2. Academic Validation
  3. 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

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

  • Crit Care. 2022 Nov 15;26(1):355. doi: 10.1186/s13054-022-04204-9.
Jean Chastre # 1,  Bruno François 2,  Marc Bourgeois 3,  Apostolos Komnos 4,  Ricard Ferrer 5,  Galia Rahav 6,  Nicolas De Schryver 7,  Alain Lepape 8,  Iftihar Koksal 9,  Charles-Edouard Luyt 10,  Miguel Sánchez-García 11,  Antoni Torres 12,  Philippe Eggimann 13,  Despoina Koulenti 14 15,  Thomas L Holland 16,  Omar Ali 17,  Kathryn Shoemaker 17 18,  Pin Ren 18,  Julien Sauser 19,  Alexey Ruzin 17,  David E Tabor 17,  Ahmad Akhgar 20,  Yuling Wu 20,  Yu Jiang 20,  Antonio DiGiandomenico 17,  Susan Colbert 21,  Drieke Vandamme 22,  Frank Coenjaerts 23,  Surbhi Malhotra-Kumar 24,  Leen Timbermont 24,  Antonio Oliver 25,  Olivier Barraud 26,  Terramika Bellamy 17,  Marc Bonten 23 27,  Herman Goossens 24,  Colin Reisner 18 28,  Mark T Esser 17,  Hasan S Jafri # 29 30,  COMBACTE-MAGNET EVADE Study Group
Affiliations

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 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.

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