A recent study reveals that a game-changer drug, Fevipiprant, has shown evidence of lowering patients’ risks of suffering an asthma attack and being admitted to a hospital.
According to Global Asthma Report 2018, asthma has affected around 339 million people worldwide, killing as many as 1,000 people every day.
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 “remodelling.”
The prevalence of asthma is on the rise, with low and middle-income countries being the most affected, partly because essential medicines are either unavailable, unaffordable or are of unreliable quality.
Airways are composed 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 are the inflammatory cells that are recruited in the event of a foreign body (such as an allergen or virus).
In health, these three elements (epithelial cells, mesenchyme and inflammatory cells) work in harmony to ensure effective airflow and appropriate response to external challenges. In asthma, these harmonic interactions are compromised, 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. This cannot be achieved through experimentation alone because so many factors contribute to the disease. The study however reveals that with mathematical models, hypotheses can be used to help reduce the complexity of the system.
In the clinical trial, Fevipiprant was observed to reduce the number of inflammatory cells and muscle mass.
Himanshu Kaul, post doctoral fellow, University of British Columbia said that to understand this process, he developed a mathematical model that combined the epithelial, mesenchymal and inflammatory elements to understand what is responsible for airway remodelling during asthma.
Explaining further, Kaul said he used “agent-based modeling”, a mathematical approach that relies on rule-sets governing interactions between various model elements.
“I 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,” said Himanshu Kaul.
He then gave the virtual patient Fevipiprant. However, while it showed the same amount of reduction ininflammatory cells as the clinical trial, it failed to show the same amount of reduction in muscle mass as observed clinically.
This led to the conclusion that Fevipiprant acted not by reducing the inflammation alone, but by also directly impacting muscle mass.
Findings from an experiment conducted by Ruth Saunders at the University of Leicester with muscle cells taken from patients suggested that Fevipiprant reduced the recruitment of cells called myofibroblasts, which add to muscle mass during remodeling.
When this secondary feature was added to the model, the observed reduction in the muscle mass of the virtual patient was consistent with clinical data.
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.