Efficacy and safety of a first-in-class inhaled PDE3/4 inhibitor (ensifentrine) vs salbutamol in asthma.

INTRODUCTION: This study aimed to investigate the dose-response and pharmacology of a range of single doses of nebulised ensifentrine (RPL554), an inhaled dual phosphodiesterase (PDE) 3/4 inhibitor in patients with asthma. METHODS: In this randomised, placebo-controlled, double-blind crossover study, patients received single nebulised doses of ensifentrine 0.4, 1.5, 6 and 24 mg, salbutamol 2.5 and 7.5 mg, and placebo. Eligible patients were adults with asthma, pre-bronchodilator forced expiratory volume in 1 s (FEV1) 60-90% predicted and ≥1.5 L, with post-salbutamol FEV1 increase ≥15%. The co-primary objectives were peak and average FEV1 over 12 h for ensifentrine vs placebo and salbutamol. Secondary endpoints included: peak and average systolic and diastolic blood pressure, pulse rate and ECG heart rate; and safety and tolerability (adverse events [AEs], and serum potassium). ClinicalTrials.gov: NCT02427165. RESULTS: A total of 29 patients were randomised, with 25 (89%) completing the study. For the two co-primary endpoints there was a clear ensifentrine dose-response relationship, with all treatments superior to placebo (p < 0.001). There was no relationship between the ensifentrine dose and AE incidence or blood pressure. Ensifentrine 0.4, 1.5 and 6 mg had significantly lower effects than both salbutamol doses on pulse and heart rates. Ensifentrine did not impact potassium, whereas there was a was a dose-related reduction for salbutamol. Inhalation of ensifentrine resulted in a dose-related increase in plasma exposure. CONCLUSIONS: Single-dose ensifentrine demonstrated dose-dependent bronchodilation, and was as effective as a therapeutic dose of nebulised salbutamol. All ensifentrine doses were similarly well tolerated, and did not show the characteristic ß2-agonist systemic adverse effects.

The short-term bronchodilator effects of the dual phosphodiesterase 3 and 4 inhibitor RPL554 in COPD.

We investigated the short-term bronchodilator effects of RPL554 (an inhaled dual phosphodiesterase 3 and 4 inhibitor) combined with other bronchodilators in chronic obstructive pulmonary disease patients with reversibility (>150 mL to short-acting bronchodilators).Study 1 was a six-way, placebo-controlled crossover study (n=36) with single doses of RPL554 (6 mg), salbutamol (200 µg), ipratropium (40 µg), RPL554 (6 mg)+salbutamol (200 µg), RPL554 (6 mg)+ipratropium (40 µg) or placebo. Study 2 was a three-way crossover study (n=30) of tiotropium (18 µg) combined with RPL554 (1.5 or 6 mg) or placebo for 3 days. Forced expiratory volume in 1 s (FEV1), lung volumes and specific airway conductance (sG aw) were measured.In study 1, peak FEV1 change compared with placebo was similar with RPL554, ipratropium and salbutamol (mean 223, 199 and 187 mL, respectively). The peak FEV1 was higher for RPL554+ipratropium versus ipratropium (mean difference 94 mL; p<0.0001) and RPL554+salbutamol versus salbutamol (mean difference 108 mL; p<0.0001). In study 2 (day 3), both RPL554 doses caused greater peak FEV1 effects than placebo. The average FEV1 (0-12 h) increase was greater with RPL554 6 mg only versus placebo (mean difference 65 mL; p=0.0009). In both studies, lung volumes and sG aw showed greater RPL554 combination treatment effects versus monotherapy.RPL554 combined with standard bronchodilators caused additional bronchodilation and hyperinflation reduction.

Neutral sphingomyelinase-2, acid sphingomyelinase, and ceramide levels in COPD patients compared to controls.

BACKGROUND: Increased pulmonary ceramide levels are suggested to play a causative role in lung diseases including COPD. Neutral sphingomyelinase-2 (nSMase-2) and acid SMase (aSMase), which hydrolyze sphingomyelin to produce ceramide, are activated by a range of cellular stresses, including inflammatory cytokines and pathogens, but notably cigarette smoke appears to only activate nSMase-2. Our primary objective was to investigate nSMase-2 and aSMase protein localization and quantification in lung tissue from nonsmokers (NS), smokers (S), and COPD patients. In addition, various ceramide species (C16, C18, and C20) were measured in alveolar macrophages from COPD patients versus controls. MATERIALS AND METHODS: Patients undergoing surgical resection for suspected or confirmed lung cancer were recruited, and nSMase-2 and aSMase protein was investigated in different areas of lung tissue (small airways, alveolar walls, subepithelium, and alveolar macrophages) by immunohistochemistry. Ceramide species were measured in alveolar macrophages from COPD patients and controls by mass spectrometry. RESULTS: nSMase-2 and aSMase were detected in the majority of small airways. There was a significant increase in nSMase-2 immunoreactivity in alveolar macrophages from COPD patients (54%) compared with NS (31.7%) (P<0.05), and in aSMase immunoreactivity in COPD (68.2%) and S (69.5%) alveolar macrophages compared with NS (52.4%) (P<0.05). aSMase labeling was also increased in the subepithelium and alveolar walls of S compared with NS. Ceramide (C20) was significantly increased in alveolar macrophages from COPD patients compared with controls. CONCLUSION: nSMase-2 and aSMase are both increased in COPD alveolar macrophages at the protein level; this may contribute toward the elevated ceramide (C20) detected in alveolar macrophages from COPD patients.

Translational models of lung disease.

The 2nd Cross Company Respiratory Symposium (CCRS), held in Horsham, U.K. in 2012, brought together representatives from across the pharmaceutical industry with expert academics, in the common interest of improving the design and translational predictiveness of in vivo models of respiratory disease. Organized by the respiratory representatives of the European Federation of Pharmaceutical Industries and Federations (EFPIA) group of companies involved in the EU-funded project (U-BIOPRED), the aim of the symposium was to identify state-of-the-art improvements in the utility and design of models of respiratory disease, with a view to improving their translational potential and reducing wasteful animal usage. The respiratory research and development community is responding to the challenge of improving translation in several ways: greater collaboration and open sharing of data, careful selection of the species, complexity and chronicity of the models, improved practices in preclinical research, continued refinement in models of respiratory diseases and their sub-types, greater understanding of the biology underlying human respiratory diseases and their sub-types, and finally greater use of human (and especially disease-relevant) cells, tissues and explants. The present review highlights these initiatives, combining lessons from the symposium and papers published in Clinical Science arising from the symposium, with critiques of the models currently used in the settings of asthma, idiopathic pulmonary fibrosis and COPD. The ultimate hope is that this will contribute to a more rational, efficient and sustainable development of a range of new treatments for respiratory diseases that continue to cause substantial morbidity and mortality across the world.

Dual PDE3/4 and PDE4 inhibitors: novel treatments for COPD and other inflammatory airway diseases.

Selective phosphodiesterase (PDE) 4 and dual PDE3/4 inhibitors have attracted considerable interest as potential therapeutic agents for the treatment of respiratory diseases, largely by virtue of their anti-inflammatory (PDE4) and bifunctional bronchodilator/anti-inflammatory (PDE3/4) effects. Many of these agents have, however, failed in early development for various reasons, including dose-limiting side effects when administered orally and lack of sufficient activity when inhaled. Indeed, only one selective PDE4 inhibitor, the orally active roflumilast-n-oxide, has to date received marketing authorization. The majority of the compounds that have failed were, however, orally administered and non-selective for either PDE3 (A,B) or PDE4 (A,B,C,D) subtypes. Developing an inhaled dual PDE3/4 inhibitor that is rapidly cleared from the systemic circulation, potentially with subtype specificity, may represent one strategy to improve the therapeutic index and also exhibit enhanced efficacy versus inhibition of either PDE3 or PDE4 alone, given the potential positive interactions with regard to anti-inflammatory and bronchodilator effects that have been observed pre-clinically with dual inhibition of PDE3 and PDE4 compared with inhibition of either isozyme alone. This MiniReview will summarize recent clinical data obtained with PDE inhibitors and the potential for these drugs to treat COPD and other inflammatory airways diseases such as asthma and cystic fibrosis.

Targeting TRP channels in airway disorders.

Novel effective therapeutic agents are actively sought for the treatment of a broad spectrum of respiratory diseases which collectively significantly impact on mortality, morbidity and quality of life of hundreds of millions of people world-wide. These include asthma, allergic rhinitis, chronic obstructive pulmonary disease, cough, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, cystic fibrosis and acute lung injury. TRP channels are broadly distributed throughout the respiratory tract and play an important physiological role in sensing and subsequently responding to a wide variety of stimuli, for example temperature, osmolarity and oxidant stress. In the context of respiratory disease however TRP channel function may be altered, eg: under conditions of oxidative stress, inflammation, hypoxia and mechanical stress. In addition there is evidence that the expression/activity of TRP channels can be affected in the disease setting. Modulators of TRP channel function are therefore under investigation for a range of diseases including disorders of the respiratory system. Several excellent review articles have discussed in detail evidence that modulation of specific TRP channels may be of benefit in specific respiratory diseases. In this article we have taken the approach of reviewing evidence that modulation of TRP channel function may be able to affect common and over-lapping characteristic features of respiratory diseases, for example bronchoconstriction, airways hyper-responsiveness, cough, airways inflammation, mucus hyper-secretion, exacerbations, lung injury, hypoxia and airways re-modelling. The therapeutic potential of TRP channel modulators, the status of these agents in the clinic along with the challenges posed in this rapidly advancing field are also discussed in this review.