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

Endry H T Lim; Alexander P J Vlaar; Sanne de Bruin; Simon Rückinger; Claus Thielert; Maria Habel; Renfeng Guo; Bruce P Burnett; James Dickinson; Matthijs C Brouwer; Niels C Riedemann; Diederik van de Beek; PANAMO study group

doi:10.1186/s40635-023-00520-8

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 Med Exp. 2023 Jun 19;11(1):37. doi: 10.1186/s40635-023-00520-8.

Authors

Collaborators

PANAMO study group:
Martin Witzenrath, Pieter van Paassen, Leo M A Heunks, Bruno Mourvillier, Matthijs C Brouwer, Pieter R Tuinman, José Francisco K Saraiva, Gernot Marx, Suzana M Lobo, Rodrigo Boldo, Jesus A Simon-Campos, Alexander D Cornet, Anastasia Grebenyuk, Johannes M Engelbrecht, Murimisi Mukansi, Philippe G Jorens, Robert Zerbib, Korinna Pilz, Niels C Riedemann, Pierre Bulpa, Fabio S Taccone, Greet Hermans, Marc Diltoer, Michael Piagnerelli, Nikolaas De Neve, Antonio T Freire, Felipe D Pizzol, Anna Karolina Marinho, Victor H Sato, Clovis Arns da Cunha, Mathilde Neuville, Jean Dellamonica, Djillali Annane, Antoine Roquilly, Jean Luc Diehl, Francis Schneider, Jean Paul Mira, Jean Baptiste Lascarrou, Luc Desmedt, Claire Dupuis, Carole Schwebel, Guillaume Thiéry, Matthias Gründling, Marc Berger, Tobias Welte, Michael Bauer, Ulrich Jaschinski, Klaus Matschke, Roberto Mercado-Longoria, Belinda Gomez Quintana, Jorge Alberto Zamudio-Lerma, Juan Moreno Hoyos Abril, Angel Aleman Marquez, Peter Pickkers, Luuk Otterspoor, Luis Hercilla Vásquez, Carlos Rafael Seas Ramos, Alejandro Peña Villalobos, Gonzalo Gianella Malca, Victoria Chávez, Victor Filimonov, Vladimir Kulabukhov, Pinak Acharya, Sjoerd A M E G Timmermans, Matthias H Busch, Floor L F van Baarle, Rutger Koning, Liora Ter Horst, Nora Chekrouni, Thijs M van Soest, Marleen A Slim, Lonneke A van Vught, Rombout B E van Amstel, Sabine E Olie, Ingeborg E van Zeggeren, Marcel C G van de Poll, Dorothee Neukirchen

Affiliations

¹ Department of Intensive Care Medicine, Amsterdam UMC Location University of Amsterdam, AMC Room C3-421, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. e.lim@amsterdamumc.nl.
² Department of Neurology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands. e.lim@amsterdamumc.nl.
³ Department of Intensive Care Medicine, Amsterdam UMC Location University of Amsterdam, AMC Room C3-421, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
⁴ Metronomia Clinical Research GmbH, Munich, Germany.
⁵ InflaRx, Munich, Germany.
⁶ InflaRx, Jena, Germany.
⁷ InflaRx Pharmaceuticals Inc, Ann Arbor, MI, USA.
⁸ Department of Neurology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.

Abstract

Background: Vilobelimab, 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.

Results: From 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.

Conclusions: This analysis shows that vilobelimab efficiently inhibits C5a in critically ill COVID-19 patients. There was no evidence of immunogenicity associated with vilobelimab treatment. Trial registration ClinicalTrials.gov, NCT04333420. Registered 3 April 2020, https://clinicaltrials.gov/ct2/show/NCT04333420.

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

Associated data

ClinicalTrials.gov/NCT04333420