Astegolimab is a fully human immunoglobulin G2 monoclonal antibody (mAb) that binds to the ST2 receptor and blocks the interleukin-33 signaling. It was evaluated in patients with uncontrolled severe asthma in the Phase 2b study (Zenyatta) at doses of 70, 210, 490 mg subcutaneous every 4 weeks (Q4W) for 52 weeks. This work aimed to characterize astegolimab pharmacokinetics, identify influential covariates contributing to its inter-individual variability, and make a descriptive assessment of the exposure-response relationships. A population pharmacokinetic model was developed using data from 368 patients in the Zenyatta study. Predicted average steady-state concentration was used in the subsequent exposure-response analyses, which evaluated efficacy (asthma exacerbation rate) and biomarker endpoints including forced expiratory volume in 1 second, fraction exhaled nitric oxide, blood eosinophils, and soluble ST2. A two-compartment disposition model with first-order elimination and first-order absorption best described the astegolimab pharmacokinetics. The relative bioavailability for the 70 mg dose was 15.3% lower. Baseline body weight, estimated glomerular filtration rate, and eosinophils were statistically correlated with pharmacokinetic parameters, but only body weight had a clinically meaningful influence on the steady-state exposure (ratios exceeding 0.8-1.25). The exposure-response of efficacy and biomarkers were generally flat with a weak trend in favor of the highest dose/exposure. This study characterized astegolimab pharmacokinetics in patients with asthma and showed typical pharmacokinetic behavior as a mAb-based drug. The exposure-response analyses suggested the highest dose tested in the Zenyatta study (490 mg Q4W) performed close to the maximum effect, and no additional response may be expected above it.

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