Pharmacokinetics, pharmacodynamics, efficacy, and safety of ravulizumab in pediatric paroxysmal nocturnal hemoglobinuria.
No Thumbnail Available
All Authors
Chonat, S.
Kulagin, A.
Maschan, A.
Bartels, M.
Buechner, J.
Punzalan, R.
Richards, M.
Ogawa, M.
Hicks, E.
Yu, J.
LTHT Author
Richards, Michael
LTHT Department
Haemophilia Comprehensive Care Centre
Haematology
Leeds Children's Hospital
Haematology
Leeds Children's Hospital
Non Medic
Publication Date
2024
Item Type
Journal Article
Multicenter Study
Clinical Trial, Phase III
Multicenter Study
Clinical Trial, Phase III
Language
Subject
Subject Headings
Abstract
ABSTRACT: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease of uncontrolled terminal complement activation leading to intravascular hemolysis, thrombotic events and increased morbidity and mortality. This phase 3, open-label, single-arm, multicenter study evaluated ravulizumab treatment in eculizumab-naive or -experienced pediatric patients (aged <18 years) with PNH over a 26-week primary evaluation period (PEP) and 4-year extension period (EP). Patients included in the study received weight-based intravenous ravulizumab dosing. Primary end points were pharmacokinetic and pharmacodynamic parameters to confirm complement component 5 (C5) inhibition by ravulizumab; secondary end points assessed the efficacy (including percentage change in lactate dehydrogenase levels over time) and safety of ravulizumab. Thirteen patients, 5 (38.5%) eculizumab-naive and 8 (61.5%) eculizumab-experienced, were enrolled. Ravulizumab Ctrough levels were above the pharmacokinetic threshold of 175 mcg/mL in the PEP and EP except in 1 patient. At the end of the study, pre- and post-infusion mean +/- standard deviation serum ravulizumab concentrations were 610.50 +/- 201.53 mcg/mL and 518.29 +/- 109.67 mcg/mL for eculizumab-naive and eculizumab-experienced patients, respectively. After the first ravulizumab infusion, serum-free C5 concentrations were <0.5 mcg/mL in both cohorts until the end of the study (0.061 +/- 0.021 mcg/mL and 0.061 +/- 0.018 mcg/mL for eculizumab-naive and eculizumab-experienced patients, respectively). Compared with baseline, ravulizumab improved and maintained efficacy outcomes in both groups. Ravulizumab had an acceptable safety profile with no new safety signals identified, and provided immediate, complete, and sustained terminal complement inhibition, translating to clinical benefit for pediatric patients with PNH. This trial was registered at www.ClinicalTrials.gov as #NCT03406507.
Journal
Blood Advances