Treatment Of Paroxysmal Nocturnal Hemoglobinuria Research Articles

Health-related quality of life and symptom-specific functional impairment among patients treated with parenterally administered complement inhibitors for paroxysmal nocturnal hemoglobinuria

AbstractThis study describes the health-related quality of life (HRQoL) and symptom-specific functional impairment of patients with paroxysmal nocturnal hemoglobinuria (PNH) in a real-world setting. 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 semi-structured qualitative interviews. 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 symptom-specific functional impairment. For each patient with PNH who completed the online survey, 3 age- and sex-matched adults from the general population (GP) also completed the survey. The HRQoL and functional impairment of the PNH sample were compared to that of the GP sample. The association between HRQoL/functional impairment and fatigue severity for the PNH sample was also investigated. Compared to the age- and sex-matched GP sample, patients treated with PACIs for PNH had significantly worse HRQoL and greater functional impairment for all measured domains (p < 0.05). Within the PNH sample, statistically significant associations (p < 0.05) were observed between fatigue severity and HRQoL/functional impairment for all outcomes except the PROMIS 29 + 2 Sleep Disturbance domain. Interview participants described fatigue-related impairments in their physical, social, and cognitive functioning. Despite receiving treatment for PNH, patients experienced deficits in HRQoL and functional impairment, suggesting that opportunities to improve patient-relevant outcomes through treatment should be identified.

Monitoring and Treatment of Paroxysmal Nocturnal Hemoglobinuria in Patients with Aplastic Anemia in Asia: An Expert Consensus

Paroxysmal nocturnal hemoglobinuria (PNH) clones can be identified in a significant proportion of patients with aplastic anemia (AA). Screening for PNH clones at the time of an AA diagnosis is recommended by national and international guidelines. In this report, an expert panel of physicians discusses current best practices and provides recommendations for managing PNH in patients with AA in the Asia–Pacific region. Plasma/serum lactate dehydrogenase (LDH) levels and reticulocyte count should be measured with every blood test. PNH clone size should be monitored regularly by flow cytometry, with on-demand testing in the event of a rise in LDH level ± reticulocyte count or development of symptoms such as thrombosis. Monitoring for PNH clones can guide the choice of initial AA treatment, although flow cytometry has resource implications which may present a challenge in some Asia–Pacific countries. The treatment of patients with both PNH and AA depends on which condition predominates; following PNH treatment guidelines if hemolysis is the main symptom and AA treatment guidelines if bone marrow failure is severe (regardless of whether hemolysis is mild or moderate). The expert panel’s recommendations on the monitoring and treatment of PNH in patients with AA are practical for healthcare systems in the Asia–Pacific region.

Advancements in PNH treatment: Crovalimab’s clinical efficacy

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, life-threatening hematologic disease which is characterized by the destruction of red blood cells, leading to a range of severe symptoms and complications. Recent advancements in drug therapies have significantly improved the prognosis for PNH patients. This editorial comprises the impact of PNH drugs, focusing on eculizumab and ravulizumab and comparing it to the recently approved complement inhibitor, crovalimab which targets the complement system to prevent hemolysis. The discussion includes an analysis of clinical trial data and patient outcomes. The editorial mainly addresses emerging therapies like Crovalimab, that promise to offer more comprehensive, complete blockage of complement system and low-dose solutions reducing the treatment hassle while simultaneously appealing to a wider range of patients.

A Retrospective Claims Analysis of the Rate of Complications in Patients Undergoing Treatment for Paroxysmal Nocturnal Hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disease associated with complications that increase morbidity, such as thrombosis and chronic kidney disease. Limited data exist regarding complications among treated patients outside of clinical trials, especially for patients treated with ravulizumab. This study leverages MarketScan claims data to examine the rate of complications in patients receiving PNH treatment. Patients with a diagnosis code of PNH [International Statistical Classification of Diseases and Related Health Problems (ICD-10) diagnosis code: D59.5] between October 2015 and December 2020, aged≥18 on the date of diagnosis, who had a≥6-month follow-up period of continuous enrollment and≥1 PNH-indicated treatment on or after the first PNH diagnosis were included. Among 211 patients diagnosed with PNH being treated with eculizumab or ravulizumab between October 2015 and December 2020, the most common complications were iron deficiency (20.4% of patients), arterial embolism and thrombosis (16.1%), and chronic kidney disease (11.8%). Overall, 44.1% of patients experienced≥1 complication. The high number of patients with PNH receiving treatment who nevertheless experienced complications demonstrates significant unmet medical need. Further analysis with larger sample sizes and including newer therapies, such as pegcetacoplan and iptacopan, is required to fully understand the scope and magnitude of this unmet need.

Beyond Recycling Antibodies: Crovalimab's Molecular Design Enables Four-Weekly Subcutaneous Injections for PNH Treatment.

The advent of recycling antibodies, leveraging pH-dependent antigen binding and optimized FcRn interaction, has advanced the field of antibody therapies, enabling extended durability and reduced dosages. Eculizumab (Soliris®) demonstrated the efficacy of C5 inhibitors for paroxysmal nocturnal hemoglobinuria (PNH), while its derivative, ravulizumab (Ultomiris®), recognized as a recycling antibody, extended the dosing intervals. However, limitations including intravenous administration and inefficacy in patients with the R885H single-nucleotide polymorphism (SNP) in C5 could necessitate alternative solutions. Crovalimab (PiaSky®), a next-generation recycling antibody, overcomes these challenges with innovative charge engineering, achieving the enhanced cellular uptake of C5-crovalimab complexes and targeting a unique C5 epitope, allowing for efficacy regardless of the R885H SNP. This study highlights crovalimab's distinctive molecular features, showing its eliminated binding to Fcγ receptors and C1q, alongside its optimized antigen binding characteristics. The impact of charge engineering was reconfirmed in mice, demonstrating faster C5 clearance than recycling antibodies. Notably, in the maintenance dosing regimen, crovalimab neutralizes approximately seven C5 molecules per antibody on average. Furthermore, its design also reduces the viscosity to facilitate high-concentration formulations suitable for subcutaneous delivery. Consequently, crovalimab offers a four-weekly subcutaneous injection regimen for PNH, marking a substantial improvement in treatment convenience and potentially transforming patients' quality of life.

Iptacopan (Fabhalta) for Paroxysmal Nocturnal Hemoglobinuria

The FDA has approved the complement factor B inhibitor iptacopan (Fabhalta – Novartis) for treatment of paroxysmal nocturnal hemoglobinuria (PNH) in adults. Iptacopan is the first oral drug to be approved in the US for this indication. Three parenterally administered drugs, the complement C5 inhibitors eculizumab (Soliris) and ravulizumab (Ultomiris) and the complement C3 inhibitor pegcetacoplan (Empaveli), are also approved for treatment of PNH.

Navigating the Complement Pathway to Optimize PNH Treatment with Pegcetacoplan and Other Currently Approved Complement Inhibitors.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and potentially life-threatening hematologic disorder caused by a somatic mutation in a relevant portion of hematopoietic stem cells. Mutation of the phosphatidylinositol glycan biosynthesis class A (PIGA) gene prevents the expression of cell-surface proteins, including the complement regulatory proteins CD55 and CD59. With decreased or a lack of CD55 and CD59 expression on their membranes, PNH red blood cells become susceptible to complement-mediated hemolysis (symptoms of which include anemia, dysphagia, abdominal pain, and fatigue), leading to thrombosis. State-of-the-art PNH treatments act by inhibiting the dysregulated complement at distinct points in the activation pathway: late at the C5 level (C5 inhibitors, eculizumab, ravulizumab, and crovalimab), centrally at the C3 level (C3/C3b inhibitors and pegcetacoplan), and early at the initiation and amplification of the alternative pathway (factor B inhibitor, iptacopan; factor D inhibitor, danicopan). Through their differing mechanisms of action, these treatments elicit varying profiles of disease control and offer valuable insights into the molecular underpinnings of PNH. This narrative review provides an overview of the mechanisms of action of the six complement inhibitors currently approved for PNH, with a focus on the C3/C3b-targeted therapy, pegcetacoplan.

CT-306 Evaluation of the Healthcare System Burden Associated With Intravenous Treatment for Paroxysmal Nocturnal Hemoglobinuria

ObjectiveTo delineate steps in the intravenous (IV) treatment workflow with ravulizumab for paroxysmal nocturnal hemoglobinuria (PNH) from a healthcare system perspective and to identify steps that could potentially be simplified with an oral therapy. DesignIndividual in-depth semi-structured qualitative interviews were conducted with 5 US hematologists between October and December 2023. Participating physicians were from large medical centers (academic and community-based) experienced in treating PNH patients with IV ravulizumab. The interview data were analyzed to identify steps in the IV treatment workflow, leading to the development of a process map covering treatment decision/planning to outpatient administration. Physicians’ perspectives on process complexities related to IV treatment and steps that could be simplified through the adoption of an oral therapy were collected. ResultsThe approximate time from treatment decision to administration ranged from 2 to 4 weeks. Delays were primarily attributed to limited vaccination access in community settings and insurance approvals. Additional delays occurred, particularly for offlabel-dosing schedules, for example for breakthrough hemolysis, due to added complexity of obtaining insurance approvals. Patients spent an average of 3–4 hours for treatment administration at the infusion center. The lack of flexibility in scheduling, given that infusion centers were operating at full capacity, was noted. Hypothetically, with an oral treatment, alleviated steps would include treatment scheduling and administration at infusion centers. ConclusionsThe study revealed complexities associated with IV treatment with ravulizumab for PNH from a healthcare system perspective. Given that IV treatment is resource- and time-intensive for both patients and providers and that infusion centers are operating at full capacity, adopting an oral treatment could potentially enhance infusion center capacity and improve scheduling flexibility for other competing conditions. Further studies are warranted to understand the IV treatment burden from the perspectives of additional healthcare personnel (nurses, pharmacists) and patients.

P42 Budget Impact Analysis of Eculizumab Biosimilar for Treatment of Paroxysmal Nocturnal Hemoglobinuria from Public Hospital Perspective in 2023

P42 Budget Impact Analysis of Eculizumab Biosimilar for Treatment of Paroxysmal Nocturnal Hemoglobinuria from Public Hospital Perspective in 2023

HSD51 Evaluation of the Healthcare System Burden Associated With Intravenous Treatment for Paroxysmal Nocturnal Hemoglobinuria

HSD51 Evaluation of the Healthcare System Burden Associated With Intravenous Treatment for Paroxysmal Nocturnal Hemoglobinuria

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.