Anti-C5a antibody vilobelimab treatment and the effect on biomarkers of inflammation and coagulation in patients with severe COVID-19: a substudy of the  phase 2 PANAMO trial

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作者
Endry H. T. Lim
Alexander P. J. Vlaar
Lieuwe D. J. Bos
Lonneke A. van Vught
Anita M. Tuip-de Boer
Romein W. G. Dujardin
Maria Habel
Zhongli Xu
Matthijs C. Brouwer
Diederik van de Beek
Sanne de Bruin
机构
[1] Amsterdam UMC Location University of Amsterdam,Department of Intensive Care Medicine
[2] Laboratory of Experimental Intensive Care and Anaesthesiology (L.E.I.C.A.),Department of Neurology
[3] Amsterdam UMC Location University of Amsterdam,Center for Experimental and Molecular Medicine
[4] Amsterdam Neuroscience,Department of Intensive Care Medicine
[5] Amsterdam UMC Location University of Amsterdam,undefined
[6] InflaRx GmbH,undefined
[7] Amsterdam UMC,undefined
[8] Location AMC,undefined
来源
Respiratory Research | / 23卷
关键词
SARS-CoV-2; COVID-19; Complement; Complement inhibition; Vilobelimab; C5a;
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摘要
We recently reported in the phase 3 PANAMO trial that selectively blocking complement 5a (C5a) with vilobelimab led to improved survival in critically ill COVID-19 patients. C5a is an important contributor to the innate immune system and can also activate the coagulation system. High C5a levels have been reported in severely ill COVID-19 patients and correlate with disease severity and mortality. Previously, we assessed the potential benefit and safety of vilobelimab in severe COVID-19 patients. In the current substudy of the phase 2 PANAMO trial, we aim to explore the effects of vilobelimab on various biomarkers of inflammation and coagulation. Between March 31 and April 24, 2020, 17 patients with severe COVID-19 pneumonia were enrolled in an exploratory, open-label, randomised phase 2 trial. Blood markers of complement, endothelial activation, epithelial barrier disruption, inflammation, neutrophil activation, neutrophil extracellular trap (NET) formation and coagulopathy were measured using enzyme-linked immunosorbent assay (ELISA) or utilizing the Luminex platform. During the first 15 days after inclusion, change in biomarker concentrations between the two groups were modelled with linear mixed-effects models with spatial splines and compared. Eight patients were randomized to vilobelimab treatment plus best supportive care (BSC) and nine patients were randomized to BSC only. A significant decrease over time was seen in the vilobelimab plus BSC group for C5a compared to the BSC only group (p < 0.001). ADAMTS13 levels decreased over time in the BSC only group compared to the vilobelimab plus BSC group (p < 0.01) and interleukin-8 (IL-8) levels were statistically more suppressed in the vilobelimab plus BSC group compared to the BSC group (p = 0.03). Our preliminary results show that C5a inhibition decreases the inflammatory response and hypercoagulability, which likely explains the beneficial effect of vilobelimab in severe COVID-19 patients. Validation of these results in a larger sample size is warranted.
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