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Clinical Trial
. 2024 Jun 11;8(11):2813-2824.
doi: 10.1182/bloodadvances.2023012267.

Pharmacokinetics, pharmacodynamics, efficacy, and safety of ravulizumab in pediatric paroxysmal nocturnal hemoglobinuria

Satheesh Chonat  1 , Alexander Kulagin  2 , Alexey Maschan  3 , Marije Bartels  4 , Jochen Buechner  5 , Rowena Punzalan  6 , Michael Richards  7 , Masayo Ogawa  8 , Eden Hicks  9 , Ji Yu  9 , André Baruchel  10 , Austin G Kulasekararaj  11
Affiliations
Clinical Trial

Pharmacokinetics, pharmacodynamics, efficacy, and safety of ravulizumab in pediatric paroxysmal nocturnal hemoglobinuria

Satheesh Chonat et al. Blood Adv. .

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 μg/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 μg/mL and 518.29 ± 109.67 μg/mL for eculizumab-naive and eculizumab-experienced patients, respectively. After the first ravulizumab infusion, serum-free C5 concentrations were <0.5 μg/mL in both cohorts until the end of the study (0.061 ± 0.021 μg/mL and 0.061 ± 0.018 μg/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.

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Conflict of interest statement

Conflict-of-interest disclosure: S.C. received consulting fees from Agios, Alexion, AstraZeneca Rare Disease, Amgen; received research funding from Alexion, AstraZeneca Rare Disease, Novartis, Global Blood Therapeutics/Pfizer; has a membership on an entity’s board of directors or advisory committees for Agios, Novartis, Roche/Genentech; and has received other fees for Alexion, AstraZeneca Rare Disease. A.K. has received honoraria, consulting fees, and research support (to Pavlov University) from Alexion, AstraZeneca Rare Disease. J.B. has received consulting fees from Novartis. M.O. is an employee and equity holder of Alexion, AstraZeneca Rare Disease. E.H. and J.Y. are employees of Alexion, AstraZeneca Rare Disease. A.B. received honoraria from AstraZeneca, Clinigen, Jazz, Novartis, and Servier, all unrelated to the subject of this publication. A.G.K. has received honoraria from Alexion, AstraZeneca Rare Disease, Amgen, Celgene/Bristol Myers Squibb, Novartis, and Ra Pharma; is on the board of directors or is an advisory board member for Alexion, AstraZeneca Rare Disease, Amgen, Celgene/Bristol Myers Squibb, Novartis, Pfizer, Roche, and Ra Pharma; and has received consulting fees from Achillion, Akari Therapeutics, Alexion, AstraZeneca Rare Disease, Biocryst, Celgene/Bristol Myers Squibb, Janssen Pharmaceuticals, Novartis, Novo Nordisk, Pfizer, Roche, and Samsung. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Study design and weight-based dosing regimen.∗Baseline was defined as last assessment before first ravulizumab dose.
Figure 2.
Figure 2.
Patient disposition. ∗Discontinued treatment to undergo bone marrow transplantation.
Figure 3.
Figure 3.
Mean (SD) change in serum ravulizumab concentration over time. The graph presents values before ravulizumab (lower values) and after ravulizumab (higher values) dosing at every visit for each patient subgroup. Dashed horizontal line indicates 175 μg/mL, the threshold for complete C5 inhibition. EOS, end of study.
Figure 4.
Figure 4.
PD parameters. (A) Mean (95% CI) serum-free complement C5 concentration over time. (B) Mean (95% CI) cRBC hemolysis over time. The graph presents values before ravulizumab (lower values) and after ravulizumab (higher values) dosing at every visit for each patient subgroup. Dashed horizontal lines indicate 0.5 μg/mL (A) and 20% hemolysis (B), the thresholds for complete C5 inhibition. BL, baseline; cRBC, chicken red blood cells.
Figure 5.
Figure 5.
Changes in LDH from baseline over time. (A) Mean (95% CI) percentage change from baseline in LDH over time. The graph presents values before ravulizumab (lower values) and after ravulizumab (higher values) dosing at every visit for each patient subgroup. (B) Proportion of patients achieving LDH normalization by visit. BL, baseline.
See this image and copyright information in PMC

References

    1. Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124(18):2804–2811. - PMC - PubMed
    1. Escalante CP, Chisolm S, Song J, et al. Fatigue, symptom burden, and health-related quality of life in patients with myelodysplastic syndrome, aplastic anemia, and paroxysmal nocturnal hemoglobinuria. Cancer Med. 2019;8(2):543–553. - PMC - PubMed
    1. Shah N, Bhatt H. StatPearls. StatPearls Publishing; 2022. Paroxysmal nocturnal hemoglobinuria. - PubMed
    1. Kulagin AD, Klimova OU, Dobronravov AV, et al. Paroxysmal nocturnal hemoglobinuria in children and adults: comparative clinical profile and long-term prognosis. Pediatr Hematol/Oncol Immunopathol. 2018;17(2):11–21.
    1. Saleem N, Graciaa S, McElfresh P, et al. The American Society of Pediatric Hematology/Oncology; 2023. Clinical outcomes of children and adolescents with paroxysmal nocturnal hemoglobinuria. Fort Worth.

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