A34-17 Serum Soluble ST2 and Blood Eosinophils Are Pharmacodynamic Biomarkers of Astegolimab Treatment in COPD

Rationale The efficacy and safety of astegolimab (anti-ST2 monoclonal antibody) in patients with COPD with frequent exacerbations was evaluated in two randomized, double-blind, placebo-controlled trials: Phase IIb ALIENTO (NCT05037929) and Phase III ARNASA (NCT05595642). Here we present exploratory pharmacodynamic (PD) biomarker analyses from ALIENTO and ARNASA. Methods Both trials enrolled patients with COPD and a history of exacerbations who were current/former smokers, regardless of their blood eosinophil counts (BEC) and whether they had chronic bronchitis (ALIENTO: aged 40-90 years; ARNASA: aged 40-80 years). Eligible patients were randomized 1:1:1 to receive 476 mg astegolimab subcutaneously Q2W or Q4W or placebo, added to maintenance therapy, for 52 weeks. Serum soluble ST2 (sST2) levels were measured at baseline and at Weeks 4, 24, and 52. BEC were measured at baseline and at Weeks 4, 12, 24, 36, and 52. BEC were measured using an automated hematology blood analyzer. Serum sST2 levels were determined by immunoassay (based on human ST2/IL-33R Quantikine® ELISA, with a lower limit of quantification of 3.125 ng/mL) at a central bioanalytical laboratory. Results 1301 patients were included in ALIENTO (Q2W, n = 433; Q4W, n = 437; placebo, n = 431) and 1375 were included in ARNASA (Q2W, n = 459; Q4W, n = 459; placebo, n = 457). In both studies, mean sST2 levels increased over time in the astegolimab arms, but not the placebo arms, reflecting ligand-receptor target engagement (Figure). In ALIENTO, the mean absolute change in sST2 from baseline to Week 52 was +373.5 ng/mL for Q2W, +370.1 ng/mL for Q4W, and +22.9 ng/mL for placebo. In ARNASA, mean absolute change in sST2 from baseline to Week 52 was +366.0 ng/mL for Q2W, +352.9 ng/mL for Q4W, and+2.8 ng/mL for placebo. In both studies, the mean BEC decreased over time from as early as Week 4 in the astegolimab arms (Figure). In ALIENTO, absolute mean change from baseline to Week 52 in BEC was -60 cells/µL for Q2W, -50 cells/µL for Q4W, and +10 cells/µL for placebo. In ARNASA, absolute mean change from baseline to Week 52 in BEC was -40 cells/µL for Q2W, -60 cells/µL for Q4W, and +10 cells/µL for placebo. Conclusions Based on consistent data from the ALIENTO and ARNASA studies, serum sST2 and BEC are PD biomarkers of astegolimab target engagement and mechanism of action in COPD. These findings are consistent with those from prior clinical studies of astegolimab. Figure This abstract is funded by: These studies were sponsored by F. Hoffman-La Roche Ltd/Genentech, a member of the Roche Group.