A recent study shows that a gamechanger drug called Fevipiprant promises to lower patients’ risks; of suffering an asthma attack and admitted to a hospital. This is the first time a drug reducing airway smooth muscle mass a key clinical indicator of disease severity that increases the likelihood; of more frequent asthma attacks and even deaths have reported.
They developed computer models that allowed us to simulate results from a Phase 2 clinical trial to predict therapy outcomes in patients. The original trial was led by Christopher Brightling, clinical professor in respiratory medicine at the University of Leicester and the principal co-ordinator of the European Lung Foundation AirPROM.
Asthma is increasingly common
Asthma affects around 339 million people worldwide, killing as many as 1,000 people every day, according to the Global Asthma Report 2018. The prevalence of asthma is on the rise, with low- and middle-income countries suffering most —in part because essential medicines are unavailable, unaffordable or are of unreliable quality. Asthma is caused by a complex set of interactions between a patient’s genes, cells, and environment that lead to an increase in airway smooth muscle mass a process referred to as “remodeling.”
The airways are composing of several different cell types that exist together in a highly ordered state. The airway lumen is lined by epithelial cells and, further inside, the mesenchyme. The latter contains muscle cells that increase in mass during asthma. Another crucial feature of the airway is the inflammatory cells that are recruited in the event of a foreign challenge (such as an allergen or virus).
Therefore in health, these three elements work in harmony to ensure effective airflow and appropriate response to external challenges. So in asthma, these harmonic interactions are resulting in increased muscle mass. Developing a sound strategy to treat asthma requires a precise understanding of the factors that contribute to the emergence of the disease. We cannot achieve this through experimentation alone because so many factors contribute to the disease.
Mesenchymal and inflammatory elements
In the clinical trial, Fenpiprane to reduce the number of inflammatory cells and muscle mass. To understand how, I developed a mathematical model that combined the epithelial, mesenchymal and inflammatory elements to understand what is responsible for airway remodeling during asthma. They used something called “agent-based modeling” a mathematical approach that relies on rule-sets governing interactions between various model elements.
They developed a “virtual patient” with severe asthma and gave them virtual drugs. I made sure that the model was capturing biological reality by first administering virtual Mepolizumab; which killed inflammatory cells in the airways. The virtual patient performance was consistent with clinical results. I then gave the virtual patient Fevipiprant. While it showed the same amount of reduction in inflammatory cells as the clinical trial; it failed to show the same amount of reduction in muscle mass as observed clinically.
When this secondary feature to the model; the observed reduction in the muscle mass of the virtual patient was consistent with clinical data. Fevipiprant could be a potential therapy to improve airway remodeling in asthma. Using this drug could allow patients to reduce their dependence on high-dose steroids; whose side-effects include weight gain, diabetes, and high blood pressure. While this does need more testing with other therapies; it is a milestone in patient-specific models and promises a new era of precision within respiratory medicine.