Safety, Pharmacokinetics, and Immunogenicity of Astegolimab, an Anti-ST2 Monoclonal Antibody, in Randomized, Phase I Clinical Studies.

Astegolimab, a fully human immunoglobulin G2 monoclonal antibody, binds with high affinity to ST2, the interleukin-33 receptor, thereby blocking ST2/interleukin-33 binding and subsequent inflammatory cascades involved in inflammatory diseases. Here, we present three randomized, double-blind, placebo-controlled, Phase I studies evaluating the safety, tolerability, pharmacokinetics, and immunogenicity of single-ascending doses of astegolimab in healthy participants and patients with mild atopic asthma (NCT01928368), multiple-ascending doses in healthy participants (NCT02170337), and single-ascending doses in healthy Japanese and White adults. Overall, 152 participants were enrolled, randomized, and treated with single- or multiple-ascending doses of astegolimab (n = 112) or placebo (n = 40) subcutaneously (2.1-560 mg) or intravenously (210 or 700 mg). No deaths, serious adverse events, or discontinuations due to adverse events occurred during the studies. No clinically meaningful differences in incidence of TEAEs were observed between treatment arms. Pharmacokinetic exposure increased more than dose proportionally over 2.1-420 mg for single-ascending doses but were approximately dose proportional for single- and multiple-ascending doses ≥ 70 mg following subcutaneous administration. No pharmacokinetic differences were observed based on ethnicity between Japanese and White participants following body weight adjustments. Incidence of antidrug antibodies to astegolimab in healthy participants in the single- and multiple-ascending dose studies was 14%-23% and 33%-50% for subcutaneous and intravenous administration, respectively. Astegolimab was well tolerated in these Phase I studies with no safety concerns identified. Thus, further assessment of astegolimab in targeted patient populations was justified; the Phase IIb ALIENTO and Phase III ARNASA trials in patients with chronic obstructive pulmonary disease are ongoing.