Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria: results of two phase 3 randomised, multicentre studies

Abstract

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.

Keywords: L-lactate dehydrogenase; complement C5; eculizumab; half-life; ravulizumab.

Conflict of interest statement

Régis Peffault de Latour has received honoraria, consulting fees, and research support from Alexion Pharmaceuticals, Inc., Pfizer, and Novartis, and has received research support from Amgen. Robert A. Brodsky is a member of the scientific advisory board for and receives grant funding from Alexion Pharmaceuticals, Inc. Stephan Ortiz is an employee and stockholder of Alexion Pharmaceuticals, Inc. Antonio M. Risitano has received research support, honoraria, and consulting fees from Alexion Pharmaceuticals, Inc., Novartis, Alnylam, and Ra Pharma, lecture fees from Alexion Pharmaceuticals, Inc., Novartis, Pfizer, and Jazz, and served as an advisory board member for Alexion Pharmaceuticals, Inc., Novartis, Pfizer, and Jazz, as well as a consultant for Amyndas. Jun H. Jang has no conflicts to declare. Peter Hillmen has received honoraria from and has been a consultant for Alexion Pharmaceuticals, Inc. Alexander D. Kulagin has received research support, honoraria, and consulting fees from Alexion Pharmaceuticals, Inc., Novartis, and JSC GENERIUM. Austin G. Kulasekararaj has received honoraria, travel support, and consulting fees from Alexion Pharmaceuticals, Inc. Scott T. Rottinghaus is an employee and stockholder of Alexion Pharmaceuticals, Inc. Rasha Aguzzi is an employee and stockholder of Alexion Pharmaceuticals, Inc. Xiang Gao is an employee and stockholder of Alexion Pharmaceuticals, Inc. Richard A. Wells has received honoraria, research support, and travel support from Alexion Pharmaceuticals, Inc. Jeff Szer has received research support (to Royal Melbourne Hospital), honoraria, consulting fees, and travel support from Alexion Pharmaceuticals, Inc.

© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

Figures

Fig 1

Study designs. aRavulizumab loading dose = 2400 mg for patients weighing ≥40 to <60 kg, 2700 mg for patients weighing ≥60 to <100 kg, and 3000 mg for patients weighing ≥100 kg. bRavulizumab maintenance dose = 3000 mg for patients weighing ≥40 to <60 kg, 3300 mg for patients weighing ≥60 to <100 kg, and 3600 mg for patients weighing ≥100 kg. cEculizumab induction dose = 600 mg (Study 301 only). dEculizumab maintenance dose = 900 mg. eApproved dose for PNH. fBlood was collected for serum drug assessment (ravulizumab and eculizumab) and free and total serum C5 quantitation on day 1 at the end of infusion, and anytime on days 8, 22, 29, 43, 57, 85, 99, 113, 141, 155, and 169, for the ravulizumab group and pre‐dose for the eculizumab group; at days 15, 71, and 127 data are from pre‐dose and end of infusion for both treatment groups; and at day 183 data are from end of the primary evaluation period (prior to dosing) for both treatment groups. gExtension period for Study 301 is planned to conclude at the end of 5 years; extension period for Study 302 is planned to conclude at the end of 3 years. C5, complement component 5; ECU, eculizumab; LDH, lactate dehydrogenase; PNH, paroxysmal nocturnal haemoglobinuria; q2w, every 2 weeks; q8w, every 8 weeks; RAV, ravulizumab; ULN, upper limit of normal (246 u/l).

Fig 2

Mean (SD) maximum and trough serum drug concentrations for ravulizumab following the last maintenance dose, stratified by dose group (PK analysis population). (A) Study 301. (B) Study 302. Cmax, maximum observed serum concentration; Ctrough, concentration at the end of the dosing interval; PK, pharmacokinetic; SD, standard deviation.

Fig 3

Mean (SD) serum drug concentrations over time (PK analysis population). (A) Study 301. (B) Study 302. Blood was collected for serum drug assessment (ravulizumab and eculizumab) and free and total serum C5 quantitation on day 1 at the end of infusion, and anytime on days 8, 22, 29, 43, 57, 85, 99, 113, 141, 155, and 169, for the ravulizumab group and pre‐dose for the eculizumab group; at days 15, 71, and 127 data are from pre‐dose and end of infusion for both treatment groups; and at day 183 data are from end of the primary evaluation period (prior to dosing) for both treatment groups. Lower limit of quantitation was 1·00 µg/ml for ravulizumab and 5·00 µg/ml for eculizumab. PK, pharmacokinetic; SD, standard deviation. [Colour figure can be viewed at wileyonlinelibrary.com]

Fig 4

Serum free C5 concentrations over time. (A) Study 301. (B) Study 302. Dashed horizontal lines indicate serum free C5 concentration of 0·5 µg/ml. Horizontal line in the middle of each box is the median; the top and the bottom mark the 75th and 25th percentiles, respectively. The diamond indicates the mean and whiskers represent the 1·5 interquartile range of the lower quartile and upper quartile. Asterisks represent outliers. Y‐axis is a log scale. For the ravulizumab group, for free C5 values that were BLOQ, LLOQ/2 = 0·00915 μg/ml was utilised. For the eculizumab group, for free C5 values that were BLOQ, LLOQ/2 = 0·0137 μg/ml was utilised. For Study 301, the following free C5 samples were excluded as they were considered biologically implausible: ravulizumab, n = 3 day 1 free C5 samples at EOI had values similar to pre‐treatment values; eculizumab, n = 3 Day 1 free C5 samples were BLOQ at pre‐treatment, n = 5 Day 1 free C5 samples at EOI had values similar to pre‐treatment values. For Study 302, day 1 baseline free C5 sample from each treatment group was excluded as the data were considered biologically implausible. The exclusions were corroborated with the paired PK data, as the PK and free C5 samples were collected from the same blood draw. BLOQ, below limit of quantitation; C5, complement component 5; EOI, end of infusion; LLOQ, lower limit of quantitation

Fig 5

Serum total C5 concentrations over time [mean (95% CI)]. (A) Study 301. (B) Study 302. Lower limit of quantitation was 2·50 µg/ml. Baseline was defined as the last non‐missing assessment value prior to the first dose of study drug. Two patients treated with eculizumab in Study 301 had missing baseline values and were omitted from this analysis. BL, baseline; C5, complement component 5; CI, confidence interval. [Colour figure can be viewed at wileyonlinelibrary.com]