population. Safety, including adverse events (AEs), serious AEs (SAEs) and adverse device effects (ADEs), were also assessed up to the 1-year data cut-off. Results: In total, 128 patients received SC ravulizumab (SC/SC: n = 84; IV/SC: n = 44; mean [range] duration of SC treatment: 486.4 [37–709] days). Efficacy endpoints (SC/SC and IV/SC) remained stable over time through 1 year of SC ravulizumab treatment. Mean (standard deviation [SD]) percentage change in LDH from baseline to SC day 351 was 0.9% (20.5%). Breakthrough hemolysis events were infrequent: 5/128 patients (3.9%); no event was considered free C5-related. Transfusion avoidance was maintained in 83.6% of patients during SC treatment, and 79.7% achieved stabilized hemoglobin. Improvement in total TASQ score with SC ravulizumab (compared with baseline IV eculizumab) was apparent at the first post-SC treatment assessment (SC day 29) and maintained until data cut-off (Figure). The most common AEs (reported by ≥ 10% of patients, excluding ADEs related to device product issues) during SC treatment were headache (14.1%, all grade ≤ 2), COVID-19 (14.1%, one death) and pyrexia (10.9%); injection site reaction (4.7%) was the most common non-device related ADE. Treatment-emergent SAEs were experienced by 21.1% of patients through to data cut-off. Although many patients had ≥ 1 device issue ADE, full SC dose administration was achieved in 99.9% of attempts. ADE incidence decreased over time. Image:Summary/Conclusion: The SC method of administration provides an additional treatment option for patients with PNH receiving ravulizumab therapy. Patients may be switched from IV eculizumab or IV ravulizumab to SC ravulizumab without loss of efficacy.

P828: NORMALIZATION OF HEMATOLOGIC AND HEALTH-RELATED QUALITY OF LIFE MARKERS IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA TREATED WITH PEGCETACOPLAN AND BASELINE HEMOGLOBIN AT OR ABOVE 10 G/DL

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare life-threatening disease characterized by chronic complement-mediated hemolysis and thrombosis. Patients living with PNH can experience anemia with associated fatigue, dyspnea, and require blood cell transfusions which can negatively impact quality of life (QoL). Pegcetacoplan (PEG), is a C3 complement-inhibitor approved by the FDA/EMA for adults with PNH. Aims: This post hoc analysis evaluated hemoglobin (Hb), lactate dehydrogenase (LDH), absolute reticulocyte count (ARC), and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue normalization rates and safety after PEG treatment in a subgroup of patients with PNH and baseline Hb levels ≥10.0g/dL from the PADDOCK (NCT02588833), PEGASUS (NCT03500549), and PRINCE (NCT04085601) studies. Methods: PADDOCK evaluated PEG treatment (270-360mg/day subcutaneously [sc]) in complement-inhibitor naïve patients. PEGASUS enrolled patients with Hb levels <10.5g/dL at screening despite stable eculizumab (ECU) treatment (≥3 months). PEGASUS patients were randomized 1:1 to ECU or PEG (1080mg sc 2x weekly) during the randomized controlled period (RCP) through Week 16. Patients who received PEG during the RCP continued with PEG monotherapy (PEG-to-PEG) and ECU patients switched to PEG monotherapy (ECU-to-PEG) during the open-label period (OLP) through Week 48. PRINCE compared PEG treatment (1080mg sc 2x weekly) in complement-inhibitor naïve patients with PNH and Hb levels below the lower limits of normal (males: ≤13.6g/dL; females: ≤12.0g/dL) to control treatment (CTRL; excluding complement-inhibitors i.e., ECU/ravulizumab). The post hoc analysis included adult patients with PNH with baseline Hb levels ≥10.0g/dL and no transfusions within 14 days of the baseline measurement. Hb, LDH, and ARC normalization, as well as FACIT-Fatigue normalization (defined as increase to population norm) was evaluated after 16 weeks of PEG monotherapy for all three studies. Patients who withdrew or were lost to follow-up without providing efficacy data at the specified timepoints were classified as non-responders. Safety endpoints included incidences of adverse events (AEs). Results: Overall, 22 patients were included in the post hoc analysis: 5 PADDOCK, 9 PEGASUS, and 8 PRINCE patients. After 16 weeks of pegcetacoplan treatment, patients in all three studies showed improvements in Hb normalization, LDH normalization, and ARC normalization (Table 1). Additionally, improvements in FACIT-Fatigue normalization were demonstrated in PADDOCK, PRINCE, and PEGASUS (PEG-to-PEG) patients (Table 1). No incidences of serious AEs were reported in PADDOCK and PRINCE subgroups. One PEGASUS patient had a serious AE of breakthrough hemolysis (severe, unrelated to PEG), following an upper respiratory infection which resolved and did not lead to study discontinuation. Incidences of injection site reactions and infections and infestations occurred at similar rates between subgroups in all three studies (Table 1). No thrombotic events occurred in this patient population. Image:Summary/Conclusion: While this patient population had near normal Hb at baseline (median: 10.4g/dL), they also had elevated ARC and LDH prior to PEG therapy, suggesting ongoing hemolysis which was normalized in most patients after PEG treatment initiation. Overall, these results suggest PEG can be efficacious long-term in patients with less severe anemia, regardless of prior complement-inhibitor treatment, resulting in further clinical improvements in markers of hemolysis and QoL. The safety profile of PEG was consistent with results from previous studies.

Safety and effectiveness of eculizumab in Japanese patients with generalized myasthenia gravis: Analysis of 1‐year postmarketing surveillance

AbstractIntroductionEculizumab, a terminal complement protein C5 inhibitor, is approved in Japan for the treatment of patients with anti‐acetylcholine receptor antibody‐positive (AChR Ab+) generalized myasthenia gravis (gMG) that is difficult to control with plasmapheresis or high‐dose intravenous immunoglobulin therapy.MethodsThis analysis of mandatory postmarketing surveillance in Japan assessed the safety and effectiveness of eculizumab in patients with AChR Ab+ gMG who had completed case‐report forms at 26 wk after eculizumab initiation up to the cutoff date of April 2021. Changes from baseline were assessed for Myasthenia Gravis‐Activities of Daily Living (MG‐ADL) and Quantitative Myasthenia Gravis (QMG) total scores overall, and MG‐ADL scores in patient subgroups according to sex, age at diagnosis and baseline, and baseline disease severity. The change in concomitant corticosteroid use was also evaluated.ResultsData were available for 134 adults (67.2% female; mean age 51.9 y); the effectiveness‐analysis set comprised 126 patients. After 26 wk, 78% of patients were continuing eculizumab treatment. Adverse drug reactions were reported by 49 patients (37%) (most frequently headache [n = 10]). Improvements in MG‐ADL scores were seen regardless of sex; age at diagnosis (&lt;50/≥50 y); baseline age (18 to &lt;40/≥40 to &lt;65/≥65 y); Myasthenia Gravis Foundation of America disease classification (IIa/IIb/IIIa/IIIb/IVa/IVb/V); or baseline MG‐ADL score (&lt;6/≥6). Of patients receiving corticosteroids, the proportion receiving low doses (average ≤5 mg/d) increased from 7.0% before eculizumab initiation to 26.4% by Week 52.ConclusionEculizumab was well tolerated and effective in treating AChR Ab+ gMG across a broad spectrum of adult Japanese patients with difficult‐to‐control gMG.

Effect of eculizumab treatment in patients with paroxysmal nocturnal hemoglobinuria with or without high disease activity: Real-world findings from the International Paroxysmal Nocturnal Hemoglobinuria Registry.

The effects of eculizumab treatment in paroxysmal nocturnal hemoglobinuria (PNH) patients with or without high-disease activity (HDA), defined by LDH ≥ 1.5 × ULN and history of major adverse vascular events (MAVEs; including thrombotic events [TEs]); anemia; and/or physician-reported abdominal pain, dyspnea, dysphagia, erectile dysfunction, fatigue, and/or hemoglobinuria, in the International PNH Registry were evaluated. Registry patients were stratified by baseline HDA and eculizumab-treatment status. Longitudinal changes in laboratory and clinical PNH-related endpoints were evaluated using linear mixed models (continuous variables) or Poisson regression (incidence rates). As of May 1, 2017, 3009 patients (HDA/eculizumab-treated, n=913; HDA/never-treated, n=651; no-HDA/eculizumab-treated, n=173; no-HDA/never-treated, n=1272) were analyzed. Higher proportions of eculizumab-treated patients had HDA and history of MAVEs. In patients with and without HDA, respectively, eculizumab treatment resulted in reductions from baseline for (1) LDH ratio (mean [SD]: -5.3 [4.0] and -2.3 [3.8]); (2) incidence rate ratio (IRR) for MAVEs (-80% and -70%); (3) IRR for TEs (-80% for both); and (4) units of red blood cell transfusions per year (from 6.8 to 2.8 and 3.6 to 2.5units). Eculizumab treatment in a real-world setting improved outcomes, including substantial decreases in hemolysis, MAVE rates, TEs, and transfusions in PNH patients regardless of HDA.

Eculizumab treatment in pregnant women with paroxysmal nocturnal hemoglobinuria: A Polish experience.

Eculizumab is an antibody targeting the C5 complement protein. Clinical trials suggest that eculizumab significantly reduces transfusion requirements and prevents disease complications in patients with paroxysmal nocturnal hemoglobinuria (PNH). To analyze the outcome of pregnancies among Polish women with PNH treated with eculizumab as a part of the Polish National Health Fund program. We report the outcomes of 3 pregnancies among women treated with eculizumab between 2017 and 2020. For 1 of these woman, it was the 1st pregnancy, while the remaining 2 patients had previously had 1 previous successful pregnancy each. All 3 mothers survived pregnancy, and all children were born alive. One of the patients had a vaginal delivery. Another required cesarean delivery at the 34th week due to a decreasing platelet count. In 1 case, premature rupture of the fetal membranes occurred at week 36, followed by artificial labor induction. All children were born without any inborn defects. The 2 prematurely born babies required a prolonged hospital stay. Treatment with eculizumab seems to reduce the risk to a mother and a child associated with PNH. However, more data are necessary to confirm this notion.

Atypical hemolytic uremic syndrome induced by SARS-CoV2 infection in infants with EXOSC3 mutation.

BackgroundAtypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by systemic thrombotic microangiopathy mainly in the kidneys and mostly due to genetic disorders leading to uncontrolled activation of the complement system. Severe complications of SARS-CoV2 infection are linked to microvascular injury and complement activation is suspected to play a role in the pathogenesis of endothelial cell damage in severe COVID-19.MethodsWe present the first two cases of aHUS triggered by SARS-CoV-2 infection in two unrelated infants with the same mutation in the RNA exosome gene EXOSC3. This mutation is known to cause pontocerebellar hypoplasia type 1b, an autosomal-recessive neurodegenerative disease. So far, no kidney involvement in affected persons was reported.ResultsAs eculizumab treatment was unsuccessful and complement-mediated disorders were ruled out, we suppose that the atypical HUS in our two patients is not due to complement-mediated thrombotic microangiopathy but rather due to a dysfunction of the RNA exosome.ConclusionsThe RNA exosome is crucial for the precise processing and degradation of nuclear and cytoplasmatic RNA. We suspect that the SARS-CoV-2 infection led to changes in RNA that could not be offset by the defective RNA exosome in our two patients. The accumulation/wrong processing of the viral RNA must have led to the endothelial cell damage resulting in aHUS. This would be a new — “RNA-induced” — mechanism of aHUS.

MO316: Eculizumab for Adult Patients With Atypical Haemolytic-Uremic Syndrome: Full Dataset Analysis of Post-Marketing Surveillance in Japan

Abstract BACKGROUND AND AIMS Atypical haemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) associated with dysregulation of the alternative complement pathway [1]. It is characterized by microangiopathic haemolytic anaemia, thrombocytopenia and acute kidney injury [1]. In the USA, two adults per million develop aHUS each year, whereas 1 to 2 patients per million are estimated in Japan [2, 3]. Eculizumab has been approved for aHUS in Japan since 2013. A regulatory-mandated post-marketing surveillance (PMS) was conducted in a real-world setting from September 2013 to July 2018, for which an interim analysis has been published [3]. Here, we report the findings from the full data set analysis of the data from the PMS. METHOD The PMS enrolled adult patients diagnosed with aHUS and treated with at least one dose of eculizumab. The patients without underlying diseases, i.e. autoimmune diseases, drugs, infection, malignant tumours, metabolic disorders or transplantation, were evaluated for serious adverse events (SAE) and clinical effectiveness endpoints, i.e. haematologic normalization, platelet count (PLT) normalization, lactic dehydrogenase (LDH) normalization, a decrease of ≥ 25% in serum creatinine (sCr) levels, TMA event-free status and a complete TMA response (haematologic normalization and a ≥ 25% decrease in sCr that persisted for ≥ 4 weeks during eculizumab treatment). In addition, the difference of baseline (i.e. at treatment initiation of eculizumab) patient characteristics between patients who met and did not meet effectiveness endpoints was evaluated. RESULTS In this analysis, 79 adult patients were included; the median age was 54.0 years. Median eculizumab treatment duration was 30 weeks. The total exposure time of eculizumab was 75.51 person-years and 94 SAEs (1.24 per person-years) were reported in 39 patients. No unexpected safety signals were identified in this population by the end of observation. No meningococcal infection was reported throughout the observation period. Mean PLT (P &amp;lt; .001), LDH (P &amp;lt; .05) and estimated glomerular filtration rate (P &amp;lt; .01) were significantly improved after 7 days. Complete TMA response, haematologic normalization, PLT normalization, LDH normalization, improvement of sCr levels, and TMA event-free status were met by 35.3%, 40.4%, 49.2%, 50.0%, 51.3% and 50.0% of patients, respectively. Median treatment duration was shorter in patients who did not meet complete TMA response than in patients who met (6 weeks versus 114 weeks; P &amp;lt; .001). Multivariate analysis suggested that the time from most recent TMA to eculizumab treatment (OR 0.899; P = .007) and the days of plasma therapy (OR 0.807; P = .008) were negatively associated with improvement of sCr levels. CONCLUSION The percentages of patients who met effectiveness endpoints were similar to the interim analysis [3], yet the percentages of patients who met complete TMA responses were lower than in clinical trials [4]; the disparity in these outcomes could be attributed to the differences between clinical and real-world studies. This PMS analysis further demonstrated the safety and effectiveness of eculizumab in Japanese patients with aHUS in a real-world setting.

FC 115: Long-Term Outcomes in Eculizumab-Treated Kidney Transplant Patients Enrolled in the Global Atypical Haemolytic Uraemic Syndrome Registry

Abstract BACKGROUND AND AIMS The global atypical haemolytic uraemic syndrome (aHUS) registry (NCT01522183), the largest repository of real-world data on patients with aHUS, provides key insights into disease course, natural history, and patient (pt) outcomes with and without complement inhibitor therapy. Prior to eculizumab availability, pts with aHUS had a reportedly high risk of disease recurrence and graft loss following a kidney transplant (KTx). We report the long-term clinical outcomes of eculizumab-treated pts who received a KTx. METHOD This analysis included pts enrolled from April 2012–November 2021. Pts were included in a long-term treatment outcomes study if they had ever been treated with eculizumab and were excluded if they had DGKE mutations or their diagnosis was later revised to any condition other than aHUS. The current analysis set included pts who had received a KTx no more than 30 days prior to eculizumab start or up to 60 days post eculizumab start date, had ≥3 years of follow-up (FU) post-transplant and had serum creatinine (SCr) measurements at baseline (BL) and post 3 years FU. Changes in kidney function, haematological parameters and clinical characteristics at last follow-up (LFU) were assessed. RESULTS A total of 329/1970 adult and paediatric registry pts met the inclusion criteria and received a KTx; 78 pts from 12 countries met sub-group inclusion criteria. BL demographics are shown in Table 1. Mean (SD) treatment duration was 5.7 (2.4) years and 47 (60%) pts had pathogenic genetic variants. Lab parameters at BL (closest measurement at or following KTx) and LFU are reported in Table 2. Despite large ranges, median SCr levels remained stable at LFU. Median eGFR and platelet levels were similar at BL and LFU, while lower median lactose dehydrogenase levels were seen at LFU. At LFU: four pts (5%)—three adult—had subsequent KTx(s); eight (10%)—seven adults—had received dialysis by last observation; and two (3%) had received plasma exchange/infusion. Two pts (3%) died during the observation period. CONCLUSION This study assessed a large, real-world population of pts at high risk of KTx failure. Lab parameters suggest most pts benefitted from eculizumab treatment, with few TMA-related complications and stable kidney function and haematological parameters for ≥3 years. Overall, the proportions of female pts and of pts with pathogenic genetic variants were consistent with previous studies. A potential study limitation was the relatively stringent sub-population-specific inclusion criteria. However, these data further demonstrate the beneficial impact of eculizumab treatment in the long-term management of aHUS in pts requiring KTx.

Real-world experience of eculizumab treatment for generalized myasthenia gravis: initial data from a registry of patients with generalized myasthenia gravis in the USA (S25.006)

Real-world experience of eculizumab treatment for generalized myasthenia gravis: initial data from a registry of patients with generalized myasthenia gravis in the USA (S25.006)

Eculizumab for paediatric patients with atypical haemolytic uraemic syndrome: full dataset analysis of post-marketing surveillance in Japan.

Eculizumab was approved for atypical haemolytic uraemic syndrome (aHUS) in Japan in 2013. Post-marketing surveillance (PMS) was mandated by regulatory authorities to assess the safety and effectiveness of eculizumab in patients with aHUS in a real-world setting. Paediatric patients in the PMS cohort who were <18 years of age at the first administration of eculizumab and diagnosed with aHUS [excluding Shiga toxin-producing Escherichia coli HUS, thrombotic thrombocytopaenic purpura and secondary thrombotic microangiopathy (TMA)] were included in the effectiveness and safety analysis. Clinical endpoints of effectiveness [complete TMA response, TMA event-free status, platelet (PLT) count and lactate dehydrogenase (LDH) normalization, serum creatinine (sCr) decrease and estimated glomerular filtration rate (eGFR) improvement] were analysed in patients treated with at least one dose of eculizumab. Serious adverse events (SAEs) were also evaluated. A total of 40 paediatric patients (median age 5 years) were included. The median eculizumab treatment duration was 66 weeks. PLT count, LDH and eGFR significantly improved at 10 days post-treatment. Complete TMA response, haematologic normalization, sCr decrease, eGFR improvement and TMA event-free status were achieved by 73.3%, 73.3%, 70.0%, 78.3% and 77.5% of patients, respectively. Discontinuation criteria were met by 18 patients: 13 patients maintained treatment discontinuation at the end of observation and 5 patients, including 1 patient with aHUS relapse, continued the treatment but extended the treatment interval. During eculizumab treatment, 59 SAEs (0.66/person-year) were reported. Although four deaths were reported, none of them were related to eculizumab. Eculizumab was well tolerated and effective for paediatric patients with aHUS in the real-world setting in Japan.

Discontinuation of Eculizumab treatment after hematological remission in patients with atypical and drug-induced hemolytic uremic syndrome.

Introduction. The aim was to evaluate the effect of therapeutic plasma exchange (TPE) and eculizumab on hematological and renal survival in atypical hemolytic uremic syndrome (aHUS), and additionally, to examine the reliability of discontinuation of eculizumab treatment.Methods. This was an observational and retrospective study of 18 patients diagnosed with aHUS.Results. The median age of the study population was 30 (22-66) years. Four of 18 patients achieved hematological remission with the TPE alone. However, one patient died after three sessions of TPE. Eculizumab was used in 13 patients and no death was observed. One year after treatment, improved kidney function was observed in 2 of 3 (66%) patients for TPE and 5 of 9 (56%) patients for Eculizumab. We discontinued eculizumab treatment in 9 patients. One of the patients who had a C3 gene mutation experienced disease relapse after Eculizumab discontinuation. None of the patients who had drug associated aHUS developed disease relapse after Eculizumab discontinuation.Conclusion. Eculizumab treatment is a life-saving therapy in aHUS. Treatment discontinuation may be considered at least six months after hematologic remission in patients who had stable renal function or no expectancy for renal survival. Moreover, drug-associated cases seem to tend not to develop disease relapse in the long term.

Quantifying the economic effects of ravulizumab versus eculizumab treatment in patients with atypical hemolytic uremic syndrome

Aims This study compared the aggregate duration of treatment administration of approved eculizumab and ravulizumab treatment regimens and resultant productivity implications for patients with atypical hemolytic uremic syndrome (aHUS) and their caregivers. Methods The aggregate duration of treatment administration (which includes waiting time for medication preparation and time for infusion, recovery, and travel to and from the clinic) was determined for a hypothetical population of patients with aHUS treated with eculizumab (10 mg/mL) or ravulizumab (10 or 100 mg/mL), in the clinic or at home, for 1 year, in Germany, Italy, the UK, and the US. The data for US patients treated in the clinic was used to extend a previously published cost-minimization model (CMM) to estimate the annual lost productivity associated with treatment administration and to compare the overall annual treatment costs for hypothetical adult and pediatric patients in the US. Results The aggregate duration of treatment administration associated with ravulizumab 10 mg/mL and 100 mg/mL was reduced by 44–52% and 69–74%, respectively, compared with eculizumab 10 mg/mL, across all four countries. Using the CMM, the adult and pediatric US patient lost productivity costs due to treatment were reduced by 56–60% and 73–76% with ravulizumab 10 mg/mL and 100 mg/mL, respectively, compared with eculizumab 10 mg/mL, and overall discounted annual treatment costs (direct and lost productivity costs owing to treatment) were reduced for ravulizumab (10 mg/mL and 100 mg/mL) vs eculizumab 10 mg/mL for adult and pediatric patients. Limitations This study was based on hypothetical patients, and assumptions were made regarding caregiver involvement, patient characteristics, and treatment patterns. Conclusions Compared with eculizumab, ravulizumab reduces the lost productivity costs associated with treatment. This reduction in costs is greater with the ravulizumab 100 mg/mL formulation, compared with ravulizumab 10 mg/mL, owing to shorter infusion times with this more concentrated formulation.

Long-term follow-up of patients with paroxysmal nocturnal hemoglobinuria treated with eculizumab: post-marketing surveillance in Japan.

All Japanese patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with eculizumab were enrolled in post-marketing surveillance (PMS) between June 2010 and August 2019 to assess the long-term effectiveness and safety of eculizumab. The reduction in intravascular hemolysis, the change in hemoglobin (Hb) level, and the change in renal function were assessed to determine the effectiveness of eculizumab. The types and frequencies of adverse events (AEs) were assessed to determine its safety. A total of 632 patients were enrolled and the median treatment duration was 3.6years. Treatment with eculizumab significantly reduced lactate dehydrogenase (LDH) levels and significantly increased Hb levels. These changes were maintained for up to 5years of treatment. An estimated glomerular filtration rate ≥ 60ml/min/1.73m2 and higher LDH level at baseline were associated with increases in Hb levels during eculizumab treatment. The overall incidence of any AE was 69.92/100 patient-years. Hemolysis was the most common AE (6.43/100 patient-years). The incidence of infection-related AEs was 20.57/100 patient-years, and included meningococcal infection in three patients (0.12/100 patient-years). This long-term follow-up of patients with PNH demonstrated the sustained effectiveness of eculizumab and supports its well-established safety profile.

Eculizumab treatment and discontinuation in pediatric patients with atypical hemolytic uremic syndrome: a multicentric retrospective study.

Eculizumab is effective treatment of pediatric atypical hemolytic uremic syndrome (aHUS). However, the optimal duration of treatment is not clearlydefined. The aim of this study was to retrospectively analyze the outcome of pediatric patients with aHUS, who started eculizumab treatment but discontinued it during the follow-up period. The clinical and laboratory findings of the pediatric patients with aHUS were recorded on a web-based, national registry system, known as the Turkish aHUS Registry. The study included 63 patients who had to have received more than four doses of eculizumab duringthe acute phase of the disease. The median age at diagnosis was 3.62 (IQR: 1.29-6.14) years. During the follow-up period, 39 patients continued to receive standard eculizumab treatment (standard treatment group, treatment every 2 weeks) while 24 received an extended dose of eculizumab at three-four-week intervals (non-standard treatment group). There was no significant difference between both groups in terms of clinical and laboratory parameters. Eculizumab treatment was discontinued in 18 patients (30.7%, F/M:11/7), and the median age of these patients at diagnosis and their median follow-up duration were 4.0 (IQR:2.7-10.2) and 4.2 (IQR:2.2-7) years respectively. The median eGFR at the last visit was 110 (84.7-146.1)ml/min/1.73 m2. Fourteen patients remained in remission without any sign of the disease. Recurrence occurred in four (22.2%) patients, inwhich eculizumab was immediately started again and completeremission was achieved. Eculizumab is a successful treatment option in pediatric patients with aHUS and it can be safely discontinued with close monitoring in a selected group of patients. In case of recurrence, eculizumab should be restarted immediately to achieve complete remission.

Eculizumab treatment in atypical hemolytic uremic syndrome: correlation between functional complement tests and drug levels.

Atypical hemolytic uremic syndrome (aHUS) is characterized by platelet consumption, hemolysis, and renal injury. Eculizumab, a humanized antibody that blocks complement activity, has been successfully used in aHUS, but the best treatment schedule has not yet been clearly defined. Herein we report our experience with eculizumab maintenance treatment, in which the interval between subsequent doses was adjusted based on classical complement pathway (CCP) activity, targeted to < 30% for the prevention of relapses. Trough circulating levels of free eculizumab were determined by an immunoenzymatic method. Genetic and serologic characteristics of the patients were also assessed. We report on 38 patients with aHUS with a median age of 25.0years (range 0.5-60.0years) treated with eculizumab. Once stable disease remission was obtained, the interval between eculizumab doses was extended based on target CCP activity. With this approach, presently, 22 patients regularly receive eculizumab infusion every 28days and 16 receive it every 21. During a median observation period of 32.3months (range 4.0-92.4months) and a cumulative period of 1295months, no patient relapsed. An inverse correlation between CCP activity and eculizumab circulating levels was present (r = -0.690, p = 0.0001), with CCP activity being inhibited as long as free eculizumab was measurable in serum. In patients with aHUS on eculizumab maintenance treatment, complement activity measurement can be used as a proxy for circulating levels of the drug. Monitoring complement activity allows for safe tailoring of the frequency of eculizumab administration, thus avoiding excessive drug exposure while keeping the disease in remission.

Retrospective evaluation of patients with diagnosis of atypical hemolytic uremic syndrome: Single center experience

Background To evaluate the demographic, clinical, laboratory findings, genetic results and final status of patients followed-up with the diagnosis of atypical hemolytic uremic syndrome (aHUS) Materials and methods Patients who were diagnosed and followed up in our pediatric nephrology center between January 2013 and June 2021 were included in the study retrospectively. Demographic data, history, age at diagnosis, physical examination, laboratory tests, organ involvement, genetic results, treatments, renal replacement therapies, follow-up and final status were evaluated. Results A total of 14 patients, 9 girls (64.3%) and 5 boys (35.7%) were included in our study over a period of 8 years. The mean age at presentation was 66.7±54.1 months (5.5±4.5 years) and the follow-up period in our center was 50.7±37.1 months. Recurrence was detected in 4 patients (28.6%) 18.5±20.4 months after diagnosis. In six of our patients (42.8%) neurological involvement was detected; 5 (35.7%) had hypertensive features and 1 (7.1%) had disease involvement. MCP mutation was detected in 4 patients (28.6%), CFH mutation in 3 patients (21.4%), and CFHR1-CFHR3 mutation in 3 patients (21.4%). While a total of 4 patients (28.6%) died in our center, 10 patients (71.4%) are still being followed up and treated. From these patients one is followed up with fresh frozen plasma therapy and the rest with eculizumab therapy. Conclusion: In conclusion we wanted to present our patients who were diagnosed with aHUS in our center in a period of eculizumab availability in our country. Satisfactory results were detected with eculizumab treatment who did not respond to plasmaphresis and/or plasma treatment. We think that eculizumab treatment may be the first choice considering with detailed genetic analysis (including antifactor H antibody) in the light of future multicenter studies with larger of patients.

Safety and efficacy of pegcetacoplan in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, hematologic disease characterized by complement-mediated hemolysis, thrombosis, and various degrees of bone marrow dysfunction. Until recently, C5 inhibition with eculizumab or ravulizumab represented the only therapies approved for patients with PNH by the United States Food and Drug Administration (US FDA). Although C5-inhibitors reduce PNH-related signs and symptoms, many patients continue to exhibit persistent anemia and require frequent blood transfusions. In May 2021, pegcetacoplan became the third US FDA-approved treatment for adults with PNH, and the first to target C3, a complement component upstream of C5. The novel strategy of inhibiting proximal complement activity with pegcetacoplan controls C5-mediated intravascular hemolysis and prevents C3-mediated extravascular hemolysis. Here, we review the results from multiple pegcetacoplan clinical studies on the efficacy and safety of pegcetacoplan treatment in adults with PNH. This review summarizes findings from three studies in complement-inhibitor-naïve patients with PNH (PADDOCK [phase Ib], PALOMINO [phase IIa], PRINCE [phase III; pegcetacoplan versus standard treatment excluding complement-inhibitors]), and one phase III study (PEGASUS) that compared eculizumab to pegcetacoplan in patients who remained anemic (hemoglobin levels < 10.5 g/dL) despite stable eculizumab treatment (⩾3 months). These studies found that pegcetacoplan contributed to superior improvements in primary and secondary endpoints related to hemoglobin levels and other hematologic parameters and provided effective management of anemia and anemia-related complications (i.e. transfusion burden, reticulocyte production, and fatigue). Furthermore, we summarize results from the 32-week open-label period from the PEGASUS trial, which confirmed the long-term safety and durable efficacy of pegcetacoplan as demonstrated by sustained improvements in clinical and hematologic outcomes in pegcetacoplan-treated patients. Pegcetacoplan is approved for the treatment of adults with PNH in the United States (Empaveli™) and for adult patients who remain anemic after at least 3 months of stable C5-inhibitor therapy in the European Union (Aspaveli®) and Australia (Empaveli; also approved for patients intolerant to C5-inhibitors).

Plasma Exchange Therapy Using Solvent Detergent-Treated Plasma: An Observational Pilot Study on Complement, Neutrophil and Endothelial Cell Activation in a Case Series of Patients Suffering from Atypical Hemolytic Uremic Syndrome.

Plasma exchange therapy (PEX) was standard treatment for thrombotic microangiopathy before eculizumab was available and is still widely applied. However, most PEX patients still ultimately progress to end-stage renal disease (ESRD). It has been suggested that infusion of plasma that contains active complement may induce additional complement activation with subsequent activation of neutrophils and endothelial cells, leading to exacerbation of organ damage and deterioration of renal function. This observational pilot study examines the effect of hemodialysis, eculizumab and PEX before and after treatment in plasma of aHUS patients on complement-, neutrophil and endothelial cell activation. Eleven patients were included in this pilot study. Six patients were treated with hemodialysis, 2 patients received regular infusions of eculizumab, and 3 patients were on a regular schedule for PEX. Patients were followed during 3 consecutive treatments. Blood samples were taken before and after patients received their treatment. Complement activation products increased in plasma of patients after PEX, as opposed to patients treated with hemodialysis or eculizumab. Increased levels of complement activation products were detected in omniplasma used for PEX. Additionally, activation of neutrophils and endothelial cells was observed in patients after hemodialysis and PEX, but not in patients receiving eculizumab treatment. In this pilot study we observed that PEX induced complement and neutrophil activation, and that omniplasma contains significant amounts of complement activation products. Additionally, we demonstrate that hemodialysis induces activation of neutrophils and endothelial cells. Complement activation with subsequent neutrophil activation may contribute to the deterioration of organ function and may result in ESRD. Further randomized controlled studies are warranted to investigate the effect of PEX on complement- and neutrophil activation in patients with thrombotic microangiopathy.