AZD8630/AMG 104一种用于治疗中重度哮喘的吸入性抗TSLP抗体片段：一项1期随机对照试验
2026/04/28
摘要
背景：AZD8630/AMG 104是一种正在研发中的吸入性抗胸腺基质淋巴细胞生成素（TSLP）抗体片段，用于治疗中重度哮喘。
目的：评估AZD8630/AMG 104在健康成年人和中重度哮喘成年人中的安全性、耐受性、免疫原性、药代动力学、药效学及靶点结合情况。
方法：这是一项首次人体、分为两部分的1期研究。A部分： 在健康成年人中进行的单盲研究，评估单次及多次递增剂量（0.2—16mg）的AZD8630/AMG 104，每日一次吸入给药，持续最多14天。B部分： 在中重度哮喘且呼出气一氧化氮分数（FeNO）升高（≥30ppb）的成年人中进行的双盲、随机、安慰剂对照研究。参与者被随机分配接受AZD8630/AMG 104（0.4、2和8mg）或安慰剂治疗，每日一次，持续28天。主要目标： 评估安全性和耐受性。次要和探索性目标： 包括药代动力学、免疫原性、药效学（FeNO相对于基线的变化）和靶点结合情况。
结果：共有181名参与者被随机分组（A部分，n=104；B部分，n=77）。AZD8630/AMG 104显示出可接受的安全性特征，治疗诱发的抗药抗体发生率较低（A部分，n=1；B部分，n=2），并呈现剂量依赖性的药代动力学特征。在B部分中，与安慰剂组相比，接受8mg AZD8630/AMG 104治疗的参与者在第28天时FeNO水平出现统计学上的显著下降（下降23%；P=0.037）。所有参与者接受AZD8630/AMG 104给药后，血清中游离TSLP水平呈剂量依赖性下降，而TSLP-AZD8630/AMG 104复合物水平升高。
结论：AZD8630/AMG 104耐受性良好，其药代动力学特性适合每日一次给药。研究结果证实了其作用机制：FeNO水平具有临床意义的降低，并提供了靶点结合的证据。有必要在中重度哮喘成年人中进一步开发AZD8630/AMG 104。临床意义 (30/30) ：AZD8630/AMG 104作为一种吸入性抗TSLP生物制剂，耐受性良好，适合每日一次给药，并显示出具有临床意义的显著FeNO降低，这支持了其药效学活性，并证明了其进入剂量反应优化阶段的合理性。要点总结 (34/35) ：在这项首次人体1期研究中，新型吸入性抗TSLP抗体片段AZD8630/AMG 104耐受性良好。研究结果通过中重度哮喘参与者FeNO水平的临床意义降低，证明了其作用机制。
AZD8630/AMG 104, an inhaled Anti-TSLP antibody fragment, for moderate-to-severe asthma: a phase 1 randomized controlled trial
Sarah R Doffman, Davinder P S Dosanjh, Muhammad Waqas Sadiq, Yuko Matsunaga, Jason D Cooper, Geoff Edwards, Sara Asimus, Lubna Abuqayyas, Xiao-Hong Zhou, Ian C Scott, Mathias Cardner, Jane R Parnes, Kristina Kovacina, Nicholas White, Michael G Cushion, Maria G Belvisi, Dinesh Saralaya, Thomas Brown, Jutta Beier, Nestor A Molfino
Abstract
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.
背景：AZD8630/AMG 104是一种正在研发中的吸入性抗胸腺基质淋巴细胞生成素（TSLP）抗体片段，用于治疗中重度哮喘。
目的：评估AZD8630/AMG 104在健康成年人和中重度哮喘成年人中的安全性、耐受性、免疫原性、药代动力学、药效学及靶点结合情况。
方法：这是一项首次人体、分为两部分的1期研究。A部分： 在健康成年人中进行的单盲研究，评估单次及多次递增剂量（0.2—16mg）的AZD8630/AMG 104，每日一次吸入给药，持续最多14天。B部分： 在中重度哮喘且呼出气一氧化氮分数（FeNO）升高（≥30ppb）的成年人中进行的双盲、随机、安慰剂对照研究。参与者被随机分配接受AZD8630/AMG 104（0.4、2和8mg）或安慰剂治疗，每日一次，持续28天。主要目标： 评估安全性和耐受性。次要和探索性目标： 包括药代动力学、免疫原性、药效学（FeNO相对于基线的变化）和靶点结合情况。
结果：共有181名参与者被随机分组（A部分，n=104；B部分，n=77）。AZD8630/AMG 104显示出可接受的安全性特征，治疗诱发的抗药抗体发生率较低（A部分，n=1；B部分，n=2），并呈现剂量依赖性的药代动力学特征。在B部分中，与安慰剂组相比，接受8mg AZD8630/AMG 104治疗的参与者在第28天时FeNO水平出现统计学上的显著下降（下降23%；P=0.037）。所有参与者接受AZD8630/AMG 104给药后，血清中游离TSLP水平呈剂量依赖性下降，而TSLP-AZD8630/AMG 104复合物水平升高。
结论：AZD8630/AMG 104耐受性良好，其药代动力学特性适合每日一次给药。研究结果证实了其作用机制：FeNO水平具有临床意义的降低，并提供了靶点结合的证据。有必要在中重度哮喘成年人中进一步开发AZD8630/AMG 104。临床意义 (30/30) ：AZD8630/AMG 104作为一种吸入性抗TSLP生物制剂，耐受性良好，适合每日一次给药，并显示出具有临床意义的显著FeNO降低，这支持了其药效学活性，并证明了其进入剂量反应优化阶段的合理性。要点总结 (34/35) ：在这项首次人体1期研究中，新型吸入性抗TSLP抗体片段AZD8630/AMG 104耐受性良好。研究结果通过中重度哮喘参与者FeNO水平的临床意义降低，证明了其作用机制。
（北京朝阳医院呼吸与危重症医学科 顾宪民 摘译 中日友好医院呼吸与危重症医学科 林江涛 审校）
（J Allergy Clin Immunol. 2026 Apr 20:S0091-6749(26)00262-9. doi: 10.1016/j.jaci.2026.03.026.）
AZD8630/AMG 104, an inhaled Anti-TSLP antibody fragment, for moderate-to-severe asthma: a phase 1 randomized controlled trial
Sarah R Doffman, Davinder P S Dosanjh, Muhammad Waqas Sadiq, Yuko Matsunaga, Jason D Cooper, Geoff Edwards, Sara Asimus, Lubna Abuqayyas, Xiao-Hong Zhou, Ian C Scott, Mathias Cardner, Jane R Parnes, Kristina Kovacina, Nicholas White, Michael G Cushion, Maria G Belvisi, Dinesh Saralaya, Thomas Brown, Jutta Beier, Nestor A Molfino
Abstract
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.
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