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Randomized Controlled Trial
. 2024 Oct 19;25(1):380.
doi: 10.1186/s12931-024-02999-5.

CHF6523 data suggest that the phosphoinositide 3-kinase delta isoform is not a suitable target for the management of COPD

Mirco Govoni  1 , Michele Bassi  2 , Luca Girardello  3 , Germano Lucci  2 , François Rony  4 , Rémi Charretier  4 , Dmitry Galkin  5 , Maria Laura Faietti  2 , Barbara Pioselli  2 , Gloria Modafferi  2 , Rui Benfeitas  6 , Martina Bonatti  2   7 , Daniela Miglietta  2 , Jonathan Clark  8 , Frauke Pedersen  9 , Anne-Marie Kirsten  9 , Kai-Michael Beeh  10 , Oliver Kornmann  11 , Stephanie Korn  12   13 , Andrea Ludwig-Sengpiel  14 , Henrik Watz  9
Affiliations
Randomized Controlled Trial

CHF6523 data suggest that the phosphoinositide 3-kinase delta isoform is not a suitable target for the management of COPD

Mirco Govoni et al. Respir Res. .

Abstract

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.

Keywords: Gene expression profiling; Multi-omics; Phosphatidylinositol 3-kinases; Proteomics; Therapeutics.

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Conflict of interest statement

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. JC declares a contract and payment to the Babraham Institute for analysis of sputum PIP3 by mass spectrometry. Outside the scope of the manuscript, he has no conflicts to disclose. FP has no other conflicts to disclose. AMK declares that her employer was contracted for the clinical work in this study. She has no other conflicts to disclose. KMB 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. OK 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. SK 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. ALS has no other conflicts to disclose. HW 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.

Figures

Fig. 1
Fig. 1
CHF6523 plasma concentration–time profile (pharmacokinetic set). Data are mean, and were available for 40–41 patients on Day 1, and for 28–29 patients on Day 28
Fig. 2
Fig. 2
(A) Cell count and (B) target biomarkers in sputum, and (C) target biomarkers in plasma (pharmacodynamic set). Sputum cell count data available from 30 and 34 patients with CHF6523 and placebo, respectively, target biomarker sputum data available from 18–31 and 25–34 patients, and target biomarker plasma data available from 28–30 and 34–36 patients. IL, interleukin; MIP-1B, macrophage inflammatory protein 1B; MCP-1, monocyte chemoattractant protein-1; MPO, myeloperoxidase; NE, neutrophil elastase; TNF, tumour necrosis factor; CRP, C-reactive protein; SP-D, surfactant protein D
Fig. 3
Fig. 3
Change from baseline in pre-dose FEV1 (pharmacodynamic set). Data are adjusted mean and 95% confidence intervals. FEV1, forced expiratory volume in 1 s
Fig. 4
Fig. 4
Change from baseline in pre-dose FVC (pharmacodynamic set). Data are adjusted mean and 95% confidence intervals. FVC, forced vital capacity
Fig. 5
Fig. 5
Olink proteomics: Modulation of 74 proteins in sputum following administration of CHF6523 in the two Olink panels (pharmacodynamic set). FDR, false discovery rate
Fig. 6
Fig. 6
Untargeted proteomics: Modulation of proteins in sputum following administration of CHF6523 (pharmacodynamic set). FDR, false discovery rate; BPIFB1, BPI fold-containing family B member 1
Fig. 7
Fig. 7
Transcriptomics: Differential expression of genes in blood and sputum following administration of CHF6523 (pharmacodynamic set). FDR, false discovery rate
Fig. 8
Fig. 8
Multi-omic integration profiles. (A) Projection of the top two latent variables (LV). (B) Top loadings on LV1. (C) Heatmap of the top variables in LV1 in all samples. (D) Area under the receiving operating curve of each group (vs. the three others), when including all data (left) and when considering only molecular data (right). PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PIP2, phosphatidylinositol (4,5)-bisphosphate; MCP1, monocyte chemotactic protein 1
See this image and copyright information in PMC

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