التفاصيل البيبلوغرافية
| العنوان: |
CHF6523 data suggest that the phosphoinositide 3-kinase delta isoform is not a suitable target for the management of COPD. |
| المؤلفون: |
Govoni, Mirco, Bassi, Michele, Girardello, Luca, Lucci, Germano, Rony, François, Charretier, Rémi, Galkin, Dmitry, Faietti, Maria Laura, Pioselli, Barbara, Modafferi, Gloria, Benfeitas, Rui, Bonatti, Martina, Miglietta, Daniela, Clark, Jonathan, Pedersen, Frauke, Kirsten, Anne-Marie, Beeh, Kai-Michael, Kornmann, Oliver, Korn, Stephanie, Ludwig-Sengpiel, Andrea |
| المصدر: |
Respiratory Research; 10/19/2024, Vol. 25 Issue 1, p1-13, 13p |
| مصطلحات موضوعية: |
PHOSPHATIDYLINOSITOL 3-kinases, CHRONIC obstructive pulmonary disease, GENE expression profiling, CHRONIC bronchitis, MULTIOMICS |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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