Effect of the inhaled PDE4 inhibitor CHF6001 on biomarkers of inflammation in COPD

Abstract

Background: CHF6001 is a novel inhaled phosphodiesterase-4 inhibitor. This Phase IIa study assessed the effects of CHF6001 on markers of inflammation in induced sputum and blood in patients with chronic obstructive pulmonary disease (COPD).

Methods: This was a multicentre, three-period (each 32 days), three-way, placebo-controlled, double-blind, complete-block crossover study. Eligible patients had COPD, chronic bronchitis, and were receiving inhaled triple therapy for ≥2 months. Patients received CHF6001 800 or 1600 μg, or matching placebo twice daily via multi-dose dry-powder inhaler (NEXThaler). Induced sputum was collected pre-dose on Day 1, and post-dose on Days 20, 26 and 32. Blood was sampled pre-dose on Day 1, and pre- and post-dose on Day 32.

Results: Of 61 randomised patients, 54 (88.5%) completed the study. There were no significant differences between groups for overall sputum cell count, or absolute numbers of neutrophils, eosinophils or lymphocytes. CHF6001 800 μg significantly decreased the absolute number and percentage of macrophages vs placebo. In sputum, compared with placebo both CHF6001 doses significantly decreased leukotriene B4, C-X-C motif chemokine ligand 8, macrophage inflammatory protein 1β, matrix metalloproteinase 9, and tumour necrosis factor α (TNFα). In blood, both CHF6001 doses significantly decreased serum surfactant protein D vs placebo. CHF6001 1600 μg significantly decreased TNFα ex-vivo (after incubation with lipopolysaccharide).

Conclusion: The data from this study show that CHF6001 inhaled twice daily has anti-inflammatory effects in the lungs of patients with COPD already treated with triple inhaled therapy.

Trial registration: The study is registered on ClinicalTrials.gov ( NCT03004417 ).

Keywords: Chronic obstructive pulmonary disease; Induced sputum; Inflammation; Pharmacology; Phosphodiesterase 4 inhibitors.

Conflict of interest statement

Dave Singh received personal fees from Chiesi during the conduct of this study. Outside the submitted work, he reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Glenmark, Menarini, Mundipharma, Novartis, Pfizer, Pulmatrix, Therevance, and Verona, and personal fees from Cipla, Genentech and Peptinnovate.

Kai Michael Beeh declares that no personal payments were received from any pharmaceutical entity in the past five years. He is a full time employee of insaf Respiratory Research Institute. The institution has received compensation for services on advisory boards or consulting for Ablynx, Almirall, AstraZeneca, Berlin Chemie, Boehringer, Chiesi, Cytos, Mundipharma, Novartis, Pohl Boskamp, Zentiva. The institution has received compensation for speaker activities in scientific meetings supported by Almirall, AstraZeneca, Berlin Chemie, Boehringer, Cytos, ERT, GSK, Novartis, Pfizer, Pohl Boskamp, Takeda. The institution has received compensation for design and performance of clinical trials from Almirall, Altana/Nycomed, AstraZeneca, Boehringer, Cytos, GSK, Infinity, Medapharma, MSD, Mundipharma, Novartis, Parexel, Pearl Therapeutics, Pfizer, Revotar, Teva, Sterna, and Zentiva.

Brendan Colgan has nothing to disclose.

Oliver Kornmann’s institution received fees from Chiesi for conducting this study as a participating site. Dr. Kornmann reports personal fees as speaker or Advisory Board member from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Sanofi and Novartis.

Brian Leaker has nothing to disclose.

Henrik Watz reports personal fees from Chiesi during the conduct of the study. Outside the submitted work, Dr. Watz reports personal fees from Bayer, personal fees from GSK, personal fees from Boehringer Ingelheim, personal fees from Novartis, personal fees from AstraZeneca, personal fees from BerlinChemie, and personal fees from Roche.

Germano Lucci, Silvia Geraci, Mirco Govoni, Aida Emirova, and Marie Anna Nandeuil are all employees of Chiesi, the sponsor of this trial.

Figures

Fig. 1

Study design. Abbreviation: BID, twice daily

Fig. 2

Screening, randomisation and study completion. Abbreviation: BID, twice daily

Fig. 3

Ratio of geometric means for CHF6001 to placebo for overall cell count, and absolute and relative differential cell counts in sputum (Pharmacodynamic population). Data are the ratios of geometric means and 95% CI. *p < 0.05. Abbreviation: BID, twice daily. A total of 56 patients were included in the CHF6001 800 μg Pharmacodynamic population, 57 in the CHF6001 1600 μg population and 57 in the placebo population

Fig. 4

Ratio of geometric means for CHF6001 to placebo for markers of inflammation in sputum (Pharmacodynamic population). Data are the ratios of geometric means and 95% CI. *p < 0.05. Abbreviation: BID, twice daily. A total of 56 patients were included in the CHF6001 800 μg Pharmacodynamic population, 57 in the CHF6001 1600 μg population and 57 in the placebo population

Fig. 5

Ratio of geometric means for CHF6001 to placebo for markers of inflammation in blood (Pharmacodynamic population). Data are the ratios of geometric means and 95% CI. *p < 0.05. Abbreviation: BID, twice daily. A total of 56 patients were included in the CHF6001 800 μg Pharmacodynamic population, 57 in the CHF6001 1600 μg population and 57 in the placebo population