CHF6523 的数据表明,磷酸肌酸 3- 激酶 delta 同工酶不是治疗慢性阻塞性肺病的合适靶点。

IF 5.8 2区 医学 Q1 Medicine Respiratory Research Pub Date : 2024-10-19 DOI:10.1186/s12931-024-02999-5
Mirco Govoni, Michele Bassi, Luca Girardello, Germano Lucci, François Rony, Rémi Charretier, Dmitry Galkin, Maria Laura Faietti, Barbara Pioselli, Gloria Modafferi, Rui Benfeitas, Martina Bonatti, Daniela Miglietta, Jonathan Clark, Frauke Pedersen, Anne-Marie Kirsten, Kai-Michael Beeh, Oliver Kornmann, Stephanie Korn, Andrea Ludwig-Sengpiel, Henrik Watz
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引用次数: 0

摘要

背景:慢性阻塞性肺病(COPD)是一种慢性炎症。尽管有有效的治疗方法,但慢性阻塞性肺病患者的病情仍在不断加重,因此需要针对新通路的抗炎治疗。激酶,尤其是磷酸肌酸 3- 激酶 (PI3K),被认为参与了慢性气道炎症,这一途径被认为是慢性阻塞性肺病中炎症和氧化应激反应的关键调节因子。CHF6523 是一种吸入式 PI3Kδ 抑制剂,临床前研究已取得积极成果。本手稿报告了一项针对慢性阻塞性肺病(慢性支气管炎表型)稳定期患者的 CHF6523 研究结果,这些患者有证据表明存在 2 型炎症:这项随机、双盲、安慰剂对照、双向交叉研究包括两个为期 28 天的治疗期,中间有 28 天的冲洗期。患者(44 人)在一个疗程中吸入 CHF6523,在另一个疗程中吸入安慰剂,每天两次。主要目的是评估CHF6523的安全性和耐受性;次要目的是评估CHF6523的药代动力学。探索性终点包括目标参与度(磷脂酰肌醇(3,4,5)-三磷酸[PIP3]的相对减少量)、药效学评估(如气流阻塞和过度充气),并利用蛋白质组学和转录组学确定药物反应的生物标志物:CHF6523的血浆药代动力学特征是早期最大浓度(Cmax),分别在用药后第1天和第28天的15分钟和10分钟达到,随后迅速下降。第 28 天的全身暴露显示出有限的蓄积,最大比值和曲线下面积从给药后 0 到 12 小时不等,第 20 天达到稳态。诱导痰 PIP3 比基线显著降低 29.7%(与安慰剂相比降低 29.5%;调整比值比为 0.705 [0.580, 0.856];p = 0.001),证实了目标参与,但这并没有转化为抗炎药效学效应,评估指标包括生物标志物和多组学。此外,尽管CHF6523的耐受性普遍良好,但95.2%的患者报告了咳嗽这一不良反应,其中大多数为轻度至中度,并在服药后一小时内缓解:这些数据以及其他 PI3K 抑制剂的数据表明,PI3Kδ 并非治疗慢性阻塞性肺病的合适途径,因为实现的目标参与并未转化为任何药效学抗炎作用:试验注册:ClinicalTrials.gov (NCT04032535);2019年7月23日发布。
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CHF6523 data suggest that the phosphoinositide 3-kinase delta isoform is not a suitable target for the management of COPD.

Background: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory condition. Given patients with COPD continue to experience exacerbations despite the availability of effective therapies, anti-inflammatory treatments targeting novel pathways are needed. Kinases, notably the phosphoinositide 3-kinases (PI3K), are thought to be involved in chronic airway inflammation, with this pathway proposed as a critical regulator of inflammation and oxidative stress response in COPD. CHF6523 is an inhaled PI3Kδ inhibitor that has shown positive preclinical results. This manuscript reports the results of a study of CHF6523 in patients with stable COPD (chronic bronchitis phenotype), and who had evidence of type-2 inflammation.

Methods: This randomised, double-blind, placebo-controlled, two-way crossover study comprised two 28-day treatment periods separated by a 28-day washout. Patients (N = 44) inhaled CHF6523 in one period, and placebo in the other, both twice daily. The primary objective was to assess the safety and tolerability of CHF6523; the secondary objective was to assess CHF6523 pharmacokinetics. Exploratory endpoints included target engagement (the relative reduction in phosphatidylinositol (3,4,5)-trisphosphate [PIP3]), pharmacodynamic evaluations such as airflow obstruction, and hyperinflation, and to identify biomarker(s) of drug response using proteomics and transcriptomics.

Results: CHF6523 plasma pharmacokinetics were characterised by an early maximum concentration (Cmax), reached 15 and 10 min after dosing on Days 1 and 28, respectively, followed by a rapid decline. Systemic exposure on Day 28 showed limited accumulation, with ratios < 1.6 for Cmax and area under the curve from 0 to 12 h post-dose, and with steady state achieved on Day 20. Target engagement was confirmed by a significant 29.7% reduction from baseline in induced sputum PIP3 (29.5% reduction vs. placebo; adjusted ratio 0.705 [0.580, 0.856]; p = 0.001), but this did not translate into an anti-inflammatory pharmacodynamic effect, as assessed through measures including biomarkers and multi-omics. Additionally, although CHF6523 was generally well-tolerated, 95.2% of patients reported cough as an adverse event, most mild to moderate and resolving within one-hour post-dose.

Conclusions: These data, together with those from other PI3K inhibitors, suggest that PI3Kδ is not a suitable pathway for the management of COPD, as the achieved target engagement did not translate into any pharmacodynamic anti-inflammatory effect.

Trial registration: ClinicalTrials.gov (NCT04032535); posted 23rd July 2019.

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来源期刊
Respiratory Research
Respiratory Research RESPIRATORY SYSTEM-
CiteScore
9.70
自引率
1.70%
发文量
314
审稿时长
4-8 weeks
期刊介绍: Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.
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