Abstract Rationale Chronic Pseudomonas aeruginosa (PA) colonization in patients with bronchiectasis (BE) is associated with poor clinical outcomes including increased exacerbations. A proof-of-concept study evaluating gremubamab, a bispecific monoclonal antibody (mAb) targeting both Psl exopolysaccharide and the type III secretion protein (PcrV) showed clinical benefit in this group of patients. AZD0292 is a novel mAb identical to gremubamab except for inclusion of an N3Y substitution in the Fc region and is being developed for the prevention of exacerbations in patients with BE and chronic PA colonization. In preclinical studies, AZD0292 demonstrated prolonged half-life and similar functional activities (i.e. opsonophagocytic killing and anti-cytotoxicity) compared to gremubamab. Here, we report the results from the Phase I study of AZD0292 in healthy participants (NCT06311760). Methods This was a first-in-human, Phase I, randomized, single-blind, single-dose, placebo-controlled clinical study. This escalation study included 4 cohorts of participants dosed with intravenous AZD0292 (100, 300, 1000, 2000 mg) or placebo. In each cohort, 6 participants were randomized to AZD0292, and 2 were randomized to receive placebo with a total of 32 participants. The primary objective was safety and tolerability. Secondary objectives included characterization of the pharmacokinetics (PK) of AZD0292 and incidence of anti-drug antibodies (ADAs). Results There was slightly higher overall frequency of treatment-emergent adverse events (TEAEs) with AZD0292 compared to placebo arms (45.8% vs 37.5%). The most common TEAEs possibly related to AZD0292 was skin and subcutaneous tissue disorders. No fatal, serious, or severe TEAEs were reported. No clinically relevant trends were observed in vital signs, physical examinations, clinical laboratory results, or electrocardiograms. The area under the curve from time 0 to infinity (AUC0-∞) of AZD0292 increased in a dose-proportional manner, and half-life of AZD0292 ranged from 24 to 47 days across the tested doses. There was no treatment-emergent ADA. Conclusion This first-in-human study showed that intravenous dosing of AZD0292 is safe and well tolerated with a half-life up to 47 days. These results support progression to clinical evaluation of AZD0292 in patients with bronchiectasis and chronic PA colonization in a Phase 2 study. Research funded by AstraZeneca This abstract is funded by: AstraZeneca
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