Efficacy and Safety of CHF6001, A Novel Inhaled PDE4 Inhibitor in COPD: The Pioneer Dose Finding Study

Singh, Dave; Nandeuil, Marie Anna; Pigeon-Francisco, C.; Emirova, Aida; Santoro, Debora; Biondaro, Sonia; Cohuet, Géraldine; Govoni, Mirco; Petruzzelli, Stefano

doi:10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a4529

Cited by 3 publications

(2 citation statements)

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“…[5][6][7] PDE4 regulates cAMP concentrations and is involved in inflammatory cell activation; consequently, inhibition has anti-inflammatory effects. [8][9][10] There is evidence to suggest that combined inhibition of PDE3 and PDE4 may have additive or synergistic effects with respect to both anti-inflammatory and bronchodilator activity given the expression of both PDE isoforms on inflammatory cells and airway smooth muscles, respectively. 11 Ensifentrine is a first-in-class inhaled dual inhibitor of PDE3 and 4.…”

Section: Introductionmentioning

confidence: 99%

A Dose-Ranging Study of the Novel Inhaled Dual PDE 3 and 4 Inhibitor Ensifentrine in Patients with COPD Receiving Maintenance Tiotropium Therapy

Ferguson¹,

Kerwin²,

Rheault³

et al. 2021

COPD

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Section: Introductionmentioning

confidence: 99%

A Dose-Ranging Study of the Novel Inhaled Dual PDE 3 and 4 Inhibitor Ensifentrine in Patients with COPD Receiving Maintenance Tiotropium Therapy

Ferguson¹,

Kerwin²,

Rheault³

et al. 2021

COPD

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“…CHF6001 is a novel PDE4 inhibitor currently in clinical development that has been specifically formulated as an inhaled extrafine formulation (i.e., mass median aerodynamic diameter ≤ 2 μm) [6], and designed to have high protein binding and rapid elimination from the systemic circulation [7] thus maximising exposure in the lung and avoiding systemic adverse effects [8]. In a 24-week dose finding study, when administered in addition to LABA therapy, CHF6001 numerically reduced the exacerbation rate in patients with chronic bronchitis, with all doses being well tolerated [9].…”

Section: Introductionmentioning

confidence: 99%

Sputum and blood transcriptomics characterisation of the inhaled PDE4 inhibitor CHF6001 on top of triple therapy in patients with chronic bronchitis

et al. 2020

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Background: Although phosphodiesterase-4 (PDE4) inhibitors have been shown to reduce COPD exacerbation rate, their biological mechanism of action is not completely elucidated at the molecular level. We aimed to characterise the whole genome gene expression profile of the inhaled PDE4-inhibitor CHF6001 on top of triple therapy in sputum cells and whole blood of patients with COPD and chronic bronchitis. Methods: Whole genome gene expression analysis was carried out by microarray in 54 patients before and after 32 days treatment with CHF6001 800 and 1600 μg and placebo twice daily (BID) in a randomised crossover study.Results: CHF6001 had a strong effect in sputum, with 1471 and 2598 significantly differentially-expressed probesets relative to placebo (p-adjusted for False Discovery Rate < 0.05) with 800 and 1600 μg BID, respectively. Functional enrichment analysis showed significant modulation of key inflammatory pathways involved in cytokine activity, pathogen-associated-pattern-recognition activity, oxidative stress and vitamin D with associated inhibition of downstream inflammatory effectors. A large number of pro-inflammatory genes coding for cytokines and matrixmetalloproteinases were significantly differentially expressed for both doses; the majority (> 87%) were downregulated, including macrophage inflammatory protein-1-alpha and 1-beta, interleukin-27-beta, interleukin-12beta, interleukin-32, tumour necrosis factor-alpha-induced-protein-8, ligand-superfamily-member-15, and matrixmetalloproteinases-7,12 and 14. The effect in blood was not significant. Conclusions: Inhaled PDE4 inhibition by CHF6001 on top of triple therapy in patients with COPD and chronic bronchitis significantly modulated key inflammatory targets and pathways in the lung but not in blood. Mechanistically these findings support a targeted effect in the lung while minimising unwanted systemic classeffects.

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Lung Deposition of Air Pollutants and Inhaled Drugs in Patients with Chronic Obstructive Pulmonary Disease (COPD) and Those on Non-Invasive Ventilation (NIV): Is It Still Challenging?

Dmitrovic,

Simonovic

2024

Pulmonary Emphysema - Recent Updates

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Chronic Obstructive Pulmonary Disease (COPD) ranks among the leading causes of mortality worldwide, particularly in low- and middle-income nations. The primary risk factors for the development of COPD are tobacco smoking and the inhalation of pollutants from both indoor and outdoor sources. The exacerbation of COPD resulting from the mentioned factors significantly affects the patient’s quality of life and is often associated with frequent hospitalizations and the potential need for mechanical ventilation. Regarding drug administration, the inhalation route is the most efficient way to deliver drugs directly to the lungs and target organs, while reducing systematic side effects. When evaluating the deposition of inhaled drugs in the lungs, the most frequently employed techniques are in vivo, scintigraphy, and functional respiratory imaging (FRI). Aside from bronchodilator therapy and corticosteroids, antibiotics, anti-inflammatory drugs, vaccines, and monoclonal antibodies are currently being studied for their potential benefits, particularly in patients receiving invasive or non-invasive mechanical ventilation.

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Efficacy and Safety of CHF6001, A Novel Inhaled PDE4 Inhibitor in COPD: The Pioneer Dose Finding Study

Cited by 3 publications

References 0 publications

A Dose-Ranging Study of the Novel Inhaled Dual PDE 3 and 4 Inhibitor Ensifentrine in Patients with COPD Receiving Maintenance Tiotropium Therapy

A Dose-Ranging Study of the Novel Inhaled Dual PDE 3 and 4 Inhibitor Ensifentrine in Patients with COPD Receiving Maintenance Tiotropium Therapy

Sputum and blood transcriptomics characterisation of the inhaled PDE4 inhibitor CHF6001 on top of triple therapy in patients with chronic bronchitis

Lung Deposition of Air Pollutants and Inhaled Drugs in Patients with Chronic Obstructive Pulmonary Disease (COPD) and Those on Non-Invasive Ventilation (NIV): Is It Still Challenging?

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