RARE DISEASE
Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria
Synonyms: Marchiafava-Micheli disease, PNH
Synonyms: Marchiafava-Micheli disease, PNH
Synonyms: Marchiafava-Micheli disease, PNH
Drug discovery
29
drugs
With orphan designations
Overview
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal disorder caused by PIGA gene mutations, leading to deficiency of GPI-anchored complement regulatory proteins (CD55/CD59). This results in chronic complement-mediated intravascular hemolysis, thrombophilia, and bone marrow failure. Clinical features include hemolytic anemia, hemoglobinuria, fatigue, and life-threatening thrombosis. Diagnosis requires flow cytometry to detect GPI-anchored protein deficiency. Treatment focuses on complement inhibition, dramatically improving outcomes [1][6][11].
Burden
Thrombosis: Leading cause of mortality (40–67% of deaths) [6][9][15].
Clinical impact: Chronic fatigue (80%), renal impairment (50%), transfusion dependence, and impaired quality of life [4][14][16].
Economic: Mean hospitalization costs exceed $125,000; 23% require annual PNH-related hospitalizations [9][14].
Therapies
Terminal complement inhibitors: Eculizumab and ravulizumab (C5 inhibitors) reduce hemolysis and thrombosis risk [3][6][18].
Proximal inhibitors: Pegcetacoplan (C3), iptacopan (factor B), and danicopan (factor D) address residual extravascular hemolysis [3][8][13].
Supportive care: Transfusions, anticoagulation; stem cell transplant for refractory cases [6][11].
Categories: rare genetic diseases, rare hematological diseases, rare inborn errors of metabolism, rare transplant-related disorders
Research Papers
1,113 drug discovery papers about Paroxysmal nocturnal hemoglobinuria, with 3 first-in-class and 49 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,113 drug discovery papers about Paroxysmal nocturnal hemoglobinuria, with 3 first-in-class and 49 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-09 | Long-Term Outcomes and Thrombosis Rates in Patients with Large PNH Clone Managed Without Complement Inhibitors: A 20-Year Follow-Up from a Tertiary Care Centre in North India.
Treatment of paroxysmal nocturnal hemoglobinuria (PNH) patients with a large-size clone is a major challenge in low and middle-income countries. In the absence of complement inhibitors, the response rates with available therapy have not been evaluated in the Indian subcontinent. Retrospective data for patients with a large PNH clone >12 years of age were collected from 2004 to 2024 and were further classified as: Group 1: Classical PNH (c-PNH); Group 2: PNH with aplastic anemia (AA) occurring simultaneously: PNH(L)/AA-s; Group 3: AA preceding the evolution of a Large PNH clone: PNH(L)/AAp. A total of 211 patients were identified with a mean age of 33 years. Of these patients, survivorship status was known for 163 (77.2%), and 111 (52.6%) were under regular follow-up. Out of a total of 211 patients, 49.8% (n-105) cases of c-PNH, 29.4% (n-62) cases of PNH(L)/AA-s, and 20.9% (n-44) cases of PNH(L)/AA-p were identified. Fourteen cases (6.6%) developed thrombosis. Response rates with available drugs in 111 patients were: complete response (CR) in 18% (n-20), partial response (PR) in 65.8% (n-73), and no response (NR) in 16.2% (n-18). Of 57 patients with classical PNH, 20 (35.1%) received low-dose Apixaban (2.5 mg BD) as primary prophylaxis. None developed thrombosis or bleeding. Survivorship status was known for 163 (77.2%) patients. Death occurred in 19% (32/163). The mean survival across all the groups (n-163) was 12.8 years. In the present study, low thrombotic rates were noted in these patients. With available therapy, the overall response rate was 80%, primarily consisting of partial responses.
2026-09-08 | Complement targeting in autoimmune diseases.
Complement is a central effector of cell and tissue injury in hematological and autoimmune diseases, and recent intensive research brought new inhibitors to the clinic. This review summarizes complement-mediated mechanisms across hematological, systemic, and kidney-specific autoimmune diseases, appraises emerging biomarker strategies, and evaluates these therapies. For years, clinical complement inhibition was possible only at C5, first in paroxysmal nocturnal hemoglobinuria. The arsenal has now expanded to the initiation pathways: sutimlimab (anti-C1s) is effective in the hematological autoimmune condition cold agglutinin disease, pegcetacoplan (C3-inhibitor) in C3 glomerulopathy and immune-complex membranoproliferative glomerulonephritis, and oral iptacopan (Factor B-inhibitor) reduces proteinuria in immunoglobulin A nephropathy and C3 glomerulopathy. Nevertheless, challenges remain. Avacopan (C5aR1-inhibitor) faces proposed withdrawal after trial manipulation and hepatotoxicity, and although complement is central to systemic lupus erythematosus and contributes to membranous nephropathy, no effective strategy has yet emerged. Recognizing complement's role in the pathophysiology of hematological and autoimmune diseases has driven effective new therapies. Comprehensive profiling complement biomarkers, now feasible through complementomics in fluids and tissues, may reveal responsive endotypes and optimal cascade steps to target in diseases where complement is implicated but trials have not yet matched the right drug to the right patients.
2026-09-02 | Interleukin-6 in hemolytic anemias: from inflammatory pathways to therapeutic targeting.
Hemolytic anemias comprise inherited and acquired disorders characterized by premature red blood cell destruction. Increasing evidence indicates that many forms of hemolysis are accompanied by sustained inflammatory and immune activation. Red blood cell breakdown releases damage-associated molecular patterns, including free heme and hemoglobin, which activate innate immune pathways, endothelial cells and coagulation cascades. Interleukin-6 (IL-6) is a central mediator linking hemolysis to systemic inflammation, iron restriction and autoimmunity. In this review, we use a heuristic dual-axis framework in which hemolysis-induced IL-6 promotes hepcidin-dependent iron sequestration and acute-phase responses, while also supporting Tfh and Th17 responses, impairing regulatory T-cell function and sustaining autoreactive or alloreactive B cells. The conceptual advance of this framework is not to propose IL-6 as a uniform pathogenic mechanism, but to position IL-6 differently across hemolytic disorders according to the dominant initiating biology and level of evidence. These pathways may aggravate anemia, thrombosis and organ injury. We summarize evidence for IL-6 involvement in autoimmune hemolytic anemia, Castleman disease-associated cytopenias, sickle cell disease, thalassemia, paroxysmal nocturnal hemoglobinuria, congenital red-cell membrane and enzyme defects, and hyperhemolysis syndrome. We also discuss therapeutic strategies targeting IL-6, IL-6 receptor, JAK/STAT signaling and IL-6 trans-signaling. Current clinical evidence remains limited, but IL-6-directed therapy may be rational in selected refractory immune-mediated or macrophage-activation-associated hemolytic disorders. Future studies should prioritize mechanism-based biomarkers and prospective, biomarker-stratified trials.
2026-08-12 | Anemia and Patient-Reported Outcomes in Patients With Paroxysmal Nocturnal Hemoglobinuria: A Real-World Observational Study.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by complement-mediated hemolysis, thrombosis, bone marrow failure, and anemia. Although current treatments improve outcomes, patients still experience hemolysis and could remain anemic with a negative impact on quality of life (QoL). The aim of this study was to assess whether patient-reported outcomes (PROs) distinguish PNH patients with/without hemolysis and evaluate factors associated with PROs. In this international, multicenter, observational study, 97 PNH patients witfrom Italy and the UK completed the EORTC QLQ-C30 and QLQ-AA/PNH measures at baseline and after 2 weeks. Clinical, biochemical, and treatment data were collected. Hemolysis was defined as LDH ≥ 1.5 × upper normal limit. PRO scores were compared between patients above and below this threshold. Associations of PROs with patient and disease factors were analyzed. Of 97 patients (mean age 49 ± 15), 24.7% were anemic (Hb < 10 g/dL) and 16% had hemolysis. QoL did not differ significantly by hemolysis status. However, anemia was associated with significantly lower EORTC QLQ-C30 global health and functional scores (p < 0.05), particularly in physical, role, and social domains, and with worse QLQ-AA/PNH emotional, cognitive, and physical functioning, as well as greater illness intrusiveness and stigmatization. Fatigue, dyspnea, and pain were common symptoms in anemic patients. QLQ-AA/PNH scores showed high internal consistency (Cronbach's α > 0.7) and test-retest reliability (ICC: 0.72-0.95). Anemia, but not residual hemolysis, was associated with impaired QoL across multiple domains. Addressing anemia alongside hemolysis may improve PROs in the management of PNH. The authors have confirmed clinical trial registration is not needed for this submission.
2026-07-15 | Switching between complement inhibitors in paroxysmal nocturnal hemoglobinuria: Analysis of strategy, efficacy, and safety.
Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-orphan disease. In 2026, approved complement inhibitors (CIs) for PNH include three C5 inhibitors (C5i) and three proximal inhibitors (PIs). Clinical trials for the approved PI pegcetacoplan, iptacopan, and C5i + danicopan had clear protocols for changing from terminal to PI, extrapolated into real-world practice. There is no guidance for patients changing from a PI to a different CI. We present the largest international cohort to date. The inclusion criteria were as follows: patients established on a PI, who have changed treatment to a different CI. Sixty-five patients with a median age at PNH diagnosis of 40 years were included. Indications for CI switch were as follows: hemolysis (extravascular/recurrent breakthrough/not specified), side effects, trial termination, patient choice, and other. CI changes (149) were classified as (1) terminal-to-proximal (75/149), 6 hemolytic events reported within 14 days of CI change; (2) proximal-to-proximal (45/149), 2 hemolytic events reported within 14 days of CI change; and (3) proximal-to-terminal (29/149), 13 hemolytic events within 14 days of CI change. This is the largest cohort of PNH patients facing multiple CI changes. With the increasing availability of different CI classes, patients may experience several treatment changes over their disease course. CI should not be interrupted. The cohort would suggest that overlapping treatment for patients changing from PI to another CI is not required. Tapering of treatment does not seem to be effective at preventing hemolysis complications. Patients should be monitored closely for hemolysis, especially when changing from proximal-to-terminal inhibition. Prospective clinical/laboratory analysis is recommended for further clarification management for this patient group.
cell therapies
2026-07-31 | Allogeneic haematopoietic stem cell transplantation for refractory perforating intestinal Behçet disease in a patient with aplastic anaemia: A case report.
Aplastic anemia (AA) rarely coexists with intestinal Behçet disease (iBD), and the post-partum period may further complicate its expression. Managing refractory iBD with recurrent perforation on a background of long-standing AA is challenging, and evidence on optimal treatment is limited. A 42-year-old woman with non-severe aplastic anemia (NSAA) diagnosed in 2005 (AA duration ≈ 20 years) developed recurrent fever, oral ulcers, and penetrating ulcers of the ileocaecum and terminal ileum shortly after cesarean delivery in June 2019, with one episode of vulvar ulceration. Histology showed transmural vasculitis with focal obliterative endarteritis, confirming iBD; HLA-B51 was negative. Pre-transplant marrow was markedly hypocellular without dysplasia, and karyotype (46,XX), flow cytometry, myelodysplastic syndrome/AML and myeloproliferative neoplasm gene panels, and paroxysmal nocturnal hemoglobinuria screening were all negative, supporting acquired AA rather than hypoplastic myelodysplastic syndrome. Despite corticosteroids, tacrolimus, tofacitinib, and tocilizumab, she sustained 2 intestinal perforations (May and September, 2023). As iBD was refractory and AA had progressed to very severe AA, she underwent human leukocyte antigen (HLA)-matched sibling peripheral-blood allogeneic hematopoietic stem cell transplantation (allo-HSCT) in June 2024 with fludarabine/busulfan/cyclophosphamide/ anti-thymocyte globulin conditioning. Neutrophil and platelet engraftment occurred around D+11 and D+15, with 100% donor chimerism at D+16 and no acute or chronic graft-versus-host disease; only transient, self-limiting cytomegalovirus (CMV) and Epstein-Barr virus DNAemia occurred, without CMV disease or post-transplant lymphoproliferative disorder. Blood counts recovered progressively, with hemoglobin 127 grams/L and platelets 118 × 109/L at the last follow-up (≈12 months), only mild residual cytopenia, transfusion independence, and sustained remission of iBD on maintenance immunosuppression. She then returned to work and was lost to follow-up. This case suggests that allo-HSCT may be an effective option for selected patients with AA and refractory iBD, achieving sustained remission of both the marrow failure and the intestinal disease. As this is a single case with limited follow-up (≈12 months), longer follow-up and additional cases are needed.
2026-05-04 | Haploidentical allogeneic haematopoietic stem cell transplantation for paroxysmal nocturnal haemoglobinuria: a retrospective analysis.
To evaluate the efficacy and prognostic factors of haploidentical haematopoietic stem cell transplantation (haplo-HSCT) for paroxysmal nocturnal haemoglobinuria (PNH). We retrospectively analyzed 36 PNH patients (2 classic PNH, 34 AA-PNH syndrome) undergoing haplo-HSCT (G-CSF/ATG-based protocol) from June 2013 to December 2024, with BU/CY/ATG (n = 28) or BU/CYlow/FLU/ATG (n = 8) conditioning and uniform GVHD prophylaxis. The overall myeloid engraftment rate was 100% (median + 12 d) and platelet engraftment rate 95.5% (median + 13 d). Competing risk analysis showed 42.7% acute GVHD (26.7% grade II-IV, 5.3% grade III-IV); 27.3% chronic GVHD (15.2% mild, 12.1% moderate-severe) among 33 evaluable patients. With a median follow-up of 57 months, the 5-year overall survival rate was 88.6 ± 5.4%. All 32 monitored patients achieved PNH clone clearance (median 3 months), 33 had normalized blood counts, and 3 died of infection, organ hemorrhage or pulmonary embolism. Haplo-HSCT yields favorable outcomes and is a curative therapy for PNH, serving as a valuable option for severe bone marrow failure patients, with G-CSF/ATG-based haplo-HSCT as a promising alternative strategy.
2025-12-10 | A rare case of littoral cell angioma with paroxysmal nocturnal hemoglobinuria.
We report a rare case of littoral cell angioma (LCA) in a patient with paroxysmal nocturnal hemoglobinuria (PNH). To our knowledge, this is the first report of these 2 rare conditions occurring together, which may help clarify their relationship and its importance in clinical practice. A 38-year-old man had recurrent anemia and dark brown urine, accompanied by abdominal pain that worsened over time, which required several hospital visits and long-term follow-up. Follow-up scans showed progressive splenomegaly with multiple nodules. In combination with histopathology and immunohistochemistry results (CD31, CD34, and ERG positive; Ki-67 around 5%), these findings confirmed a final diagnosis of LCA in a patient with previously diagnosed PNH. The patient received treatment with oral prednisone, sodium bicarbonate, and vitamin E for PNH. As the splenic lesions enlarged and blood counts worsened, he subsequently underwent laparoscopic splenectomy in February 2025. After surgery, both LCA and anemia concurrently resolved, with normalization of hematologic parameters and resolution of abdominal symptoms. This case suggests a potential association between LCA and PNH. Splenectomy provided dual benefits by treating the splenic tumor and improving hemolysis. Given the possible risk of malignant transformation, long-term follow-up is recommended.
2025-11-03 | Paroxysmal nocturnal hemoglobinuria: Transplant experience using post-transplant cyclophosphamide in a resource-limited setting
Abstract Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, debilitating clonal hematopoietic stem cell disorder characterized by complement-mediated intravascular hemolysis, thrombosis, and varying degrees of bone marrow failure. PNH is broadly classified into classical PNH, which typically presents with hemolysis and thrombotic complications, and secondary PNH, which occurs in association with bone marrow failure syndromes such as aplastic anemia or myelodysplastic syndromes. While allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative modality, it is associated with considerable morbidity and mortality. On the other hand, complement inhibitors (eculizumab, ravulizumab) have emerged as effective treatments with lower toxicity, though they are not curative. However, in low-resource settings like Nepal, the prohibitively high cost of complement inhibitors running into millions of rupees renders them inaccessible. Conversely, an allogeneic transplant in Nepal costs under $10,000, making it a more feasible albeit riskier option. Here, we report our single-center experience with allogeneic HSCT using post-transplant cyclophosphamide (PTCy) for PNH patients in a low-income setting. Methods: Medical records of seven patients with classical PNH who underwent allogeneic HSCT between 2020 and 2023 were retrospectively reviewed. Data on patient demographics, type of transplant, time from diagnosis to transplant, transplant-related complications, and outcomes were collected and analyzed. Result: The mean age of patients was 30.7 years (median: 31; range: 25–36 years), with all seven patients being male. The median time from diagnosis to transplant was 8 months, primarily due to scheduling delays associated with a limited transplant capacity and a waiting list at the only HSCT center currently operating in Nepal. All donors were siblings: 4 (57.1%) fully matched related donors (MRD) and 3 (42.9%) haploidentical donors. MRD transplant patients received Fludarabine/Melphalan (Flu/Mel) and haploidentical transplant received standard Baltimore protocol. All patients received peripheral blood stem cells (PBSCs), with a mean CD34+ cell dose of 10.57 × 10⁶/kg. All patient received post-transplant cyclophosphamide as GVHD prophylaxis along with tacrolimus and MMF. Six patients achieved neutrophil and platelet engraftment. Median time to neutrophil engraftment: 15.5 days (range: 13–21 days) Median time to platelet engraftment: 17.5 days (range: 13–35 days). Three patients (42.9%) died due to transplant-related complications. Causes of death included veno-occlusive disease in one MRD recipient at 40 days post-transplant, CMV pneumonitis with gastroenteritis in one haploidentical recipient at 24 days, and severe mucositis complicated by neutropenic fever and fungal pneumonia in another haploidentical recipient at 12 days post-transplant. Four patients (57.1%) are alive and disease-free at a median follow-up of over 24 months. Among them, two patients developed CMV reactivation, which was well controlled with valganciclovir. One patient, who received a haploidentical transplant, developed mild oral chronic GVHD. Conclusion: Allogeneic HSCT remains a potentially curative but high risk option for PNH patients, particularly in resource limited settings. Our experience highlights the significant transplant related morbidity and mortality, even with modern GVHD prophylaxis such as PTCy.Given the availability of safer, though non-curative, therapeutic alternatives like complement inhibitors, urgent advocacy is needed. Patient groups, healthcare providers, policy-makers, and international aid organizations must collaborate to improve access to life-saving treatments in low-income countries.
2025-11-02 | Long-term outcomes of αβ T-cell/CD19 B-cell-depleted peripheral blood stem cell transplantation from unrelated donors in pediatric and adolescent patients with severe aplastic anemia: a single-center study.
Hematopoietic stem cell transplantation (HSCT) from matched unrelated donor (MUD) is a curative option for severe aplastic anemia (SAA) patients, refractory to horse anti-thymocyte globulin (ATG) and cyclosporin A (CsA) mmunosuppression. Although the results of MUD HSCT in SAA have improved significantly, graft-versus host disease (GVHD) remains a serious problem, associated with significant morbidity and mortality. We investigated the role of alpha/beta T cell depletion of the graft as a way to improve the results of MUD HSCT in SAA. Forty-seven patients with SAA were treated since September 2012 till February 2022. Median age at HSCT was 12.4 (3-22.7) years, 26 males/21 females. All patients were either refractory or relapsed (35:12) after combined immune suppression therapy, 5 pts had concurrent severe hemolytic paroxysmal nocturnal hemoglobinuria (PNH). The median time from diagnosis to transplant was 1.2 years (0.5-11.8 years). Preparative regimen included cyclophosphamide 100 mg/kg, fludarabine 150 mg/kg, ATGAM at 100 mg/kg (27pts) or thymoglobulin 5 mg/kg (15 pts) and 6 Gy thoraco-abdominal irradiation. Thiotepa at 10 mg/kg and rituximab at 200 mg/m2 were used in a proportion of cases. Patients with PNH (n = 5) received eculizumab 600 mg once every 7 days from -7 to +14 days. Post-transplant GVHD prophylaxis included tacrolimus till day 180. Peripheral blood stem cell (PBSC) grafts were depleted of T cell receptor (TCR) alpha/beta cells and CD19 cells with CliniMACS device, as recommended by the manufacturer. Patients received a median of 9.2 (2.7-18.30) х106 CD34 per kg, 21.8 (0.85-316)x103 αβ T cells per kg. Forty-six patients (cumulative incidence (CI) 0.96 (95% 0.9-1)) engrafted with a median of 14 (7-24) days for white blood cells (WBC) and 12 (9-18) days for platelets. In 8 patients after MUD transplantation secondary graft failure (rejection) developed, cumulative incidence was 0.15 (95% 0.08-0.3), three of them was successfully retransplanted. CI of acute graft-versus host disease (aGVHD) grade II-IV was 0.15 (95% 0.08-0.29). No cases of grade III-IV aGVHD were registered. CI of chronic graft versus host disease (cGVHD) was 0.11 (95% 0.05-0.25). All were mild and off-IST at last follow-up. A median follow-up is 9 years. Ten patients died. At a median follow-up of 9 years, the overall survival was 79% (67-90). Failure-free survival was 72% (60-85) and the GRFS was 72% (60-85). TCR alpha/beta depletion is a robust platform for allogeneic HSCT from MUD in severe aplastic anemia. Results should be further improved by additional measures to control viral infections and prevent rejection.
antibodies
2026-08-24 | Indirect treatment comparisons find enhanced effectiveness of pegcetacoplan versus crovalimab in both complement inhibitor-naïve and -experienced patients with paroxysmal nocturnal hemoglobinuria.
Aim: Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare hematological condition, which if undertreated, is associated with significant morbidity and early mortality. This indirect treatment comparison (ITC) evaluated the effectiveness of pegcetacoplan (the first approved proximal inhibitor) versus crovalimab, a new C5i inhibitor (C5i), for treatment of PNH in C5i-naive and C5i-experienced patients. Materials & methods: In the C5i-naive, an unanchored matching-adjusted indirect comparison (MAIC) was conducted with patient-level data for pegcetacoplan-versus-best-supportive-care from PRINCE (NCT0408560) and published data for crovalimab-versus-eculizumab from COMMODORE 2 (NCT04434092)/COMMODORE 3 (NCT04654468). In the C5i-experienced ITC (Bucher's method), patient-level data were from PEGASUS (NCT03500549; pegcetacoplan vs eculizumab) and aggregated data from COMMODORE 1 (NCT04432584; crovalimab-vs-eculizumab). Evaluated outcomes in both settings included red-blood-cell transfusion-avoidance; hemoglobin (Hb) stabilization; hemolysis control; mean change-from-baseline on Functional Assessment of Chronic Illness Therapy-Fatigue total scores; additionally, the C5i-experienced ITC evaluated, mean change-from-baseline to week-25 for red blood cell units and domain scores on the European Organization for Research and Treatment of Cancer instrument. Results: Pegcetacoplan versus crovalimab in the C5i-naive was associated with significantly (p < 0.05) higher probabilities of transfusion-avoidance and Hb stabilization, and greater odds of hemolysis control. In the C5i-experienced, all outcomes significantly (p < 0.05) favored pegcetacoplan. Conclusion: Pegcetacoplan provides high clinical advantages across the full PNH treatment pathway.
2026-08-04 | Complement inhibitor therapy should be available to patients with paroxysmal nocturnal hemoglobinuria throughout the world.
The development of several complement-inhibiting medicines has been a major advance in the management of paroxysmal nocturnal hemoglobinuria (PNH), a rare and life-threatening disease. Patients now have a life expectancy close to that of the general population, and the quality of life of most patients has improved substantially. In addition, by targeting either the proximal or the terminal complement pathway, we have also been able to improve our understanding of the pathophysiology of PNH. Within the landscape of this rather spectacular progress, a major drawback has been the rather astronomic price of all of these medicines: This means, in practice, that in many countries they are not available at all, and a conservative estimate is that at least one-half of the PNH patients in the world have no access to complement inhibitors. It is urgent to correct this inequality that is also an injustice. Very recently, the Max Foundation, a global nonprofit organization, has announced that it will collaborate with a pharmaceutical company to make 'innovative treatment for PNH' available in many countries: We may now hope that other companies will join such collaborations.
2026-07-04 | High Proportion of PNH Type II Neutrophils Is Associated With Thrombosis in Patients Displaying a PNH Clone ≥ 1.
The clinical significance of PNH Type II white blood cells (WBCs) remains unclear. We assessed the relative percentage (rel%) of Type II neutrophils in 355 patients with a PNH clone ≥ 1% on neutrophils enrolled by 33 flow cytometry laboratories in the 5-year French nation-wide multicenter prospective observational study. We first analyzed 127 of 133 patients with a major PNH clone (≥ 50%) and evaluable Type II neutrophil rel%. Using hemolysis data available for 107 patients, a threshold of 3% Type II neutrophils rel% distinguished two groups: 22 "high Type II" and 105 "low Type II" patients. Hemolysis was less frequent in the "high Type II" group. Thrombosis was more frequent at diagnosis and during cumulative long-term follow-up in this group. High neutrophil rel% ≥ 3% was independently associated with thrombotic events. Among 222 patients with smaller PNH clones (1%-50%), 207 displayed evaluable Type II neutrophil rel%, of which 87 were classified as "high Type II" and 120 as "low Type II". Although no thrombosis was present at diagnosis, two thrombotic events occurred during follow-up in the "high Type II" group, whereas none were observed in the "low Type II" group. Long-term follow-up showed no major changes in Type II neutrophil rel%, irrespective of variations in total clone size. These findings suggest that, regardless of the total PNH clone size, PNH Type II neutrophil rel% is a stable parameter and may represent a reliable predictor of thrombosis, potentially supporting earlier consideration of anticomplement therapy initiation.
2026-06-23 | Thromboembolic Events in Indian Patients with Paroxysmal Nocturnal Hemoglobinuria: A Single Centre Experience.
Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, acquired clonal hematopoietic stem cell disorder. Thrombosis is the most common complication leading to high mortality in PNH patients. The mechanisms of thrombosis in PNH are diverse, and the exact mechanism is still unclear. There is a paucity of data on the incidence of thrombosis in Indian patients with PNH. We retrospectively analyzed the data of 95 patients with a positive PNH clone treated at our center. Ten patients (9.5%), including 07 patients with classical PNH and 03 patients with PNH associated with aplastic anemia or myelodysplastic neoplasm (PNH-AA/MDS), had thromboembolic events. Thrombosis was present in 38% of classical PNH and 10% of PNH AA/MDS. One-third of the patients had 2 or more episodes of thrombosis during the disease. The most common site of thrombosis in our study was the abdominal veins. Fatal thrombosis occurred in 50% of the patients. None of the patients received Eculizumab. The median clone size was higher in cPNH patients compared to PNH AA/MDS. All patients developing thrombosis had a large granulocyte PNH clone and high disease activity. 50% of the patients died as a direct consequence of thrombosis and its complications. Thrombosis despite prophylactic anticoagulation was seen in 25% of patients. The findings, notwithstanding the limited number of patients, confirm that thrombosis continues to remain a significant cause of mortality in patients with PNH.
2026-06-15 | Exploring individualized crovalimab dosing in PNH through in silico modelling: Potential for improved convenience and cost efficiency.
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired haematopoietic stem cell disorder. Crovalimab, a complement C5-inhibitor, is approved for PNH and can be self-administered subcutaneously every 4 weeks, offering a more convenient route than intravenous C5-inhibitors. Since exposure often exceeds pharmacokinetic targets and varies with body weight, we aimed to explored individualized dosing of crovalimab using clinical trial simulations to optimize therapy. We compared standard, weight-based and therapeutic drug monitoring (TDM)-guided regimens in treatment-naïve PNH patients over 52 weeks by means of clinical trial simulations based on the population pharmacokinetic model developed by the market authorization holder. Maintenance-phase crovalimab concentrations were generally supratherapeutic with substantial variability. Weight-based dosing reduced this variability, while TDM-guided dosing further minimized it and allowed dose intervals to be prolonged in 24% of patients to a mean of 5.0 weeks, while maintaining exposure comparable to the standard regimen. Individualized dosing of crovalimab may reduce exposure variability and enable less frequent dosing, supporting the feasibility of more flexible cost-effective and patient-tailored treatment regimens.
proteins
2026-08-29 | A fusion protein of the two tick-derived C5 inhibitors OmCI and RaCI: complete C5 inhibition despite strong complement activation.
The complement system must be tightly regulated to prevent tissue damage and disease, yet current C5 inhibitors like the anti-C5 monoclonal antibody Eculizumab - though clinically approved (e.g., for paroxysmal nocturnal haemoglobinuria, PNH) - fail to achieve complete terminal pathway blockade under conditions of strong complement activation. To address this limitation, we investigated tick-derived C5 inhibitors and discovered that combinatorial targeting of non-overlapping C5 epitopes enables full inhibition. Leveraging this insight, we engineered a bifunctional fusion protein RaCI-gly-OmCI (R-g-O), recombinantly merging OmCI (Ornithodoros moubata Complement Inhibitor) and RaCI (Rhipicephalus appendiculatus Complement Inhibitor), which bind distinct sites on C5. Surface plasmon resonance experiments demonstrate subnanomolar binding of the building blocks and the fusion protein to C5. In contrast to the building blocks OmCI and RaCI, R-g-O achieves complete C5 inhibition under strong complement activation conditions in an alternative pathway haemolysis experiment. In classical pathway haemolysis settings, OmCI and R-g-O completely protected from lysis while RaCI only achieved about 50% protection. The fusion protein R-g-O represents a highly effective tool for blocking terminal pathway activity in research, surpassing the limitations of single-agent C5 inhibitors.
2026-06-20 | Efficacy and Safety of the C3 Inhibitor Pegcetacoplan in Paroxysmal Nocturnal Hemoglobinuria: A Systematic Review and Meta-Analysis.
To evaluate the efficacy and safety of the complement C3 inhibitor pegcetacoplan in patients with paroxysmal nocturnal hemoglobinuria (PNH). PubMed, Embase, Web of Science, and Cochrane Library were systematically searched for studies reporting pegcetacoplan use in PNH. Outcomes included transfusion-requirement, hemoglobin normalization, mean hemoglobin levels, lactate dehydrogenase normalization, reticulocyte count normalization, and safety endpoints. Pooled proportions with 95% confidence intervals were calculated using random-effects models, and heterogeneity was assessed using the I2 statistic. Five studies comprising 271 patients were included. Transfusion avoidance was observed in 80.6% of patients, with a pooled transfusion-requirement rate of 19.4%. LDH normalization occurred in 68.5% of patients (I2 = 0%). Hemoglobin normalization was observed in 42.9%, while reticulocyte count normalization reached 66%. Any-grade adverse events occurred in 83.5% of patients, most commonly pyrexia, headache, and dizziness. Serious adverse events occurred in 16.6%, decreasing to 12% after sensitivity analysis. Breakthrough hemolysis was reported in 14.8%, and infections in 17%. Pegcetacoplan demonstrates consistent efficacy signals across key hematologic endpoints and an acceptable safety profile, supporting its potential role as an important therapeutic option, particularly in patients with persistent extravascular hemolysis despite C5 inhibition.
2025-12-28 | Disease-modifying treatments in paroxysmal nocturnal hemoglobinuria: a systematic review of economic evaluations.
BACKGROUND: Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, life-threatening hematologic disorder characterized by chronic hemolysis, bone marrow and organ failure, and thrombotic events. Without effective treatment, PNH can lead to severe complications, including organ damage, increased morbidity, and heightened mortality risk. The high expense and therapeutic revolution that has emerged in PNH necessitates a careful appraisal of its cost-effectiveness. This study aimed to systematically review the cost-effectiveness of disease-modifying therapies (DMTs) in PNH. METHODS: A comprehensive search syntax was developed to identify relevant studies using online databases. Criteria used in health economic evaluations include costs, effectiveness assessment with life-years gained (LYG) or quality-adjusted life-years (QALY), incremental cost-effectiveness ratio (ICER), and other clinico-economic outcomes. To enable comparison across different countries, the results of economic evaluations allow for the comparison of costs and ICERs across all studies, which were converted into United States Dollars (USD) values using the time model developed. The quality of the studies was assessed using the Quality of Health Economic Studies (QHES) instrument. This study is conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: Nine papers were included in the 351 screened records. Pegcetacoplan was a dominant (i.e., less costly and more effective) option compared to C5 complement inhibitors and iptacopan. Eculizumab was not cost-effective compared with other DMTs or the standard of care. The current annual price of $12,300-$13,100 for adding danicopan to ravulizumab was not cost-effective compared to ravulizumab alone. The results of nine studies indicated that the majority of costs are related to the DMTs themselves. CONCLUSION: The cost-effectiveness analyses of DMTs in PNH suggest that the newer options, pegcetacoplan and iptacopan, are cost-effective and provide greater clinical utility than complement C5 inhibitors, especially eculizumab.
2025-11-19 | Paroxysmal Nocturnal Hemoglobinuria in Pregnancy Treated With Pegcetacoplan: Case Report and Pharmacokinetic Analysis
ABSTRACT There is an unmet clinical need for effective treatment of paroxysmal nocturnal hemoglobinuria (PNH) in pregnancy for patients with inadequate response to C5 inhibitors. We report the first case of pegcetacoplan use in pregnancy with accompanying pharmacokinetic analysis. In a patient with transfusion‐dependent anemia on eculizumab, third‐trimester initiation of pegcetacoplan led to hematological stabilization, transfusion independence, and an uncomplicated term cesarean delivery of a healthy infant. Pegcetacoplan was undetectable in cord blood and breast milk despite therapeutic maternal levels, suggesting fetal and neonatal safety due to lack of significant placental and lactational transfer, and advancing evidence for pegcetacoplan use in pregnancy. Trial Registration : The authors have confirmed clinical trial registration is not needed for this submission.
2025-10-29 | Improved Iron Overload with Pegcetacoplan in Eculizumab-Experienced Patients with Paroxysmal Nocturnal Hemoglobinuria.
Complement factor 5 (C5) inhibitors for paroxysmal nocturnal hemoglobinuria (PNH) may cause iron overload due to residual intravascular hemolysis (IVH) and emergent extravascular hemolysis (EVH). In PEGASUS (phase 3; NCT03500549), adults with PNH with residual anemia (hemoglobin concentration < 10.5 g/dL) after ≥3 months of eculizumab received eculizumab and pegcetacoplan for 4 weeks and were then randomized (1:1) to eculizumab or pegcetacoplan monotherapy for 16 weeks; in the following 32-week, open-label period, patients either continued pegcetacoplan or switched from eculizumab to pegcetacoplan. This post hoc analysis reports PEGASUS transfusion-related data and iron-related biomarkers to evaluate pegcetacoplan's effects on iron regulation. Of 80 patients randomized in PEGASUS, 27 (33.8%) had baseline iron overload (serum transferrin saturation ≥ 50%). Iron overload resolved within 52 weeks of pegcetacoplan treatment in 16 of 22 patients (72.7%) with baseline and postbaseline data; 10 experienced resolution after 20 weeks. With pegcetacoplan, transfusion numbers decreased for patients with and without iron overload, hepcidin concentrations increased, and absolute reticulocyte counts (ARCs) decreased to normal range. Mean ferritin concentrations were above normal throughout the study, regardless of iron overload status. Pegcetacoplan improves iron overload-related biomarkers, including increased hepcidin concentrations and decreased ARCs, by blocking IVH and EVH and preventing anemia.
other
2025-09-26 | Biosynthesis of GPI anchored proteins, its deficiencies and treatment.
Glycosylphosphatidylinositol (GPI) anchoring is a widely conserved post-translational modification in eukaryotes, in which various proteins-such as receptors, cell adhesion molecules, and complement regulatory proteins-are modified with a GPI moiety and tethered to the cell membrane. GPI anchors are synthesized in the endoplasmic reticulum (ER), where they are attached to newly translated proteins. These GPI-anchored proteins (GPI-APs) then undergo structural remodeling and are transported to the cell surface. To date, approximately 30 gene products have been identified as essential for the GPI biosynthetic and remodeling pathways. In addition to paroxysmal nocturnal hemoglobinuria (PNH), a well-characterized acquired hematologic disorder caused by somatic mutations in GPI biosynthesis genes, an increasing number of inherited GPI deficiencies (IGDs) have recently been reported. These congenital disorders are typically caused by hypomorphic mutations in GPI biosynthetic genes and present with neurological abnormalities. In this review, we provide an overview of the biosynthetic pathway of GPI anchors in mammalian cells and the genetic disorders resulting from its dysfunction. We also discuss emerging therapeutic approaches currently under investigation, including gene therapy, which hold promise for improving clinical outcomes in patients with IGD.
2024-02-02 | Abnormal expression of CUX1 influences autophagy activation in paroxysmal nocturnal hemoglobinuria.
Abstract The mechanism underlying autophagy in paroxysmal nocturnal hemoglobinuria (PNH) remains largely unknown. We previously sequenced the entire genome exon of the CD59– cells from 13 patients with PNH and found genes such as CUX1 encoding Cut-like homeobox 1. Peripheral blood samples from nine patients with PNH and seven healthy controls were obtained to measure CUX1 expression. The correlation between CUX1 mRNA expression and PNH clinical indicators was analyzed. To simulate CUX1 expression in patients with PNH, we generated a panel of PNH cell lines by knocking out PIGA in K562 cell lines and transfected lentivirus with CUX1. CCK-8 and EDU assay assessed cell proliferation. Western blotting was used to detect Beclin1, LC3A, LC3B, ULK1, PI3K, AKT, p-AKT, mTOR, and p-mTOR protein levels. Autophagosomes were observed with transmission electron microscopy. Chloroquine was used to observe CUX1 expression in PNH after autophagy inhibition. Leukocytes from patients with PNH had lower levels of CUX1 mRNA expression and protein content than healthy controls. The lactose dehydrogenase level and the percentage of PNH clones were negatively correlated with CUX1 relative expression. We reduced CUX1 expression in a PIGA-knockout K562 cell line, leading to increased cell proliferation. Levels of autophagy markers Beclin1, LC3B, LC3A and ULK1 increased, and autophagosomes increased. Furthermore, PI3K/AKT/mTOR protein phosphorylation levels were lower. CUX1 expression did not change and cell proliferation decreased in CUX1 knocked down PNH cells after inhibition of autophagy by chloroquine. In brief, CUX1 loss-of-function mutation resulted in stronger autophagy in PNH.
2023-09-01 | The Features of COVID-19’s Course and the Efficacy of the Gam-COVID-Vac Vaccine in Patients with Paroxysmal Nocturnal Hemoglobinuria
COVID-19 and other infectious diseases can exacerbate the course of paroxysmal nocturnal hemoglobinuria (PNH). The efficacy and safety of the Gam-COVID-Vac vaccine in patients with PNH has not been adequately studied. A retrospective, observational, cohort, non-comparative study was performed to assess the course of COVID-19 as well as the safety and efficacy of the Gam-COVID-Vac (Sputnik V) vaccine in patients with paroxysmal nocturnal hemoglobinuria (PNH). The study included data from 52 patients with PNH aged 18 to 75 years, 38 of whom received background therapy with eculizumab (Elizaria®) between March 2020 and January 2022. COVID-19 was diagnosed according to the results of PCR testing. The patients were divided into two groups for comparison of the incidence of COVID-19. Group 1 included non-vaccinated patients with PNH, and Group 2 included patients vaccinated prior to the onset of COVID-19. According to vaccination, patients were subdivided into non-vaccinated and vaccinated groups without signs of previous COVID-19 at the beginning of the analyzed period, and patients vaccinated half a year or more after recovery from COVID-19. Testing for anti-SARS-CoV-2 IgG levels was carried out in patients with PNH in the year after their COVID-19. Tests for anti-SARS-CoV-2 RBD IgG levels were performed on vaccinated patients. In total, 28 (53.8%) of the enrolled patients had COVID-19, including asymptomatic forms in 7 (25%) and mild forms in 16 (57%) patients. A total of 22 (42.3%) patients were fully vaccinated with Gam-COVID-Vac, of which 13 (25%) patients were vaccinated without the signs of previous SARS-CoV-2infection, and 9 (17.3%) patients were vaccinated after COVID-19. The number of patients who had COVID-19 was about two times higher in Group 1 (non-vaccinated; 24) (61.5%), whereas in Group 2 (vaccinated), the number of patients with COVID-19 was only 4 (30.8%). The proportion and number of patients who did not have COVID-19 was higher in the group of vaccinated patients (9; 69.2%) than in the group of non-vaccinated patients (15; 38.5%) (p = 0.054). In patients who had been infected with COVID-19, maximum concentrations of anti-SARS-CoV-2 IgG were observed 2-3 months after the acute infection phase, followed by a gradual decline by month 9-10. The mean RBD IgG concentration was higher in the group of patients who had been infected by COVID-19 than in the group of patients without COVID-19 (p = 0.047). Therapy type, including eculizumab, did not have a significant impact on RBD IgG titers (p > 0.05). Hospitalization was required in five (18%) patients, all of whom had breakthrough hemolysis and severe lung damage on CT scans. After the first dose, adverse events (AEs) were reported in 41% of the patients (body temperature increased in 18%; headache in 13.6%; and pain in joints in 4.5%; colitis exacerbation was observed in 4.5%). After the second dose, no AEs were reported. The performed study suggests the possible efficacy and demonstrates the safety of Gam-COVID-Vac (Sputnik V) for the prophylaxis of COVID-19 in patients with PNH who experience immunosuppression due to target therapy.
2023-07-13 | Dysregulation of the miRNA-30a-5p/B4GALT5 axis leads to cell proliferation and is associated with M1 Macrophage Polarization in PNH
Abstract Background： MicroRNAs (miRNAs) play diverse roles in various biological processes. However, their role in Paroxysmal Nocturnal Hemoglobinuria (PNH) is not well understood. To investigate the involvement of miRNAs in PNH, we conducted a re-analysis of the GEO database and identified miRNA-30a-5p as the most promising candidate for further mechanism research. Methods: We have constructed a PIGA knock-out K562 cell line and PIGA conditional knock-out mice model by CRISPR/cas9 technology. Furthermore, FACS and colony formation assays were used to clarify proliferative and apoptosis abilities of PNH cells. FACS was used to clarify M1 Macrophage Polarization in mouse bone marrow-derived macrophages (BMDMs). Luciferase assay was used to indicate miRNA target gene. RT-PCR and western blot were used to verify the relationship between miR-30a-5p, B4GALT5 and PI3K/AKT signaling. Results: Our study revealed a significant upregulation of miR-30a-5p in Flaer negative cells compared to Flaer positive cells, in a cohort of 10 PNH patients. Cell colony formation and cell cycle analysis demonstrated that the miRNA-30a-5p mimics group exhibited a higher capacity for proliferation, while the miRNA-30a-5p inhibitor group showed opposite effects. Subsequent luciferase assay results confirmed that miRNA-30a-5p targeted the B4GALT5 gene, which was found to be significantly downregulated in Flaer negative cells from 15 PNH patients. In vitro assays showed that the miRNA-30a-5p/B4GALT5 axis significantly promoted cell proliferation by activating PI3K/AKT signaling. Additionally, our study is the first to describe the polarization state of macrophages in the bone marrow microenvironment of PNH patients, where we observed a higher mean fluorescence intensity (MFI) of CD80 and CD86, markers of M1 macrophages, on macrophages from PNH patients compared to normal controls. Furthermore, siB4GALT5 increased the markers of M1 macrophages in BMDMs, and miRNA-30a-5p inhibitor induced M2-like macrophage polarization, which was markedly reversed in the miRNA-30a-5p inhibition+siB4GALT5 group. Conclusion: Our study has identified that the miRNA-30a-5p targets the B4GALT5 gene, and miRNA-30a-5p/B4GALT5 axis facilitates the proliferation of PNH clones via the PI3K/AKT signaling pathway. Additionally, our findings provide initial evidence that the miRNA-30a-5p/B4GALT5 axis may play a potential role in M1 macrophage polarization in the bone marrow of PNH patients.
2023-01-06 | Long noncoding RNA FAM157C contributes to clonal proliferation in paroxysmal nocturnal hemoglobinuria
Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease of hematopoietic stem cells (HSCs). Long noncoding RNAs (lncRNAs) perform a wide range of biological functions, including the regulation of gene expression, cell differentiation, and proliferation, but their role in PNH remains unclear. CD59 − and CD59 + granulocytes and monocytes from 35 PNH patients were sorted. High-throughput sequencing was analyzed in 5 PNH patients, and differentially expressed lncRNAs and mRNAs were identified. The mRNAs with fragments per kilobase of exon model per million mapped fragments (FPKM) > 10 in at least 3 patients were selected, and experiments were performed to identify their upstream regulatory lncRNAs. The expression of selected mRNAs and lncRNAs was verified by qRT‒PCR, and the correlation of these expression patterns with clinical data from other 30 PNH patients was analyzed. Then, the functions of the lncRNAs were studied in the PIGA-KO-THP-1 cell line. Transcription analysis revealed 742 upregulated and 1376 downregulated lncRNAs and 3276 upregulated and 213 downregulated mRNAs. After deep screening, 8 highly expressed mRNAs that were related to the NF-κB pathway were analyzed to determine coexpression patterns. LINC01002, FAM157C, CTD-2530H12.2, XLOC-064331 and XLOC-106677 were correlated with the 8 mRNAs. After measuring the expression of these molecules in 30 PNH patients by qRT‒PCR, lncRNA FAM157C was verified to be upregulated in the PNH clone, and its expression levels were positively correlated with the LDH levels and CD59 − granulated and monocyte cell ratios. After knockdown of the FAM157C gene in the PIGA-KO-THP-1 cell line, we found that the cells were arrested in the G0/G1 phase and S phase, the apoptosis rate increased, and the cell proliferation decreased. LncRNA FAM157C was proven to promote PNH clone proliferation, and this is the first study to explore the role of lncRNAs in PNH.
small molecules
2026-09-09 | Long-Term Outcomes and Thrombosis Rates in Patients with Large PNH Clone Managed Without Complement Inhibitors: A 20-Year Follow-Up from a Tertiary Care Centre in North India.
Treatment of paroxysmal nocturnal hemoglobinuria (PNH) patients with a large-size clone is a major challenge in low and middle-income countries. In the absence of complement inhibitors, the response rates with available therapy have not been evaluated in the Indian subcontinent. Retrospective data for patients with a large PNH clone >12 years of age were collected from 2004 to 2024 and were further classified as: Group 1: Classical PNH (c-PNH); Group 2: PNH with aplastic anemia (AA) occurring simultaneously: PNH(L)/AA-s; Group 3: AA preceding the evolution of a Large PNH clone: PNH(L)/AAp. A total of 211 patients were identified with a mean age of 33 years. Of these patients, survivorship status was known for 163 (77.2%), and 111 (52.6%) were under regular follow-up. Out of a total of 211 patients, 49.8% (n-105) cases of c-PNH, 29.4% (n-62) cases of PNH(L)/AA-s, and 20.9% (n-44) cases of PNH(L)/AA-p were identified. Fourteen cases (6.6%) developed thrombosis. Response rates with available drugs in 111 patients were: complete response (CR) in 18% (n-20), partial response (PR) in 65.8% (n-73), and no response (NR) in 16.2% (n-18). Of 57 patients with classical PNH, 20 (35.1%) received low-dose Apixaban (2.5 mg BD) as primary prophylaxis. None developed thrombosis or bleeding. Survivorship status was known for 163 (77.2%) patients. Death occurred in 19% (32/163). The mean survival across all the groups (n-163) was 12.8 years. In the present study, low thrombotic rates were noted in these patients. With available therapy, the overall response rate was 80%, primarily consisting of partial responses.
2026-09-08 | Complement targeting in autoimmune diseases.
Complement is a central effector of cell and tissue injury in hematological and autoimmune diseases, and recent intensive research brought new inhibitors to the clinic. This review summarizes complement-mediated mechanisms across hematological, systemic, and kidney-specific autoimmune diseases, appraises emerging biomarker strategies, and evaluates these therapies. For years, clinical complement inhibition was possible only at C5, first in paroxysmal nocturnal hemoglobinuria. The arsenal has now expanded to the initiation pathways: sutimlimab (anti-C1s) is effective in the hematological autoimmune condition cold agglutinin disease, pegcetacoplan (C3-inhibitor) in C3 glomerulopathy and immune-complex membranoproliferative glomerulonephritis, and oral iptacopan (Factor B-inhibitor) reduces proteinuria in immunoglobulin A nephropathy and C3 glomerulopathy. Nevertheless, challenges remain. Avacopan (C5aR1-inhibitor) faces proposed withdrawal after trial manipulation and hepatotoxicity, and although complement is central to systemic lupus erythematosus and contributes to membranous nephropathy, no effective strategy has yet emerged. Recognizing complement's role in the pathophysiology of hematological and autoimmune diseases has driven effective new therapies. Comprehensive profiling complement biomarkers, now feasible through complementomics in fluids and tissues, may reveal responsive endotypes and optimal cascade steps to target in diseases where complement is implicated but trials have not yet matched the right drug to the right patients.
2026-09-02 | Interleukin-6 in hemolytic anemias: from inflammatory pathways to therapeutic targeting.
Hemolytic anemias comprise inherited and acquired disorders characterized by premature red blood cell destruction. Increasing evidence indicates that many forms of hemolysis are accompanied by sustained inflammatory and immune activation. Red blood cell breakdown releases damage-associated molecular patterns, including free heme and hemoglobin, which activate innate immune pathways, endothelial cells and coagulation cascades. Interleukin-6 (IL-6) is a central mediator linking hemolysis to systemic inflammation, iron restriction and autoimmunity. In this review, we use a heuristic dual-axis framework in which hemolysis-induced IL-6 promotes hepcidin-dependent iron sequestration and acute-phase responses, while also supporting Tfh and Th17 responses, impairing regulatory T-cell function and sustaining autoreactive or alloreactive B cells. The conceptual advance of this framework is not to propose IL-6 as a uniform pathogenic mechanism, but to position IL-6 differently across hemolytic disorders according to the dominant initiating biology and level of evidence. These pathways may aggravate anemia, thrombosis and organ injury. We summarize evidence for IL-6 involvement in autoimmune hemolytic anemia, Castleman disease-associated cytopenias, sickle cell disease, thalassemia, paroxysmal nocturnal hemoglobinuria, congenital red-cell membrane and enzyme defects, and hyperhemolysis syndrome. We also discuss therapeutic strategies targeting IL-6, IL-6 receptor, JAK/STAT signaling and IL-6 trans-signaling. Current clinical evidence remains limited, but IL-6-directed therapy may be rational in selected refractory immune-mediated or macrophage-activation-associated hemolytic disorders. Future studies should prioritize mechanism-based biomarkers and prospective, biomarker-stratified trials.
2026-08-12 | Anemia and Patient-Reported Outcomes in Patients With Paroxysmal Nocturnal Hemoglobinuria: A Real-World Observational Study.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by complement-mediated hemolysis, thrombosis, bone marrow failure, and anemia. Although current treatments improve outcomes, patients still experience hemolysis and could remain anemic with a negative impact on quality of life (QoL). The aim of this study was to assess whether patient-reported outcomes (PROs) distinguish PNH patients with/without hemolysis and evaluate factors associated with PROs. In this international, multicenter, observational study, 97 PNH patients witfrom Italy and the UK completed the EORTC QLQ-C30 and QLQ-AA/PNH measures at baseline and after 2 weeks. Clinical, biochemical, and treatment data were collected. Hemolysis was defined as LDH ≥ 1.5 × upper normal limit. PRO scores were compared between patients above and below this threshold. Associations of PROs with patient and disease factors were analyzed. Of 97 patients (mean age 49 ± 15), 24.7% were anemic (Hb < 10 g/dL) and 16% had hemolysis. QoL did not differ significantly by hemolysis status. However, anemia was associated with significantly lower EORTC QLQ-C30 global health and functional scores (p < 0.05), particularly in physical, role, and social domains, and with worse QLQ-AA/PNH emotional, cognitive, and physical functioning, as well as greater illness intrusiveness and stigmatization. Fatigue, dyspnea, and pain were common symptoms in anemic patients. QLQ-AA/PNH scores showed high internal consistency (Cronbach's α > 0.7) and test-retest reliability (ICC: 0.72-0.95). Anemia, but not residual hemolysis, was associated with impaired QoL across multiple domains. Addressing anemia alongside hemolysis may improve PROs in the management of PNH. The authors have confirmed clinical trial registration is not needed for this submission.
2026-07-15 | Switching between complement inhibitors in paroxysmal nocturnal hemoglobinuria: Analysis of strategy, efficacy, and safety.
Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-orphan disease. In 2026, approved complement inhibitors (CIs) for PNH include three C5 inhibitors (C5i) and three proximal inhibitors (PIs). Clinical trials for the approved PI pegcetacoplan, iptacopan, and C5i + danicopan had clear protocols for changing from terminal to PI, extrapolated into real-world practice. There is no guidance for patients changing from a PI to a different CI. We present the largest international cohort to date. The inclusion criteria were as follows: patients established on a PI, who have changed treatment to a different CI. Sixty-five patients with a median age at PNH diagnosis of 40 years were included. Indications for CI switch were as follows: hemolysis (extravascular/recurrent breakthrough/not specified), side effects, trial termination, patient choice, and other. CI changes (149) were classified as (1) terminal-to-proximal (75/149), 6 hemolytic events reported within 14 days of CI change; (2) proximal-to-proximal (45/149), 2 hemolytic events reported within 14 days of CI change; and (3) proximal-to-terminal (29/149), 13 hemolytic events within 14 days of CI change. This is the largest cohort of PNH patients facing multiple CI changes. With the increasing availability of different CI classes, patients may experience several treatment changes over their disease course. CI should not be interrupted. The cohort would suggest that overlapping treatment for patients changing from PI to another CI is not required. Tapering of treatment does not seem to be effective at preventing hemolysis complications. Patients should be monitored closely for hemolysis, especially when changing from proximal-to-terminal inhibition. Prospective clinical/laboratory analysis is recommended for further clarification management for this patient group.
cell therapies
2026-07-31 | Allogeneic haematopoietic stem cell transplantation for refractory perforating intestinal Behçet disease in a patient with aplastic anaemia: A case report.
Aplastic anemia (AA) rarely coexists with intestinal Behçet disease (iBD), and the post-partum period may further complicate its expression. Managing refractory iBD with recurrent perforation on a background of long-standing AA is challenging, and evidence on optimal treatment is limited. A 42-year-old woman with non-severe aplastic anemia (NSAA) diagnosed in 2005 (AA duration ≈ 20 years) developed recurrent fever, oral ulcers, and penetrating ulcers of the ileocaecum and terminal ileum shortly after cesarean delivery in June 2019, with one episode of vulvar ulceration. Histology showed transmural vasculitis with focal obliterative endarteritis, confirming iBD; HLA-B51 was negative. Pre-transplant marrow was markedly hypocellular without dysplasia, and karyotype (46,XX), flow cytometry, myelodysplastic syndrome/AML and myeloproliferative neoplasm gene panels, and paroxysmal nocturnal hemoglobinuria screening were all negative, supporting acquired AA rather than hypoplastic myelodysplastic syndrome. Despite corticosteroids, tacrolimus, tofacitinib, and tocilizumab, she sustained 2 intestinal perforations (May and September, 2023). As iBD was refractory and AA had progressed to very severe AA, she underwent human leukocyte antigen (HLA)-matched sibling peripheral-blood allogeneic hematopoietic stem cell transplantation (allo-HSCT) in June 2024 with fludarabine/busulfan/cyclophosphamide/ anti-thymocyte globulin conditioning. Neutrophil and platelet engraftment occurred around D+11 and D+15, with 100% donor chimerism at D+16 and no acute or chronic graft-versus-host disease; only transient, self-limiting cytomegalovirus (CMV) and Epstein-Barr virus DNAemia occurred, without CMV disease or post-transplant lymphoproliferative disorder. Blood counts recovered progressively, with hemoglobin 127 grams/L and platelets 118 × 109/L at the last follow-up (≈12 months), only mild residual cytopenia, transfusion independence, and sustained remission of iBD on maintenance immunosuppression. She then returned to work and was lost to follow-up. This case suggests that allo-HSCT may be an effective option for selected patients with AA and refractory iBD, achieving sustained remission of both the marrow failure and the intestinal disease. As this is a single case with limited follow-up (≈12 months), longer follow-up and additional cases are needed.
2026-05-04 | Haploidentical allogeneic haematopoietic stem cell transplantation for paroxysmal nocturnal haemoglobinuria: a retrospective analysis.
To evaluate the efficacy and prognostic factors of haploidentical haematopoietic stem cell transplantation (haplo-HSCT) for paroxysmal nocturnal haemoglobinuria (PNH). We retrospectively analyzed 36 PNH patients (2 classic PNH, 34 AA-PNH syndrome) undergoing haplo-HSCT (G-CSF/ATG-based protocol) from June 2013 to December 2024, with BU/CY/ATG (n = 28) or BU/CYlow/FLU/ATG (n = 8) conditioning and uniform GVHD prophylaxis. The overall myeloid engraftment rate was 100% (median + 12 d) and platelet engraftment rate 95.5% (median + 13 d). Competing risk analysis showed 42.7% acute GVHD (26.7% grade II-IV, 5.3% grade III-IV); 27.3% chronic GVHD (15.2% mild, 12.1% moderate-severe) among 33 evaluable patients. With a median follow-up of 57 months, the 5-year overall survival rate was 88.6 ± 5.4%. All 32 monitored patients achieved PNH clone clearance (median 3 months), 33 had normalized blood counts, and 3 died of infection, organ hemorrhage or pulmonary embolism. Haplo-HSCT yields favorable outcomes and is a curative therapy for PNH, serving as a valuable option for severe bone marrow failure patients, with G-CSF/ATG-based haplo-HSCT as a promising alternative strategy.
2025-12-10 | A rare case of littoral cell angioma with paroxysmal nocturnal hemoglobinuria.
We report a rare case of littoral cell angioma (LCA) in a patient with paroxysmal nocturnal hemoglobinuria (PNH). To our knowledge, this is the first report of these 2 rare conditions occurring together, which may help clarify their relationship and its importance in clinical practice. A 38-year-old man had recurrent anemia and dark brown urine, accompanied by abdominal pain that worsened over time, which required several hospital visits and long-term follow-up. Follow-up scans showed progressive splenomegaly with multiple nodules. In combination with histopathology and immunohistochemistry results (CD31, CD34, and ERG positive; Ki-67 around 5%), these findings confirmed a final diagnosis of LCA in a patient with previously diagnosed PNH. The patient received treatment with oral prednisone, sodium bicarbonate, and vitamin E for PNH. As the splenic lesions enlarged and blood counts worsened, he subsequently underwent laparoscopic splenectomy in February 2025. After surgery, both LCA and anemia concurrently resolved, with normalization of hematologic parameters and resolution of abdominal symptoms. This case suggests a potential association between LCA and PNH. Splenectomy provided dual benefits by treating the splenic tumor and improving hemolysis. Given the possible risk of malignant transformation, long-term follow-up is recommended.
2025-11-03 | Paroxysmal nocturnal hemoglobinuria: Transplant experience using post-transplant cyclophosphamide in a resource-limited setting
Abstract Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, debilitating clonal hematopoietic stem cell disorder characterized by complement-mediated intravascular hemolysis, thrombosis, and varying degrees of bone marrow failure. PNH is broadly classified into classical PNH, which typically presents with hemolysis and thrombotic complications, and secondary PNH, which occurs in association with bone marrow failure syndromes such as aplastic anemia or myelodysplastic syndromes. While allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative modality, it is associated with considerable morbidity and mortality. On the other hand, complement inhibitors (eculizumab, ravulizumab) have emerged as effective treatments with lower toxicity, though they are not curative. However, in low-resource settings like Nepal, the prohibitively high cost of complement inhibitors running into millions of rupees renders them inaccessible. Conversely, an allogeneic transplant in Nepal costs under $10,000, making it a more feasible albeit riskier option. Here, we report our single-center experience with allogeneic HSCT using post-transplant cyclophosphamide (PTCy) for PNH patients in a low-income setting. Methods: Medical records of seven patients with classical PNH who underwent allogeneic HSCT between 2020 and 2023 were retrospectively reviewed. Data on patient demographics, type of transplant, time from diagnosis to transplant, transplant-related complications, and outcomes were collected and analyzed. Result: The mean age of patients was 30.7 years (median: 31; range: 25–36 years), with all seven patients being male. The median time from diagnosis to transplant was 8 months, primarily due to scheduling delays associated with a limited transplant capacity and a waiting list at the only HSCT center currently operating in Nepal. All donors were siblings: 4 (57.1%) fully matched related donors (MRD) and 3 (42.9%) haploidentical donors. MRD transplant patients received Fludarabine/Melphalan (Flu/Mel) and haploidentical transplant received standard Baltimore protocol. All patients received peripheral blood stem cells (PBSCs), with a mean CD34+ cell dose of 10.57 × 10⁶/kg. All patient received post-transplant cyclophosphamide as GVHD prophylaxis along with tacrolimus and MMF. Six patients achieved neutrophil and platelet engraftment. Median time to neutrophil engraftment: 15.5 days (range: 13–21 days) Median time to platelet engraftment: 17.5 days (range: 13–35 days). Three patients (42.9%) died due to transplant-related complications. Causes of death included veno-occlusive disease in one MRD recipient at 40 days post-transplant, CMV pneumonitis with gastroenteritis in one haploidentical recipient at 24 days, and severe mucositis complicated by neutropenic fever and fungal pneumonia in another haploidentical recipient at 12 days post-transplant. Four patients (57.1%) are alive and disease-free at a median follow-up of over 24 months. Among them, two patients developed CMV reactivation, which was well controlled with valganciclovir. One patient, who received a haploidentical transplant, developed mild oral chronic GVHD. Conclusion: Allogeneic HSCT remains a potentially curative but high risk option for PNH patients, particularly in resource limited settings. Our experience highlights the significant transplant related morbidity and mortality, even with modern GVHD prophylaxis such as PTCy.Given the availability of safer, though non-curative, therapeutic alternatives like complement inhibitors, urgent advocacy is needed. Patient groups, healthcare providers, policy-makers, and international aid organizations must collaborate to improve access to life-saving treatments in low-income countries.
2025-11-02 | Long-term outcomes of αβ T-cell/CD19 B-cell-depleted peripheral blood stem cell transplantation from unrelated donors in pediatric and adolescent patients with severe aplastic anemia: a single-center study.
Hematopoietic stem cell transplantation (HSCT) from matched unrelated donor (MUD) is a curative option for severe aplastic anemia (SAA) patients, refractory to horse anti-thymocyte globulin (ATG) and cyclosporin A (CsA) mmunosuppression. Although the results of MUD HSCT in SAA have improved significantly, graft-versus host disease (GVHD) remains a serious problem, associated with significant morbidity and mortality. We investigated the role of alpha/beta T cell depletion of the graft as a way to improve the results of MUD HSCT in SAA. Forty-seven patients with SAA were treated since September 2012 till February 2022. Median age at HSCT was 12.4 (3-22.7) years, 26 males/21 females. All patients were either refractory or relapsed (35:12) after combined immune suppression therapy, 5 pts had concurrent severe hemolytic paroxysmal nocturnal hemoglobinuria (PNH). The median time from diagnosis to transplant was 1.2 years (0.5-11.8 years). Preparative regimen included cyclophosphamide 100 mg/kg, fludarabine 150 mg/kg, ATGAM at 100 mg/kg (27pts) or thymoglobulin 5 mg/kg (15 pts) and 6 Gy thoraco-abdominal irradiation. Thiotepa at 10 mg/kg and rituximab at 200 mg/m2 were used in a proportion of cases. Patients with PNH (n = 5) received eculizumab 600 mg once every 7 days from -7 to +14 days. Post-transplant GVHD prophylaxis included tacrolimus till day 180. Peripheral blood stem cell (PBSC) grafts were depleted of T cell receptor (TCR) alpha/beta cells and CD19 cells with CliniMACS device, as recommended by the manufacturer. Patients received a median of 9.2 (2.7-18.30) х106 CD34 per kg, 21.8 (0.85-316)x103 αβ T cells per kg. Forty-six patients (cumulative incidence (CI) 0.96 (95% 0.9-1)) engrafted with a median of 14 (7-24) days for white blood cells (WBC) and 12 (9-18) days for platelets. In 8 patients after MUD transplantation secondary graft failure (rejection) developed, cumulative incidence was 0.15 (95% 0.08-0.3), three of them was successfully retransplanted. CI of acute graft-versus host disease (aGVHD) grade II-IV was 0.15 (95% 0.08-0.29). No cases of grade III-IV aGVHD were registered. CI of chronic graft versus host disease (cGVHD) was 0.11 (95% 0.05-0.25). All were mild and off-IST at last follow-up. A median follow-up is 9 years. Ten patients died. At a median follow-up of 9 years, the overall survival was 79% (67-90). Failure-free survival was 72% (60-85) and the GRFS was 72% (60-85). TCR alpha/beta depletion is a robust platform for allogeneic HSCT from MUD in severe aplastic anemia. Results should be further improved by additional measures to control viral infections and prevent rejection.
antibodies
2026-08-24 | Indirect treatment comparisons find enhanced effectiveness of pegcetacoplan versus crovalimab in both complement inhibitor-naïve and -experienced patients with paroxysmal nocturnal hemoglobinuria.
Aim: Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare hematological condition, which if undertreated, is associated with significant morbidity and early mortality. This indirect treatment comparison (ITC) evaluated the effectiveness of pegcetacoplan (the first approved proximal inhibitor) versus crovalimab, a new C5i inhibitor (C5i), for treatment of PNH in C5i-naive and C5i-experienced patients. Materials & methods: In the C5i-naive, an unanchored matching-adjusted indirect comparison (MAIC) was conducted with patient-level data for pegcetacoplan-versus-best-supportive-care from PRINCE (NCT0408560) and published data for crovalimab-versus-eculizumab from COMMODORE 2 (NCT04434092)/COMMODORE 3 (NCT04654468). In the C5i-experienced ITC (Bucher's method), patient-level data were from PEGASUS (NCT03500549; pegcetacoplan vs eculizumab) and aggregated data from COMMODORE 1 (NCT04432584; crovalimab-vs-eculizumab). Evaluated outcomes in both settings included red-blood-cell transfusion-avoidance; hemoglobin (Hb) stabilization; hemolysis control; mean change-from-baseline on Functional Assessment of Chronic Illness Therapy-Fatigue total scores; additionally, the C5i-experienced ITC evaluated, mean change-from-baseline to week-25 for red blood cell units and domain scores on the European Organization for Research and Treatment of Cancer instrument. Results: Pegcetacoplan versus crovalimab in the C5i-naive was associated with significantly (p < 0.05) higher probabilities of transfusion-avoidance and Hb stabilization, and greater odds of hemolysis control. In the C5i-experienced, all outcomes significantly (p < 0.05) favored pegcetacoplan. Conclusion: Pegcetacoplan provides high clinical advantages across the full PNH treatment pathway.
2026-08-04 | Complement inhibitor therapy should be available to patients with paroxysmal nocturnal hemoglobinuria throughout the world.
The development of several complement-inhibiting medicines has been a major advance in the management of paroxysmal nocturnal hemoglobinuria (PNH), a rare and life-threatening disease. Patients now have a life expectancy close to that of the general population, and the quality of life of most patients has improved substantially. In addition, by targeting either the proximal or the terminal complement pathway, we have also been able to improve our understanding of the pathophysiology of PNH. Within the landscape of this rather spectacular progress, a major drawback has been the rather astronomic price of all of these medicines: This means, in practice, that in many countries they are not available at all, and a conservative estimate is that at least one-half of the PNH patients in the world have no access to complement inhibitors. It is urgent to correct this inequality that is also an injustice. Very recently, the Max Foundation, a global nonprofit organization, has announced that it will collaborate with a pharmaceutical company to make 'innovative treatment for PNH' available in many countries: We may now hope that other companies will join such collaborations.
2026-07-04 | High Proportion of PNH Type II Neutrophils Is Associated With Thrombosis in Patients Displaying a PNH Clone ≥ 1.
The clinical significance of PNH Type II white blood cells (WBCs) remains unclear. We assessed the relative percentage (rel%) of Type II neutrophils in 355 patients with a PNH clone ≥ 1% on neutrophils enrolled by 33 flow cytometry laboratories in the 5-year French nation-wide multicenter prospective observational study. We first analyzed 127 of 133 patients with a major PNH clone (≥ 50%) and evaluable Type II neutrophil rel%. Using hemolysis data available for 107 patients, a threshold of 3% Type II neutrophils rel% distinguished two groups: 22 "high Type II" and 105 "low Type II" patients. Hemolysis was less frequent in the "high Type II" group. Thrombosis was more frequent at diagnosis and during cumulative long-term follow-up in this group. High neutrophil rel% ≥ 3% was independently associated with thrombotic events. Among 222 patients with smaller PNH clones (1%-50%), 207 displayed evaluable Type II neutrophil rel%, of which 87 were classified as "high Type II" and 120 as "low Type II". Although no thrombosis was present at diagnosis, two thrombotic events occurred during follow-up in the "high Type II" group, whereas none were observed in the "low Type II" group. Long-term follow-up showed no major changes in Type II neutrophil rel%, irrespective of variations in total clone size. These findings suggest that, regardless of the total PNH clone size, PNH Type II neutrophil rel% is a stable parameter and may represent a reliable predictor of thrombosis, potentially supporting earlier consideration of anticomplement therapy initiation.
2026-06-23 | Thromboembolic Events in Indian Patients with Paroxysmal Nocturnal Hemoglobinuria: A Single Centre Experience.
Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, acquired clonal hematopoietic stem cell disorder. Thrombosis is the most common complication leading to high mortality in PNH patients. The mechanisms of thrombosis in PNH are diverse, and the exact mechanism is still unclear. There is a paucity of data on the incidence of thrombosis in Indian patients with PNH. We retrospectively analyzed the data of 95 patients with a positive PNH clone treated at our center. Ten patients (9.5%), including 07 patients with classical PNH and 03 patients with PNH associated with aplastic anemia or myelodysplastic neoplasm (PNH-AA/MDS), had thromboembolic events. Thrombosis was present in 38% of classical PNH and 10% of PNH AA/MDS. One-third of the patients had 2 or more episodes of thrombosis during the disease. The most common site of thrombosis in our study was the abdominal veins. Fatal thrombosis occurred in 50% of the patients. None of the patients received Eculizumab. The median clone size was higher in cPNH patients compared to PNH AA/MDS. All patients developing thrombosis had a large granulocyte PNH clone and high disease activity. 50% of the patients died as a direct consequence of thrombosis and its complications. Thrombosis despite prophylactic anticoagulation was seen in 25% of patients. The findings, notwithstanding the limited number of patients, confirm that thrombosis continues to remain a significant cause of mortality in patients with PNH.
2026-06-15 | Exploring individualized crovalimab dosing in PNH through in silico modelling: Potential for improved convenience and cost efficiency.
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired haematopoietic stem cell disorder. Crovalimab, a complement C5-inhibitor, is approved for PNH and can be self-administered subcutaneously every 4 weeks, offering a more convenient route than intravenous C5-inhibitors. Since exposure often exceeds pharmacokinetic targets and varies with body weight, we aimed to explored individualized dosing of crovalimab using clinical trial simulations to optimize therapy. We compared standard, weight-based and therapeutic drug monitoring (TDM)-guided regimens in treatment-naïve PNH patients over 52 weeks by means of clinical trial simulations based on the population pharmacokinetic model developed by the market authorization holder. Maintenance-phase crovalimab concentrations were generally supratherapeutic with substantial variability. Weight-based dosing reduced this variability, while TDM-guided dosing further minimized it and allowed dose intervals to be prolonged in 24% of patients to a mean of 5.0 weeks, while maintaining exposure comparable to the standard regimen. Individualized dosing of crovalimab may reduce exposure variability and enable less frequent dosing, supporting the feasibility of more flexible cost-effective and patient-tailored treatment regimens.
proteins
2026-08-29 | A fusion protein of the two tick-derived C5 inhibitors OmCI and RaCI: complete C5 inhibition despite strong complement activation.
The complement system must be tightly regulated to prevent tissue damage and disease, yet current C5 inhibitors like the anti-C5 monoclonal antibody Eculizumab - though clinically approved (e.g., for paroxysmal nocturnal haemoglobinuria, PNH) - fail to achieve complete terminal pathway blockade under conditions of strong complement activation. To address this limitation, we investigated tick-derived C5 inhibitors and discovered that combinatorial targeting of non-overlapping C5 epitopes enables full inhibition. Leveraging this insight, we engineered a bifunctional fusion protein RaCI-gly-OmCI (R-g-O), recombinantly merging OmCI (Ornithodoros moubata Complement Inhibitor) and RaCI (Rhipicephalus appendiculatus Complement Inhibitor), which bind distinct sites on C5. Surface plasmon resonance experiments demonstrate subnanomolar binding of the building blocks and the fusion protein to C5. In contrast to the building blocks OmCI and RaCI, R-g-O achieves complete C5 inhibition under strong complement activation conditions in an alternative pathway haemolysis experiment. In classical pathway haemolysis settings, OmCI and R-g-O completely protected from lysis while RaCI only achieved about 50% protection. The fusion protein R-g-O represents a highly effective tool for blocking terminal pathway activity in research, surpassing the limitations of single-agent C5 inhibitors.
2026-06-20 | Efficacy and Safety of the C3 Inhibitor Pegcetacoplan in Paroxysmal Nocturnal Hemoglobinuria: A Systematic Review and Meta-Analysis.
To evaluate the efficacy and safety of the complement C3 inhibitor pegcetacoplan in patients with paroxysmal nocturnal hemoglobinuria (PNH). PubMed, Embase, Web of Science, and Cochrane Library were systematically searched for studies reporting pegcetacoplan use in PNH. Outcomes included transfusion-requirement, hemoglobin normalization, mean hemoglobin levels, lactate dehydrogenase normalization, reticulocyte count normalization, and safety endpoints. Pooled proportions with 95% confidence intervals were calculated using random-effects models, and heterogeneity was assessed using the I2 statistic. Five studies comprising 271 patients were included. Transfusion avoidance was observed in 80.6% of patients, with a pooled transfusion-requirement rate of 19.4%. LDH normalization occurred in 68.5% of patients (I2 = 0%). Hemoglobin normalization was observed in 42.9%, while reticulocyte count normalization reached 66%. Any-grade adverse events occurred in 83.5% of patients, most commonly pyrexia, headache, and dizziness. Serious adverse events occurred in 16.6%, decreasing to 12% after sensitivity analysis. Breakthrough hemolysis was reported in 14.8%, and infections in 17%. Pegcetacoplan demonstrates consistent efficacy signals across key hematologic endpoints and an acceptable safety profile, supporting its potential role as an important therapeutic option, particularly in patients with persistent extravascular hemolysis despite C5 inhibition.
2025-12-28 | Disease-modifying treatments in paroxysmal nocturnal hemoglobinuria: a systematic review of economic evaluations.
BACKGROUND: Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, life-threatening hematologic disorder characterized by chronic hemolysis, bone marrow and organ failure, and thrombotic events. Without effective treatment, PNH can lead to severe complications, including organ damage, increased morbidity, and heightened mortality risk. The high expense and therapeutic revolution that has emerged in PNH necessitates a careful appraisal of its cost-effectiveness. This study aimed to systematically review the cost-effectiveness of disease-modifying therapies (DMTs) in PNH. METHODS: A comprehensive search syntax was developed to identify relevant studies using online databases. Criteria used in health economic evaluations include costs, effectiveness assessment with life-years gained (LYG) or quality-adjusted life-years (QALY), incremental cost-effectiveness ratio (ICER), and other clinico-economic outcomes. To enable comparison across different countries, the results of economic evaluations allow for the comparison of costs and ICERs across all studies, which were converted into United States Dollars (USD) values using the time model developed. The quality of the studies was assessed using the Quality of Health Economic Studies (QHES) instrument. This study is conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: Nine papers were included in the 351 screened records. Pegcetacoplan was a dominant (i.e., less costly and more effective) option compared to C5 complement inhibitors and iptacopan. Eculizumab was not cost-effective compared with other DMTs or the standard of care. The current annual price of $12,300-$13,100 for adding danicopan to ravulizumab was not cost-effective compared to ravulizumab alone. The results of nine studies indicated that the majority of costs are related to the DMTs themselves. CONCLUSION: The cost-effectiveness analyses of DMTs in PNH suggest that the newer options, pegcetacoplan and iptacopan, are cost-effective and provide greater clinical utility than complement C5 inhibitors, especially eculizumab.
2025-11-19 | Paroxysmal Nocturnal Hemoglobinuria in Pregnancy Treated With Pegcetacoplan: Case Report and Pharmacokinetic Analysis
ABSTRACT There is an unmet clinical need for effective treatment of paroxysmal nocturnal hemoglobinuria (PNH) in pregnancy for patients with inadequate response to C5 inhibitors. We report the first case of pegcetacoplan use in pregnancy with accompanying pharmacokinetic analysis. In a patient with transfusion‐dependent anemia on eculizumab, third‐trimester initiation of pegcetacoplan led to hematological stabilization, transfusion independence, and an uncomplicated term cesarean delivery of a healthy infant. Pegcetacoplan was undetectable in cord blood and breast milk despite therapeutic maternal levels, suggesting fetal and neonatal safety due to lack of significant placental and lactational transfer, and advancing evidence for pegcetacoplan use in pregnancy. Trial Registration : The authors have confirmed clinical trial registration is not needed for this submission.
2025-10-29 | Improved Iron Overload with Pegcetacoplan in Eculizumab-Experienced Patients with Paroxysmal Nocturnal Hemoglobinuria.
Complement factor 5 (C5) inhibitors for paroxysmal nocturnal hemoglobinuria (PNH) may cause iron overload due to residual intravascular hemolysis (IVH) and emergent extravascular hemolysis (EVH). In PEGASUS (phase 3; NCT03500549), adults with PNH with residual anemia (hemoglobin concentration < 10.5 g/dL) after ≥3 months of eculizumab received eculizumab and pegcetacoplan for 4 weeks and were then randomized (1:1) to eculizumab or pegcetacoplan monotherapy for 16 weeks; in the following 32-week, open-label period, patients either continued pegcetacoplan or switched from eculizumab to pegcetacoplan. This post hoc analysis reports PEGASUS transfusion-related data and iron-related biomarkers to evaluate pegcetacoplan's effects on iron regulation. Of 80 patients randomized in PEGASUS, 27 (33.8%) had baseline iron overload (serum transferrin saturation ≥ 50%). Iron overload resolved within 52 weeks of pegcetacoplan treatment in 16 of 22 patients (72.7%) with baseline and postbaseline data; 10 experienced resolution after 20 weeks. With pegcetacoplan, transfusion numbers decreased for patients with and without iron overload, hepcidin concentrations increased, and absolute reticulocyte counts (ARCs) decreased to normal range. Mean ferritin concentrations were above normal throughout the study, regardless of iron overload status. Pegcetacoplan improves iron overload-related biomarkers, including increased hepcidin concentrations and decreased ARCs, by blocking IVH and EVH and preventing anemia.
other
2025-09-26 | Biosynthesis of GPI anchored proteins, its deficiencies and treatment.
Glycosylphosphatidylinositol (GPI) anchoring is a widely conserved post-translational modification in eukaryotes, in which various proteins-such as receptors, cell adhesion molecules, and complement regulatory proteins-are modified with a GPI moiety and tethered to the cell membrane. GPI anchors are synthesized in the endoplasmic reticulum (ER), where they are attached to newly translated proteins. These GPI-anchored proteins (GPI-APs) then undergo structural remodeling and are transported to the cell surface. To date, approximately 30 gene products have been identified as essential for the GPI biosynthetic and remodeling pathways. In addition to paroxysmal nocturnal hemoglobinuria (PNH), a well-characterized acquired hematologic disorder caused by somatic mutations in GPI biosynthesis genes, an increasing number of inherited GPI deficiencies (IGDs) have recently been reported. These congenital disorders are typically caused by hypomorphic mutations in GPI biosynthetic genes and present with neurological abnormalities. In this review, we provide an overview of the biosynthetic pathway of GPI anchors in mammalian cells and the genetic disorders resulting from its dysfunction. We also discuss emerging therapeutic approaches currently under investigation, including gene therapy, which hold promise for improving clinical outcomes in patients with IGD.
2024-02-02 | Abnormal expression of CUX1 influences autophagy activation in paroxysmal nocturnal hemoglobinuria.
Abstract The mechanism underlying autophagy in paroxysmal nocturnal hemoglobinuria (PNH) remains largely unknown. We previously sequenced the entire genome exon of the CD59– cells from 13 patients with PNH and found genes such as CUX1 encoding Cut-like homeobox 1. Peripheral blood samples from nine patients with PNH and seven healthy controls were obtained to measure CUX1 expression. The correlation between CUX1 mRNA expression and PNH clinical indicators was analyzed. To simulate CUX1 expression in patients with PNH, we generated a panel of PNH cell lines by knocking out PIGA in K562 cell lines and transfected lentivirus with CUX1. CCK-8 and EDU assay assessed cell proliferation. Western blotting was used to detect Beclin1, LC3A, LC3B, ULK1, PI3K, AKT, p-AKT, mTOR, and p-mTOR protein levels. Autophagosomes were observed with transmission electron microscopy. Chloroquine was used to observe CUX1 expression in PNH after autophagy inhibition. Leukocytes from patients with PNH had lower levels of CUX1 mRNA expression and protein content than healthy controls. The lactose dehydrogenase level and the percentage of PNH clones were negatively correlated with CUX1 relative expression. We reduced CUX1 expression in a PIGA-knockout K562 cell line, leading to increased cell proliferation. Levels of autophagy markers Beclin1, LC3B, LC3A and ULK1 increased, and autophagosomes increased. Furthermore, PI3K/AKT/mTOR protein phosphorylation levels were lower. CUX1 expression did not change and cell proliferation decreased in CUX1 knocked down PNH cells after inhibition of autophagy by chloroquine. In brief, CUX1 loss-of-function mutation resulted in stronger autophagy in PNH.
2023-09-01 | The Features of COVID-19’s Course and the Efficacy of the Gam-COVID-Vac Vaccine in Patients with Paroxysmal Nocturnal Hemoglobinuria
COVID-19 and other infectious diseases can exacerbate the course of paroxysmal nocturnal hemoglobinuria (PNH). The efficacy and safety of the Gam-COVID-Vac vaccine in patients with PNH has not been adequately studied. A retrospective, observational, cohort, non-comparative study was performed to assess the course of COVID-19 as well as the safety and efficacy of the Gam-COVID-Vac (Sputnik V) vaccine in patients with paroxysmal nocturnal hemoglobinuria (PNH). The study included data from 52 patients with PNH aged 18 to 75 years, 38 of whom received background therapy with eculizumab (Elizaria®) between March 2020 and January 2022. COVID-19 was diagnosed according to the results of PCR testing. The patients were divided into two groups for comparison of the incidence of COVID-19. Group 1 included non-vaccinated patients with PNH, and Group 2 included patients vaccinated prior to the onset of COVID-19. According to vaccination, patients were subdivided into non-vaccinated and vaccinated groups without signs of previous COVID-19 at the beginning of the analyzed period, and patients vaccinated half a year or more after recovery from COVID-19. Testing for anti-SARS-CoV-2 IgG levels was carried out in patients with PNH in the year after their COVID-19. Tests for anti-SARS-CoV-2 RBD IgG levels were performed on vaccinated patients. In total, 28 (53.8%) of the enrolled patients had COVID-19, including asymptomatic forms in 7 (25%) and mild forms in 16 (57%) patients. A total of 22 (42.3%) patients were fully vaccinated with Gam-COVID-Vac, of which 13 (25%) patients were vaccinated without the signs of previous SARS-CoV-2infection, and 9 (17.3%) patients were vaccinated after COVID-19. The number of patients who had COVID-19 was about two times higher in Group 1 (non-vaccinated; 24) (61.5%), whereas in Group 2 (vaccinated), the number of patients with COVID-19 was only 4 (30.8%). The proportion and number of patients who did not have COVID-19 was higher in the group of vaccinated patients (9; 69.2%) than in the group of non-vaccinated patients (15; 38.5%) (p = 0.054). In patients who had been infected with COVID-19, maximum concentrations of anti-SARS-CoV-2 IgG were observed 2-3 months after the acute infection phase, followed by a gradual decline by month 9-10. The mean RBD IgG concentration was higher in the group of patients who had been infected by COVID-19 than in the group of patients without COVID-19 (p = 0.047). Therapy type, including eculizumab, did not have a significant impact on RBD IgG titers (p > 0.05). Hospitalization was required in five (18%) patients, all of whom had breakthrough hemolysis and severe lung damage on CT scans. After the first dose, adverse events (AEs) were reported in 41% of the patients (body temperature increased in 18%; headache in 13.6%; and pain in joints in 4.5%; colitis exacerbation was observed in 4.5%). After the second dose, no AEs were reported. The performed study suggests the possible efficacy and demonstrates the safety of Gam-COVID-Vac (Sputnik V) for the prophylaxis of COVID-19 in patients with PNH who experience immunosuppression due to target therapy.
2023-07-13 | Dysregulation of the miRNA-30a-5p/B4GALT5 axis leads to cell proliferation and is associated with M1 Macrophage Polarization in PNH
Abstract Background： MicroRNAs (miRNAs) play diverse roles in various biological processes. However, their role in Paroxysmal Nocturnal Hemoglobinuria (PNH) is not well understood. To investigate the involvement of miRNAs in PNH, we conducted a re-analysis of the GEO database and identified miRNA-30a-5p as the most promising candidate for further mechanism research. Methods: We have constructed a PIGA knock-out K562 cell line and PIGA conditional knock-out mice model by CRISPR/cas9 technology. Furthermore, FACS and colony formation assays were used to clarify proliferative and apoptosis abilities of PNH cells. FACS was used to clarify M1 Macrophage Polarization in mouse bone marrow-derived macrophages (BMDMs). Luciferase assay was used to indicate miRNA target gene. RT-PCR and western blot were used to verify the relationship between miR-30a-5p, B4GALT5 and PI3K/AKT signaling. Results: Our study revealed a significant upregulation of miR-30a-5p in Flaer negative cells compared to Flaer positive cells, in a cohort of 10 PNH patients. Cell colony formation and cell cycle analysis demonstrated that the miRNA-30a-5p mimics group exhibited a higher capacity for proliferation, while the miRNA-30a-5p inhibitor group showed opposite effects. Subsequent luciferase assay results confirmed that miRNA-30a-5p targeted the B4GALT5 gene, which was found to be significantly downregulated in Flaer negative cells from 15 PNH patients. In vitro assays showed that the miRNA-30a-5p/B4GALT5 axis significantly promoted cell proliferation by activating PI3K/AKT signaling. Additionally, our study is the first to describe the polarization state of macrophages in the bone marrow microenvironment of PNH patients, where we observed a higher mean fluorescence intensity (MFI) of CD80 and CD86, markers of M1 macrophages, on macrophages from PNH patients compared to normal controls. Furthermore, siB4GALT5 increased the markers of M1 macrophages in BMDMs, and miRNA-30a-5p inhibitor induced M2-like macrophage polarization, which was markedly reversed in the miRNA-30a-5p inhibition+siB4GALT5 group. Conclusion: Our study has identified that the miRNA-30a-5p targets the B4GALT5 gene, and miRNA-30a-5p/B4GALT5 axis facilitates the proliferation of PNH clones via the PI3K/AKT signaling pathway. Additionally, our findings provide initial evidence that the miRNA-30a-5p/B4GALT5 axis may play a potential role in M1 macrophage polarization in the bone marrow of PNH patients.
2023-01-06 | Long noncoding RNA FAM157C contributes to clonal proliferation in paroxysmal nocturnal hemoglobinuria
Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease of hematopoietic stem cells (HSCs). Long noncoding RNAs (lncRNAs) perform a wide range of biological functions, including the regulation of gene expression, cell differentiation, and proliferation, but their role in PNH remains unclear. CD59 − and CD59 + granulocytes and monocytes from 35 PNH patients were sorted. High-throughput sequencing was analyzed in 5 PNH patients, and differentially expressed lncRNAs and mRNAs were identified. The mRNAs with fragments per kilobase of exon model per million mapped fragments (FPKM) > 10 in at least 3 patients were selected, and experiments were performed to identify their upstream regulatory lncRNAs. The expression of selected mRNAs and lncRNAs was verified by qRT‒PCR, and the correlation of these expression patterns with clinical data from other 30 PNH patients was analyzed. Then, the functions of the lncRNAs were studied in the PIGA-KO-THP-1 cell line. Transcription analysis revealed 742 upregulated and 1376 downregulated lncRNAs and 3276 upregulated and 213 downregulated mRNAs. After deep screening, 8 highly expressed mRNAs that were related to the NF-κB pathway were analyzed to determine coexpression patterns. LINC01002, FAM157C, CTD-2530H12.2, XLOC-064331 and XLOC-106677 were correlated with the 8 mRNAs. After measuring the expression of these molecules in 30 PNH patients by qRT‒PCR, lncRNA FAM157C was verified to be upregulated in the PNH clone, and its expression levels were positively correlated with the LDH levels and CD59 − granulated and monocyte cell ratios. After knockdown of the FAM157C gene in the PIGA-KO-THP-1 cell line, we found that the cells were arrested in the G0/G1 phase and S phase, the apoptosis rate increased, and the cell proliferation decreased. LncRNA FAM157C was proven to promote PNH clone proliferation, and this is the first study to explore the role of lncRNAs in PNH.
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Drug Discovery Landscape
29 orphan drug designations for Paroxysmal nocturnal hemoglobinuria, including 9 approved therapies.
29 orphan drug designations for Paroxysmal nocturnal hemoglobinuria, including 9 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
small molecule inhibitor of complement factor B | small molecules | FDA | Wuhan Createrna Science and Technology Co., Ltd. | |
Recombinant, Humanized, Aglycosylated, Immunoglobulin G1 kappa Anti-Factor Bb Monoclonal Antibody | antibodies | FDA | NovelMed Therapeutics, Inc. | |
Recombinant, Humanized, aglycosylated, IgG1 Kappa Anti-Properdin Monoclonal Antibody | antibodies | FDA | NovelMed Therapeutics, Inc. | |
Humanized immunoglobulin G4 monoclonal antibody directed against mannan-binding lectin-associated serine protease-3 (MASP-3) | antibodies | FDA | Novo Nordisk Inc. | |
Recombinant IgG-fusion protein containing a humanized anti-C5 monoclonal antibody fused with a truncated human complement FH to the heavy chain C-terminus | proteins | FDA | Kira Pharmaceuticals, LLC | |
cemdisiran | RNAs | FDA | Regeneron Pharamecuticals, Inc. | |
Vemircopan | small molecules | EMA | Alexion Europe | |
(1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide | small molecules | FDA | Alexion Pharmaceuticals Inc. | |
Pozelimab/Cemdisiran Combination | combination | FDA | Regeneron Pharamecuticals, Inc. | |
a small molecule inhibitor of human complement factor D | small molecules | FDA | BioCryst Pharmaceuticals, Inc. | |
iptacopan [Fabhalta] | small molecules | FDA | Approved | Novartis Pharmaceuticals Corporation |
(4-{(2S,4S)-4-ethoxy-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl}benzoic acid-hydrogen chloride(1/1)) [FABHALTA] | small molecules | EMA | Approved | Novartis Europharm Limited |
pozelimab | antibodies | FDA | Regeneron Pharmaceuticals Inc | |
(2S,4R)-1-(2-(3-acetyl-5-(2-methylpyrimidine-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromopyridine-2-yl)-4-fluoropyrrolidine-2-carboxamide [Voydeya] | small molecules | EMA | Approved | Alexion Europe SAS |
danicopan [Voydeya] | small molecules | FDA | Approved | Alexion Pharmaceuticals, Inc |
crovalimab-akkz [Piasky] | antibodies | FDA | Approved | Genentech Inc. |
Synthetic 15-amino-acid macrocyclic peptide acylated with a ethyleneglycol palmitoylated linker | peptides | FDA | Ra Pharmaceuticals, Inc. | |
Poly(oxy-1,2-ethanediyl), .alpha.-hydro-.omega.-hydroxy-,15,15'-diester with N-acetyl-L-isoleucyl-L-cysteinyl-L-valyl-1-methyl-L-tryptophyl-L-glutaminyl-L-.alpha.-aspartyl-L-tryptophylglycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteinyl-L-threonyl-2-[2-(2-aminoethoxy)ethoxy]acetyl-N6-carboxy-L-lysinamide cyclic (2.fwdarw.12)-(disulfide); where two identical synthetic peptide domains are covalently linked at the ends of the polyethylene glycol chain [ASPAVELI] | peptides | EMA | Approved | Swedish Orphan Biovitrum AB (publ) |
Ravulizumab-cwvz [Ultomiris] | antibodies | FDA | Approved | Alexion Pharmaceuticals, Inc. |
Zilucoplan [RA101495] | peptides | EMA | UCB Pharma | |
nomacopan | proteins | FDA | Akari Therapeutics Plc | |
Recombinant protein derived from the saliva of the Ornithodoros moubata tick | proteins | EMA | Akari Malta Limited | |
Ravulizumab [Ultomiris] | antibodies | EMA | [INACTIVE] Alexion Europe | |
S3,S13-cyclo(D-tyrolsyl-L-isoleucyl-L-cysteinyl-L-valyl-1-methyl-L-tryptophyl-L-glutaminyl-L-aspartyl-L-tryptophyl-N-methyl-L-glycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteinyl-N-methyl-L-isoleucinamide) | peptides | FDA | Amyndas Pharmaceuticals | |
S3,S13-cyclo(D-tyrolsyl-L-isoleucyl-L-cysteinyl-L-valyl-1-methyl-L-tryptophyl-L-glutaminyl-L-aspartyl-L-tryptophyl-N-methyl-L-glycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteinyl-N-methyl-L-isoleucinamide) | peptides | EMA | Amyndas Pharmaceuticals S.A. | |
pegcetacoplan [Empaveli] | peptides | FDA | Approved | Apellis Pharmaceuticals, Inc. |
Bardoxolone methyl [Soliris] | small molecules | EMA | Alexion Europe | |
eculizumab [Soliris] | antibodies | FDA | Approved | Alexion Pharmaceuticals, Inc. |
Mirococept | proteins | EMA | — | [INACTIVE] Aligen Therapeutics S.L. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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