chf6001 and Asthma

CHF6001 is an inhaled phosphodiesterase 4 (PDE4) inhibitor in development for the treatment of obstructive lung diseases. The efficacy and safety of CHF6001 were investigated in a double blind, placebo controlled, 3-way cross-over study using the allergen challenge model. Thirty-six atopic asthmatics who were not taking inhaled corticosteroids and who demonstrated a late asthmatic response (LAR) to inhaled allergen at screening were randomised to receive CHF6001 400 μg or 1200 μg or placebo administered once a day using a dry powder inhaler. The three treatment periods were 9 days; allergen challenges were performed on day 9 and induced sputum was obtained after 10 h from challenge. Washout periods between treatments were up to 5 weeks. Both CHF6001 doses significantly attenuated the LAR; the primary endpoint analysis showed that CHF6001 400 μg and 1200 μg caused reductions of 19.7% (p = 0.015) and 28.2% (p < 0.001) respectively of the weighted FEV1 AUC4-10h compared with placebo. The difference between the CHF6001 doses was not statistically significant (p = 0.223). Compared with placebo, CHF6001 caused greater reduction in sputum eosinophil counts, although these changes were not statistically significant. CHF6001 was well tolerated, with similar numbers of adverse events in each treatment period. This inhaled PDE4 inhibitor has the potential to provide clinical benefits in patients with atopic asthma.

Topics: Administration, Inhalation; Adult; Allergens; Asthma; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Dry Powder Inhalers; Female; Forced Expiratory Volume; Humans; Male; para-Aminobenzoates; Phosphodiesterase 4 Inhibitors; Sputum; Sulfonamides; Treatment Outcome

Acute respiratory virus infections, such as influenza and RSV, are predominant causes of asthma exacerbations. Eosinophils act as a double-edged sword in exacerbations in that they are activated by viral infections but also can capture and inactivate respiratory viruses. Phosphodiesterase type 4 (PDE4) is abundantly expressed by eosinophils and has been implicated in their activation. This exploratory study aims to determine whether these opposing roles of eosinophils activation of eosinophils upon interaction with virus can be modulated by selective PDE4 inhibitors and whether eosinophils from healthy, moderate and severe asthmatic subjects respond differently. Eosinophils were purified by negative selection from blood and subsequently exposed to RSV or influenza. Prior to exposure to virus, eosinophils were treated with vehicle or selective PDE4 inhibitors CHF6001 and GSK256066. After 18 hours of exposure, influenza, but not RSV, increased CD69 and CD63 expression by eosinophils from each group, which were inhibited by PDE4 inhibitors. ECP release, although not stimulated by virus, was also attenuated by PDE4 inhibitors. Eosinophils showed an increased Nox2 activity upon virus exposure, which was less pronounced in eosinophils derived from mild and severe asthmatics and was counteracted by PDE4 inhibitors. PDE4 inhibitors had no effect on binding of virus by eosinophils from each group. Our data indicate that PDE4 inhibitors can attenuate eosinophil activation, without affecting virus binding. By attenuating virus-induced responses, PDE4 inhibitors may mitigate virus-induced asthma exacerbations.

Topics: Aminoquinolines; Asthma; Case-Control Studies; Eosinophils; Humans; Orthomyxoviridae; para-Aminobenzoates; Phosphodiesterase 4 Inhibitors; Respiratory Syncytial Viruses; Severity of Illness Index; Sulfonamides; Sulfones; Virus Attachment

Lymphocytes play a key role in asthma pathophysiology, secreting various cytokines involved in chronic inflammation. CHF6001 is a highly potent and selective phosphodiesterase type 4 (PDE4) inhibitor designed for inhaled administration and has been shown to reduce the late asthmatic response. However, the effect of PDE4 inhibition on the different cytokines produced by lung lymphocytes from asthma patients has not been examined.. This study investigated the anti-inflammatory effects of CHF6001 and the corticosteroid, 17-BMP, on T-cell receptor (TCR) stimulated Th1, Th2 and Th17 cytokine release from bronchoalveolar lavage (BAL) cells from mild (n = 12) and moderate asthma (n = 12) patients.. CHF6001 inhibited IFNγ, IL-2 and IL-17, but not IL-13, secretion from both mild and moderate asthma patient BAL cells; there was a greater effect on IFNγ and IL-2 than IL-17. The corticosteroid inhibited all four cytokines from both patient groups, but was less effective in cells from more severe patients. CHF6001 had a greater inhibitory effect on IFNγ and IL-2 than 17-BMP.. The PDE4 inhibitor CHF6001 had a greater effect on Th1 cytokines from TCR-stimulated BAL cells than corticosteroid. This pharmacological effect suggests the therapeutic potential for PDE4 inhibitors to be used in the subset of more severe asthma patients with increased airway levels of IFNγ.

Topics: Adult; Anti-Inflammatory Agents; Asthma; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cell Line; Cyclic Nucleotide Phosphodiesterases, Type 4; Cytokines; Female; Humans; Lung; Lymphocytes; Male; Middle Aged; para-Aminobenzoates; Phosphodiesterase 4 Inhibitors; Receptors, Antigen, T-Cell; Sulfonamides

The first steps in the selection process of a new anti-inflammatory drug for the inhaled treatment of asthma and chronic obstructive pulmonary disease are herein described. A series of novel ester derivatives of 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl) ethanol have been synthesized and evaluated for inhibitory activity toward cAMP-specific phosphodiesterase-4 (PDE4). In particular, esters of variously substituted benzoic acids were extensively explored, and structural modification of the alcoholic and benzoic moieties were performed to maximize the inhibitory potency. Several compounds with high activity in cell-free and cell-based assays were obtained. Through the evaluation of opportune in vitro ADME properties, a potential candidate suitable for inhaled administration in respiratory diseases was identified and tested in an in vivo model of pulmonary inflammation, proving its efficacy.

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Benzoates; Cell Line; Chronic Disease; Crystallography, X-Ray; Eosinophilia; Esters; Guinea Pigs; Humans; Leukocytes, Mononuclear; Lung; Lung Diseases, Obstructive; Molecular Docking Simulation; Ovalbumin; para-Aminobenzoates; Phosphodiesterase 4 Inhibitors; Protein Conformation; Rats; Stereoisomerism; Structure-Activity Relationship; Sulfonamides