Treatment Of Paroxysmal Nocturnal Hemoglobinuria Research Articles

The Budd-Chiari Syndrome as a Complication of Paroxysmal Nocturnal Hemoglobinuria (Clinical Case)

Among the main causes of recurrent thrombosis in young patients there is paroxysmal nocturnal hemoglobinuria (PNH), a complication of which is Budd-Chiari syndrome (BCS), characterized by thrombosis of the hepatic veins and/or inferior vena cava. Detection of PNH is an extremely important task, because its untimely diagnosis leads to recurrent thrombosis, deterioration of the patient’s quality of life, and increased mortality from complications which accompany PNH. The article analyzes a clinical case of PNH in a young patient with recurrent BCS, which illustrates the relevance and timely diagnosis of this disease. As a result of unsuccessful pharmacological treatment and progression of liver insufficiency, the patient had liver transplantation. After surgery and standard post-transplantation therapy the patient’s condition improved, but after some time a recurrence of hepatic vein thrombosis was developed. After hematologist consultation and performing flow cytometry, the patient was diagnosed PNH. However, on the background of recurrent hepatic vein thrombosis, immunosuppressive therapy, and the lack of targeted treatment for PNH, multiple organ failure was developed, which led to the patient’s death. PNG is one of the orphan diseases, which is characterized by a severe, chronic, progressive course and accompanied by the formation of degenerative changes in the body, a decrease in the quality and shortening of the patient’s life. Targeted therapy can reduce the risk of thrombosis, red blood cell transfusions and improve the quality of life of patients with PNH.

Crovalimab: First Approval.

Crovalimab (®; PiaSky) is a humanized, anti-complement component C5 (anti-C5) recycling monoclonal antibody developed by Chugai Pharmaceutical, in collaboration with Roche, which is being investigated for the treatment of complement-mediated diseases, including paroxysmal nocturnal haemoglobinuria (PNH), atypical haemolytic uremic syndrome, lupus nephritis and sickle cell disease. Crovalimab targets C5, inhibiting its cleavage to C5a and C5b, thus blocking the terminal complement pathway and preventing intravascular haemolysis in PNH. Crovalimab is designed to bind to the antigen repeatedly, resulting in sustained complement inhibition at a lower dosage, and allowing for once-monthly subcutaneous administration. In February 2024, subcutaneous crovalimab received its first approval in China for the treatment of adolescents and adults (aged ≥ 12 years) with PNH who have not been previously treated with complement inhibitors. Crovalimab has since been approved in Japan in March for use in the treatment of PNH, including in treatment-naïve and previously treated patients. Crovalimab is also under regulatory review for the treatment of naïve and previously treated patients with PNH in multiple countries, including the USA and the European Union. This article summarizes the milestones in the development of crovalimab leading to this first approval in China for the treatment of PNH.

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

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

Cost-Utility Analysis Comparing Pegcetacoplan to Anti-C5 Monoclonal Antibodies in the Treatment of Paroxysmal Nocturnal Hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria is a rare, acquired disease characterized by hemolytic episodes and associated with significant clinical burden. The introduction of C5 inhibitory monoclonal antibodies (C5i) represented a major breakthrough in PNH treatment, effectively reducing intravascular hemolysis (IVH) but showing limited impact on extravascular hemolysis (EVH). In 2021, the C3 inhibitor pegcetacoplan was approved by EMA and recently reimbursed in Italy, which also has the advantages in the reduction of both IVH and EVH, increasing hemoglobin values and simultaneously improving the quality of life and fatigue of patients. A cost-utility analysis was developed to compare pegcetacoplan to C5i (eculizumab and ravulizumab) in the PNH population who remain anemic after treatment with C5i for at least 3 months. The analysis employed a Markov model with a 5-year time horizon whereby patients can transition among 3 PNH health states, adopting the perspective of the Italian NHS. Efficacy data were sourced from the PEGASUS study, with drug prices reflecting ex-factory costs. Additionally, costs associated with resource utilization, adverse events, and complications were estimated based on outpatient and hospital care rates, excluding indirect expenses. Utility and disutility values related to transfusions were also considered, with pegcetacoplan allowing for dose escalation. The cumulative cost of treatment per individual patient at 5 years was estimated to be €1,483,454 for pegcetacoplan, €1,585,763 for eculizumab, and €1,574,826 for ravulizumab. Pegcetacoplan demonstrated a superior increase in quality-adjusted life years (QALYs) compared to both eculizumab (0.51 increase) and ravulizumab (0.27 increase). Furthermore, pegcetacoplan showed a reduction in complication management costs (€22,891 less compared to eculizumab and €22,611 less compared to ravulizumab) and lower transfusion-related expenses (€14,147 less than both C5i treatments). Pegcetacoplan emerged as the dominant strategy in this analysis, being more effective, less expensive and improves quality of life in the analyzed population affected by PNH.

Development of a target concentration intervention to individualize paroxysmal nocturnal hemoglobinuria treatment with pegcetacoplan

Pegcetacoplan (Aspaveli®/Empaveli™) is a factor C3 inhibitor that is approved for the treatment of paroxysmal nocturnal hemoglobinuria. An individualized dosing strategy might be useful to improve patient-friendliness and cost-effectiveness of this very expensive drug. Therefore, the aim of this study was to develop an individualized treatment regimen for pegcetacoplan based on the pharmacokinetic-pharmacodynamic data of the manufacturer. We conducted a clinical trial simulation with the approved dosing regimen of 1080 mg twice-weekly and a target concentration intervention-based dosing regimen in patients with and without prior eculizumab use. For eculizumab-naïve patients, the target concentration intervention-based dosing regimen resulted in a comparable fraction of patients with LDH normalization (LDH < 226 U/L) and hemoglobulin normalization (> 12 g/dL) compared to the approved regimen (LDH 50.2% and 50.0% respectively and hemoglobulin 45.6% and 44.4%). A modest dose reduction of ~ 5% was possible with target concentration intervention-based dosing. An intensified dosing interval was necessary in 2.3% of the patients however an interval prolongation was possible in 28.2% of the patients. Similar results were obtained for patients prior treated with eculizumab. In this study we show the potential of an individualized dosing regimen of pegcetacoplan with can improve patient friendliness in approximately 30% of the patients and improve therapy in approximately 2% of the patients at slightly reduced costs.

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.

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.

A Critical Appraisal of Clinical Practice Guidelines for Pharmacological Treatments of Paroxysmal Nocturnal Hemoglobinuria

Aims: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare chronic disease characterized by complement-mediated hemolysis, thrombosis, and bone marrow failure. This study aims to identify methodological limitations in Clinical Practice Guidelines (CPG) for the treatment of PNH. Thus, we critically evaluate the guidelines, highlighting relevant recommendations supported by high-quality evidence to improve healthcare strategies.&#x0D; Methodology: A systematic search was carried out in PubMed/MEDLINE, Scopus, Embase, COCHRANE, and TRIP databases. From 1995 initially identified references, 1649 articles underwent title and abstract screening. Twenty-three references were selected for full-text screening. Ultimately, 12 CPGs were included. Four independent reviewers assessed the CPGs’ methodological quality using the instruments “Appraisal of Guidelines for Research and Evaluation II” (AGREE II) and “Recommendation Excellence” (AGREE-REX). Their characteristics, as well as any differences in recommendations, were summarized and compared.&#x0D; Results: Twelve guidelines published from 2011 to 2022 by Spain, Brazil, Mexico, Israel, Canada, Turkey, Scotland, and the United Kingdom were included. The UK’s and Brazil’s CPGs received the highest scores. Overall, the CPGs scored strongly in the domains of “Scope and Purpose” and “Clarity of Presentation” since they addressed fundamental aspects, such as aim, specific health questions, target population, and language. All guidelines presented deficiencies in the “Editorial Independence” in AGREE II, and “Values and Preferences” in AGREE-REX, demonstrating the need for a careful revision and improvement of future versions.&#x0D; Conclusion: We found disparities in the methodological quality of the available CPGs. Despite being extremely important, recommendations on adapting treatment to local policies and further updates that include newly approved medications were absent. Approaches that prioritize the engagement of methodologists and multidisciplinary collaborators may also lead to higher quality CPGs for treating PNH.

Unraveling the Clinical Spectrum: A Case Study of Classic and Aplasia-Related Paroxysmal Nocturnal Hemoglobinuria

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare nonmalignant clonal disorder of hematopoietic stem cells characterized by a phosphatidylinositol glycan protein A (PIGA) gene mutation. This mutation results in the deficiency of glycosylphosphatidylinositol (GPI)-anchored proteins, CD55 and CD59, on the cell surface, rendering red blood cells (RBC) susceptible to complement-mediated destruction. This leads to hemolytic anemia, thromboses, and bone marrow failure. Here we describe two cases of PNH presenting to a tertiary care center. Case 1 A 29-year-old male with a history of polysubstance use presented to the Emergency Department with a 2-day history of progressively worsening left lower quadrant abdominal pain. CT abdomen pelvis showed multiple renal infarcts and findings suggestive of pneumatosis intestinalis. A complete blood count (CBC) revealed pancytopenia with a leukocyte count (WBC) of 3 x 10 9/L, hemoglobin (Hb) of 94 g/L, and platelet count (Plt) of 48 x 10 9/L. Lactate dehydrogenase (LDH) was elevated (900 IU/L), haptoglobin level was low ( &amp;lt;8mg/dL), and direct antiglobulin test (DAT) was negative. Urine was positive for hemosiderin, and flow cytometry showed RBCs (6.7%), granulocytes (97.97%), and monocytes (89.02%) with PNH phenotype. Bone marrow biopsy (BMB) was negative for dysplasia and fibrosis with normal hematopoiesis but showed increased erythroid precursors. Enoxaparin was started for thromboses and levofloxacin for neutropenia. Treatment for PNH was initiated with a loading dose of ravulizumab and meningococcal vaccination. The patient was lost to follow-up after receiving the first maintenance dose. Case 2 An 81-year-old female with a medical history of hypertension and coronary artery disease was hospitalized for gradually worsening shortness of breath and fatigue ongoing for 2 months. She reported easy bruising but denied a history of obvious bleeding from any orifice. Physical exam was significant for petechial rash in her lower extremities. Labs revealed pancytopenia (WBC 1.44 x 10 9/L, Hb 68 g/L, Plt 8 x 10 9/L), low reticulocyte count, LDH of 276 IU/L, and negative DAT. BMB showed marked aplasia, and she became transfusion dependent. Subsequently, flow cytometry revealed PNH phenotype in 1.45% of RBCs, 54% granulocytes, and 54% monocytes. Eculizumab therapy was started for the diagnosis of PNH. However, her transfusion requirements did not decrease. She developed iron overload and showed positive conversion on DAT. Darbepoetin alfa and romiplostim were added. Her Hb stabilized at &amp;gt;70g/L in 3 years, following which she only required romiplostim to maintain Plt &amp;gt;20,000 ( Graph 1). After 5 years, she opted to discontinue all treatment. She is being followed up regularly and has since remained stable. Discussion The two cases above are reflective of how PNH can present in different ways, ranging from the classic triad of symptoms to those with subclinical findings associated with other underlying conditions, such as aplastic anemia or myelodysplastic syndrome. The introduction of complement inhibitors completely changed the natural history of PNH, as patients' median survival shifted from 15-20 years to align with age-matched controls. Indications for treatment include severe anemia, thrombosis, or PNH symptoms like dyspnea, fatigue, and painful paroxysms. Currently, eculizumab and ravulizumab are the only FDA-approved drugs for PNH treatment. Ravulizumab is non-inferior to eculizumab, with the added advantage of less frequent dosing (every 8 weeks versus 2 weeks). Regular monitoring for hemolysis is warranted with treatment. Many patients require long-term therapy, which continues to be a significant challenge, even with the spaced dosing of ravulizumab. Eculizumab protects from terminal complement-mediated damage preventing intravascular hemolysis. However, these cells are still deficient in CD55, making them vulnerable to opsonization by C3 and premature removal in the spleen. As a result, &amp;gt;50% of PNH patients receiving treatment show positive conversion on DAT, as seen in case 2. Heparin is preferred in acute thrombotic states. Most hematologists recommend anticoagulation till a few months after starting complement inhibition.

Alternative Pathway Masp-3 Inhibitor OMS906 Effectively and Potently Inhibits Complement-Mediated Hemolysis in Preclinical Models Mechanistically Similar to Paroxysmal Nocturnal Hemoglobinuria

Introduction: Mannan-binding lectin-associated serine protease-3 (MASP-3) activates pro-complement Factor D (CFD) to form mature CFD, a rate-limiting enzyme in the alternative pathway (AP) of the complement system. CFD controls cleavage of complement Factor B (CFB) to form AP C3 convertase, which drives an amplification loop of protease complexes that activates both C3b-mediated opsonization and the terminal pathway. OMS906 is a humanized IgG4 monoclonal antibody (mAb) that binds to and inhibits MASP-3, thereby blocking maturation of CFD and downstream AP activity. Data from mice and monkeys demonstrated that OMS906 is highly selective and effectively inhibits AP activity. MASP-3 inhibition could provide therapeutic benefit in a variety of AP-mediated diseases, such as paroxysmal nocturnal hemoglobinuria (PNH). In PNH, a rare and life-threatening disorder, red blood cells (RBCs) lacking CD59 and CD55 regulatory surface proteins are targeted for rapid clearance via intravascular hemolysis and extravascular hemolysis, due to AP dysregulation. Clinical efficacy of OMS906 in a study of patients with PNH has been reported. To provide mechanistic support, we conducted in vitro and in vivo studies using preclinical models of complement-mediated hemolysis that have mechanistic overlap with PNH. Methods: In vitro potency of OMS906 was assessed using RBCs deficient in CD55 and CD59 to mimic the physiological effect of PNH. Healthy human donor RBCs were treated with inhibitory CD55 and CD59 antibodies, then incubated under AP assay conditions with human serum (diluted to 50%) containing OMS906, anti-C5 IgG4 mAb, or an isotype mAb control. The potency of OMS906, expressed as the half-maximal inhibitory concentration (IC 50), was assessed based on prevention of hemolysis of the PNH-like RBCs in vitro. Lysis was quantified by measuring hemoglobin released into sample supernatants using spectrophotometric absorbance. The in vivo effect of OMS906 on survival of murine RBCs prone to rapid clearance was assessed using RBCs from Crry -/- mice, which lack a rodent-specific complement regulatory protein that blocks AP activation. C57BL/6J male mice were intravenously injected with fluorescent labelled Crry -/- RBCs and received OMS906 or isotype mAb control via subcutaneous injection, or anti-CFB mAb via intraperitoneal injection. Blood samples were taken daily until Day 14 and the remaining number of Crry -/- RBCs measured by flow cytometry. Results: In vitro, OMS906 inhibited terminal cell lysis in human PNH-like RBCs more potently than a C5 inhibitor. Comparison of representative drug concentration-response showed that the average functional potency was 58-fold greater with OMS906 (IC 50: 0.8 μg/mL; 3 experiments; 12 total RBC donors) than with anti-C5 mAb (IC 50: 46.2 μg/mL; 2 experiments; 4 total RBC donors). In addition, the maximal extent to which lysis was inhibited was consistently greater with OMS906 than with anti-C5 mAb. In vivo, the rate of decline in number of Crry -/- RBCs was significantly slowed in mice treated with OMS906, in contrast to the rapid loss observed in isotype mAb control-treated mice ( Figure). OMS906 recipients showed a rate of Crry -/- RBC survival similar to the anti-CFB mAb group. Conclusion: OMS906 inhibited RBC lysis more potently than a C5 inhibitor, providing evidence that MASP-3 inhibition blocks downstream terminal activity and thus intravascular hemolysis. In addition, OMS906 improved survival of Crry -/- RBCs comparably to a CFB inhibitor, indicating that MASP-3 inhibition prevents the AP-mediated destruction of RBCs predictive of extravascular hemolysis. OMS906 is currently in clinical development for the treatment of PNH.

A Case Report of a Patient with Paroxysmal Nocturnal Hemoglobinuria Treated with Pegcetacoplan Who Underwent Major Surgery

Paroxysmal Nocturnal Hemoglobinuria (PNH) is characterized by intravascular hemolysis, thrombosis and bone marrow failure. The appearance of the anti-C5 monoclonal antibody eculizumab revolutionized the treatment of PNH, controlling hemolysis and the incidence of thrombosis. However, some patients persist with anemia, due in part to extravascular C3-mediated hemolysis. More recently, the anti-C3 monoclonal antibody pegcetacoplan, which blocks the most proximal part of the complement cascade, has been marketed in Europe, achieving improvements in anemia in these patients. However, intercurrent infectious episodes or surgical interventions can trigger a hemolytic flare, so dose adjustments are necessary to prevent their occurrence. There is hardly any published information or established consensus on how to treat these patients. We present this case as an example of a successful treatment of a patient diagnosed with PNH under treatment with pegcetacoplan who has undergone major surgery. A 67 year-old man was diagnosed with aplastic anemia in 1997 and treated with immunosuppression (cyclosporine and oxytosone). In 2000, he presented his first intravascular hemolytic crisis with HPN clone detection. He presented several intravascular hemolytic crises for which he was treated with erythropoiesis-stimulating agents, corticosteroids and transfusions. In 2010, due to deterioration of renal function because of acute hemolysis episode, he started treatment with eculizumab. A reduction in the number of hemolytic crises was observed. However, he required an increase in the dose and frequency of administration of eculizumab due to pharmacokinetic breakthrough hemolysis. After one month of treatment, a positive direct coombs test appeared and presented anemia due to extravascular hemolysis, for which he again required treatment with corticosteroids on specific occasions. For this reason, in December 2022, he started treatment with pegcetacoplan at the usual dose of 1080 mg twice a week subcutaneously (sc). Prior to the start of pegcetacoplan, the patient had hemoglobin levels of 10.3 g/dL, hyperbilirubinemia of 3.2 mg/dL (indirect 2.6 mg/dL), consumed haptoglobin, elevated lactate dehydrogenase (LDH) of 281 U/L and reticulocytosis of 5-6%. Subsequently, since the beginning of pegcetacoplan, he presented clinical improvement, stable hemoglobin (12-13 g/dL) and normalization of reticulocytes, LDH and bilirubin levels. The haptoglobin has remained low until the present time. In June 2023, the patient underwent major surgery consisting of radical prostatectomy due to a benign prostatic hypertrophy. Suspecting that it might provoke a hemolytic crisis due to surgical stress, the dose of pegcetacoplan was increased as recommended by clinical experts to a dose of 1080 mg every 72 hours sc from one week prior to surgery until one week after. The procedure was carried out without incident and without an increase in hemolysis parameters. This is the first case report of a patient with PNH treated with pegcetacoplan undergoing major surgery in Spain. In this patient, the perioperative dose increase was successful in preventing the development of a hemolytic crisis.

Efficacy and Safety Is Maintained in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria Receiving Pegcetacoplan for up to 3 Years

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease characterized by complement-mediated hemolysis and thrombosis. Pegcetacoplan, the first complement component 3 (C3) inhibitor for PNH, increased hemoglobin (Hb) levels in complement component 5 inhibitor (C5i)-experienced and -naive adult patients with PNH in 2 phase 3 clinical trials (PEGASUS [NCT03500549] and PRINCE [NCT04085601], respectively). This integrated analysis of data from the pivotal phase 3 trials and the subsequent open-label extension (study 307; NCT03531255) evaluated the long-term efficacy and safety of pegcetacoplan for PNH treatment. Methods: For this integrated analysis, baseline was defined as the initiation of pegcetacoplan, regardless of when in the trials this occurred. Patients initially received pegcetacoplan 1080 mg subcutaneously twice weekly; dose escalations to once every 3 days or 3 times weekly were permitted. Efficacy was evaluated from baseline up to Weeks 132 (2.5 years, PRINCE) and 156 (3 years, PEGASUS) by Hb, lactate dehydrogenase (LDH; upper limit of normal [ULN] 226 IU/L), absolute reticulocyte count (ARC), and indirect bilirubin values; Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores; and transfusion avoidance rates (percentages of patients who did not require a transfusion during treatment). Safety was assessed by incidence of adverse events (AEs) and serious AEs (SAEs) during pegcetacoplan monotherapy for up to 3 years. Results: Of the 133 patients in the phase 3 trials (PEGASUS, 80; PRINCE, 53), 114 enrolled in the extension study (PEGASUS, 64; PRINCE, 50). At least 75% had received a transfusion in the year before enrolling in PEGASUS or PRINCE. Prior to pegcetacoplan initiation, mean (SD) Hb levels were 8.95 (1.09) g/dL in PEGASUS, 9.27 (1.44) g/dL in PRINCE, and 9.08 (1.24) g/dL in the total population; median (interquartile range) LDH levels were 217.0 (184.8, 276.5) IU/L in PEGASUS, 1964.0 (1409.0, 2503.3) IU/L in PRINCE; and mean (SD) FACIT-Fatigue scores were 31.6 (11.7) in PEGASUS, 36.6 (10.0) in PRINCE, and 33.6 (11.3) in the total population. After pegcetacoplan initiation, mean Hb levels markedly improved from baseline and remained stable through Weeks 132 (2.5 years, PRINCE) and 156 (3 years, PEGASUS) ( Figure). Median LDH rapidly decreased and stabilized below the ULN ( Figure). Improvements in ARC and indirect bilirubin were similarly maintained. Average FACIT-Fatigue scores increased (indicating less fatigue) rapidly and were maintained near the general population norm of 43.6. Annual transfusion avoidance ranged from 71%-79% in PEGASUS and 80%-86% in PRINCE, with 52% of patients from PEGASUS avoiding transfusion for up to 3 years of pegcetacoplan treatment and 67% of patients from PRINCE avoiding transfusion for up to 2.5 years. Overall, &amp;gt;92% patients had compliance rates of at least 95%. Over 3 years, most patients experienced an AE; SAEs were reported in 50.0% of patients, with 4.5% experiencing a SAE deemed related to pegcetacoplan. Overall, 17 patients discontinued pegcetacoplan due to an AE; of those, 9 discontinued due to a hemolytic disorder, 7 of which discontinued within 1 year of starting pegcetacoplan. Over 3 years, 4 (3.0%) deaths occurred, none were deemed related to pegcetacoplan; 3 (2.3%) patients experienced a thrombotic event (in the context of multiple associated comorbidities or discontinuation of pegcetacoplan) and no cases of meningitis were reported. Overall, no new or unexpected safety findings were identified. Conclusions: Rapid improvements in Hb, LDH, ARC, indirect bilirubin, and FACIT-Fatigue values were observed and maintained up to 3 years in C5i-experienced patients and up to 2.5 years in C5i-naive patients. The transfusion burden was significantly reduced. No new safety findings were identified. This analysis demonstrates sustained efficacy and continued safety of long-term pegcetacoplan for patients with PNH, regardless of prior C5i treatment.

Efficacy and Safety of Single Agent Proximal Complement Inhibitors in Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients with Residual Anemia Despite of Adequate Terminal Complement Inhibitor Use

Background: Introduction of C5 inhibitors is a major advancement in the treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH) patients. First Eculizumab and then Ravulizumab significantly improved anemia by controlling intravascular hemolysis (IVH), reduced thrombosis risk, improved quality of life and prolonged survival. However, a significant proportion of PNH patients remain anemic with transfusion dependence despite maximal C5 inhibition due to C3 mediated residual extravascular hemolysis (EVH). Recently two randomized, open label, controlled trials with proximal complement inhibitors were studied in this patient population comparing against C5 inhibitors as single agents with excellent results. Here we compare efficacy and safety data of proximal complement inhibitors pegcetacoplan (C3 inhibitor), Iptacopan (factor b inhibitor) based on published or presented data. Methods: We compared the efficacy and safety data of randomized portion of PEGASUS and APPLY-PNH trials. PEGASUS trial is a phase 3, randomized, open label, active-comparator controlled trial with Pegcetacoplan (a pegylated pentadecapeptide that targets C3) compared efficacy and safety against eculizumab in PNH patients with Hb &amp;lt;10.5 despite of treatment with Eculizumab (Hillerman, et al NEJM 2021;384). Primary end point of the study was mean change in Hb level from baseline to week 16. APPLY-PNH is an open label randomized, multicenter phase 3 trial compared Iptacopan 200 mg BID (oral factor b inhibitor) monotherapy with standard of care C5 inhibition therapy. (Regis P. de Latour et al. Blood (2022) 140 (Suppl 2): LBA-2). Primary end points of the trial were Hematological response defined as an increase in Hb of ≥ 2 g/dL from baseline and Hb ≥ 12 g/dL in absence of transfusions. Secondary end points included number of clinical and hematological markers of hemolysis and safety. Results: Summarized in table 1. PEGASUS trial included 80 patients with 41 in pegcetacoplan arm and 39 in Eculizumab arm. APPLY-PNH included 97 patients with 62 in Iptacopan arm compared to 35 in standard of care anti C5 therapy. Majority of baseline characteristics were similar between two studies. Mean age in both studies was around 50 years and close to 2/3rd of patients in each study were females. Median duration of prior C5 therapy was between 3-4 years in both studies. More than half of patients in both studies required PRBC transfusions in preceding months prior to enrollment. Baseline mean Hb was between 8-9 g/dL, LDH between 250-300 U/L, mean absolute retic count (ARC) 190-200x109/L. Both studies showed superiority in change from baseline Hb with +2.69 g/dL in PEGASUS trial with all available data regardless of transfusion events and +3.63 in APPLY-PNH trial. Both studies showed either noninferiority or superiority in freedom from transfusions and change in ARC. Interestingly, LDH change was not significant in both studies. Change from baseline fatigue FACIT-score was numerically better but not tested in PEGASUS trial and was superior in APPLY-PNH. No major vascular events or serious infections by encapsulated bacteria were reported in either study. Breakthrough hemolysis was reported in 4 out of 40 patients in PEGASUS trial that led to treatment discontinuation in 3 patients and 2 out of 62 patients in APPLY-PNH trial, however none of them required treatment discontinuation. Conclusions: PEGASUS and APPLY-PNH trials showed that in patients with persistent anemia despite C5 inhibitor therapy, proximal complement inhibition with either pegcetacoplan (C3 inhibitor) or Iptacopan (factor b inhibitor) as a single agent showed significant improvement in Hemoglobin with higher rate of transfusion independence with control of extra vascular hemolysis while maintaining intravascular hemolysis control with no serious infections. These studies represent another major advancement in the management of PNH patients. Long term follow up is needed regarding safety and to identify better ways to manage breakthrough hemolysis in patients on proximal complement inhibitors.

Factor B Inhibition with Oral Iptacopan Monotherapy Demonstrates Sustained Long-Term Efficacy and Safety in Anti-C5-Treated Patients (pts) with Paroxysmal Nocturnal Hemoglobinuria (PNH) and Persistent Anemia: Final 48-Week Results from the Multicenter, Phase III APPLY-PNH Trial

Drs Roeth and Kulasekararaj contributed equally as authors. Background: Iptacopan is the first oral complement inhibitor that acts proximally in the complement system to target factor B in the alternative pathway. Iptacopan has shown efficacy/safety in PNH pts with persistent anemia despite anti-C5 therapy and complement inhibitor-naive pts. In the Phase III APPLY-PNH trial (NCT04558918), iptacopan monotherapy led to clinically meaningful hemoglobin (Hb) increases and normal/near-normal Hb levels in a majority of pts, transfusion avoidance and improved pt-reported fatigue, showing superiority vs C5 inhibitors at Week (Wk) 24. Aim: We report the final APPLY-PNH data after a 24-wk extension period in which all pts received iptacopan monotherapy (study completion: 6 March 2023). Methods: Adult PNH pts (mean Hb &amp;lt;10 g/dL, receiving anti-C5 therapy for ≥6 months) were randomized to receive iptacopan 200 mg twice daily or continue their anti-C5 regimen for 24 wks. Pts could then opt to enter an extension period; pts in the iptacopan arm received iptacopan for another 24 wks and pts who had been receiving anti-C5 switched to iptacopan monotherapy. Results: In the extension period, 95 pts received iptacopan: 61/62 in the iptacopan arm (1 discontinued iptacopan in the randomized period because of pregnancy) and 34/35 in the anti-C5-to-iptacopan arm (1 did not enter the extension period [investigator's decision]). In the iptacopan arm, the improvements at 24 wks were sustained at 48 wks, with maintenance of increased Hb, normal/near-normal mean Hb levels (Figure), improved Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) scores, decreased absolute reticulocyte counts (ARCs) and transfusion avoidance (Table). Pts who switched from anti-C5 to iptacopan had rapid changes in Hb, FACIT-F and ARC, achieving comparable improvements to the iptacopan arm. Mean Hb levels at Wk 48 were 12.2 and 12.1 g/dL in the iptacopan and anti-C5-to-iptacopan arms, respectively (standard deviations 1.6 and 1.4). At Wk 48, the adjusted mean change from baseline in the iptacopan arm was +3.35 g/dL for Hb, +9.80 FACIT-F points and −106.26 × 10 9/L for ARC. In the anti-C5-to-iptacopan arm, the adjusted mean change from baseline at Wk 48 was +3.36 g/dL for Hb, +10.96 FACIT-F points and −107.95 × 10 9/L for ARC (adjusted mean difference in change from baseline at Wk 48 vs Wk 24: +3.02 g/dL, +10.79 points and −102.29 × 10 9/L, respectively). Transfusion avoidance was achieved by 93.5% of pts in the iptacopan arm (Wks 2 to 48) and 94.1% in the anti-C5-to-iptacopan arm (Wks 26 to 48). Mean lactate dehydrogenase levels were generally maintained &amp;lt;1.5 × upper limit of normal in both arms. In the trial, 6/62 pts in the iptacopan arm had clinical breakthrough hemolysis (BTH). One pt in the anti-C5-to-iptacopan arm had clinical BTH after switching to iptacopan. BTH resolved without changing iptacopan dosing. Three pts had major adverse vascular events (MAVEs; randomized period: 1 serious transient ischemic attack [TIA]; extension period: 1 non-serious TIA, 1 serious portal vein thrombosis [PVT]). The pt with PVT had a history of PVT and discontinued heparin prior to the MAVE. All MAVEs were considered unrelated to iptacopan and resolved without changing iptacopan dosing. After 48 wks in the iptacopan arm, the most frequently reported treatment-emergent adverse events (TEAEs) were COVID-19 (29.0% of pts), headache (19.4%), diarrhea (16.1%) and nasopharyngitis (14.5%). There were no deaths, no serious hemolysis TEAEs on iptacopan, no serious infections caused by N. meningitidis, S. pneumoniae or H. influenzae and no pts discontinued treatment because of TEAEs. Conclusions: Long-term data from the Phase III APPLY-PNH trial show a durable response to iptacopan monotherapy in anti-C5-treated PNH pts with persistent anemia. Pts who received iptacopan for 48 wks had sustained improvements in multiple hematological and clinical outcomes, including maintenance of increased Hb, mean normal/near-normal Hb levels, transfusion avoidance and decreased pt-reported fatigue; these benefits quickly emerged in the anti-C5-to-iptacopan arm, supporting the benefit of switching from C5 inhibitors to iptacopan monotherapy. The data indicate good control of hemolysis by iptacopan and a similar safety profile at Wk 48 vs Wk 24. Our findings continue to support oral iptacopan monotherapy as a potentially practice-changing treatment for hemolytic PNH.

Health-Related Quality of Life and Symptom-Specific Functional Impairment Among Patients Treated with Parenterally Administered Complement Inhibitors for Paroxysmal Nocturnal Hemoglobinuria

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening, stem cell disorder that renders red blood cells vulnerable to complement-mediated hemolysis. This study describes the health-related quality of life (HRQoL) and symptom-specific functional impairment of patients with PNH in a real-world setting. Methods: US-based adults with PNH treated with a parenterally administered complement inhibitor (PACI) for ≥6 months completed an online, cross-sectional, observational survey; a subset of patients also participated in individual semi-structured qualitative interviews after completing the survey. The survey included the PROMIS® 29+2 Profile v2.1 (PROMIS 29+2) to measure HRQoL. The FACIT Fatigue, Neuro-QOL Item Bank v2.0 Cognitive Function Short Form, and PROMIS Item Bank v1.0 Dyspnea Functional Limitations 10a Short Form measured functional impairment associated with specific symptoms of PNH. For each patient with PNH who completed the online survey, up to 3 age- (+/- 3 years) and sex-matched adults without PNH also completed the survey. The HRQoL and functional impairment of the PNH sample was compared to that of general population (GP) sample using independent samples t-tests or Mann-Whitney tests. To further explore the experiences of patients with PNH, the association between HRQoL/functional impairment and fatigue severity was investigated. Patients with PNH were grouped according to their self-reported fatigue severity over the past 7 days (very mild or mild vs moderate, severe, or very severe [no patients reported no fatigue]). Differences in scores across these 2 groups were tested. Data from the qualitative interviews were coded using thematic analysis to explore key concepts related to HRQoL and impairment due to PNH symptoms. Data collection began in March 2023; results are based on interim data. Results: Demographic characteristics of the study samples (PNH survey sample: N=31, GP survey sample: N=62, PNH interview sample: N=10) are shown in Table 1. Patients were treated for PNH with eculizumab, pegcetacoplan, or ravulizumab, with an average duration of current PACI treatment of 3.4 years. Compared to the age and sex-matched GP sample, patients with PNH had significantly higher median scores on the PROMIS 29+2 fatigue domain (GP: 48.70 vs PNH: 57.10, p=0.041) and PROMIS Dyspnea Functional Limitations short form (GP: 40.70 vs PNH: 48.60, p=0.036), indicating that patients with PNH experience more fatigue and dyspnea limitations than the GP sample. Patients with PNH also had significantly lower median scores on the PROMIS 29+2 ability to participate in social roles/activities domain (GP: 53.50 vs PNH: 44.20, p=0.013), indicating greater role/activity limitations among patients with PNH. Compared to the GP sample, patients with PNH had numerically lower (i.e., worse) median PROMIS 29+2 cognitive functioning domain scores (GP: 50.00 vs PNH: 46.30, p=0.058) and FACIT Fatigue scores (GP: 39.50 vs PNH: 30.00, p=0.057). Within the PNH sample, statistically significant associations (p&amp;lt;0.05) were observed between fatigue severity and HRQoL/functional impairment for all outcomes except for the PROMIS 29+2 sleep disturbance and cognitive functioning domains (Table 2). Patients with more severe fatigue had worse HRQoL and more functional impairment than patients with less severe fatigue. Interview participants described fatigue-related functional impairments in their physical, social, and cognitive functioning. Fatigue made daily activities (e.g., cooking, cleaning, going for a walk) difficult and sometimes impossible. Planning social activities in advance was also challenging as patients could not predict how they would feel on any given day, and often found they had to miss, postpone, or cancel social engagements. Finally, patients described experiencing “brain fog” including difficulty concentrating, forgetfulness, and delayed cognitive processing. Conclusions: Despite receiving treatment for PNH, patients experienced deficits in areas of HRQoL related to fatigue, participation in social roles, cognitive function, and functional limitations due to dyspnea, relative to a sample of GP adults. During follow-up interviews, patients emphasized the deep and broad impacts that fatigue and cognitive functioning had, making daily activities and their social lives very difficult.

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 ≥ 1year 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.

Paroxysmal Nocturnal Hemoglobinuria: Biology and Treatment.

Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal hematopoietic disorder characterized by the lack of glycosylphosphatidylinositol-anchored proteins (GPI-APs) as a consequence of somatic mutations in the phosphatidylinositol glycan anchor biosynthesis class A (PIGA) gene. Clinical manifestations of PNH are intravascular hemolysis, thrombophilia, and bone marrow failure. Treatment of PNH mainly relies on the use of complement-targeted therapy (C5 inhibitors), with the newest agents being explored against other factors involved in the complement cascade to alleviate unresolved intravascular hemolysis and extravascular hemolysis. This review summarizes the biology and current treatment strategies for PNH with the aim of reaching a general audience with an interest in hematologic disorders.

MDS-539 Understanding the Real-World Clinical Effectiveness of Pegcetacoplan for the Treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH)

MDS-539 Understanding the Real-World Clinical Effectiveness of Pegcetacoplan for the Treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH)

The Current Treatment of Rare Disease, Lysosomal Acid Lipase Deficiency (LAL-D) and Paroxysmal Nocturnal Haemoglobinuria (PNH)

The Paroxysmal Nocturnal Hemoglobinuria (PNH) and Lysosomal acid Lipase Deficiency (LAL-D) are rare disorder disease. Ultomiris and Soliris for PNH and Kanuma for LAL-D are innovative treatments for PNH and LAL-D, respectively. These therapies can treat each ultra-rare condition by alleviating symptoms and lowering mortality rates for both diseases. The aim of this research is to investigate the rare diseases PNH and LAL-D, as well as the existing treatments for both. Each medicine should be safe and have a good therapeutic effect, with a wide range of benefits and few adverse effects. PRISMA (Preferred Reporting Items for Systematic Reviews) was used to evaluate three treatments: Ultomiris and Soliris for PNH and Kanuma for LAL-D. The search was limited to scientific research articles and clinical trials (Publication years between 2007 and 2022). In the analysis, 20 studies were chosen based on their treatment, concentration, population, year of publication, outcomes, and references. Extensive study on the present treatment of PNH and LAL-D was used to draw conclusions on the overall benefits, distribution, efficacy, and safety of the medicines. This study was also utilised to validate the overall improvement in the lives of people with PNH and LAL-D. Ultomiris has an average effect of 96.5% on PNH symptoms, including hemolysis events. Kanuma has a 90% typical impact against LAL-D by reducing symptoms such as LDL-C and normalising Aspartate Aminotransferase (AST) levels (LAL-D symptoms), whilst Soliris has an average 97% effect against PNH, by reducing the presence of lactate dehydrogenase, for example.

PCR187 Patient and Physician Satisfaction of Treatment with Eculizumab or Ravulizumab in Paroxysmal Nocturnal Hemoglobinuria: Results from a Real-World Disease-Specific Programme

Using patient-level data from an Adelphi Disease Specific Programme (DSP), we describe physician-reported and self-reported patient satisfaction with eculizumab or ravulizumab for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).