[Expert consensus on clonal screening and monitoring of complement inhibitor therapy in paroxysmal nocturnal hemoglobinuria (2024)].

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease with abnormal hematopoietic stem cells that causes intravascular hemolytic anemia, thrombosis, and peripheral blood cytopenia. It has a chronic progressive course and can be fatal in severe cases if not treated aggressively. Complement inhibitors are the first-line recommended treatment for hemolysis-related symptoms of PNH. With the rapid development of new complement inhibitors, it is critical to quickly screen and confirm the diagnosis, identify patients with complement inhibitor indications, and monitor breakthrough hemolysis and extravascular hemolysis during complement inhibitor therapy. Drawing on the most recent guidelines, works of literature, and meta-reviews from around the world, as well as combining with experience from the experts, this consensus focused on PNH screening principles, the significance of PNH cloning detection, and post-treatment monitoring of terminal complement inhibitors, which may contribute to a better understanding of diagnosis and treatment monitoring in the era of complement inhibitors.

[Eculizumab in patients with paroxysmal nocturnal hemoglobinuria: a real-world study in China].

Objective: To evaluate the efficacy and safety of eculizumab in the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in China. Methods: Data from PNH patients who received at least 3 months of full-dose eculizumab and were followed for at least 3 months between December 2022 and July 2023 were retrospectively collected. We evaluated changes in clinical and laboratory parameters after 1, 2, 3, and 6 months of eculizumab treatment. The rates of breakthrough hemolysis (BTH), extravascular hemolysis (EVH), and the occurrence of adverse reactions were also monitored. Results: The study included nine patients, six males and three females, with a median age of 54 (28-69) years. 5 of the patients had classic PNH, while 4 had PNH/AA. The number of episodes of hemoglobinuria was 5 (1-25) per month before eculizumab. 4 patients required blood transfusion, 5 had thrombosis and one had renal impairment before eculizumab. The median time to eculizumab was 6 (3-7) months and the followup period was 3 (3-6) months after treatment. The number of episodes of hemoglobinuria following eculizumab was 0 (0-1). During the followup period, no additional thrombotic events occurred. LDH at any time after eculizumab was lower than at baseline, and some patients' HGB increased. All transfused patients became transfusion-independent after receiving eculizumab. The FACIT-Fatigue score improved by an average of 17.3 points following treatment. 2 patients developed BTH and improved with symptomatic treatment. There were three adverse events that caused mild symptoms. There are no serious adverse events or deaths. Conclusion: Eculizumab can effectively control the hemolytic-related symptoms of PNH in China, reducing the need for blood transfusions to some extent, while also demonstrating a higher safety profile.

Safety Profile of Monoclonal Antibodies and Subsequent Drug Developments in the Treatment of Paroxysmal Nocturnal Hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal stem cell disease characterized by intravascular hemolysis due to the targeting of affected red blood cells by the complement system. Eculizumab and ravulizumab are two monoclonal antibodies that inhibit the complement system's components and have been shown to significantly improve survival and quality of life. This review describes the role of these monoclonal antibodies in the treatment of PNH with an emphasis on their safety profile. The challenges in the use of these drugs and new drugs in various stages of drug development are also described, which may be helpful in addressing some of these challenges.

Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).

Management of acute breakthrough hemolysis with intensive pegcetacoplan dosing in patients with PNH.

ABSTRACT: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated intravascular hemolysis leading to anemia, fatigue, and potentially life-threatening thrombotic complications. Breakthrough hemolysis (BTH) was first described in patients with PNH treated with terminal complement C5 inhibitors when intravascular hemolysis reoccurred despite treatment. Pegcetacoplan, the first proximal complement C3 inhibitor, offers broad hemolysis control in patients with PNH. While experience of managing BTH on C5 inhibitors is documented, very limited guidance exists for proximal complement inhibitors. This interim analysis assessed the effect of intensive treatment with pegcetacoplan following an acute BTH event in a subset of patients enrolled in the ongoing open-label extension study of pegcetacoplan in PNH. Thirteen patients with acute BTH included in the analysis received either a single IV dose of 1080 mg (n = 4) or 1080 mg subcutaneous (SC) dosing on 3 consecutive days (n = 9). A potential, clinically-relevant complement-amplifying condition, such as infection or vaccination, was reported in approximately half of the patients experiencing an acute BTH. Lactate dehydrogenase (LDH) levels decreased between day 1 and day 2 in 8 of 12 evaluable patients and in all 13 patients at day 7 to 12. Nine of 13 patients (69%) achieved LDH <2× the upper limit of normal by day 14 to 19. All adverse events associated with the acute BTH event were considered resolved by the investigators. Overall, intensive treatment with pegcetacoplan was safe and well tolerated. These novel data support effective management of acute BTH events in patients on pegcetacoplan with intensive IV or SC pegcetacoplan dosing. This trial was registered at www.clinicaltrials.gov as #NCT03531255.

Ravulizumabe no tratamento da hemoglobinúria paroxística noturna / Ravulizumabe not treated for paroxysmal nocturnal hemoglobinuria

INTRODUÇÃO: A Hemoglobinúria Paroxística Noturna (HPN) é uma doença rara, com incidência anual estimada de 1,3 novos casos por um milhão de indivíduos. Esta se caracteriza pela ativação descontrolada do complemento, que pode levar à hemólise intravascular (que por sua vez causa os episódios de hemoglobinúria), danos a órgãos (por exemplo, insuficiência renal e hipertensão pulmonar), eventos trombóticos, aumento da morbidade e mortalidade. Inibidores do C5 são opções de tratamento primário para esta doença, tendo sido o primeiro desta classe licenciado no mundo o eculizumabe em 2007. Em 2019 foi lançado o PCDT da HPN, que conta com a inclusão do eculizumabe. Dados de uma coorte nacional de pacientes com HPN mostram que 16% dos pacientes tiveram síndrome mielodisplásica e cerca de metade da amostra apresentava outras anemias aplásticas e/ou outras síndromes de falha de produção de outras linhas celulares sanguíneas (plaquetas e leucócitos). Embolia venosa e trombose venosa ocorreram em 4

Burden of illness in Japanese patients with paroxysmal nocturnal hemoglobinuria receiving C5 inhibitors.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening blood disorder characterized by hemolysis and resulting in anemia and fatigue. Current therapies for PNH in Japan rely on complement inhibitors targeting the C5 component of the complement. However, the disease burden of Japanese patients with PNH treated with C5 inhibitors (C5i) remains unclear. To investigate this topic, we conducted a cross-sectional survey study that included 59 Japanese patients with PNH treated with C5i. Although many participants received C5i for 1 year or longer, the mean hemoglobin (Hb) level was 10.2 g/dL. Fatigue and shortness of breath were the most common symptoms at the time of diagnosis and survey. In addition, patients with Hb levels ≥ 10.5 g/dL also reported fatigue, depression and reduced quality of life, albeit to a lesser extent. These results suggest that a substantial burden of illness remains in patients with C5i-treated PNH, likely resulting in low quality of life and effects of symptoms on daily life. This study contributes to understanding the unmet needs of the current therapies for PNH, highlighting the need for novel therapeutics.

Treatment Patterns and Healthcare Resource Utilization of Patients With Paroxysmal Nocturnal Hemoglobinuria: A Retrospective Claims Data Analysis.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder commonly treated with complement inhibitors such as eculizumab, ravulizumab, and pegcetacoplan. This study aims to describe treatment patterns, healthcare resource utilization, and cost for newly diagnosed PNH patients in 2 large, health insurance claims databases: MarketScan and Optum. Among the 271 patients meeting the inclusion criteria in MarketScan, 57.9% were female, and the average age was 46.6 years. Among these newly diagnosed patients, 25.1% (n = 68) of patients received a PNH-specific pharmacologic treatment, and the average time from diagnosis to treatment was 4.7 months. The medication possession ratio was 97.0%, but discontinuation was common (58.8%). The average per-patient-per-month costs were $18,978, driven by pharmacy and infusion ($11,182), outpatient ($4086), and inpatient ($3318) costs. Despite the availability of multiple treatments, 39.9% of patients had an inpatient stay, and 50.9% had an emergency department visit. Better care management and the introduction of new treatment options are needed to address delays between diagnosis and treatment, and high rates of hospitalization and emergency department use among patients with PNH.

Complement in human disease: approved and up-and-coming therapeutics.

The complement system is recognised as a protector against blood-borne pathogens and a controller of immune system and tissue homoeostasis. However, dysregulated complement activity is associated with unwanted or non-resolving immune responses and inflammation, which induce or exacerbate the pathogenesis of a broad range of inflammatory and autoimmune diseases. Although the merit of targeting complement clinically has long been acknowledged, the overall complement drug approval rate has been modest. However, the success of the humanised anti-C5 antibody eculizumab in effectively treating paroxysmal nocturnal haemoglobinuria and atypical haemolytic syndrome has revitalised efforts to target complement therapeutically. Increased understanding of complement biology has led to the identification of novel targets for drug development that, in combination with advances in drug discovery and development technologies, has resulted in a surge of interest in bringing new complement therapeutics into clinical use. The rising number of approved drugs still almost exclusively target rare diseases, but the substantial pipeline of up-and-coming treatment options will possibly provide opportunities to also expand the clinical targeting of complement to common diseases.

Predictors for improvement in patient-reported outcomes: post hoc analysis of a phase 3 randomized, open-label study of eculizumab and ravulizumab in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled terminal complement activation leading to intravascular hemolysis (IVH), thrombosis, and impairments in quality of life (QoL). The aim of this study was to identify the clinical drivers of improvement in patient-reported outcomes (PROs) in patients with PNH receiving the complement component 5 (C5) inhibitors eculizumab and ravulizumab.This post hoc analysis assessed clinical outcomes and PROs from 246 complement inhibitor-naive patients with PNH enrolled in a phase 3 randomized non-inferiority study that compared the C5 inhibitors ravulizumab and eculizumab (study 301; NCT02946463). The variables of interest were lactate dehydrogenase (LDH) levels, a surrogate measure of IVH, and hemoglobin (Hb) levels. PROs were collected using Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) to assess fatigue and QoL, respectively.Improvements in absolute mean LDH levels were significantly associated with improvements in mean FACIT-F score (p = 0.0024) and EORTC QLQ-C30 global health (GH) score (p < 0.0001) from baseline to day 183. Improvements in scores were achieved despite a non-significant increase in Hb levels. To understand the interaction between LDH and Hb, a regression analysis was performed: LDH response with Hb improvements was a significant predictor of improvement in fatigue. The independent effect of improved Hb did not significantly affect FACIT-F or EORTC QLQ-C30 GH scores.These findings suggest that LDH levels are an important determinant of fatigue and QoL outcomes in patients with PNH. CTR: NCT02946463, October 27, 2016.

Dosing Patterns of Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with Ravulizumab in the United States: A Retrospective Claims-Based Analysis.

INTRODUCTION: Complement factor 5 inhibitors eculizumab and, recently, ravulizumab are standard therapies for paroxysmal nocturnal hemoglobinuria (PNH). However, some patients experience suboptimal response and may benefit from dosage adjustments. Ravulizumab is administered less frequently than eculizumab on the basis of patient's body weight. This retrospective analysis of insurance claims investigated ravulizumab dosing patterns among patients with PNH from the USA. METHODS: Patients aged ≥ 12 years with ≥ 2 ravulizumab infusions between June 21, 2019 and May 6, 2021, and ≥ 6 months of continuous clinical activity prior to first ravulizumab infusion (index date) were identified from the Symphony Health Integrated Dataverse (IDV®) database. Observed mean (standard deviation, SD) ravulizumab doses administered were reported and stratified by previous eculizumab use. Scenarios adjusting for patients' body weights (unavailable in Symphony Health IDV) based on the US general population distribution were performed to estimate percentages of patients receiving label-recommended doses. RESULTS: Among 433 patients (mean [SD] age 47 [17] years), the mean (SD) loading dose was 3316.3 (2931.7) mg, greater than the maximal label-recommended loading dose (3000 mg for patients ≥ 100 kg). The mean (SD) loading doses were 3581.3 (3673.7) mg for eculizumab-naive versus 3093.1 (2096.8) mg for eculizumab-experienced patients. Over a mean (SD) treatment period of 11.8 (6.9) months, the mean (SD) average maintenance dose was 3403.7 (1024.4) mg, falling between label-recommended maintenance dose categories (3300 mg for ≥ 60 to < 100 kg; 3600 mg for ≥ 100 kg). Estimated percentages of patients receiving label-recommended loading and maintenance doses were 23.1% and 39.2%, respectively; 59.1% and 28.4% were estimated to receive above label-recommended loading and average maintenance doses, respectively. CONCLUSION: Although limited by missing clinical characteristics including body weight, this study of ravulizumab dosing patterns in patients with PNH identified potential deviations from label-recommended dosing, warranting further investigations of treatment response to complement inhibitors in PNH.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disease. Complement factor 5 (C5) inhibitors can help treat PNH symptoms; health care providers administer C5 inhibitors to patients during clinic or office visits. Eculizumab was the first C5 inhibitor approved for PNH. Some patients still experience symptoms with approved eculizumab doses and may need to receive larger or more frequent doses than recommended. The new C5 inhibitor ravulizumab offers reduced dosing frequency and is dosed on the basis of patients' body weights. This study assessed ravulizumab doses administered to patients with PNH in the USA using insurance claim records. Studied patients were 12 years or older and received two or more ravulizumab doses between June 21, 2019 and May 6, 2021. Researchers assessed ravulizumab doses administered to patients on the basis of body weight distribution of the US general population. The average first (loading) ravulizumab dose administered to 433 patients was 3316 mg. This was above the largest recommended loading dose of 3300 mg for patients weighing 100 kg (220 pounds) or more. Over nearly 12 months on average, the average maintenance dose administered was 3403 mg. Researchers estimated that larger loading doses than recommended were administered to almost 6 out of 10 patients and larger maintenance doses than recommended were administered to almost 3 out of 10 patients. This study found that larger than recommended ravulizumab doses may have been administered to some patients with PNH. More studies are needed to evaluate treatment response to complement inhibitors in patients with PNH.

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.

Long-Term Efficacy and Safety of Eculizumab in Patients With Paroxysmal Nocturnal Hemoglobinuria and High Disease Burden: Real-World Data From Korea.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by uncontrolled terminal complement activation. Eculizumab, a monoclonal antibody C5 inhibitor was introduced in Korea in 2009 and has been the standard treatment option for PNH. METHODS: This study assessed the long-term efficacy/safety of eculizumab in PNH using real-world data from the Korean Health Insurance Review and Assessment Service. Eighty patients who initiated eculizumab from 2009-2020 were enrolled. RESULTS: At eculizumab initiation, the median age was 51.5 years, lactate dehydrogenase (LDH) 6.8 × upper limit of normal, and granulocyte clone size 93.0%. All patients had at least one PNH-related complication before eculizumab initiation, including renal failure (n = 36), smooth muscle spasm (n = 24), thromboembolism (n = 20), and pulmonary hypertension (n = 15). The median (range) duration of eculizumab treatment was 52.7 (1.0, 127.3) months (338.6 total treated patient-years). Despite high disease activity in the study population before treatment initiation, overall survival was 96.2% and LDH levels were stabilized in most patients during treatment. PNH-related complications at treatment initiation were resolved in 44.4% of patients with renal failure, 95.8% with smooth muscle spasm, 70.0% with thromboembolism, and 26.7% with pulmonary hypertension. Extravascular hemolysis occurred in 28.8% of patients (n = 23; 0.09 per patient-year) and breakthrough hemolysis in 18.8% (n = 15; 0.06 per patient-year). No treatment discontinuation cases related to eculizumab were observed. CONCLUSION: These data provided evidence for the long-term efficacy and safety of eculizumab in Korean PNH patients with high disease burdens.

Non-capsulated Neisseria meningitidis sepsis in a paroxysmal nocturnal hemoglobinuria patient treated with ravulizumab: case report and review of the literature.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired haematopoietic stem cell disease characterized by complement-mediated intravascular hemolysis, thrombosis, and bone marrow failure. Eculizumab and ravulizumab are anti-C5 monoclonal antibodies that reduce hemolysis, anaemia and thrombotic risk, but are associated with increased risk of infection with encapsulated bacteria, including Neisseria meningitidis. We report a case of life-threatening infection by non-groupable Neisseria meningitidis in a young PNH patient treated with ravulizumab. Despite prompt admission to the intensive care unit, microbe isolation was delayed due to the negativity of capsular antigens, and the patient required intubation, dialysis, and transfusion support for pancytopenia. Notably, PNH disease activity remained controlled and no additional anti-C5 doses were administered. Increasing awareness regarding septic risk in PNH patients on complement inhibitors despite vaccinations is pivotal. A warning about serotypes generally not pathogenetic and not covered by vaccination, such as non-capsulated forms, is emerging.

Pozelimab: First Approval.

Pozelimab (pozelimab-bbfg; VEOPOZ™) is a fully human immunoglobulin (Ig) G4P (i.e. IgG4 with a proline substitution to promote stabilization of the disulfide bonds between the two heavy chains) monoclonal antibody developed by Regeneron Pharmaceuticals Inc., to block the activity of complement factor 5 (C5) and prevent diseases mediated by the complement pathway. In August 2023, pozelimab received its first approval for the treatment of adults, and paediatric patients aged ≥ 1 year with CD55-deficient protein-losing enteropathy (PLE), also known as CHAPLE disease, in the USA. It is the first US FDA-approved treatment for this disease. In the USA, pozelimab has been granted orphan drug designations for the treatment of paroxysmal nocturnal haemoglobinuria (PNH) [both as a monotherapy and in combination with cemdisiran] and for the treatment of myasthenia gravis (in combination with cemdisiran). Pozelimab is also undergoing clinical development in several other countries worldwide for the treatment of CD55-deficient PLE, PNH and myasthenia gravis. This article summarizes the milestones in the development of pozelimab leading to this first approval for the treatment of adults, and paediatric patients aged ≥ 1 year with CD55-deficient PLE, also known as CHAPLE disease, in the USA.

[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.