Clinical Trial

. 2022 Nov 15;26(1):355.

doi: 10.1186/s13054-022-04204-9.

Safety, efficacy, and pharmacokinetics of gremubamab (MEDI3902), an anti-Pseudomonas aeruginosa bispecific human monoclonal antibody, in P. aeruginosa-colonised, mechanically ventilated intensive care unit patients: a randomised controlled trial

Jean Chastre^#¹, Bruno François², Marc Bourgeois³, Apostolos Komnos⁴, Ricard Ferrer⁵, Galia Rahav⁶, Nicolas De Schryver⁷, Alain Lepape⁸, Iftihar Koksal⁹, Charles-Edouard Luyt¹⁰, Miguel Sánchez-García¹¹, Antoni Torres¹², Philippe Eggimann¹³, Despoina Koulenti^{14

15}, Thomas L Holland¹⁶, Omar Ali¹⁷, Kathryn Shoemaker^{17

18}, Pin Ren¹⁸, Julien Sauser¹⁹, Alexey Ruzin¹⁷, David E Tabor¹⁷, Ahmad Akhgar²⁰, Yuling Wu²⁰, Yu Jiang²⁰, Antonio DiGiandomenico¹⁷, Susan Colbert²¹, Drieke Vandamme²², Frank Coenjaerts²³, Surbhi Malhotra-Kumar²⁴, Leen Timbermont²⁴, Antonio Oliver²⁵, Olivier Barraud²⁶, Terramika Bellamy¹⁷, Marc Bonten^{23

27}, Herman Goossens²⁴, Colin Reisner^{18

28}, Mark T Esser¹⁷, Hasan S Jafri^#^{29

30}; COMBACTE-MAGNET EVADE Study Group

Collaborators, Affiliations

Collaborators

COMBACTE-MAGNET EVADE Study Group:
Michael Joannidis, Walter Klimscha, Elisabeth De Waele, Jacques Devriendt, Vincent Huberlant, Pieter Depuydt, Sam Van Boxstael, Mladen Peric, Jasminka Kopic, Michal Hanauer, Tomas Hruby, Vladimir Sramek, Petr Svoboda, Tomas Vymazal, Martin Novacek, Djillali Annane, Jean-Paul Mira, Bertrand Souweine, Pierre-François Dequin, Ferhat Meziani, François Stephan, Saadalla Nseir, Sebastien Gibot, Carole Schwebel, Gaetan Plantefeve, Jean-Luc Diehl, Christian Richard, Christian Lamer, Kada Klouche, Samir Jaber, Epaminondas Zakynthinos, Georgios Filntisis, Spyros Zakynthinos, Antonia Koutsoukou, Georgios Saroglou, Charikleia Nikolaou, Glykeria Vlachogianni, Ioannis Pnevmatikos, Konstantinos Mandragos, Ildiko Kremer, Zsolt Dezso Rozgonyi, Zsuzsa Marjanek, Ignacio Martin-Loeches, Pierre Singer, Vernon Van Heerden, Yehuda Carmeli, Pedro Povoa, Antonio Alvarez Seoane, Pedro Moura, Filipe Gonzalez, Paula Ramirez, Antonio Torres Marti, Ricard Ferrer Roca, Lorena Oteiza, Dolores Escudero, Enrique Piacentini, Paula Vera, Luis Tamayo, Miguel Angel Gonzalez Gallego, Borja Suberviola Canas, Iglesias Figueira, Rafael Leon, Volkan Korten, Murat Akova, Duncan Wyncoll, Tony Whitehouse, Phil Hopkins, Malcolm Sim, Yoav Golan, Marcus Zervos, Jose Vazquez, Kartikeya Cherabuddi, George Smulian, Nadine Rouphael, James Welker, Mathew Sims, David Van Duin, Todd McCarthy, Christopher Polk

Affiliations

¹ Service de Médecine Intensive Réanimation, Institut de Cardiologie, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Sorbonne University, 47-83 Bd de l'Hôpital, 75651, Paris, France. jean.chastre@gmail.com.
² Réanimation Polyvalente and Inserm CIC 1435 & UMR 1092, CHU, Limoges, France.
³ AZ Sint-Jan Brugge-Oostende AV, Brugge, Belgium.
⁴ General Hospital of Larissa, Larissa, Greece.
⁵ SODIR-VHIR Research Group, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
⁶ Chaim Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
⁷ Clinique Saint-Pierre, Ottignies, Belgium.
⁸ Hospices Civils de Lyon Hôpital Lyon Sud, Lyon, France.
⁹ Faculty of Medicine, Trabzon and Acibadem University Faculty of Medicine, Karadeniz Technical University, Istanbul, Turkey.
¹⁰ Service de Médecine Intensive Réanimation, Institut de Cardiologie, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Sorbonne University, 47-83 Bd de l'Hôpital, 75651, Paris, France.
¹¹ Critical Care Department, Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain.
¹² Servei de Pneumologia, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERES, ICREA, Barcelona, Spain.
¹³ Department of Locomotor Apparatus, Centre Hospitalier Universitaire Vaudois CHUV, Lausanne, Switzerland.
¹⁴ The University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
¹⁵ 2nd Critical Care Department, Attikon University Hospital, National and Kapodistrian, University of Athens, Athens, Greece.
¹⁶ Duke Clinical Research Institute, Durham, NC, USA.
¹⁷ Clinical Research and Development, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca Biopharmaceuticals, One MedImmune Way, Gaithersburg, MD, 20878, USA.
¹⁸ Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
¹⁹ Infection Control Program, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.
²⁰ Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
²¹ Oncology, US SM&M, AstraZeneca, Wilmington, NC, USA.
²² Inserm CIC 1435, CHU, Limoges, France.
²³ Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
²⁴ Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
²⁵ Servicio de Microbiología y Unidad de Investigación, Hospital Universitari Son Espases, Institut d'Investigació Sanitaria Illes Balears, Palma, Spain.
²⁶ INSERM U1092, Centre Hospitalier Universitaire de Limoges, Université Limoges, Limoges, France.
²⁷ Julius Center for Health Science and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
²⁸ DevPro Biopharma, Basking Ridge, NJ, USA.
²⁹ Clinical Research and Development, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca Biopharmaceuticals, One MedImmune Way, Gaithersburg, MD, 20878, USA. hasan.jafri.md@gmail.com.
³⁰ Late-Stage Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA. hasan.jafri.md@gmail.com.

^# Contributed equally.

PMID: 36380312
PMCID: PMC9666938
DOI: 10.1186/s13054-022-04204-9

Clinical Trial

Safety, efficacy, and pharmacokinetics of gremubamab (MEDI3902), an anti-Pseudomonas aeruginosa bispecific human monoclonal antibody, in P. aeruginosa-colonised, mechanically ventilated intensive care unit patients: a randomised controlled trial

Jean Chastre et al. Crit Care. 2022.

. 2022 Nov 15;26(1):355.

doi: 10.1186/s13054-022-04204-9.

Authors

Collaborators

COMBACTE-MAGNET EVADE Study Group:
Michael Joannidis, Walter Klimscha, Elisabeth De Waele, Jacques Devriendt, Vincent Huberlant, Pieter Depuydt, Sam Van Boxstael, Mladen Peric, Jasminka Kopic, Michal Hanauer, Tomas Hruby, Vladimir Sramek, Petr Svoboda, Tomas Vymazal, Martin Novacek, Djillali Annane, Jean-Paul Mira, Bertrand Souweine, Pierre-François Dequin, Ferhat Meziani, François Stephan, Saadalla Nseir, Sebastien Gibot, Carole Schwebel, Gaetan Plantefeve, Jean-Luc Diehl, Christian Richard, Christian Lamer, Kada Klouche, Samir Jaber, Epaminondas Zakynthinos, Georgios Filntisis, Spyros Zakynthinos, Antonia Koutsoukou, Georgios Saroglou, Charikleia Nikolaou, Glykeria Vlachogianni, Ioannis Pnevmatikos, Konstantinos Mandragos, Ildiko Kremer, Zsolt Dezso Rozgonyi, Zsuzsa Marjanek, Ignacio Martin-Loeches, Pierre Singer, Vernon Van Heerden, Yehuda Carmeli, Pedro Povoa, Antonio Alvarez Seoane, Pedro Moura, Filipe Gonzalez, Paula Ramirez, Antonio Torres Marti, Ricard Ferrer Roca, Lorena Oteiza, Dolores Escudero, Enrique Piacentini, Paula Vera, Luis Tamayo, Miguel Angel Gonzalez Gallego, Borja Suberviola Canas, Iglesias Figueira, Rafael Leon, Volkan Korten, Murat Akova, Duncan Wyncoll, Tony Whitehouse, Phil Hopkins, Malcolm Sim, Yoav Golan, Marcus Zervos, Jose Vazquez, Kartikeya Cherabuddi, George Smulian, Nadine Rouphael, James Welker, Mathew Sims, David Van Duin, Todd McCarthy, Christopher Polk

Affiliations

¹ Service de Médecine Intensive Réanimation, Institut de Cardiologie, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Sorbonne University, 47-83 Bd de l'Hôpital, 75651, Paris, France. jean.chastre@gmail.com.
² Réanimation Polyvalente and Inserm CIC 1435 & UMR 1092, CHU, Limoges, France.
³ AZ Sint-Jan Brugge-Oostende AV, Brugge, Belgium.
⁴ General Hospital of Larissa, Larissa, Greece.
⁵ SODIR-VHIR Research Group, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
⁶ Chaim Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
⁷ Clinique Saint-Pierre, Ottignies, Belgium.
⁸ Hospices Civils de Lyon Hôpital Lyon Sud, Lyon, France.
⁹ Faculty of Medicine, Trabzon and Acibadem University Faculty of Medicine, Karadeniz Technical University, Istanbul, Turkey.
¹⁰ Service de Médecine Intensive Réanimation, Institut de Cardiologie, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Sorbonne University, 47-83 Bd de l'Hôpital, 75651, Paris, France.
¹¹ Critical Care Department, Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain.
¹² Servei de Pneumologia, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERES, ICREA, Barcelona, Spain.
¹³ Department of Locomotor Apparatus, Centre Hospitalier Universitaire Vaudois CHUV, Lausanne, Switzerland.
¹⁴ The University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
¹⁵ 2nd Critical Care Department, Attikon University Hospital, National and Kapodistrian, University of Athens, Athens, Greece.
¹⁶ Duke Clinical Research Institute, Durham, NC, USA.
¹⁷ Clinical Research and Development, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca Biopharmaceuticals, One MedImmune Way, Gaithersburg, MD, 20878, USA.
¹⁸ Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
¹⁹ Infection Control Program, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.
²⁰ Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
²¹ Oncology, US SM&M, AstraZeneca, Wilmington, NC, USA.
²² Inserm CIC 1435, CHU, Limoges, France.
²³ Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
²⁴ Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
²⁵ Servicio de Microbiología y Unidad de Investigación, Hospital Universitari Son Espases, Institut d'Investigació Sanitaria Illes Balears, Palma, Spain.
²⁶ INSERM U1092, Centre Hospitalier Universitaire de Limoges, Université Limoges, Limoges, France.
²⁷ Julius Center for Health Science and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
²⁸ DevPro Biopharma, Basking Ridge, NJ, USA.
²⁹ Clinical Research and Development, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca Biopharmaceuticals, One MedImmune Way, Gaithersburg, MD, 20878, USA. hasan.jafri.md@gmail.com.
³⁰ Late-Stage Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA. hasan.jafri.md@gmail.com.

^# Contributed equally.

PMID: 36380312
PMCID: PMC9666938
DOI: 10.1186/s13054-022-04204-9

Abstract

Background: Ventilator-associated pneumonia caused by Pseudomonas aeruginosa (PA) in hospitalised patients is associated with high mortality. The effectiveness of the bivalent, bispecific mAb MEDI3902 (gremubamab) in preventing PA nosocomial pneumonia was assessed in PA-colonised mechanically ventilated subjects.

Methods: EVADE (NCT02696902) was a phase 2, randomised, parallel-group, double-blind, placebo-controlled study in Europe, Turkey, Israel, and the USA. Subjects ≥ 18 years old, mechanically ventilated, tracheally colonised with PA, and without new-onset pneumonia, were randomised (1:1:1) to MEDI3902 500, 1500 mg (single intravenous dose), or placebo. The primary efficacy endpoint was the incidence of nosocomial PA pneumonia through 21 days post-dose in MEDI3902 1500 mg versus placebo, determined by an independent adjudication committee.

Results: Even if the initial sample size was not reached because of low recruitment, 188 subjects were randomised (MEDI3902 500/1500 mg: n = 16/87; placebo: n = 85) between 13 April 2016 and 17 October 2019. Out of these, 184 were dosed (MEDI3902 500/1500 mg: n = 16/85; placebo: n = 83), comprising the modified intent-to-treat set. Enrolment in the 500 mg arm was discontinued due to pharmacokinetic data demonstrating low MEDI3902 serum concentrations. Subsequently, enrolled subjects were randomised (1:1) to MEDI3902 1500 mg or placebo. PA pneumonia was confirmed in 22.4% (n = 19/85) of MEDI3902 1500 mg recipients and in 18.1% (n = 15/83) of placebo recipients (relative risk reduction [RRR]: - 23.7%; 80% confidence interval [CI] - 83.8%, 16.8%; p = 0.49). At 21 days post-1500 mg dose, the mean (standard deviation) serum MEDI3902 concentration was 9.46 (7.91) μg/mL, with 80.6% (n = 58/72) subjects achieving concentrations > 1.7 μg/mL, a level associated with improved outcome in animal models. Treatment-emergent adverse event incidence was similar between groups.

Conclusions: The bivalent, bispecific monoclonal antibody MEDI3902 (gremubamab) did not reduce PA nosocomial pneumonia incidence in PA-colonised mechanically ventilated subjects. Trial registration Registered on Clinicaltrials.gov ( NCT02696902 ) on 11th February 2016 and on EudraCT ( 2015-001706-34 ) on 7th March 2016.

Keywords: Monoclonal antibody; Pharmacokinetics; Prevention; Pseudomonas aeruginosa ventilator-associated pneumonia; Safety.

PubMed Disclaimer

Conflict of interest statement

Jean Chastre received personal fees during the conduct of the study from COMBACTE-MAGNET, personal fees from outside of the submitted work from Aridis, Bayer, Inotrem, Shionogi, and Tigenix/Takeda, and grants from AstraZeneca/Medimmune. Bruno François consulted for AM-Pharma, Aridis, Enlivex, GSK, and Inotrem and was part of an adjudication committee for Takeda. Ricard Ferrer received fees for conferences from BD, Grifols, MSD, and Pfizer. Alain Lepape received personal fees outside of the study from Fresenius and Tigenix/Takeda (DSMD committee). Iftihar Koksal has served on advisory boards for Abbvie, MSD, Pfizer, Gilead, GSK, and Roche; lectures: Abbvie, Gilead, Pfizer, and MSD. Charles-Edouard Luyt received fees from Bayer Healthcare, ThermoFisher Brahms, Biomérieux, Faron, Carmat, Aerogen, and Merck Sharp & Dohme outside of the submitted work. Miguel Sánchez-García received funding for speaker fees from Biotest AG, Pfizer, Merck, Sharp & Dohme, AstraZeneca, Orion, and Cepheid; for consulting fees from Bayer, GlaxoSmithKline, Pfizer, and Masimo; for research grants from the European Union, 7th Framework Programme IMI, H2020; was part of an adjudication committee for Takeda. Antoni Torres has served on advisory boards for Pfizer, MSD, Biomérieux, Menarini, Chiesi, and Jansen; lectures: Pfizer and MSD; grants: Bayer, AstraZeneca, and Cardeas. Despoina Koulenti was part of the adjudication committee of EVADE. Thomas L. Holland consulted for Basilea Pharmaceutica, Genentech, and Motif Bio and took part in a Scientific Advisory Board for Motif Bio. Antonio Oliver received grants from and participated as a speaker and in advisory boards for Pfizer, MSD, and Shionogi. Olivier Barraud received speaker fees and/or travel grants from MSD, Pfizer, Roche, and Sanofi and has been a consultant to bioMérieux and Mylan. Herman Goossens received grants from European Union IMI Grant (in collaboration with Novartis). Omar Ali, Ahmad Akhgar, Pin Ren, Terramika Bellamy, Colin Reisner, Alexey Ruzin and Hasan S. Jafri were employees of AstraZeneca during the conduct of the study and hold shares in the company. Kathryn Shoemaker, David E. Tabor, Yuling Wu, Yu Jiang, Antonio DiGiandomenico, Susan Colbert and Mark Esser are employees of AstraZeneca and hold shares in the company. Marc Bourgeois, Apostolos Komnos, Galia Rahav, Nicolas De Schryver, Drieke Vandamme, Surbhi Malhotra-Kumar, Philippe Eggimann, Julien Sauser Frank Coenjaerts, Leen Timbermont, and Marc Bonten have no conflicts of interest to disclose.

Figures

**Fig. 1**
Subject disposition. *Subjects signed informed consent

**Fig. 2**
Concentration–time profile following a single IV dose of MEDI3902 500 mg and 1500 mg in serum (a) and endotracheal aspirate (b) PK geometric mean profile. ETA = endotracheal aspirate. IV = intravenous. LLOQ = lower limit of quantification. PK = pharmacokinetic. SE = standard error

**Fig. 3**
a Mean (SE) serum MEDI3902 concentrations in subjects with or without PA pneumonia. LLOQ = lower limit of quantification. SE = standard error. b MEDI3902 area under the curve from 0 to 21 days and concentrations obtained after a single IV dose of 1500 mg in patients with and without PA pneumonia. Cmax = maximal observed concentration; C₂₁ = concentration 21 days post-dosing; AUC_0to21 = Area under the curve from 0 to 21 days post-dose

See this image and copyright information in PMC

References

1. Ramírez-Estrada S, Borgatta B, Rello J. Pseudomonas aeruginosa ventilator-associated pneumonia management. Infect Drug Resist. 2016;9:7–18. - PMC - PubMed
1. Kollef MH, Chastre J, Fagon JY, Francois B, Niederman MS, Rello J, et al. Global prospective epidemiologic and surveillance study of ventilator-associated pneumonia due to Pseudomonas aeruginosa. Crit Care Med. 2014;42(10):2178–2187. doi: 10.1097/CCM.0000000000000510. - DOI - PubMed
1. Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Clin Infect Dis. 2010;51(Suppl. 1):S81–S87. doi: 10.1086/653053. - DOI - PubMed
1. Micek ST, Wunderink RG, Kollef MH, Chen C, Rello J, Chastre J, et al. An international multicenter retrospective study of Pseudomonas aeruginosa nosocomial pneumonia: impact of multidrug resistance. Crit Care. 2015;19(1):219. doi: 10.1186/s13054-015-0926-5. - DOI - PMC - PubMed
1. Tumbarello M, De Pascale G, Trecarichi EM, Spanu T, Antonicelli F, Maviglia R, et al. Clinical outcomes of Pseudomonas aeruginosa pneumonia in intensive care unit patients. Intensive Care Med. 2013;39(4):682–692. doi: 10.1007/s00134-013-2828-9. - DOI - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

Associated data

Actions
- Search in PubMed
- Search in ClinicalTrials.gov

Grants and funding

UM1 AI104681/AI/NIAID NIH HHS/United States

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Safety, efficacy, and pharmacokinetics of gremubamab (MEDI3902), an anti-Pseudomonas aeruginosa bispecific human monoclonal antibody, in P. aeruginosa-colonised, mechanically ventilated intensive care unit patients: a randomised controlled trial

Collaborators

Affiliations

Safety, efficacy, and pharmacokinetics of gremubamab (MEDI3902), an anti-Pseudomonas aeruginosa bispecific human monoclonal antibody, in P. aeruginosa-colonised, mechanically ventilated intensive care unit patients: a randomised controlled trial

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous