C103-13 A Randomized Phase 1 Study in Healthy Volunteers Investigating the Safety, Tolerability, Pharmacokinetics, and Target Engagement of AZD8965, a Novel Oral Arginase Inhibitor Under Development as a Treatment for Pulmonary Fibrosis

Abstract Rationale Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by abnormal alveolar interstitial accumulation of extracellular matrix proteins, including type I collagen. IPF is a disease with high unmet need due to limited efficacy and tolerability of currently approved anti-fibrotic therapies. AZD8965 is a novel oral inhibitor of arginase, an enzyme involved in type I collagen biosynthesis, under development as an anti-fibrotic therapy. We report initial results from a Phase I study of AZD8965 in healthy volunteers (NCT06502379). Methods We conducted a randomized, blinded, placebo-controlled clinical study in healthy volunteers (HVs). Part A was a single-ascending dose (SAD) study; Part B was a multiple-ascending dose (MAD) study with 8 days of dosing. Each SAD cohort included 6 participants randomized to AZD8965 and 2 participants randomized to placebo. Each MAD cohort included 11 participants (AZD8965, n = 8; placebo, n = 3). The primary objective was to evaluate the safety and tolerability of AZD8965. The secondary objective was to evaluate the pharmacokinetics of AZD8965. Exploratory objectives included assessment of target engagement, which was evaluated by measuring inhibition of arginase activity in plasma. Results Fifty-six and 33 HVs participated in the SAD and MAD cohorts, respectively. Adverse events were reported in 9 participants in SAD cohorts and 9 participants in MAD cohorts. All AEs were Grade 1, except for one AE (vasovagal reaction during venipuncture), which was Grade 2. All AEs resolved before the end of the study. No serious AEs or AEs leading to discontinuation were reported. No clinically relevant trends were observed in vital signs, physical examination findings, laboratory results, or electrocardiograms. Dose proportional PK and an elimination half-life of approximately 4-9 hours were observed. Target engagement was demonstrated in plasma with significant reduction from baseline in arginase activity after 8 days of dosing with AZD8965. Conclusions Oral dosing of AZD8965 for up to 8 days was well tolerated and no SAEs or AEs leading to discontinuation were reported in the doses evaluated in healthy volunteers. The observed PK characteristics support multiple daily dosing. Target engagement was demonstrated by arginase inhibition in plasma. These results support further investigation of AZD8965 as an anti-fibrotic therapy. This abstract is funded by: AstraZeneca