635 - Efficacy, Pharmacokinetics (PK), and Safety Profile of MEDI3902, an Anti-Pseudomonas aeruginosa Bispecific Human Monoclonal Antibody in Mechanically Ventilated Intensive Care Unit Patients; Results of the Phase 2 EVADE Study Conducted by the Public-Private COMBACTE-MAGNET Consortium in the Innovative Medicines Initiative (IMI) Program.

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Presenting Author(s)

Jean Chastre

Professor in the Medical ICU
Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, APHP Sorbonne Université
Paris, Ile-de-France, France
Disclosure: AstraZeneca (Scientific Research Study Investigator)

Co-Author(s)

BF

Bruno François

MD
CHU Limoges
Limoges, Limousin, France
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
MB

Marc Bourgeois

Intensivist
AZ Sint-Jan Brugge-Oostende AV
Brugge, West-Vlaanderen, Belgium
Disclosure: AstraZeneca (Scientific Research Study Investigator)
AK

Apostolos Komnos

Director of ICU
General Hospital of Larisa
Larissa, Larisa, Greece
Disclosure: AstraZeneca (Scientific Research Study Investigator)
RF

Ricard Ferrer

Critical Care physician
Vall d’Hebron University Hospital
Barcelona, Catalonia, Spain
Disclosure: Shionogi B.V. (Advisor or Review Panel member)
GR

Galia Rahav

Head of Infectious Disease Unit
Sheba Medical Center and Tel Aviv University
Ramat Gan, HaMerkaz, Israel
Disclosure: AstraZeneca (Scientific Research Study Investigator)
ND

Nicolas De Schryver

Critical Care physician
Clinique Saint-Pierre
Ottignies, Brabant Wallon, Belgium
Disclosure: AstraZeneca (Scientific Research Study Investigator)
AL

Alain Lepape

Critical Care physician
Centre Hospitalier Lyon Sud, Hospices Civils de Lyon
Lyon, Rhone-Alpes, France
Disclosure: AstraZeneca (Scientific Research Study Investigator)
IK

Iftihar Koksal

Prof. MD
Acibadem University
Istanbul, Istanbul, Turkey
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
CHARLES-EDOUARD LUYT

Professor in the Medical ICU
Assistance publique hopitaux de Paris
Paris, Ile-de-France, France
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
MS

Miguel Sanchez Garcia

Head of Department of Intensive Care
Hospital Clínico San Carlos
Madrid, Madrid, Spain
Disclosure: AstraZeneca (Scientific Research Study Investigator)
AT

Antoni Torres

Professor of Medicine
Hospital Clinic, University of Barcelona, IDIBAPS, CIBERES
Barcelona, Catalonia, Spain
Disclosure: AstraZeneca (Scientific Research Study Investigator)
Thomas L. Holland

Associate Professor, Department of Medicine, Division of Infectious Diseases
Duke University Medical Center
Durham, NC
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
OA

Omar Ali

Associate Director
AstraZeneca
Gaithersburg, Maryland
Disclosure: AstraZeneca (Employee)
KS

Kathryn Shoemaker

Senior Principal Statistician
Biometrics, Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA
Gaithersburg, Maryland
Disclosure: AstraZeneca (Employee)
PR

Pin Ren

Statistician
AstraZeneca
Gaithersburg, Maryland
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
AR

Alexey Ruzin

Principal Scientist
AstraZeneca
Gaithersburg, Maryland
Disclosure: AstraZeneca (Employee, Shareholder)
YJ

Yu Jiang

PK Scientist
AstraZeneca
Gaithersburg, Maryland
Disclosure: AstraZeneca (Employee)
SC

Susan Colbert

Clinical Program Manager
Astrazeneca
Gaithersburg, Maryland
Disclosure: AstraZeneca (Employee)
DV

Drieke Vandamme

Project manager
CHU Limoges
Limoges, Limousin, France
Disclosure: AstraZeneca (Scientific Research Study Investigator)
TB

Terramika Bellamy

Director, Clinical Operations
AstraZeneca
Gaithersburg, Maryland
Disclosure: AstraZeneca (Employee)
CR

Colin Reisner

Senior VP, Late Stage Development, Respiratory Diseases
AstraZeneca
Gaithersburg, Maryland
Disclosure: AstraZeneca (Employee)
FD

Filip Dubovsky

Clinical Engagement and Policy, Chief Medical Office
AstraZeneca
Gaithersburg, Maryland
Disclosure: AstraZeneca (Employee)
HJ

Hasan S. Jafri

Senior Director, Clinical Development
AstraZeneca
Gaithersburg, Maryland
Disclosure: AstraZeneca (Employee)

Background: Pseudomonas aeruginosa (PA) pneumonia is associated with morbidity and mortality in mechanically ventilated, intensive care unit (MV ICU) patients despite best clinical care. We assessed efficacy, PK, and safety of MEDI3902 in MV ICU subjects in the placebo-controlled, randomized Phase 2 EVADE study (NCT02696902; EudraCT 2015-001706-34).

Methods: Subjects with PCR-confirmed PA colonization of the lower respiratory tract were randomized to either a single IV infusion of 1,500 mg MEDI3902 (n = 85) or placebo (n = 83). Primary Efficacy endpoint was Endpoint Adjudication Committee-determined relative risk reduction (RRR) of PA pneumonia incidence in MEDI3902 vs. placebo recipients within 21 days post dose (2-sided α = 0.2). Serum MEDI3902 PK levels were measured through 49 days post dose. Treatment-emergent adverse events (TEAEs) and serious AEs (SAEs) were assessed through 49 days post dose.

Results: Baseline characteristics were similar between groups. MEDI3902 did not meet the primary endpoint of PA pneumonia vs. placebo (22.4% vs. 18.1%; RRR -23.7%, P = 0.491). Mean serum MEDI3902 level was 9.46 µg/mL (target 1.7µg/mL) at 21 days post dose, with a t½ 5.6 days. Proportion of subjects with TEAEs was similar between groups: ≥1 TEAE (98.8% MEDI3902; 97.6% placebo); ≥1 serious; and/or ≥grade 3 severity SAE (70.6% MEDI3902; 66.3% placebo). Deaths were numerically higher, although not statistically significant (24 (28.2%) MEDI3902 vs 19 (22.9%) Placebo; RRR -23.3%, P 0.429). Post-hoc analyses suggested RRR 47% among ~70% of the study population who had baseline Procalcitonin levels < 0.55 µg/L (12.5% MEDI3902 vs 23.7% placebo; 80%CI 6.1%-69.9%; P 0.135). Similarly, RRR 83% was observed among 50% of study subjects with baseline absolute neutrophil count (ANC) of < 8170 /µL (2.8% MEDI3902 vs 17.0% placebo; 80%CI 39.5%-95.5%; P 0.038). Subjects with Procalcitonin < 0.55 µg/L and ANC < 8170/ µL also had higher serum PK exposure.

Conclusion: A single IV dose of MEDI3902 provided PK exposure above the target level but did not achieve primary efficacy endpoint of reduction in PA pneumonia. Efficacy trends were observed in subjects with lower levels of baseline inflammatory biomarkers. MEDI3902 may have a path forward in certain patient populations such as ICU patients with lower baseline inflammation.