(University of Leicester)
14 Feb. 2019. An experimental drug is shown in a clinical trial and computer modeling to reduce the mass of smooth muscle tissue that builds up in airways of people with asthma. A team from University of Leicester in the U.K., University of British Columbia in Vancouver, Canada, and drug maker Novartis describe their findings in yesterday’s issue of the journal Science Translational Medicine.
Asthma is a chronic condition, where the airways become inflamed and narrow, causing wheezing, shortness of breath, tightness in the chest, and coughing for periods of time. Among asthma’s underlying causes are infections, pollutants in the air, and allergies to pollen, molds, fungi, or dust mites that trigger airway inflammation. A study calculating the global burden of respiratory diseases, estimates asthma affected some 350 million people in 2015, making it the most common chronic respiratory disorder, and responsible for about 400,000 deaths each year.
Most of today’s treatments for asthma aim to reduce inflammation in the airways, but the authors note that a build-up of smooth muscles in the airways also contribute to their narrowing and the asthma symptoms. The team led by Leicester respiratory medicine professor Chris Brightling is assessing a new drug made by Novartis called fevipiprant to address both inflammation and smooth muscle mass build up in the airways. Fevipiprant works by blocking a protein associated with airway inflammation and muscle build-up, prostaglandin D2 type 2 receptor.
A mid-stage clinical study tested fevipiprant in 61 participants diagnosed with asthma against a placebo. Participants were randomly assigned to take the fevipiprant capsules or placebo twice a day for 12 weeks. The study team measured the amount of eosinophils, or disease-fighting white blood cells in the airway saliva-mucous discharge as an indicator of efficacy, as well as signs of adverse effects, and scores on an asthma control questionnaire.
The trial’s results show participants taking fevipiprant had fewer asthma symptoms, improved lung function, less inflammation, and reduced smooth muscle mass. While the trial’s results supported further development and testing of fevipiprant, data showing fewer eosinophils in the airways still did not explain the all of the reduction in airway smooth muscle mass. Something else was going on.
A computational model conducted by colleagues at University of British Columbia confirmed reductions in eosinophilia from fevipiprant had help in reducing smooth muscle mass in the airways of people with asthma. The model indicated the reduced numbers of eosinophils were accompanied by lower accumulations of myofibroblasts and fibrocytes, precursor connective tissue cells associated with fibrosis in lung inflammation and asthma. Lab tests with fevipiprant show the drug lowers the recruitment of myofibroblasts and fibrocytes in remodeling smooth airway muscle tissue, as well as reducing eosinophils.
“Our latest research,” says Brightling in a University of Leicester statement, “gives us a better understanding of the mechanisms behind the efficacy of the drug and how changes in one part of the airway wall can impact on others. Our findings suggest that fevipiprant could have positive long-term effects upon the progression of the disease through remodeling, as well as improve symptoms and reduce attacks.”
Himanshu Kaul, a postdoctoral researcher at University of British Columbia, who led the project’s computational modeling says the technology could also “play a role in furthering precision medicine by helping predict the optimal intervention tailored to individual patients given their genomic information.”
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