Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

Abstract

Respiratory virus infections precipitate asthma and chronic obstructive pulmonary disease (COPD) exacerbations, with most exacerbations due to rhinovirus infection. Both asthma and COPD exacerbations are not well controlled by steroid therapies, and there is a much research interest in finding improved therapies or combinations of therapies for controlling exacerbations. CHF6001 is a new, inhaled highly potent and selective phosphodiesterase type 4 (PDE4) inhibitor. Using in vitro human bronchial epithelial cells (BEAS‐2B), we investigated the potential anti‐inflammatory effects of CHF6001 on rhinovirus (RV1B)‐induced cytokines. Cytokine mRNA was measured by real‐time PCR, while protein release was measured by ELISA. CHF6001 was used in a 7‐point dose–response curve (1000–0.001 nmol/L) as a 1.5‐h pretreatment prior to infection in comparison with roflumilast. Both roflumilast and CHF6001 reduced RV1B‐induced IL‐8, IL‐29, IP‐10, and RANTES mRNA and protein in a concentration‐dependent manner. Generally, CHF6001 was 13‐ to 16‐fold more potent (subnanomolar EC 50 values) than roflumilast at reducing IL‐8, IL‐29, IP‐10, and RANTES mRNA and protein release, but had similar efficacies. In combination with the steroid fluticasone propionate (1 nmol/L), CHF6001 had additive effects, significantly reducing RV‐induced cytokines when compared with steroid or CHF6001 alone. Combined low‐dose steroid and low‐dose CHF6001 had a similar efficacy as high‐dose steroid or CHF6001 alone, indicating the combination had steroid and PDE4 inhibitor sparing effects. Overall results indicate that PDE4 inhibitors have anti‐inflammatory activity against virus‐induced inflammatory mediators and that CHF6001 is more potent than roflumilast.

Phosphodiesterase 4 inhibitors attenuate virus‐induced activation of eosinophils from asthmatics without affecting virus binding

“…Selective inhibitors specifically designed for inhaled treatment, such as CHF6001 and GSK256066 may combine potent anti‐inflammatory activity with limited systemic exposure and, consequently, improved tolerability. CHF6001, in particular, was shown to be more potent than Roflumilast in eliciting anti‐inflammatory effects on virus‐inducible cytokines in human bronchial epithelial cell lines . Both CHF6001 and GSK256066 are effective in reducing allergen challenge responses in asthma patients .…”

“…CHF6001, in particular, was shown to be more potent than Roflumilast in eliciting anti-inflammatory effects on virus-inducible cytokines in human bronchial epithelial cell lines. 29 Both CHF6001 and GSK256066 are effective in reducing allergen challenge responses in asthma patients. 27,30 While GSK256066 clinical development appears discontinued (ClinicalTrials.gov identifier: NCT00549679), CHF6001 is currently undergoing phase 2 clinical trials (ClinicalTrials.gov identifier: NCT02986321) in COPD patients as inhaled agent.…”

Safety, tolerability, and pharmacokinetics of single and repeat ascending doses of CHF6001, a novel inhaled phosphodiesterase-4 inhibitor: two randomized trials in healthy volunteers

“… 7 In addition, following rhinovirus challenge of human bronchial epithelial cells, CHF6001 reduced the levels of a range of cytokines in a concentration-dependent manner, both alone and in combination with low-dose corticosteroids, indicating anti-inflammatory activity against virus-induced inflammatory mediators. 8 CHF6001 is highly plasma protein bound (>99% in humans), 9 with low systemic bioavailability after intratracheal administration and very low bioavailability after oral administration suggesting that any portion ingested following inhaled administration is likely to have a negligible contribution to overall systemic exposure. 6 It is metabolically stable in human liver, with the main metabolites, which are pharmacologically inactive, being related to hydrolysis, and is rapidly eliminated following intravenous administration, predominantly via the fecal route.…”

Propentofylline, phosphodiesterase and adenosine reuptake inhibitor modulates lymphocyte subsets and lymphocyte activity after in-vivo administration in non-immunized and SRBC-immunized mice

“…Nowadays, PDE inhibitors are used in the treatment of numerous pathological conditions such as asthma, chronic obstructive pulmonary disease (COPD), congestive heart failure and erectile dysfunction. Additionally, many new and older compounds from this group are still extensively evaluated for clinical potential and are considered promising drugs for future therapies …”

“…Additionally, many new and older compounds from this group are still extensively evaluated for clinical potential and are considered promising drugs for future therapies. [1][2][3][4] PDE4 is a predominant cAMP-degrading enzyme in most immune and inflammatory cells, including T and B lymphocytes, neutrophils, monocytes or macrophages. [1,5] Therefore, as regards the effect on immune system, PDE4 family is a major pharmacological target.…”