TY - JOUR
T1 - Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria
T2 - results of two phase 3 randomised, multicentre studies
AU - Peffault de Latour, Régis
AU - Brodsky, Robert A.
AU - Ortiz, Stephan
AU - Risitano, Antonio M.
AU - Jang, Jun H.
AU - Hillmen, Peter
AU - Kulagin, Alexander D.
AU - Kulasekararaj, Austin G.
AU - Rottinghaus, Scott T.
AU - Aguzzi, Rasha
AU - Gao, Xiang
AU - Wells, Richard A.
AU - Szer, Jeff
N1 - Funding Information:
The sponsor and investigators thank the patients and their families for their participation in and support for this clinical study. The authors thank Rodrigo Pavani, MD, PhD, and Masayo Ogawa, MD, of Alexion Pharmaceuticals, Inc., for their contribution to the implementation of the 301 and 302 studies. Statistical analysis, PK/PD assessments, and editorial review were provided by Andrew I. Damokosh, PhD, and Rajendra Pradhan, PhD, of Alexion Pharmaceuticals, Inc. Editorial review for scientific accuracy was also provided by Shweta Rane, PhD, CMPP, and Kenneth Pomerantz, PhD, of Alexion Pharmaceuticals, Inc. Medical writing and editorial support were provided by Jennifer M. Kulak, PhD (ApotheCom) and Michael D. Morren, RPh, MBA (Peloton Advantage, LLC, an OPEN Health Company), with funding from Alexion Pharmaceuticals, Inc.
Funding Information:
The sponsor and investigators thank the patients and their families for their participation in and support for this clinical study. The authors thank Rodrigo Pavani, MD, PhD, and Masayo Ogawa, MD, of Alexion Pharmaceuticals, Inc., for their contribution to the implementation of the 301 and 302 studies. Statistical analysis, PK/PD assessments, and editorial review were provided by Andrew I. Damokosh, PhD, and Rajendra Pradhan, PhD, of Alexion Pharmaceuticals, Inc. Editorial review for scientific accuracy was also provided by Shweta Rane, PhD, CMPP, and Kenneth Pomerantz, PhD, of Alexion Pharmaceuticals, Inc. Medical writing and editorial support were provided by Jennifer M. Kulak, PhD (ApotheCom) and Michael D. Morren, RPh, MBA (Peloton Advantage, LLC, an OPEN Health Company), with funding from Alexion Pharmaceuticals, Inc.
Publisher Copyright:
© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd
PY - 2020/11/1
Y1 - 2020/11/1
N2 - Ravulizumab, a novel long-acting complement component 5 (C5) inhibitor administered every 8 weeks (q8w), was non-inferior to eculizumab for all efficacy outcomes in two randomised, open-label, phase 3 trials in C5 inhibitor-naïve (Study 301) and eculizumab-experienced (Study 302) adult patients with paroxysmal nocturnal haemoglobinuria (PNH). This pre-specified analysis characterised ravulizumab pharmacokinetics (PK), pharmacodynamics (PD; free C5 levels), and PD differences between medications (Study 301, n = 246; Study 302, n = 195). Ravulizumab PK parameters were determined using non-compartmental analysis. Serum free C5 was quantified with a Gyros-based fluorescence assay (ravulizumab) and an electrochemiluminescence ligand-binding assay (eculizumab). Ravulizumab PK parameters were numerically comparable in both studies; the median time to maximum concentrations ranged from 2·3 to 2·8 and 2·3 to 2·6 h in studies 301 and 302, respectively. Ravulizumab steady-state serum concentrations were achieved immediately after the first dose and sustained throughout treatment. For ravulizumab, the mean (SD) post hoc terminal elimination half-life was 49·7 (8·9) days. Serum free C5 concentrations <0·5 µg/ml were achieved after the first ravulizumab dose and sustained throughout treatment in both studies. In a minority of patients, free C5 concentrations <0·5 µg/ml were not consistently achieved with eculizumab in either study. Ravulizumab q8w was more consistent in providing immediate, complete, sustained C5 inhibition than eculizumab every-2-weeks in patients with PNH.
AB - Ravulizumab, a novel long-acting complement component 5 (C5) inhibitor administered every 8 weeks (q8w), was non-inferior to eculizumab for all efficacy outcomes in two randomised, open-label, phase 3 trials in C5 inhibitor-naïve (Study 301) and eculizumab-experienced (Study 302) adult patients with paroxysmal nocturnal haemoglobinuria (PNH). This pre-specified analysis characterised ravulizumab pharmacokinetics (PK), pharmacodynamics (PD; free C5 levels), and PD differences between medications (Study 301, n = 246; Study 302, n = 195). Ravulizumab PK parameters were determined using non-compartmental analysis. Serum free C5 was quantified with a Gyros-based fluorescence assay (ravulizumab) and an electrochemiluminescence ligand-binding assay (eculizumab). Ravulizumab PK parameters were numerically comparable in both studies; the median time to maximum concentrations ranged from 2·3 to 2·8 and 2·3 to 2·6 h in studies 301 and 302, respectively. Ravulizumab steady-state serum concentrations were achieved immediately after the first dose and sustained throughout treatment. For ravulizumab, the mean (SD) post hoc terminal elimination half-life was 49·7 (8·9) days. Serum free C5 concentrations <0·5 µg/ml were achieved after the first ravulizumab dose and sustained throughout treatment in both studies. In a minority of patients, free C5 concentrations <0·5 µg/ml were not consistently achieved with eculizumab in either study. Ravulizumab q8w was more consistent in providing immediate, complete, sustained C5 inhibition than eculizumab every-2-weeks in patients with PNH.
KW - L-lactate dehydrogenase
KW - complement C5
KW - eculizumab
KW - half-life
KW - ravulizumab
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U2 - 10.1111/bjh.16711
DO - 10.1111/bjh.16711
M3 - Article
C2 - 32449174
AN - SCOPUS:85085611500
SN - 0007-1048
VL - 191
SP - 476
EP - 485
JO - British journal of haematology
JF - British journal of haematology
IS - 3
ER -