The anti-C5a antibody vilobelimab efficiently inhibits C5a in patients with severe COVID- 19

Alexander P. J. Vlaar, Endry H. T. Lim, Sanne de Bruin, Simon Rückinger, Korinna Pilz, Matthijs C. Brouwer, Ren- Feng Guo, Leo M. A. Heunks, Matthias H. Busch, Pieter van Paassen, Niels C. Riedemann, Diederik van de Beek

https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13213

Source

Clinical and Translational Science Volume 15, Issue 4 Apr 2022, Pages 801-1086

Abstract

Recently, we reported the phase II portion of the adaptive phase II/III PANAMO trial exploring potential benefit and safety of selectively blocking C5a with the monoclonal antibody vilobelimab (IFX- 1) in patients with severe coronavirus dis-ease 2019 (COVID- 19). The potent anaphylatoxin C5a attracts neutrophils and monocytes to the infection site, causes tissue damage by oxidative radical for-mation and enzyme releases, and leads to activation of the coagulation system. Results demonstrated that C5a inhibition with vilobelimab was safe and second-ary outcomes appeared in favor of vilobelimab. We now report the pharmacoki-netic/pharmacodynamic (PK/PD) analysis of the phase II study. Between March 31 and April 24, 2020, 30 patients with severe COVID- 19 pneumonia confirmed by real- time polymerase chain reaction were randomly assigned 1:1 to receive vilobelimab plus best supportive care or best supportive care only. Samples for measurement of vilobelimab, C3a and C5a blood concentrations were taken. Vilobelimab predose (trough) drug concentrations in plasma ranged from 84,846 to 248,592 ng/ml (571 to 1674 nM) with a geometric mean of 151,702 ng/ml (1022 nM) on day 2 and from 80,060 to 200,746 ng/ml (539 to 1352 nM) with a geometric mean of 139,503 ng/ml (939 nM) on day 8. After the first vilobelimab infusion, C5a concentrations were suppressed in the vilobelimab group (median 39.70 ng/ml 4.8 nM, IQR 33.20– 45.55) as compared to the control group (median 158.53 ng/ml 19.1 nM, IQR 60.03– 200.89, p = 0.0006). The suppression was main-tained on day 8 (p = 0.001). The current PK/PD analysis shows that vilobelimab efficiently inhibits C5a in patients with severe COVID- 19.

Study Highlights

What is the current knowledge on the topic?

High concentrations of the potent anaphylatoxin C5a have been reported in patients with severe coronavirus disease 2019 (COVID- 19), and the C5a– C5aR1 sign-aling axis has been suggested to be crucial in COVID- 19 associated inflammation.

What question did this study address?

Does the anti- C5a antibody vilobelimab efficiently inhibit C5a in patients with severe COVID- 19?

What does this study add to our knowledge?

The current pharmacokinetic/pharmacodynamic analysis of the phase II part of the adaptive phase II/III PANAMO trial shows that vilobelimab efficiently inhibits C5a in patients with severe COVID- 19. Our results confirm that C5a is strongly elevated in patients with severe COVID- 19.

How might this change clinical pharmacology or translational science?

These results suggest a potential important role of C5a- inhibition for patients with severe COVID- 19. With our previous report on the clinical outcome, this underlines the need to investigate, within the currently enrolling phase III trial, whether C5a- inhibition may positively impact 28- day survival in critically ill patients with COVID- 19.