AZD8630/AMG 104, an inhaled anti-thymic stromal lymphopoietin antibody fragment, for moderate-to-severe asthma: Phase 1 randomized controlled trial.

Abstract

AZD8630/AMG 104 is an inhaled anti-thymic stromal lymphopoietin (TSLP) antibody fragment in development for the treatment of patients with moderate-to-severe asthma. We sought to evaluate the safety, tolerability, immunogenicity, pharmacokinetics, pharmacodynamics, and target engagement of AZD8630/AMG 104 in healthy adults and adults with moderate-to-severe asthma. This was a first-in-human, 2-part, phase 1 study of AZD8630/AMG 104. Part A was a single-blind study in healthy adults evaluating single and multiple ascending doses (0.2-16 mg) inhaled once daily for up to 14 days; part B was a double-blind, randomized, placebo-controlled study in adults with moderate-to-severe asthma and elevated fractional exhaled nitric oxide (Feno; ≥30 ppb) randomized to AZD8630/AMG 104 (0.4, 2, and 8 mg) or placebo once daily for 28 days. The primary objective was safety and tolerability. Secondary and exploratory objectives included pharmacokinetics, immunogenicity, pharmacodynamics (change from baseline in Feno), and target engagement. In total, 181 participants (part A, n = 104; part B, n = 77) were randomized. AZD8630/AMG 104 showed an acceptable safety profile, with low incidence of treatment-induced antidrug antibodies (part A, n = 1; part B, n = 2), and dose-dependent pharmacokinetics. In part B, there was a statistically significant reduction in Feno in AZD8630/AMG 104 8 mg recipients versus placebo (day 28, 23%; P = .037). AZD8630/AMG 104 dosing led to a dose-dependent decrease of free TSLP levels and increased TSLP-AZD8630/AMG 104 levels in serum in all participants. AZD8630/AMG 104 was well tolerated, with pharmacokinetics suitable for once-daily dosing. Results demonstrate proof of mechanism: clinically meaningful reductions in Feno levels and evidence of target engagement. Further development of AZD8630/AMG 104 in adults with moderate-to-severe asthma is warranted.