{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T04:19:50Z","timestamp":1781929190872,"version":"3.54.5"},"reference-count":17,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,10,19]],"date-time":"2024-10-19T00:00:00Z","timestamp":1729296000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,10,19]],"date-time":"2024-10-19T00:00:00Z","timestamp":1729296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Respir Res"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>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 PI3K\u03b4 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>This randomised, double-blind, placebo-controlled, two-way crossover study comprised two 28-day treatment periods separated by a 28-day washout. Patients (<jats:italic>N<\/jats:italic>\u2009=\u200944) 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 [PIP<jats:sub>3<\/jats:sub>]), pharmacodynamic evaluations such as airflow obstruction, and hyperinflation, and to identify biomarker(s) of drug response using proteomics and transcriptomics.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>CHF6523 plasma pharmacokinetics were characterised by an early maximum concentration (C<jats:sub>max<\/jats:sub>), reached 15 and 10\u00a0min after dosing on Days 1 and 28, respectively, followed by a rapid decline. Systemic exposure on Day 28 showed limited accumulation, with ratios\u2009&lt;\u20091.6 for C<jats:sub>max<\/jats:sub> and area under the curve from 0 to 12\u00a0h 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 PIP<jats:sub>3<\/jats:sub> (29.5% reduction vs. placebo; adjusted ratio 0.705 [0.580, 0.856]; <jats:italic>p<\/jats:italic>\u2009=\u20090.001), 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>These data, together with those from other PI3K inhibitors, suggest that PI3K\u03b4 is not a suitable pathway for the management of COPD, as the achieved target engagement did not translate into any pharmacodynamic anti-inflammatory effect.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>ClinicalTrials.gov (NCT04032535); posted 23rd July 2019.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12931-024-02999-5","type":"journal-article","created":{"date-parts":[[2024,10,19]],"date-time":"2024-10-19T12:02:50Z","timestamp":1729339370000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["CHF6523 data suggest that the phosphoinositide 3-kinase delta isoform is not a suitable target for the management of COPD"],"prefix":"10.1186","volume":"25","author":[{"given":"Mirco","family":"Govoni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Bassi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Girardello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Germano","family":"Lucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Rony","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00e9mi","family":"Charretier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry","family":"Galkin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Laura","family":"Faietti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Pioselli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Modafferi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Benfeitas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Bonatti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Miglietta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frauke","family":"Pedersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Marie","family":"Kirsten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Michael","family":"Beeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Kornmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Korn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Ludwig-Sengpiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Watz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,19]]},"reference":[{"key":"2999_CR1","unstructured":"Global Initiative for Chronic Obstructive Lung Disease. 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Participants gave written informed consent to participate in the study before taking part.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"MG, MBa, GL, FR, RC, DG, MLF, BP, RB, and DM are employees of Chiesi, the sponsor of this study, LG was engaged as a consultant by Chiesi, and GM and MBo were employees of Chiesi at the time the study was conducted.\u00a0JC declares a contract and payment to the Babraham Institute for analysis of sputum PIP<sub>3<\/sub> by mass spectrometry. Outside the scope of the manuscript, he has no conflicts to disclose.\u00a0FP has no other conflicts to disclose.\u00a0AMK declares that her employer was contracted for the clinical work in this study. She has no other conflicts to disclose.\u00a0KMB declares consulting fees from Berlin Chemie, Sanofi, Bosch Healthcare, and Clario, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Berlin Chemie, GlaxoSmithKline, AstraZeneca, Sanofi, and Orion, and participation on a data safety monitoring board or advisory board for Chiesi and GlaxoSmithKline, all outside the scope of the current manuscript.\u00a0OK declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca and Novartis, and participation on a data safety monitoring board or advisory board for Sanofi, all outside the scope of the current manuscript.\u00a0SK declares consulting fees, participation in advisory boards, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Sanofi, all outside the scope of the current manuscript.\u00a0ALS has no other conflicts to disclose.\u00a0HW declares that his employer was contracted for the clinical work in this study. Outside the scope of the current manuscript he declares consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, support for attending meetings and\/or travel, and participation on a data safety monitoring board or advisory board, all for AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Sanofi. In addition, he is a speaker in COPD for the German Center for Lung Research.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"380"}}