Pharmacokinetic analysis of vilobelimab, anaphylatoxin C5a and antidrug antibodies in PANAMO: a phase 3 study in critically ill, invasively mechanically ventilated COVID-19 patients

Intensive Care Medicine Experimental

Research Articles

Alexander P. J. Vlaar¹  Sanne de Bruin¹  Endry H. T. Lim²  Matthijs C. Brouwer³  Diederik van de Beek³  Renfeng Guo⁴  Bruce P. Burnett⁴  Maria Habel⁵  Niels C. Riedemann⁵  Claus Thielert⁶  James Dickinson⁶  Simon Rückinger⁷ 

[1] Department of Intensive Care Medicine, Amsterdam UMC Location University of Amsterdam, AMC Room C3-421, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;Department of Intensive Care Medicine, Amsterdam UMC Location University of Amsterdam, AMC Room C3-421, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;Department of Neurology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands;Department of Neurology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands;InflaRx Pharmaceuticals Inc, Ann Arbor, MI, USA;InflaRx, Jena, Germany;InflaRx, Munich, Germany;Metronomia Clinical Research GmbH, Munich, Germany;

关键词: PK;    Pharmacokinetic;    C5a;    Complement;    Vilobelimab;    ADA;    Antidrug antibodies;    SARS-CoV-2;    COVID-19;    RCT;   

DOI  :  10.1186/s40635-023-00520-8

 received in 2023-02-28, accepted in 2023-05-15,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundVilobelimab, a complement 5a (C5a)-specific monoclonal antibody, reduced mortality in critically ill COVID-19 patients in a phase 3 multicentre, randomized, double-blind, placebo-controlled study. As part of the study, vilobelimab concentrations and C5a levels as well as antidrug antibodies (ADAs) to vilobelimab were analysed.ResultsFrom Oct 1, 2020 to Oct 4, 2021, 368 invasively mechanically ventilated COVID-19 patients were randomized: 177 patients were randomly assigned to receive vilobelimab while 191 patients received placebo. Pharmacokinetic sampling was only performed at sites in Western Europe. Blood samples for vilobelimab measurements were available for 93 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. On day 8, after three infusions, mean vilobelimab (trough) concentrations ranged from 21,799.3 to 302,972.1 ng/mL (geometric mean 137,881.3 ng/mL). Blood samples for C5a measurements were available for 94 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. At screening, C5a levels were highly elevated and comparable between groups. In the vilobelimab group, median C5a levels were 118.3 ng/mL [IQR 71.2–168.2 ng/mL] and in the placebo group, median C5a levels were 104.6 ng/mL [IQR 77.5–156.6 ng/mL]. By day 8, median C5a levels were reduced by 87% in the vilobelimab group (median 14.5 ng/mL [IQR 9.5–21.0 ng/mL], p < 0.001) versus an 11% increase in the placebo group (median 119.2 ng/mL [IQR 85.9–152.1 ng/mL]). Beyond day 8, though plasma sampling was sparse, C5a levels did not reach screening levels in the vilobelimab group while C5a levels remained elevated in the placebo group. Treatment-emergent ADAs were observed in one patient in the vilobelimab group at hospital discharge on day 40 and in one patient in the placebo group at hospital discharge on day 25.ConclusionsThis analysis shows that vilobelimab efficiently inhibits C5a in critically ill COVID-19 patients. There was no evidence of immunogenicity associated with vilobelimab treatment.Trialregistration ClinicalTrials.gov, NCT04333420. Registered 3 April 2020, https://clinicaltrials.gov/ct2/show/NCT04333420

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

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Fig. 4

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