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, Bruno François, Marc Bourgeois, Apostolos Komnos, Ricard Ferrer, Galia Rahav, Nicolas De Schryver, Alain Lepape, İftihar Köksal, Charles‐Édouard Luyt, Miguel Sánchez García, Antoní Torres, Philippe Eggimann, Despoina Koulenti, Thomas L Holland, Omar Ali, Kathryn Shoemaker, Pin Ren, Julien Sauser, Alexey Ruzin, David E. Tabor, Ahmad Akhgar, Yuling Wu, Yu Jiang, Antonio DiGiandomenico, Susan Colbert, Drieke Vandamme, Frank E. J. Coenjaerts, Surbhi Malhotra‐Kumar, Leen Timbermont, Antonio Oliver, Olivier Barraud, Terramika Bellamy, Marc J. M. Bonten, Herman Goossens, Colin Reisner, Mark T. Esser, Hasan S. Jafri, The COMBACTE-MAGNET EVADE Study Group, Michael Joannidis, Walter Klimscha, Elisabeth De Waele, Jacques Devriendt, Vincent Huberlant, Pieter Depuydt, Sam Van Boxstael, Mladen Perić, Jasminka Kopić, Michal Hanauer, Tomas Hruby, Vladimír Šrámek, Petr Svoboda, Tomáš Vymazal, Martin Nováček, Djillali Annane, Jean‐Paul Mira, Bertrand Souweine, Pierre‐François Dequin, Ferhat Meziani, François Stéphan, Saadalla Nseir, Sébastien Gibot, Carole Schwebel, Gaëtan Plantefève, 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, Ildikó Krémer, Zsolt Dezso Rozgonyi, Zsuzsa Marjanek, Ignacio Martín‐Loeches, Pierre Singer, Vernon van Heerden, Yehuda Carmeli, Pedro Póvoa, Antonio Alvarez Seoane, Pedro Henrique de Moura, Filipe Gonzalez, Paula Ramírez, Antonio Torres Martí, Ricard Ferrer, Lorena Oteiza, D. Escudero, Enrique Piacentini, Paula Vera, Luis Tamayo, Miguel Angel Gonzalez Gallego, B. Suberviola Cañas, Iglesias Figueira
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.