• Peter Hillmen, Jeff Szer, Ilene Weitz, Alexander Röth, Britta Höchsmann, Jens Panse, Kensuke Usuki, Morag Griffin, Jean-Jacques Kiladjian, Carlos de Castro, Hisakazu Nishimori, Lisa Tan, Mohamed Hamdani, Pascal Deschatelets, Cedric Francois, Federico Grossi, Temitayo Ajayi, Antonio Risitano, and Régis Peffault de Latour.
• 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 Hospital, Okayama (H.N.) - both in Japan; Centre d'Investigations Cliniques (J.-J.K.) and the French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria (R.P.T.), Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris; the Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, NC (C.C.); Apellis Pharmaceuticals, Waltham, MA (M.H., P.D., C.F., F.G., T.A.); and the Hematology and BMT Unit, AORN San Giuseppe Moscati, Avellino, Italy (A. Risitano).
• N. Engl. J. Med. 2021 Mar 18; 384 (11): 102810371028-1037.

BackgroundParoxysmal 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.MethodsWe 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.ResultsPegcetacoplan 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.ConclusionsPegcetacoplan 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.).Copyright © 2021 Massachusetts Medical Society.

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