Clinical Trials in Asthma and COPD: Trial Designs, Clinical Endpoints, and Biomarkers

I. Introduction: summary The incidence of asthma and chronic obstructive pulmonary disease (COPD) is increasing throughout the world and acts as a major incentive for the development of new and improved drug therapy. However, the cytokine storm caused in human volunteers after administration of TGN1412 (TeGenero, Wu¨rzburg, Germany) has emphasized the need for caution in dose selection in phase I with biologics and the need for predictive assays based on human cells. For first-in-man studies, ex vivo whole blood stimulation can be employed with systemic therapies to establish specific target pharmacology, pharmacokinetic/pharmacodynamic modeling, and an optimal dosage regimen. For the large range of bronchodilator and anti-inflammatory agents entering studies in human, reliable decision making is imperative in phase II before entering large scale phase III clinical studies. In phase II studies, it is important to establish the clinical efficacy and tissue anti-inflammatory properties of the new therapy. Many studies have been performed utilizing the inhaled allergen challenge (IAC) in asthmatics as a proof of concept study, although the latest methods of nasal allergen challenge (NAC) in subjects with allergic rhinitis offer advantages in terms of repeated direct sampling of the nasal lining fluid. Airway hyperreactivity (AHR) is commonly measured as provocative concentration to cause a 20% fall in forced expiratory volume in one second (FEV1) (PC20) in relation to methacholine, adenosine monophosphate (AMP), or mannitol. It is also possible to directly study clinical effects of new therapies on limited numbers of symptomatic asthma patients through morning and evening electronic monitoring of lung function and symptoms. Alternative clinical trial designs in asthma include studies to assess bronchodilation and bronchoprotection, exercise tolerance, add-on and titration studies with inhaled and oral corticosteroids, and a considerable recent focus in phase III on prevention and treatment of exacerbations. In contrast, there is a major challenge for the development of new anti-inflammatory drugs for COPD, as phase II studies have been poorly predictive of efficacy in phase III trials, resulting in difficulties for oral phosphodiesterase (PDE)4 inhibitors to achieve registration after large clinicaldevelopment. In COPD, clinical trial designs range from studies on lung function, symptoms and exercise performance, inflammatory biomarkers, natural history of chronic stable disease, prevention and treatment of exacerbations, and effects on the BODE score and cachexia and muscle function. Compared with asthma, inclusion criteria, monitoring parameters, comparator therapies, and trial design are less well established for COPD. The large variety of potential clinical endpoints includes lung function, symptoms, walking tests, hyperinflation, health-related quality of life (HRQOL), frequency and severity of exacerbations, natural history, and mortality. In addition, for both asthma and COPD, surrogate biomarkers may be assessed in blood, exhaled breath, induced sputum, bronchial mucosal biopsy, bronchoalveolar lavage (BAL), and through advanced radiographic imaging. There have been considerable recent advances in the development of noninvasive biomarkers and novel clinical trial designs, as well as clarification of regulatory requirements, that will facilitate the clinical development of new therapies for patients with asthma and COPD.