Pulmonary Assessments in Early Clinical Research
Respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis continue to be an unmet medical need despite advances in clinical and scientific understanding of these diseases. The prevalence of asthma in particular continues to rise and while current drugs provide symptomatic relief to some patients, not all patients can be effectively treated with existing drug therapies. Consequently, there is a huge research effort towards developing new therapies for asthma and other pulmonary diseases.
As is true for many other therapeutic areas, early clinical research of new drugs for treating pulmonary diseases is evolving to speed up timelines to proof-of-concept. This means adaptive study designs are increasingly employed, and studies in patients are initiated earlier (in some cases cohorts of patients with mild to moderate disease are included in the very first clinical study). Biomarkers are also increasingly applied to validate the drug’s mechanism of action and obtain early indication of potential efficacy or toxicity.
Spirometry is one of the most common pulmonary function tests included in Phase I studies of respiratory drugs (or non-respiratory drugs where the lung may be a potential target organ for adverse effects). FEV1 is the volume of air that is forcibly exhaled in the first second, and forced vital capacity (FVC) is the total volume of air exhaled after a full inspiration. The methodology for obtaining these forced expiratory parameters has been standardized jointly by the American Thoracic Society (ATS) and the European Respiratory Society (ERS), and reference values are available for normal healthy populations based on race/ethnicity and age. In patients with respiratory diseases such as COPD, the FEV1 has been used to classify patients by severity and disease progression. Spirometry uses relatively simple and inexpensive equipment, the procedures are non-invasive and safe to administer (although some patients may experience light-headedness or even syncope) and measurements are reproducible when performed by trained technicians. Plethysmography or spirometry with helium dilution are methods for determining functional residual capacity (FRC) which is the volume of gas remaining in the lung at the end of tidal expiration. Inspiratory capacity (IC) is the maximum volume of gas that can be inspired from end-tidal expiration, which is the difference between total lung capacity (TLC) and FRC. Residual volume (RV) is the volume of gas remaining in the lung at the end of a maximal expiration. The methods for measuring absolute lung volume and its subdivisions have also been standardized in a joint ATS/ERS document. Measurement of lung volumes is technically more demanding than simple spirometry and specific training is necessary for technicians conducting these tests.
Lung function, however, is not an independent predictor of quality of life for people suffering from pulmonary diseases. For example, shortness of breath predicts quality of life at all levels of asthma severity [insert ref], and asthma symptom frequency is the most important determinant of the subjective experience of asthma. Tools for assessing quality of life and the related decrease in physical functioning should therefore be included in clinical study protocols, where appropriate, to evaluate a new drug therapy for early signs of potential efficacy. Several quality of life questionnaires have been developed and validated in asthma and COPD patients.
FEV1 is a non-specific endpoint that does not diagnose the cause of airflow obstruction. More sophisticated technologies such as computed tomography (CT) and magnetic resonance imaging (MRI) can provide information on lung density and structural changes to enable diagnosis and monitor changes in response to drug treatment. High-resolution computed tomography (HRCT) imaging is a technology that provides quantitative assessments and can be used to distinguish between different disease pathologies, for example, differentiating COPD patients who have predominant parenchymal disease from those who have predominant airway pathology. However, this methodology has not been fully validated yet, the associated costs are high, and there are concerns about the safety risk of repeated exposure of patients to the ionizing radiation associated with the procedure.
Other minimally invasive measurements for pulmonary studies include sputum analysis for biomarkers of inflammation and exhaled nitric oxide measurements. An increase in exhaled nitric oxide concentration has been shown to correlate with the degree of eosinophilic inflammation of the airways [insert ref]. Bronchoalveolar lavage (BAL) can be used to collect fluid and cells from the lung periphery. The cellular component of BAL is mostly made up of alveolar macrophages which may be separated and cultured in vitro. Macrophages from COPD patients have increased expression of inflammatory biomarkers such as TNF-alpha, IL-8 and matrix metalloprotein (MMP)-9. Several inflammatory proteins can also be measured in the BAL fluid although quantitation is challenged by the lack of a suitable marker for the dilution of the saline lavage fluid. Moreover, BAL is an invasive procedure and can cause discomfort to the subject. By contrast, induced sputum samples are relatively easy to collect. The sputum is obtained after inhaling nebulized hypertonic saline, a procedure which is well tolerated by patients. There are several technical challenges to measuring inflammatory cytokines in sputum (e.g. potential for degradation by sputum proteases), however, this is a promising approach to monitoring pulmonary biomarkers. It should be noted that induced sputum samples are obtained from predominantly large airways and may not reflect the peripheral inflammation that may be important for clinical outcomes in diseases such as COPD.
Airway hyperresponsiveness is a characteristic feature of asthma. Methods to evaluate airway hyperresponsiveness include the widely used bronchoprovocation challenges with methacholine or histamine. As well, allergens or exercise challenges can be used to stimulate airway hyperresponsiveness in subjects whose asthma is triggered by these stimuli. Such challenge tests can be safely performed in patients with mild to moderate asthma in a controlled clinical setting under the supervision of appropriately trained medical personnel.
Celerion’s Phase I clinic in Belfast is a member of the UK’s Translational Research Partnership in Respiratory. This Partnership is a unique cooperative of internationally leading clinicians and scientists whose aim is to improve the speed of developing innovative therapies for respiratory diseases by working in collaboration with research groups of the pharmaceutical industry. The collaboration with the UK’s Translational Research Partnership in Respiratory provides Celerion with access to patients suffering from asthma, COPD, cystic fibrosis, bronchiectasis and interstitial lung disease. Celerion also has access to laboratory capabilities (flow cytometry, flow cytometric cell sorting, microbiology, 16S, deep sequencing, MLST, transcriptomics) as well as lung imaging techniques (CT acquisition of images, dedicated MRI time, advanced CT analysis capabilities and MRI acquisition of images). For more information, please contact us today.