Hemolysis events in the phase 3 PEGASUS study of pegcetacoplan in patients with paroxysmal nocturnal hemoglobinuria

Author:

Peffault de Latour Régis1,Griffin Morag2,Kelly Richard J.2,Szer Jeff3ORCID,de Castro Carlos4ORCID,Horneff Regina5,Tan Lisa56,Yeh Michael7,Panse Jens89ORCID

Affiliation:

1. 1French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Paris, France

2. 2Department of Haematology, St James’s University Hospital, Leeds, United Kingdom

3. 3Department of Clinical Haematology, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, Australia

4. 4Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, NC

5. 5Swedish Orphan Biovitrum AB, Stockholm, Sweden

6. 6Lisa Tan Pharma Consulting Ltd, Cambridge, United Kingdom

7. 7Apellis Pharmaceuticals, Inc, Waltham, MA

8. 8Department of Oncology, Hematology, Hemostaseology, and Stem Cell Transplantation, University Hospital RWTH Aachen, Aachen, Germany

9. 9Centre for Integrated Oncology Aachen Bonn Cologne Düsseldorf, Aachen, Germany

Abstract

Abstract Patients with paroxysmal nocturnal hemoglobinuria (PNH) experience complement-mediated intravascular hemolysis leading to anemia, fatigue, and potentially life-threatening thrombotic complications. Pegcetacoplan, a C3 inhibitor, demonstrated sustained improvements in hematologic and clinical parameters in the phase 3 PEGASUS trial in patients with PNH who remained anemic despite C5 inhibitor therapy. The present post hoc analysis describes 26 hemolysis adverse events (AEs) experienced in 19 patients during pegcetacoplan therapy in PEGASUS and baseline patient characteristics potentially associated with increased hemolysis risk. Lactate dehydrogenase (LDH) ≥2× the upper limit of normal (ULN) was observed in 19 events, including 2 with LDH ≥10× ULN. All patients experienced decreased hemoglobin during hemolysis (mean decrease, 3.0 g/dL). In 16 events (62%), a potential complement-amplifying condition underlying the event could be identified. Hemolysis AEs led to study discontinuation in 5 patients. However, of 26 hemolysis AEs, 17 (65%) were manageable without pegcetacoplan discontinuation. A greater proportion of patients with hemolysis AEs (n = 19) had key characteristics of higher disease activity at baseline compared to patients without hemolysis AEs (n = 61), namely higher-than-label eculizumab dose (53% vs 23%), detectable CH50 (total complement function; 74% vs 54%), and ≥4 transfusions in the previous 12 months (68% vs 51%). These characteristics may be useful predictors of potential future hemolysis events. This trial was registered at www.ClinicalTrials.gov as #NCT03500549.

Publisher

American Society of Hematology

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