Effects of anumigilimab, an anti–G-CSF receptor mAb, after segmental LPS challenge: A Phase 1b trial in healthy volunteers

BACKGROUND: Acute respiratory distress syndrome (ARDS) is characterized by increased alveolar-capillary permeability and neutrophil-driven inflammation. Anumigilimab, a novel, fully human, monoclonal antibody, competitively antagonizes the granulocyte colony-stimulating factor (G-CSF) receptor. This trial aimed to assess its potential in modulating pulmonary inflammation induced by segmental lipopolysaccharide (LPS) challenge. METHODS: In this randomized, double-blind, placebo-controlled Phase 1b trial (NCT05653713), healthy adults were randomized 1:1 to receive a single intravenous dose of anumigilimab 0.6 mg/kg or placebo (0.9% saline), followed by LPS challenge on Day 3. Biomarkers were measured in bronchoalveolar lavage (BAL) and blood before and after LPS challenge. The primary endpoint was the percentage reduction from baseline in mean absolute neutrophil cell count in BAL following LPS challenge. Secondary endpoints included additional BAL biomarkers of neutrophilic inflammation and tissue injury. Pharmacokinetics, pharmacodynamics, and safety were also assessed. RESULTS: Participants were randomly assigned to anumigilimab (n = 23) or placebo (n = 22). LPS challenge induced expected increases in BAL neutrophils and inflammatory biomarkers, with no significant difference between groups. Target engagement was confirmed by elevated plasma and BAL G-CSF concentrations and transient reductions in peripheral neutrophil counts following anumigilimab administration. Pharmacokinetic/pharmacodynamic parameters were consistent with prior clinical data. Anumigilimab was well tolerated; mild transient neutropenia occurred in four participants treated, with no serious adverse events. CONCLUSIONS: While anumigilimab had an acceptable safety profile in healthy volunteers, and favorable pharmacokinetic/pharmacodynamic characteristics, it did not attenuate LPS-induced neutrophilic inflammation. Further preclinical investigations are warranted before advancing its clinical development in ARDS.