C3 inhibition with pegcetacoplan in subjects with paroxysmal nocturnal hemoglobinuria treated with eculizumab

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, life‐threatening hematologic disease characterized by chronic complement‐mediated hemolysis and thrombosis. Despite treatment with eculizumab, a C5 inhibitor, 72% of individuals remain anemic. Pegcetacoplan (APL‐2), a PEGylated C3 inhibitor,...

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Veröffentlicht in:American journal of hematology Jg. 95; H. 11; S. 1334 - 1343
Hauptverfasser: Castro, Carlos, Grossi, Federico, Weitz, Ilene Ceil, Maciejewski, Jaroslaw, Sharma, Vivek, Roman, Eloy, Brodsky, Robert A., Tan, Lisa, Di Casoli, Carl, El Mehdi, Delphine, Deschatelets, Pascal, Francois, Cedric
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Hoboken, USA John Wiley & Sons, Inc 01.11.2020
Wiley Subscription Services, Inc
Schlagworte:
Adult
Anemia, Hemolytic - drug therapy
Anemia, Hemolytic - etiology
Anemia, Hemolytic - prevention & control
Antibodies, Monoclonal, Humanized - adverse effects
Antibodies, Monoclonal, Humanized - therapeutic use
Bilirubin
Bilirubin - blood
Blood diseases
Chemical and Drug Induced Liver Injury - etiology
Complement C3 - antagonists & inhibitors
Complement C5 - antagonists & inhibitors
Complement component C3
Drug Substitution
Female
Fever - chemically induced
Hematological diseases
Hematology
Hemoglobin
Hemoglobins - analysis
Hemoglobinuria, Paroxysmal - blood
Hemoglobinuria, Paroxysmal - drug therapy
Hemoglobinuria, Paroxysmal - immunology
Hemolysis
Hemolysis - drug effects
Humans
L-Lactate dehydrogenase
L-Lactate Dehydrogenase - blood
Lactic acid
Male
Middle Aged
Monoclonal antibodies
Pancreatitis - chemically induced
Paroxysmal nocturnal hemoglobinuria
Pharmacodynamics
Pharmacokinetics
Prospective Studies
Reticulocyte Count
Thrombosis
ISSN:0361-8609, 1096-8652, 1096-8652
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Zusammenfassung:Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, life‐threatening hematologic disease characterized by chronic complement‐mediated hemolysis and thrombosis. Despite treatment with eculizumab, a C5 inhibitor, 72% of individuals remain anemic. Pegcetacoplan (APL‐2), a PEGylated C3 inhibitor, has the potential to provide more complete hemolysis control in patients with PNH. This open‐label, phase Ib study was designed to assess the safety, tolerability, and pharmacokinetics of pegcetacoplan in subjects with PNH who remained anemic during treatment with eculizumab. Pharmacodynamic endpoints were also assessed as an exploratory objective of this study. Data are presented for six subjects in cohort 4 who received treatment for up to 2 years. In total, 427 treatment‐emergent adverse events (TEAEs) were reported, 68 of which were possibly related to the study drug. Eight serious TEAEs occurred in two subjects; three of these events were considered possibly related to the study drug. Pegcetacoplan pharmacokinetic concentrations accumulated with repeated dosing, and steady state was reached at approximately 6‐8 weeks. Lactate dehydrogenase levels were well controlled by eculizumab at baseline. Pegcetacoplan increased hemoglobin levels and decreased both reticulocyte count and total bilirubin in all six subjects. Improvements were observed in Functional Assessment of Chronic Illness Therapy Fatigue scores. Two subjects discontinued for reasons unrelated to pegcetacoplan. All four subjects who completed the study transitioned to pegcetacoplan monotherapy following eculizumab discontinuation and avoided transfusions. In this small study, pegcetacoplan therapy was generally well‐tolerated, and resulted in an improved hematological response by achieving broad hemolysis control, enabling eculizumab discontinuation.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:0361-8609
1096-8652
1096-8652
DOI:10.1002/ajh.25960