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: Chastre Jean , François Bruno , Bourgeois Marc , Komnos Apostolos , Ferrer Ricard , Rahav Galia , De Schryver Nicolas , Lepape Alain , Koksal Iftihar , Luyt Charles-Edouard , Sánchez-García Miguel , Torres Antoni , Eggimann Philippe , Koulenti Despoina , Holland Thomas L. , Ali Omar , Shoemaker Kathryn , Ren Pin , Sauser Julien , Ruzin Alexey , Tabor David E. , Akhgar Ahmad , Wu Yuling , Jiang Yu , DiGiandomenico Antonio , Colbert Susan , Vandamme Drieke , Coenjaerts Frank , Malhotra-Kumar Surbhi , Timbermont Leen , Oliver Antonio , Barraud Olivier , Bellamy Terramika , Bonten Marc , Goossens Herman , Reisner Colin , Esser Mark T. , Jafri Hasan S. ,   The COMBACTE-MAGNET EVADE Study Group, Joannidis Michael , Klimscha Walter , De Waele Elisabeth , Devriendt Jacques , Huberlant Vincent , Depuydt Pieter , Van Boxstael Sam , Peric Mladen , Kopic Jasminka , Hanauer Michal , Hruby Tomas , Sramek Vladimir , Svoboda Petr , Vymazal Tomas , Novacek Martin , Annane Djillali , Mira Jean-Paul , Souweine Bertrand , Dequin Pierre-François , Meziani Ferhat , Stephan François , Nseir Saadalla , Gibot Sebastien , Schwebel Carole , Plantefeve Gaetan , Diehl Jean-Luc , Richard Christian , Lamer Christian , Klouche Kada , Jaber Samir , Zakynthinos Epaminondas , Filntisis Georgios , Zakynthinos Spyros , Koutsoukou Antonia , Saroglou Georgios , Nikolaou Charikleia , Vlachogianni Glykeria , Pnevmatikos Ioannis , Mandragos Konstantinos , Kremer Ildiko , Rozgonyi Zsolt Dezso , Marjanek Zsuzsa , Martin-Loeches Ignacio , Singer Pierre , Van Heerden Vernon , Carmeli Yehuda , Povoa Pedro , Seoane Antonio Alvarez , Moura Pedro , Gonzalez Filipe , Ramirez Paula , Marti Antonio Torres , Roca Ricard Ferrer , Oteiza Lorena , Escudero Dolores , Piacentini Enrique , Vera Paula , Tamayo Luis , Gallego Miguel Angel Gonzalez , Canas Borja Suberviola , Figueira Iglesias , Leon Rafael , Korten Volkan , Akova Murat , Wyncoll Duncan , Whitehouse Tony , Hopkins Phil , Sim Malcolm , Golan Yoav , Zervos Marcus , Vazquez Jose , Cherabuddi Kartikeya , Smulian George , Rouphael Nadine , Welker James , Sims Mathew , Van Duin David , McCarthy Todd , Polk Christopher 
Published: November 2022

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.