Characterization of breakthrough hemolysis events observed in the phase 3 randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria
Robert A. Brodsky,
Régis Peffault de Latour,
Scott T. Rottinghaus,
Alexander Röth,
Antonio M. Risitano,
Ilene C. Weitz,
Peter Hillmen,
Jaroslaw P. Maciejewski,
Jeff Szer,
Jong Wook Lee,
Austin G. Kulasekararaj,
Lori Volles,
Andrew I. Damokosh,
Stephan Ortiz,
Lori Shafner,
Peng Liu,
Anita Hill,
Hubert Schrezenmeier
Affiliations
Robert A. Brodsky
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA;
Régis Peffault de Latour
Université Paris Diderot and Hôpital Saint-Louis AP-HP, Paris
Scott T. Rottinghaus
Alexion Pharmaceuticals, Inc., Boston, MA,
Alexander Röth
Department of Hematology, University Hospital Essen, University of Duisburg-Essen, Essen,
Antonio M. Risitano
Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples
Ilene C. Weitz
Jane Anne Nohl Division of Hematology, Keck-USC School of Medicine, Los Angeles, CA, USA;
Peter Hillmen
Department of Haematology, St James's University Hospital, Leeds,
Jaroslaw P. Maciejewski
Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH, USA;
Jeff Szer
Clinical Haematology, Royal Melbourne Hospital, Melbourne;
Jong Wook Lee
The Catholic University of Korea, College of Medicine, Seoul,
Austin G. Kulasekararaj
Department of Haematological Medicine, King College Hospital, London,
Lori Volles
Alexion Pharmaceuticals, Inc., Boston, MA,
Andrew I. Damokosh
Alexion Pharmaceuticals, Inc., Boston, MA,
Stephan Ortiz
Alexion Pharmaceuticals, Inc., Boston, MA,
Lori Shafner
Alexion Pharmaceuticals, Inc., Boston, MA, USA;
Peng Liu
Alexion Pharmaceuticals, Inc., Boston, MA
Anita Hill
Department of Haematology, St James's University Hospital, Leeds
Hubert Schrezenmeier
German Red Cross Blood Transfusion Service, Baden-Wurttemberg-Hessen and University Hospital Ulm
Eculizumab is first-line treatment for paroxysmal nocturnal hemoglobinuria (PNH); however, approximately 11%-27% of patients may experience breakthrough hemolysis (BTH) on approved doses of eculizumab. Ravulizumab, a new long-acting C5 inhibitor with a four-times longer mean half-life than eculizumab, provides immediate, complete, and sustained C5 inhibition over 8-week dosing intervals. In two phase 3 studies, ravulizumab was noninferior to eculizumab (Pinf ≤0.0004) for the BTH endpoint; fewer patients experienced BTH with ravulizumab versus eculizumab in both studies (301 [complement inhibitor-naive patients], 4.0% vs 10.7%; 302 [patients stabilized on eculizumab at baseline], 0% vs 5.1%). In the current analysis, patient-level data were evaluated to assess causes and clinical parameters associated with incidents of BTH reported during the 26-week treatment periods in the ravulizumab phase 3 PNH studies. Of the five BTH events occurring in ravulizumab-treated patients across the studies, none were temporally associated with suboptimal C5 inhibition (free C5 ≥0.5 μg/mL); four (80.0%) were temporally associated with complement-amplifying conditions (CACs). Of the 22 events occurring in eculizumab-treated patients, eleven were temporally associated with suboptimal C5 inhibition, including three events also associated with concomitant infection. Six events were associated with CACs only. Five events were unrelated to free C5 elevation or reported CACs. These results suggest that the immediate, complete, and sustained C5 inhibition achieved through weight-based dosing of ravulizumab reduces the risk of BTH by eliminating BTH associated with suboptimal C5 inhibition in patients with PNH. Clinicaltrials.gov identifiers: Study 301, NCT02946463; Study 302, NCT03056040.
