Presentation Details
| Efficacy and Safety Is Maintained in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria Receiving Pegcetacoplan for Up to 3 Years Carlos de Castro1, Brian Mulherin2, 3, Christopher J.Patriquin4, Veena Selvaratnam5, Raymond Siu Ming Wong6, Richard J.Kelly7, Lisa Tan8, 9, Peter Hillmen10, Dale Zhang10, Regis Peffault de Latour11, 12. 1Duke University, Durham, NC, USA.2Hematology Oncology of Indiana, Indianapolis, IN, USA.3Ascension St.Vincent Carmel, Carmel, IN, USA.4University Health Network, Toronto, ON, Canada.5Ampang Hospital, Ampang, Malaysia.6The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong.7Department of Haematology, St.James’s University Hospital, Leeds, United Kingdom.8Swedish Orphan Biovitrum AB, Stockholm, Sweden.9Lisa Tan Pharma Consulting Ltd., Cambridge, United Kingdom.10Apellis Pharmaceuticals, Inc., Waltham, MA, USA.11French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Paris, France.12Université Paris Cité, Paris, France |
Abstract
Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease of complement-mediated hemolysis and thrombosis. Pegcetacoplan, the first complement component 3–targeted therapy for PNH, increased hemoglobin (Hb) in adult patients with PNH from phase 3 trials who were either complement component 5 inhibitor (C5i)–experienced (PEGASUS [NCT03500549]) or -naive (PRINCE [NCT04085601]). Objectives: We evaluated long-term efficacy and safety of pegcetacoplan for PNH via an integrated analysis of data from PEGASUS, PRINCE, and the subsequent open-label extension study 307 (NCT03531255). Methods: Patients received pegcetacoplan 1080 mg subcutaneously twice weekly, with dose escalations as permitted (e.g., once every 3 days or 3 times weekly). Efficacy was evaluated: Hb concentration, lactate dehydrogenase (LDH) concentration (upper limit of normal [ULN] 226 IU/L), absolute reticulocyte count (ARC), indirect bilirubin concentration, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, and rates of transfusion avoidance (patients did not require a transfusion during treatment) from baseline (pegcetacoplan initiation) through Weeks 156 (3 years, PEGASUS) or 132 (2.5 years, PRINCE). Safety was assessed during pegcetacoplan monotherapy for up to 3 years and included adverse events (AEs), serious AEs (SAEs), and breakthrough hemolysis (BTH) (defined as reporting an AE of hemolytic disorder, LDH >2 × ULN, any prior LDH <1.5 × ULN, and median Hb decline of ≥2 g/dL). Results: Of 133 patients (PEGASUS, n=80; PRINCE, n=53), 114 enrolled in study 307 (PEGASUS, n=64; PRINCE, n=50), of whom ≥75% had a transfusion in the year before initial enrollment. Prior to pegcetacoplan initiation, mean (standard deviation [SD]) Hb concentrations were 8.95 (1.09) g/dL (PEGASUS) and 9.27 (1.44) g/dL (PRINCE), median (interquartile range) LDH concentrations were 217.0 (184.8, 276.5) IU/L (PEGASUS) and 1964.0 (1409.0, 2503.3) IU/L (PRINCE), and mean (SD) FACIT-Fatigue scores were 31.6 (11.7) (PEGASUS) and 36.6 (10.0) (PRINCE). After pegcetacoplan initiation, mean Hb and median LDH concentrations (Figure 1) markedly improved and remained stable through Weeks 156 (PEGASUS) or 132 (PRINCE). Improvements in ARC and indirect bilirubin were similarly maintained. FACIT-Fatigue scores increased (indicating less fatigue) and were maintained near the population norm (43.6). Annual transfusion avoidance rates ranged from 71%–79% (PEGASUS) and 80%–86% (PRINCE) (Figure 2), with 52% avoiding transfusions for up to 3 years in PEGASUS and 67% for up to 2.5 years in PRINCE. Overall, >92% of patients had ≥95% compliance. Over 3 years, most patients experienced an AE, with SAEs reported in 50.0% of patients (deemed pegcetacoplan-related in 4.5%). Overall, 17 patients discontinued pegcetacoplan due to an AE: 9 due to a hemolytic disorder which occurred for most within 1 year (n=7). Over 3 years, 4 (3.0%) deaths occurred (none deemed pegcetacoplan-related) and 3 (2.3%) patients experienced a thrombotic event (in the context of multiple comorbidities or pegcetacoplan discontinuation); no meningitis cases were reported. Overall, 39 of 132 (29.5%) patients experienced BTH (PEGASUS, n=23/80 [28.8%]; PRINCE, n=16/52 [30.8%]). No new or unexpected safety findings were identified. Conclusions: This analysis demonstrates rapid and sustained efficacy, reduced transfusion burden, and continued safety with long-term pegcetacoplan treatment of patients with PNH, regardless of prior C5i treatment.
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No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.