A First-in-Human, Single- and Multiple-Dose Study of APG777, a Half-Life-Extended Anti-IL-13 Monoclonal Antibody, in Healthy Volunteers.

Interleukin (IL)-13 plays a central role in Type 2 inflammation, contributing to the pathogenesis of atopic dermatitis, asthma, and related inflammatory diseases. APG777 is a novel anti-IL-13 monoclonal antibody engineered for improved pharmacokinetics and reduced dosing frequency. This first-in-human, randomized, double-blind, placebo-controlled phase 1 study evaluated the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of single and multiple subcutaneous doses of APG777 in healthy adults. Forty participants were enrolled in single ascending dose (300-1200 mg) and multiple dose (300 mg × 2) cohorts. APG777 was well tolerated, with only mild-to-moderate treatment-emergent adverse events, predominantly unrelated to the study drug. No serious or severe drug-related treatment-emergent adverse events occurred. Following single doses, APG777 exhibited dose-proportional increases in C(max) and area under the curve, with a terminal half-life ranging from 75.3 to 77.5 days across the dose range tested. Immunogenicity was low, with anti-drug antibodies detected in 23.3% of treated participants, generally without impact on pharmacokinetics or safety. APG777 led to rapid and durable inhibition of the IL-13-driven biomarkers phosphorylated signal transducer and activator of transcription 6 (pSTAT6), thymus and activation-regulated chemokine (TARC), and immunoglobulin E (IgE), with near-complete suppression of pSTAT6 observed for up to 12 months post-dose. The safety and optimized pharmacokinetic profile of APG777 supports evaluation of extended dosing intervals (every 3-6 months) and higher exposures, which could improve outcomes and reduce injection burden in patients with Type 2 inflammatory diseases including atopic dermatitis and asthma.