Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria
Open accessAbstract
BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease characterized by chronic complement-mediated hemolysis. C5 inhibition controls intravascular hemolysis in untreated PNH but cannot address extravascular hemolysis. Pegcetacoplan, a pegylated peptide targeting proximal complement protein C3, potentially inhibits both intravascular and extravascular hemolysis. METHODS: We conducted a phase 3 open-label, controlled trial to assess the efficacy and safety of pegcetacoplan as compared with eculizumab in adults with PNH and hemoglobin levels lower than 10.5 g per deciliter despite eculizumab therapy. After a 4-week run-in phase in which all patients received pegcetacoplan plus eculizumab, we randomly assigned patients to subcutaneous pegcetacoplan monotherapy (41 patients) or intravenous eculizumab (39 patients). The primary end point was the mean change in hemoglobin level from baseline to week 16. Additional clinical and hematologic markers of hemolysis and safety were assessed. RESULTS: Pegcetacoplan was superior to eculizumab with respect to the change in hemoglobin level from baseline to week 16, with an adjusted (least squares) mean difference of 3.84 g per deciliter (P<0.001). A total of 35 patients (85%) receiving pegcetacoplan as compared with 6 patients (15%) receiving eculizumab no longer required transfusions. Noninferiority of pegcetacoplan to eculizumab was shown for the change in absolute reticulocyte count but not for the change in lactate dehydrogenase level. Functional Assessment of Chronic Illness Therapy-Fatigue scores improved from baseline in the pegcetacoplan group. The most common adverse events that occurred during treatment in the pegcetacoplan and eculizumab groups were injection site reactions (37% vs. 3%), diarrhea (22% vs. 3%), breakthrough hemolysis (10% vs. 23%), headache (7% vs. 23%), and fatigue (5% vs. 15%). There were no cases of meningitis in either group. CONCLUSIONS: Pegcetacoplan was superior to eculizumab in improving hemoglobin and clinical and hematologic outcomes in patients with PNH by providing broad hemolysis control, including control of intravascular and extravascular hemolysis. (Funded by Apellis Pharmaceuticals; PEGASUS ClinicalTrials.gov, NCT03500549.).
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Complement inhibition has been associated with an increased risk of encapsulated bacterial infection and the loading of host cells with complement proteins upstream of the inhibited molecule.
“Complement inhibition, in particular, has been associated with an increased risk of encapsulated bacterial infection and the loading of host cells with complement proteins upstream of the inhibited molecule [231,232]”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [231]
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- Authors
- Hillmen, P., Szer, J., Weitz, I., Röth, A., Höchsmann, B., Panse, J., Usuki, K., Griffin, M., Kiladjian, J.-J., de Castro, C., Nishimori, H., Tan, L., Hamdani, M., Deschatelets, P., Francois, C., Grossi, F., Ajayi, T., Risitano, A., & Peffault de Latour, R.
- Affiliations
- The Royal Melbourne Hospital (AU)
- University of Southern California (US)
- From the Department of Haematology, St. James’s University Hospital, Leeds (P.H., M.G.), and Lisa Tan Pharma Consulting, Cambridge (L.T.) — both in the United Kingdom; the Department of Clinical Haematology, Peter MacCallum Cancer Center and Royal Melbourne Hospital, Melbourne, VIC, Australia (J.S.); Jane Anne Nohl Division of Hematology, Keck School of Medicine of USC, Los Angeles (I.W.); the Department of Hematology, West German Cancer Center University Hospital Essen, University of Duisburg-Essen, Essen (A. Röth), the Institute of Transfusion Medicine, University of Ulm and Institute of Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service and University Hospital Ulm, Ulm (B.H.), and the Department of Oncology, Hematology, Hemostaseology and Stem Cell Transplantation, University Hospital RWTH Aachen, Aachen (J.P.) — all in Germany; the Department of Hematology, NTT Medical Center Tokyo, Tokyo (K.U.), and the Department of Hematology and Oncology, Okayama University...
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2021-03-18
- Volume
- 384
- Issue
- 11
- Pages
- 1028-1037
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W3136167138
- Cited by
- 440
- References
- 25
- Citations by year
- 2026: 58 · 2025: 81 · 2024: 84 · 2023: 71 · 2022: 91 · 2021: 34 · 2020: 18 · 2019: 1
- FWCI
- 26.12
- Type
- journal article
- Language
- en
- Open access
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Okayama University Scientific Achievement Repository (Okayama University) (submittedVersion)
- Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- Apellis Pharmaceuticals, Inc.
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Keywords
- paroxysmal nocturnal hemoglobinuria, pegcetacoplan, eculizumab, extravascular hemolysis, intravascular hemolysis, hemoglobin levels, transfusion requirements, reticulocyte count, lactate dehydrogenase, breakthrough hemolysis, fatigue, non-inferiority, complement C5 inhibition
- MeSH terms
- Adult, Aged, Aged, 80 and over, Complement C3, Complement C5, Diarrhea, Drug Therapy, Combination, Hemoglobins, Hemoglobinuria, Paroxysmal, Humans, Injections, Subcutaneous, Middle Aged, Peptides, Peptides, Cyclic, Erythrocyte Transfusion, Complement Inactivating Agents, Antibodies, Monoclonal, Humanized
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