Pharmacokinetic analysis of vilobelimab, anaphylatoxin C5a and antidrug antibodies in PANAMO: a phase 3 study in critically ill, invasively mechanically ventilated COVID-19 patients
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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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SpringerOpen
2023-06-01
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| Series: | Intensive Care Medicine Experimental |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40635-023-00520-8 |
| _version_ | 1797795948992135168 |
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| author | 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 the PANAMO study group |
| author_facet | 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 the PANAMO study group |
| author_sort | Endry H. T. Lim |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-03-13T03:25:44Z |
| format | Article |
| id | doaj.art-e86ee766afad44129031898eb17d0604 |
| institution | Directory Open Access Journal |
| issn | 2197-425X |
| language | English |
| last_indexed | 2024-03-13T03:25:44Z |
| publishDate | 2023-06-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | Intensive Care Medicine Experimental |
| spelling | doaj.art-e86ee766afad44129031898eb17d06042023-06-25T11:03:53ZengSpringerOpenIntensive Care Medicine Experimental2197-425X2023-06-0111111310.1186/s40635-023-00520-8Pharmacokinetic analysis of vilobelimab, anaphylatoxin C5a and antidrug antibodies in PANAMO: a phase 3 study in critically ill, invasively mechanically ventilated COVID-19 patientsEndry H. T. Lim0Alexander P. J. Vlaar1Sanne de Bruin2Simon Rückinger3Claus Thielert4Maria Habel5Renfeng Guo6Bruce P. Burnett7James Dickinson8Matthijs C. Brouwer9Niels C. Riedemann10Diederik van de Beek11the PANAMO study groupDepartment of Intensive Care Medicine, Amsterdam UMC Location University of AmsterdamDepartment of Intensive Care Medicine, Amsterdam UMC Location University of AmsterdamDepartment of Intensive Care Medicine, Amsterdam UMC Location University of AmsterdamMetronomia Clinical Research GmbHInflaRxInflaRxInflaRx Pharmaceuticals IncInflaRx Pharmaceuticals IncInflaRxDepartment of Neurology, Amsterdam UMC Location University of AmsterdamInflaRxDepartment of Neurology, Amsterdam UMC Location University of AmsterdamAbstract 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/NCT04333420https://doi.org/10.1186/s40635-023-00520-8PKPharmacokineticC5aComplementVilobelimabADA |
| spellingShingle | 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 the PANAMO study group 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 PK Pharmacokinetic C5a Complement Vilobelimab ADA |
| title | Pharmacokinetic analysis of vilobelimab, anaphylatoxin C5a and antidrug antibodies in PANAMO: a phase 3 study in critically ill, invasively mechanically ventilated COVID-19 patients |
| title_full | Pharmacokinetic analysis of vilobelimab, anaphylatoxin C5a and antidrug antibodies in PANAMO: a phase 3 study in critically ill, invasively mechanically ventilated COVID-19 patients |
| title_fullStr | Pharmacokinetic analysis of vilobelimab, anaphylatoxin C5a and antidrug antibodies in PANAMO: a phase 3 study in critically ill, invasively mechanically ventilated COVID-19 patients |
| title_full_unstemmed | Pharmacokinetic analysis of vilobelimab, anaphylatoxin C5a and antidrug antibodies in PANAMO: a phase 3 study in critically ill, invasively mechanically ventilated COVID-19 patients |
| title_short | Pharmacokinetic analysis of vilobelimab, anaphylatoxin C5a and antidrug antibodies in PANAMO: a phase 3 study in critically ill, invasively mechanically ventilated COVID-19 patients |
| title_sort | pharmacokinetic analysis of vilobelimab anaphylatoxin c5a and antidrug antibodies in panamo a phase 3 study in critically ill invasively mechanically ventilated covid 19 patients |
| topic | PK Pharmacokinetic C5a Complement Vilobelimab ADA |
| url | https://doi.org/10.1186/s40635-023-00520-8 |
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