Innovations in COPD – A Breath of Fresh Air

Chronic obstructive pulmonary disease (COPD) describes a cluster of diseases linked to breathing problems and airflow blockage, such as emphysema and chronic bronchitis. COPD is often associated with cigarette smoking, and prolonged exposure to poor air quality or toxic gaseous pollutants. This chronic disease affects over 3 million people in the US each year, and is currently the third leading cause of death worldwide. COPD results in difficulty breathing due to limited airflow availability in the lungs, and symptoms include shortness of breath, wheezing or chronic coughing. Periods of sustained or severe COPD episodes are referred to as exacerbations.  While there is no cure for COPD, current treatments increase bronchodilation (opening of the airways) to provide symptom relief.  For nearly 50 years, bronchodilators such as beta-2-adrenoreceptor agonists and muscarinic antagonists have been at the cornerstone of COPD treatments and are available in; short-acting, long-acting, single-, dual- or glucocorticoids combined triple-therapy.

Over the last decade, a surge in COPD research has greatly expanded our understanding of the disease and the key inflammatory players involved in airway blockage. This global initiative has led to the clinical development of over 25 novel drug targets. Roflumilast, a phosphodiesteratse type 4 (PDE4) inhibitor, was the first approved COPD add-on therapy which specifically targets the inflammatory processes underlying COPD.  Ongoing research has identified pivotal roles for neutrophils and eosinophils (inflammatory cells) in COPD development, and resulted in a number of exciting drug targets in the pipeline. By addressing the underlying mechanisms responsible for disease development, this may lead to treatments that alter the course of disease progression and possibly a cure for COPD.

Along with new drug targets, the COPD biomarker landscape has also changed. While spirometer and patient-reported outcome remain critical clinical study endpoints, a role for soluble biomarkers to characterize patient populations and demonstrate drug efficacy has emerged. Fibrinogen is a soluble biomarker drug development tool approved by the FDA for COPD patient selection. Plasma fibrinogen levels are elevated in patients with COPD and are likely to experience an exacerbation, a key inclusion criteria for clinical trials aiming to demonstrate a reduction in exacerbation rates. In addition, validated assays for pro-inflammatory cytokines such as TNFa, IL-5, IL-8 and IL-17 are also of interest as increased levels of such cytokines may reflect an upregulation of neutrophilic and eosinophilic immune cell activity, and their attenuation can be indicative of reduced inflammation. Moreover, these biomarkers can be measured in either serum or right at the site of the airway blockage and inflammation, in lung fluid. Sputum collection (coughed up saliva and mucus mixture) and bronchoalveolar lavage (BAL) are two manners to retrieve lung fluid secretions. BAL is a minimally invasive endoscopic technique performed by a trained bronchoscopist to obtain cellular and biochemical components from lung fluid during a saline wash. Various cell types, cytokines and drug concentrations can all be measured to better understand pharmacokinetic – pharmacodynamic relationships.

With the development of new technologies and more sensitive bioanalytical assays, novel, non-invasive breath tests have entered the investigational scene in recent years. For instance, methodologies have been applied in exploratory clinical studies to analyze volatile organic compounds (VOC) in breath,  exhaled breath condensate (EBC), and particles in exhaled air (PExA). Due to the nature and origin of VOCs which are derived from the entire body and microbiome, metabolomic analyses of VOCs have been explored as a potential tool to support early diagnosis of a broad range of systemic diseases, but it may also be useful for respiratory disease. For instance, VOC biomarkers have been shown to correlate with sputum markers from inflammatory cells and cell counts in COPD.  Distinct patterns have also been associated with COPD disease staging. In contrast to VOC, EBC and PExA analytes are considered respiratory tract-specific, reflecting airway lining fluid and immune cell mediators from the lower airways. Their analysis allows identification and quantification of inorganic anions and cations, proteins, lipids and genes known to play a role in immune response. In addition, drug concentrations can be assessed in EBC and PExA samples.

Altogether, novel biomarkers and non-invasive breath test technologies may help diagnose respiratory pathologies, identify pathogens and distinguish treatable traits. Moreover, these innovations in COPD may provide new insights into inflammatory pathways in relation to pulmonary disease and disease stages. Finally, novel biomarkers in exhaled breath are likely to provide new tools to monitor disease state and treatment effects for specific drug targets.

Links:

Third leading cause of death – https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death

Roflumilast – https://www.daliresp.com/

Drug development tool – https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm453496.pdf

Validated assays – https://www.celerion.com/category/assays

Bronchoalverolar lavage (BAL) –  http://www.celerion.com/news/2013/01/09/bronchoscopy-suite

COPD disease staging – https://goldcopd.org/gold-reports/