Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial.

BACKGROUND: Symptoms of anaemia due to clinically significant extravascular haemolysis can affect patients with paroxysmal nocturnal haemoglobinuria (PNH) treated with C5 inhibitors (ravulizumab or eculizumab). The aim of this study was to assess the efficacy and safety of danicopan (ALXN2040), an investigational, first-in-class, oral complement factor D inhibitor, as add-on therapy to ravulizumab or eculizumab in patients with PNH and clinically significant extravascular haemolysis. METHODS: ALPHA is an ongoing, international, phase 3, randomised, double-blind, placebo-controlled trial evaluating danicopan as add-on therapy to ravulizumab or eculizumab. Eligible patients were adults (age ≥18 years) with PNH and clinically significant extravascular haemolysis (haemoglobin ≤9·5 g/dL; absolute reticulocyte count ≥120 × 109/L) on ravulizumab or eculizumab for at least 6 months. Patients were randomly assigned (2:1) to danicopan or placebo added to ravulizumab or eculizumab for 12 weeks using an interactive response technology system. Randomisation was stratified based on transfusion history, haemoglobin, and patients enrolled from Japan. The initial oral danicopan dose was 150 mg three times a day; escalation to 200 mg three times a day was permitted based on clinical response. The infusion dose level of eculizumab (every 2 weeks) ranged from 900 mg to 1500 mg, and for ravulizumab (monthly or every 8 weeks) ranged from 3000 mg to 3600 mg. The primary endpoint was change in haemoglobin concentration from baseline to week 12. Here we present the protocol-prespecified interim analysis, planned when approximately 75% of participants were randomly assigned to treatment and completed or discontinued at 12 weeks. This trial is registered with ClinicalTrials.gov (NCT04469465). FINDINGS: Individuals were randomly assigned between Dec 16, 2020, and Aug 29, 2022. At data cutoff (June 28, 2022), 73 individuals were randomly assigned, received treatment, and were analysed for safety (danicopan, n=49; placebo, n=24). The protocol-prespecified interim efficacy analysis set included the first 63 participants (danicopan, n=42; placebo, n=21). At week 12, danicopan plus ravulizumab or eculizumab increased haemoglobin versus placebo plus ravulizumab or eculizumab (least squares mean [LSM] change from baseline: danicopan, 2·94 g/dL [95% CI 2·52 to 3·36]; placebo, 0·50 g/dL [-0·13 to 1·12]; LSM difference, 2·44 g/dL [1·69 to 3·20]; p<0·0001). Grade 3 adverse events in the danicopan group were increased alanine aminotransferase (two [4%] of 49 patients), leukopenia (one [2%]), neutropenia (two [4%]), cholecystitis (one [2%]), COVID-19 (one [2%]), increased aspartate aminotransferase (one [2%]), and increased blood pressure (one [2%]), and in the placebo group were anaemia (one [4%] of 24 patients), thrombocytopenia (one [4%]), and asthenia (one [4%]). The serious adverse events reported in the danicopan group were cholecystitis (one [2%] patient) and COVID-19 (one [2%]) and in the placebo group were anaemia and abdominal pain, both in one (4%) patient. There were no serious adverse events related to study drug or deaths reported in the study. INTERPRETATION: These primary efficacy and safety results show that danicopan as add-on treatment to ravulizumab or eculizumab significantly improved haemoglobin concentrations at week 12 with no new safety concerns, suggesting an improved benefit-risk profile in patients with PNH and clinically significant extravascular haemolysis. FUNDING: Alexion, AstraZeneca Rare Disease.

[Novel therapeutic agents for hemolytic anemia].

In recent years, it has become clear that various diseases are caused by complement (related molecule) abnormalities (complementopathies) or are exacerbated by complement (complement-related diseases), and novel therapeutic agents targeting complement (anti-complement agents) are now being developed. Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disorder characterized by complement-mediated intravascular hemolysis due to a deficiency of complement regulatory factors, making it a perfect candidate for anti-complement agents. In 2007, the anti-C5 monoclonal antibody eculizumab was approved for PNH, as the first anti-complement agent. The indications for eculizumab are expanding, and aggressive development is underway for new anti-complement agents, not only for PNH but also a variety of other diseases. In addition, the anti-C1s antibody sutimlimab was approved last year for the treatment of cold agglutinin disease, a form of autoimmune hemolytic anemia. This presentation overviews novel anti-complement agents for these hemolytic anemias.

A longitudinal analysis of paroxysmal nocturnal haemoglobinuria-type cells in patients with bone marrow failure: Results of a prospective multi-centre study in Japan.

To determine the prevalence and clinical relevance of glycosylphosphatidylinositol-anchored protein-deficient (GPI[-]) cell populations (paroxysmal nocturnal haemoglobinuria [PNH]-type cells) in patients with acquired aplastic anaemia (AA) or myelodysplastic syndrome (MDS), we prospectively studied peripheral blood samples of 2402 patients (1075 with AA, 900 with MDS, 144 with PNH, and 283 with other anaemia) using a high-sensitivity flow cytometry assay in a nationwide multi-centre observational study. PNH-type cells were detected in 52.6% of AA and 13.7% of MDS patients. None of the 35 patients with refractory anaemia (RA) with ringed sideroblasts or the 86 patients with RA with excess of blasts carried PNH-type cells. Among the 317 patients possessing PNH-type granulocytes, the percentage of PNH-type granulocytes increased by ≥10% in 47 patients (14.8%), remained unchanged in 240 patients (75.7%), and decreased by ≥10% in 30 patients (9.5%) during 3 years of follow-up. PNH-type granulocyte expansion occurred more frequently (27.1%) in the 144 patients who originally carried PNH-type granulocytes ≥1% than in the 173 patients with PNH-type granulocytes <1% (4.6%). This study confirmed that PNH-type cells are undetectable in authentic clonal MDS patients, and the presence of ≥1% PNH-type granulocytes predicts a higher likelihood of PNH-type cell expansion than with <1% PNH-type granulocytes.

[Novel anti-complement therapeutics for hemolytic anemia].

The anti-C5 antibody eculizumab was approved in 2007 as the first anti-complement agent for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). While eculizumab's indication has been expanded to include other diseases, the development of new anti-complement agents has been aggressively pursued for various diseases. In PNH, the anti-C5 recycling antibody ravulizumab, which is an improved version of eculizumab, has been developed, with an extended dosing interval of 2 to 8 weeks, vastly improving convenience. The treatment of PNH with terminal complement inhibitors such as eculizumab and ravulizumab presents a new challenge-extravascular hemolysis. To address this issue, the proximal complement inhibitor, a C3 inhibitor called pegcetacoplan, was approved in the United States of America. Furthermore, the amplification loop inhibitors-a factor B inhibitor iptacopan, and a factor D inhibitor danicopan-are being developed. Recently, the anti-C1s antibody sutimlimab was approved for the treatment of cold agglutinin disease, a type of autoimmune hemolytic anemia. This article discusses novel anti-complement therapies for hemolytic anemia.

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.

Interim analysis of post-marketing surveillance of ravulizumab for paroxysmal nocturnal hemoglobinuria in Japan.

Ravulizumab is a long-acting C5 inhibitor available for treating paroxysmal nocturnal hemoglobinuria (PNH). Post-marketing surveillance (PMS) was implemented following its approval in September 2019 in Japan. We report safety data obtained through to December 2021 for 218 patients and effectiveness data for 194 patients (182 switched from eculizumab and 12 complement inhibitor-naïve). Over a median follow-up of 74.4 weeks, 193 adverse events (AEs) were reported in 66/218 patients (30.3%; incidence 72.73/100 patient-years). The two most frequent AEs were anemia and pyrexia (each 3.01/100 patient-years). The incidence of serious AEs was 36.93/100 patient-years. In patients who switched from eculizumab, lactate dehydrogenase (LDH) and hemoglobin (Hb) levels were maintained over 26 weeks of ravulizumab treatment. In complement inhibitor-naïve patients, LDH decreased significantly and Hb increased significantly over 26 weeks of ravulizumab treatment. These data for Japanese patients with PNH who were naïve to complement inhibitors and patients who switched from eculizumab show that the safety and effectiveness of ravulizumab are consistent with the published clinical trial data. However, transfusion independence was less likely in patients with bone marrow failure. Further follow-up data from this PMS will help to elucidate the long-term clinical safety and effectiveness of ravulizumab for treating PNH.

Crovalimab treatment in patients with paroxysmal nocturnal haemoglobinuria: Long-term results from the phase I/II COMPOSER trial.

OBJECTIVES: This study reports long-term outcomes from the open-label extension (OLE) period of the Phase I/II COMPOSER trial (NCT03157635) that evaluated crovalimab in patients with paroxysmal nocturnal haemoglobinuria, who were treatment-naive or switched from eculizumab at enrolment. METHODS: COMPOSER consists of four sequential parts followed by the OLE. The primary OLE objective was to assess long-term crovalimab safety, with a secondary objective to assess crovalimab pharmacokinetics and pharmacodynamics. Exploratory efficacy endpoints included change in lactate dehydrogenase (LDH), transfusion avoidance, haemoglobin stabilisation and breakthrough haemolysis (BTH). RESULTS: A total 43 of 44 patients entered the OLE after completing the primary treatment period. Overall, 14 of 44 (32%) experienced treatment-related adverse events. Steady state exposure levels of crovalimab and terminal complement inhibition were maintained over the OLE. During the OLE, mean normalised LDH was generally maintained at ≤1.5× upper limit of normal, transfusion avoidance was achieved in 83%-92% of patients and haemoglobin stabilisation was reached in 79%-88% of patients across each 24-week interval. Five BTH events occurred with none leading to withdrawal. CONCLUSIONS: Over a 3-year median treatment duration, crovalimab was well tolerated and sustained C5 inhibition was achieved. Intravascular haemolysis control, haemoglobin stabilisation and transfusion avoidance were maintained, signifying long-term crovalimab efficacy.

[Japanese patient preferences between ravulizumab and eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria].

Ravulizumab is the first long-acting complement inhibitor approved for paroxysmal nocturnal hemoglobinuria (PNH) treatment. We evaluated patient preference for ravulizumab or eculizumab among Japanese adults with PNH. The ALXN1210-PNH-301 (NCT02946463) and ALXN1210-PNH-302 (NCT03056040) studies included 23 Japanese adults who are enrolled in complement inhibitor treatment-naive and eculizumab (≥6 months) treatment. Patient preference was assessed using the PNH-specific patient preference questionnaire (PNH-PPQ©). Most patients preferred ravulizumab (19/23, 82.6%), none preferred eculizumab, and four (17.4%) reported no preference (χ2 test, p<0.005). The preference for ravulizumab was driven by its lower infusion frequency (every 8 weeks) compared with eculizumab (every 2 weeks). The included Japanese patients with PNH preferred ravulizumab because of its reduced infusion frequency, which increases activity planning ability, treatment convenience, and overall quality of life, as compared with eculizumab. These data provide useful insight into patient perspectives and may aid decision-making for PNH treatment.

Mitigating Drug-Target-Drug Complexes in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Switch C5 Inhibitors.

Drug-target-drug complexes (DTDCs) are phenomena newly observed in patients who switch from the complement component 5 (C5) inhibitor eculizumab to crovalimab, a novel, anti-C5 antibody in development for paroxysmal nocturnal hemoglobinuria (PNH), because these agents bind to different C5 epitopes. In Part 3 of the four-part, phase I/II COMPOSER study, 19 patients with PNH switching from eculizumab received 1,000-mg crovalimab intravenously, then subcutaneous maintenance doses from Day 8 (680 mg every 4 weeks (q4w), 340 mg every 2 weeks, or 170 mg every week). Crovalimab exposure was transiently reduced, and size-exclusion chromatography and crovalimab-specific enzyme-linked immunosorbent assays revealed DTDCs in all 19 patients' sera. Additionally, self-limiting mild to moderate symptoms suggestive of type III hypersensitivity reactions occurred in two patients. Mathematical modeling simulations of DTDC kinetics and effects of dosing on DTDC size distribution using Part 3 data predicted that increased crovalimab concentrations could reduce the proportion of large, slow-clearing DTDCs in the blood. A simulation-guided, optimized crovalimab regimen (1,000 mg intravenously; four weekly, subcutaneous 340-mg doses; then 680 mg q4w from Day 29) was evaluated in Part 4. Confirming the model's predictions, mean proportions of large DTDCs in patients who switched from eculizumab to this optimized regimen decreased by > 50% by Day 22, and target crovalimab concentrations were maintained. No type III hypersensitivity reactions occurred in Part 4. Optimizing crovalimab dosing thus reduced the proportion of large DTDCs, ensured adequate complement inhibition, and may improve safety. Model-based dosing optimization to mitigate DTDC formation offers a useful strategy for patients switching to novel antibody treatments targeting soluble epitopes.

Medical Economic Benefit Derived from the Use of Tracing Reports by Pharmacy-Based Pharmacists for Pharmaceutical Intervention and Reduction of Leftover Medicines.

This study aimed to evaluate the effects on the medical economy of the use of tracing reports by pharmacy-based pharmacists for pharmaceutical interventions, including to reduce leftover medicines. These effects were estimated by analyzing 267 tracing reports issued by pharmacy pharmacists over a period of 1 year, 2020-2021. We estimate that these interventions created cost savings of USD108170.02/year (USD104800 via pharmaceutical interventions, USD3370.02 via interventions to reduce leftover medicines). The cost savings from pharmaceutical interventions prompted by patient follow-up was estimated to be USD47650. The medical economic effect per tracing report was estimated to be USD392.51 from pharmaceutical interventions, USD12.62 from reducing leftover medicines, and USD445.33 from pharmaceutical intervention prompted by patient follow-up. Overall, therefore, pharmaceutical interventions by pharmacy pharmacists using tracing reports, including those designed to reduce leftover medicines, may benefit the medical economy.

Two Case Studies on Inferior Mesenteric Artery Embolization for Primary Postpartum Hemorrhage.

Postpartum hemorrhage (PPH) remains a leading cause of maternal mortality. Transcatheter arterial embolization (TAE) is an effective treatment option for PPH. Among the vessels embolized, the inferior mesenteric artery (IMA) is usually not the first choice for TAE, because it is a rare source of bleeding in PPH. In this report, we describe our experience with two patients with PPH, in whom the IMA was selected on the basis of contrast-enhanced computed tomography (CECT) findings, and prompt hemostasis was achieved with TAE. CECT can provide useful clues as to the culprit artery based on the anatomical location of the hematoma and extravasation. These useful findings of CECT allow prompt TAE of rare sources of bleeding in PPH, such as the IMA.

The role of the alternative pathway in paroxysmal nocturnal hemoglobinuria and emerging treatments.

INTRODUCTION: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled activation of the terminal complement pathway, leading to intravascular hemolysis (IVH) and a prothrombotic state. Treatment with terminal complement (C5) inhibitors, the current standard of care, suppresses IVH and reduces the risk of thrombosis and the associated morbidity and mortality. Opportunities exist to further improve care by alternative modes of administration and the reduction of clinically significant anemia and transfusion dependence caused by extravascular hemolysis in some patients. AREAS COVERED: This review describes the pathophysiology of PNH, provides an overview of the current standard of care, and discusses potential avenues for enhancing patient care, with a focus on the literature describing new and emerging treatments that target the alternative pathway. Emerging treatments include biosimilars and novel C5 inhibitors as well as agents with novel mechanisms of action that target the proximal complement pathways (C3 inhibitors, factor B inhibitors, and factor D inhibitors). EXPERT OPINION: Alternative complement pathway inhibitors may offer further benefit as long as terminal complement is completely inhibited to reduce IVH and disease activity. This may lead to improvements in adherence and health-related quality of life for patients with PNH.

CD8+ T-cell Responses Are Boosted by Dual PD-1/VEGFR2 Blockade after EGFR Inhibition in Egfr-Mutant Lung Cancer.

Epidermal growth factor receptor (EGFR) is the most frequently mutated driver oncogene in nonsmoking-related, non-small cell lung cancer (NSCLC). EGFR-mutant NSCLC has a noninflamed tumor microenvironment (TME), with low infiltration by CD8+ T cells and, thus, immune-checkpoint inhibitors, such as antiprogrammed cell death-1 (anti-PD-1), have weak antitumor effects. Here, we showed that CD8+ T-cell responses were induced by an EGFR-tyrosine kinase inhibitor (TKI) in syngeneic Egfr-mutant NSCLC tumors, which was further pronounced by the sequential dual blockade of PD-1 and vascular endothelial growth factor receptor 2 (VEGFR2). However, the simultaneous triple blockade had no such effect. The PD-1/VEGFR2 dual blockade did not exert tumor-inhibitory effects without pretreatment with the EGFR-TKI, suggesting that the treatment schedule is crucial for the efficacy of the dual blockade therapy. Pretreatment with EGFR-TKI increased the CD8+ T-cell/regulatory T-cell (Treg) ratio, while also increasing the expression of immunosuppressive chemokines and chemokine receptors, as well as increasing the number of M2-like macrophages, in the TME. Discontinuing EGFR-TKI treatment reversed the transient increase of immunosuppressive factors in the TME. The subsequent PD-1/VEGFR2 inhibition maintained increased numbers of infiltrating CD8+ T cells and CD11c+ dendritic cells. Depletion of CD8+ T cells in vivo abolished tumor growth inhibition by EGFR-TKI alone and the sequential triple therapy, suggesting that EGFR inhibition is a prerequisite for the induction of CD8+ T-cell responses. Our findings could aid in developing an alternative immunotherapy strategy in patients with cancers that have driver mutations and a noninflamed TME.

The importance of terminal complement inhibition in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic hematologic disorder associated with inappropriate terminal complement activity on blood cells that can result in intravascular hemolysis (IVH), thromboembolic events (TEs), and organ damage. Untreated individuals with PNH have an increased risk of morbidity and mortality. Patients with PNH experiencing IVH often present with an elevated lactate dehydrogenase (LDH; ⩾ 1.5 × the upper limit of normal) level which is associated with a significantly higher risk of TEs, one of the leading causes of death in PNH. LDH is therefore used as a biomarker for IVH in PNH. The main objective of PNH treatment should therefore be prevention of morbidity and mortality due to terminal complement activation, with the aim of improving patient outcomes. Approval of the first terminal complement inhibitor, eculizumab, greatly changed the treatment landscape of PNH by giving patients an effective therapy and demonstrated the critical role of terminal complement and the possibility of modulating it therapeutically. The current mainstays of treatment for PNH are the terminal complement component 5 (C5) inhibitors, eculizumab and ravulizumab, which have shown efficacy in controlling terminal complement-mediated IVH, reducing TEs and organ damage, and improving health-related quality of life in patients with PNH since their approval by the United States Food and Drug Administration in 2007 and 2018, respectively. Moreover, the use of eculizumab has been shown to reduce mortality due to PNH. More recently, interest has arisen in developing additional complement inhibitors with different modes of administration and therapeutics targeting other components of the complement cascade. This review focuses on the pathophysiology of clinical complications in PNH and explores why sustained inhibition of terminal complement activity through the use of complement inhibitors is essential for the management of patients with this chronic and debilitating disease.

Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial.

Sutimlimab, a first-in-class humanized immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits the classical complement pathway at C1s, rapidly halted hemolysis in the single-arm CARDINAL study in recently transfused patients with cold agglutinin disease (CAD). CADENZA was a 26-week randomized, placebo-controlled phase 3 study to assess safety and efficacy of sutimlimab in patients with CAD without recent (within 6 months prior to enrollment) transfusion history. Forty-two patients with screening hemoglobin ≤10 g/dL, elevated bilirubin, and ≥1 CAD symptom received sutimlimab (n = 22) or placebo (n = 20) on days 0 and 7 and then biweekly. Composite primary endpoint criteria (hemoglobin increase ≥1.5 g/dL at treatment assessment timepoint [mean of weeks 23, 25, 26], avoidance of transfusion, and study-prohibited CAD therapy [weeks 5-26]) were met by 16 patients (73%) on sutimlimab, and 3 patients (15%) on placebo (odds ratio, 15.9 [95% confidence interval, 2.9, 88.0; P < .001]). Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint. Sutimlimab normalized mean bilirubin by week 1. Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at week 1) and C4 normalization. Twenty-one (96%) sutimlimab patients and 20 (100%) placebo patients experienced ≥1 treatment-emergent adverse event. Headache, hypertension, rhinitis, Raynaud phenomenon, and acrocyanosis were more frequent with sutimlimab vs placebo, with a difference of ≥3 patients between groups. Three sutimlimab patients discontinued owing to adverse events; no placebo patients discontinued. These data demonstrate that sutimlimab has potential to be an important advancement in the treatment of CAD. This trial was registered at www.clinicaltrials.gov as #NCT03347422.

Long-term safety and efficacy of ravulizumab in patients with paroxysmal nocturnal hemoglobinuria: 2-year results from two pivotal phase 3 studies.

OBJECTIVES: The complement component 5 (C5) inhibitor ravulizumab demonstrated non-inferiority to eculizumab following 26 weeks of treatment in complement inhibitor-naïve and complement inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH; studies 301 and 302, respectively). This study aims to describe the results of both studies from 27 weeks to 2 years. METHODS: Patients (N = 441) continued to receive ravulizumab throughout the extension period. Efficacy endpoints included lactate dehydrogenase (LDH) normalization, transfusion avoidance and fatigue score (FACIT-F). Safety analyses were also performed. RESULTS: From 27 weeks to 2 years, improvements in LDH levels were maintained in both study populations. Transfusion avoidance was maintained in 81.9% (study 301) and 85.6% (study 302) of patients, and FACIT-F scores remained stable. Ravulizumab was well tolerated, and the incidence of adverse events (AEs) were similar between patients of both studies. Incidence of serious AEs deemed related to ravulizumab treatment was low (<3%). CONCLUSIONS: This study reports, to date, the longest period of follow-up in over 400 patients with PNH treated with ravulizumab (662 patient-years). Long-term, ravulizumab demonstrated durable efficacy and was well tolerated, highlighting the importance of C5 inhibitors as the mainstay of PNH treatment.

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 3.6 years. Treatment with eculizumab significantly reduced lactate dehydrogenase (LDH) levels and significantly increased Hb levels. These changes were maintained for up to 5 years of treatment. An estimated glomerular filtration rate ≥ 60 ml/min/1.73 m2 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.