Pharmacokinetic analysis of vilobelimab, anaphylatoxin C5a and antidrug antibodies in PANAMO: a phase 3 study in critically ill, invasively mechanically ventilated COVID-19 patients
Authors: Lim Endry H. T. , Vlaar Alexander P. J. , de Bruin Sanne , Rückinger Simon , Thielert Claus , Habel Maria , Guo Renfeng , Burnett Bruce P. , Dickinson James , Brouwer Matthijs C. , Riedemann Niels C. , van de Beek Diederik ,   the PANAMO study group, Witzenrath Martin , van Paassen Pieter , Heunks Leo M. A. , Mourvillier Bruno , Brouwer Matthijs C. , Tuinman Pieter R. , Saraiva José Francisco K. , Marx Gernot , Lobo Suzana M. , Boldo Rodrigo , Simon-Campos Jesus A. , Cornet Alexander D. , Grebenyuk Anastasia , Engelbrecht Johannes M. , Mukansi Murimisi , Jorens Philippe G. , Zerbib Robert , Pilz Korinna , Riedemann Niels C. , Bulpa Pierre , Taccone Fabio S. , Hermans Greet , Diltoer Marc , Piagnerelli Michael , De Neve Nikolaas , Freire Antonio T. , Pizzol Felipe D. , Marinho Anna Karolina , Sato Victor H. , Arns da Cunha Clovis , Neuville Mathilde , Dellamonica Jean , Annane Djillali , Roquilly Antoine , Diehl Jean Luc , Schneider Francis , Mira Jean Paul , Lascarrou Jean Baptiste , Desmedt Luc , Dupuis Claire , Schwebel Carole , Thiéry Guillaume , Gründling Matthias , Berger Marc , Welte Tobias , Bauer Michael , Jaschinski Ulrich , Matschke Klaus , Mercado-Longoria Roberto , Quintana Belinda Gomez , Zamudio-Lerma Jorge Alberto , Moreno Hoyos Abril Juan , Aleman Marquez Angel , Pickkers Peter , Otterspoor Luuk , Hercilla Vásquez Luis , Seas Ramos Carlos Rafael , Peña Villalobos Alejandro , Gianella Malca Gonzalo , Chávez Victoria , Filimonov Victor , Kulabukhov Vladimir , Acharya Pinak , Timmermans Sjoerd A. M. E. G. , Busch Matthias H. , van Baarle Floor L. F. , Koning Rutger , ter Horst Liora , Chekrouni Nora , van Soest Thijs M. , Slim Marleen A. , van Vught Lonneke A. , van Amstel Rombout B. E. , Olie Sabine E. , van Zeggeren Ingeborg E. , van de Poll Marcel C. G. , Neukirchen Dorothee 
Published: June 2023

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.
Trialregistration ClinicalTrials.gov, NCT04333420. Registered 3 April 2020, https://clinicaltrials.gov/ct2/show/NCT04333420