Medical Research Institute of New Zealand, Wellington, New Zealand.
Genentech, Inc, South San Francisco, Calif.
J Allergy Clin Immunol. 2021 Sep;148(3):783-789. doi: 10.1016/j.jaci.2021.02.042. Epub 2021 Mar 17.
The Janus kinase (JAK) pathway mediates the activity of many asthma-relevant cytokines, including IL-4 and IL-13. GDC-0214 is a potent, inhaled, small-molecule JAK inhibitor being developed for the treatment of asthma.
We sought to determine whether GDC-0214 reduces fractional exhaled nitric oxide (Feno), a JAK1-dependent biomarker of airway inflammation, in patients with mild asthma.
We conducted a double-blind, randomized, placebo-controlled, phase 1 proof-of-activity study in adults with mild asthma and Feno higher than 40 parts per billion (ppb). Subjects were randomized 2:1 (GDC-0214:placebo) into 4 sequential ascending-dose cohorts (1 mg once daily [QD], 4 mg QD, 15 mg QD, or 15 mg twice daily). All subjects received 4 days of blinded placebo, then 10 days of either active drug or placebo. The primary outcome was placebo-corrected percent reduction in Feno from baseline to day 14. Baseline was defined as the average Feno during the blinded placebo period. Pharmacokinetics, safety, and tolerability were also assessed.
Thirty-six subjects (mean age, 28 years; 54% females) were enrolled. Mean Feno at baseline across all subjects was 93 ± 43 ppb. At day 14, placebo-corrected difference in Feno was -23% (95% CI, -37.3 to -9) for 15 mg QD and -42% (95% CI, -57 to -27.4) for 15 mg twice daily. Higher plasma exposure was associated with greater Feno reduction. No dose-limiting adverse events, serious adverse events, or treatment discontinuations occurred. There were no major imbalances in adverse events or laboratory findings, or evidence of systemic JAK inhibition.
GDC-0214, an inhaled JAK inhibitor, caused dose-dependent reductions in Feno in mild asthma and was well tolerated without evidence of systemic toxicity.
Janus 激酶（JAK）通路介导许多与哮喘相关的细胞因子的活性，包括 IL-4 和 IL-13。GDC-0214 是一种有效的、吸入式的小分子 JAK 抑制剂，正在开发用于治疗哮喘。
我们旨在确定 GDC-0214 是否可以降低轻度哮喘患者的呼出气一氧化氮分数（Feno），这是一种依赖于 JAK1 的气道炎症生物标志物。
我们进行了一项双盲、随机、安慰剂对照、1 期活性研究，纳入了呼出气一氧化氮（Feno）高于 40 皮克/每十亿（ppb）的轻度哮喘成年患者。患者按照 2:1（GDC-0214:安慰剂）随机分为 4 个递增剂量队列（1 毫克每日 1 次[QD]、4 毫克 QD、15 毫克 QD 或 15 毫克每日 2 次）。所有患者先接受 4 天的盲法安慰剂治疗，然后接受 10 天的活性药物或安慰剂治疗。主要结局是从基线到第 14 天 Feno 的安慰剂校正百分比降低。基线定义为盲法安慰剂期间的平均 Feno。还评估了药代动力学、安全性和耐受性。
共纳入 36 名患者（平均年龄 28 岁；54%为女性）。所有患者的平均基线 Feno 为 93±43 ppb。在第 14 天，15 毫克 QD 的 Feno 安慰剂校正差异为-23%（95%CI，-37.3 至-9），15 毫克每日 2 次的 Feno 安慰剂校正差异为-42%（95%CI，-57 至-27.4）。更高的血浆暴露与更大的 Feno 降低相关。未发生剂量限制的不良事件、严重不良事件或治疗中断。不良事件或实验室检查结果无明显失衡，也没有全身 JAK 抑制的证据。
GDC-0214，一种吸入式 JAK 抑制剂，可导致轻度哮喘患者的 Feno 呈剂量依赖性降低，且耐受性良好，无全身毒性证据。
