吸入JAK抑制剂GDC-4379对呼出一氧化氮和炎症周围生物标志物的影响

IF 2.8 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics Pub Date : 2022-08-01 DOI:10.1016/j.pupt.2022.102133

Hubert Chen , Rebecca Kunder , Yixuan Zou , Tracy Staton , Rui Zhu , Joshua Galanter , Hallam Gugelmann , Ryan Owen , Michele A. Grimbaldeston , Joanna K. Chang , Matthew R. Durk , Avi Eliahu , Mark S. Wilson , David F. Choy , Maria Wilson , Melissa Black , Marjan Doppen , Stacey Kung , Karen Oldfield , Jenny Sparks , Irene Braithwaite

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引用次数: 2

摘要

janus激酶(JAKs)介导许多哮喘相关细胞因子的活性。GDC-0214是一种吸入小分子JAK1抑制剂，先前已被证明可减少轻度哮喘患者呼出一氧化氮(FeNO)的分数，但需要过量吸入。目的评估新型吸入型JAK抑制剂GDC-4379是否能降低FeNO和炎症外周生物标志物。本研究在轻度哮喘患者中开展了一项双盲、随机、安慰剂对照的i期研究，以评估GDC-4379的活性。参与者包括诊断为哮喘≥6个月的成年人(18 - 65岁)，1 s用力呼气量(FEV1)>70%的人预测，FeNO >40 ppb，根据需要只使用短效β激动剂药物。4个顺序，14天，递增剂量队列(10mg QD, 30mg QD, 40mg BID和80mg QD)的12名参与者每个随机2:1至GDC-4379或安慰剂。与合并安慰剂组相比，主要活动结果是FeNO至第14天的基线变化百分比(CFB)。安全性、耐受性、药代动力学和药效学生物标志物，包括血液嗜酸性粒细胞、血清CCL17和血清CCL18，也进行了评估。结果48名参与者的平均年龄为25岁，54%为女性。基线时的中位(范围)FeNO为79 (41-222)ppb。GDC-4379治疗导致FeNO的剂量依赖性降低。与安慰剂相比，FeNO至第14天的平均(95% CI) CFB百分比为:10 mg QD时为- 6 (- 43,32)，30 mg QD时为- 26 (- 53,2)，40 mg BID时为- 55 (- 78，- 32)，80 mg QD时为- 52(- 72，- 32)。还观察到血嗜酸性粒细胞和血清CCL17的剂量依赖性降低。较高的血浆药物浓度与较大的FeNO降低相对应。未发生严重不良事件。大多数ae为轻度至中度。最常见的ae是头痛和口咽痛。在80mg QD时，中性粒细胞有轻微变化，但不认为有临床意义。结论在轻度哮喘患者中，GDC-4379治疗14 d可降低FeNO水平和炎症周围生物标志物。治疗耐受性良好，没有任何主要的安全问题。澳大利亚新西兰临床试验注册:ACTRN12619000227190。

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Effects of inhaled JAK inhibitor GDC-4379 on exhaled nitric oxide and peripheral biomarkers of inflammation

Background

Janus Kinases (JAKs) mediate activity of many asthma-relevant cytokines. GDC-0214, an inhaled small molecule JAK1 inhibitor, has previously been shown to reduce fractional exhaled nitric oxide (FeNO) in patients with mild asthma, but required an excessive number of inhalations.

Aim

To assess whether GDC-4379, a new inhaled JAK inhibitor, reduces FeNO and peripheral biomarkers of inflammation.

Methods

This study assessed the activity of GDC-4379 in a double-blind, randomized, placebo-controlled, Phase 1 study in patients with mild asthma. Participants included adults (18–65y) with a diagnosis of asthma for ≥6 months, forced expiratory volume in 1 s (FEV₁)> 70% predicted, FeNO >40 ppb, using as-needed short-acting beta-agonist medication only. Four sequential, 14-day, ascending-dose cohorts (10 mg QD, 30 mg QD, 40 mg BID, and 80 mg QD) of 12 participants each were randomized 2:1 to GDC-4379 or placebo. The primary activity outcome was percent change from baseline (CFB) in FeNO to Day 14 compared to the pooled placebo group. Safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers, including blood eosinophils, serum CCL17, and serum CCL18, were also assessed.

Results

Of 48 enrolled participants, the mean age was 25 years and 54% were female. Median (range) FeNO at baseline was 79 (41–222) ppb. GDC-4379 treatment led to dose-dependent reductions in FeNO. Compared to placebo, mean (95% CI) percent CFB in FeNO to Day 14 was: −6 (−43, 32) at 10 mg QD, −26 (−53, 2) at 30 mg QD, −55 (−78, −32) at 40 mg BID and −52 (−72, −32) at 80 mg QD. Dose-dependent reductions in blood eosinophils and serum CCL17 were also observed. Higher plasma drug concentrations corresponded with greater FeNO reductions. No serious AEs occurred. The majority of AEs were mild to moderate. The most common AEs were headache and oropharyngeal pain. Minor changes in neutrophils were noted at 80 mg QD, but were not considered clinically meaningful.

Conclusions

In patients with mild asthma, 14-day treatment with GDC-4379 reduced FeNO levels and peripheral biomarkers of inflammation. Treatment was well tolerated without any major safety concerns.

Australian New Zealand Clinical Trials Registry: ACTRN12619000227190.

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来源期刊

Pulmonary pharmacology & therapeutics 医学-呼吸系统

CiteScore

6.20

自引率

0.00%

发文量

审稿时长

42 days

期刊介绍： Pulmonary Pharmacology and Therapeutics (formerly Pulmonary Pharmacology) is concerned with lung pharmacology from molecular to clinical aspects. The subject matter encompasses the major diseases of the lung including asthma, cystic fibrosis, pulmonary circulation, ARDS, carcinoma, bronchitis, emphysema and drug delivery. Laboratory and clinical research on man and animals will be considered including studies related to chemotherapy of cancer, tuberculosis and infection. In addition to original research papers the journal will include review articles and book reviews. Research Areas Include: • All major diseases of the lung • Physiology • Pathology • Drug delivery • Metabolism • Pulmonary Toxicology.