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

Background 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. Objective 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. Methods First-in-human, two-part, Phase 1 study of AZD8630/AMG 104. Part A: single-blind study in healthy adults evaluating single and multiple ascending doses (0.2–16mg) inhaled once-daily for up to 14 days; Part B: double-blind, randomized, placebo-controlled study in adults with moderate-to-severe asthma and elevated fractional exhaled nitric oxide (FeNO; ≥30ppb), randomized to AZD8630/AMG 104 (0.4, 2, and 8mg), 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. Results 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 anti-drug 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 8mg recipients versus placebo (day 28, 23%; P =0.037). 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. Conclusion 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. Clinical implication (30/30) AZD8630/AMG 104, an inhaled anti-TSLP biologic, was well tolerated, suitable for once-daily dosing, and demonstrated clinically meaningful, significant FeNO reduction supporting pharmacodynamic activity and justifying progression to dose response optimization. Capsule summary (34/35) In this first-in-human Phase 1 study, AZD8630/AMG 104, a novel inhaled anti-TSLP antibody fragment, was well tolerated. Results demonstrated proof-of-mechanism as shown by clinically meaningful reductions in FeNO levels in participants with moderate-to-severe asthma.