A novel way of identifying patients with acute asthma worsening, reported this week in The Lancet Respiratory Medicine, may speed up development of new medicines for people whose asthma is not controlled by current therapies.
The new technique, called CompEx, has been developed by AstraZeneca scientists in IMED Biotech Unit and Global Medical Affairs in collaboration with academic researchers at the Universities of Colorado and Lund, and commercial partners GlaxoSmithKline (GSK) and Innovation & Design AB.
“CompEx has the potential to reduce the size and duration of Phase II clinical trials of new asthma medicines by at least 50%, and accelerate and improve the accuracy of decisions about whether to move forward to full development,” says Dr Malin Fagerås, from RIA Global Medical Affairs, AstraZeneca, Gothenburg. “CompEx is an extension of the current definition of severe exacerbations. By the addition of objective measures of acute asthma worsening to the more subjective definition of severe exacerbation based on medical treatment, CompEx could also change how exacerbations is captured in later development, may also prove useful for monitoring patients in routine clinical practice and preventing severe exacerbations.”
Anne Fuhlbrigge, MD and study physician at University of Colorado School of Medicine added “The CompEx is an exciting collaborative effort, allowing development of a composite exacerbation endpoint that will facilitate evaluation of new therapeutic interventions for asthma.”
A reduction in severe asthma exacerbation is currently used to measure the effectiveness of new asthma medicines in clinical trials. But severe exacerbations is usually reserved for Phase III studies as these events are rare, and large, lengthy studies are needed to show differences between the effects of interventions. Previous efforts to develop measures of more common, milder exacerbations, generally based on variations in single symptom criteria, have proved unsuccessful.
CompEx combines patient-recorded deterioration in lung function and asthma symptoms, and increased use of reliever medication with traditional measurement of severe exacerbations. For the patient recorded component of CompEx, an algorithm was developed based on deterioration below threshold limits and gradual deterioration over a five-day period. Signs of worsening of 2+ criteria were found to be indicative of asthma deterioration.
“Although patients routinely record the information we have used in CompEx, the data have never previously been combined in this structured way. By understanding the relationship between these different variables, we have shown how changes that indicate changes associated with exacerbations can be used in clinical trials as a surrogate endpoint for severe exacerbations,” says Dr Carla Da Silva, from IMED Biotech Unit, AstraZeneca, Gothenburg.
A promising composite endpoint
CompEx was tested in an analysis of data from over 17,000 patients in 12 studies of asthma medication carried out by AstraZeneca and GSK. At three months follow up, three times as many events indicating worsening asthma were recorded with CompEx (8-31%) compared with SevEx (4-12%). Further analysis showed that CompEx results at three months were good predictors of SevEx at 12 months.
“The results suggest that CompEx has the power to enable the number of patients in Phase II asthma trials to be halved, and duration reduced from 12 months to 3 months. The fact that the effect on CompEx is highly predictive of that on SevEx – the regulatory endpoint used in Phase III trials – is off course crucial,” concludes Dr Da Silva.
Ruth Tal-Singer, Vice President of Clinical Discovery in Respiratory R&D, GSK said: “The development of CompEx is a promising step forward in our collaborative efforts to improve and accelerate the development of medicines for patients. We now look forward to progressing discussions with clinicians and regulators to determine how this new endpoint could potentially be adopted in early phase asthma clinical trials to support decision making based on a medicines potential.”
Freely available tool
CompEx is being made freely available to clinicians and other pharmaceutical companies for use in clinical trials, to monitor patients with asthma in routine clinical practice and for consideration by organisations responsible for development of asthma management guidelines. In addition, a similar composite approach to measuring disease deterioration has potential for clinical trials of related respiratory diseases, such as chronic obstructive pulmonary disease (COPD).