An NIH-funded trial identifies asthma-associated gene networks affected by the drug.
August 10, 2022 – A monoclonal antibody, mepolizumab, decreased asthma attacks by 27% in black and Hispanic children and adolescents who have a severe form of asthma, are prone to asthma attacks and live in neighborhoods low-income urban dwellers, a National Institutes of Health clinical trial found. This population has been underrepresented in previous clinical trials of asthma treatments. The results were published today in the journal The Lancet.
Study researchers undertook a novel exploratory analysis of gene activity in cells taken from the nasal secretions of study participants at the start and end of the trial in an attempt to explain how the mepolizumab and to link it to its clinical effect. The antibody reduced the activity of three gene networks associated with airway inflammation and asthma attacks in the study population, but did not reduce the activity of six other such networks.
“Asthma takes a heavy toll, especially on disadvantaged school-aged children of color who live in urban areas,” said Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases. (NIAID), which is part of the National Institutes. Health and trial sponsor. “The results of this study indicate that more research is needed to develop therapies that significantly reduce asthma attacks in these children.”
NIAID; the National Center for the Advancement of Translational Sciences, which is also part of the NIH; and GlaxoSmithKline funded the Phase 2 trial, titled Mechanisms Underlying Prevented and Persistent Asthma Exacerbations with Immunity-Based Therapy: A Phase 2 Systems Approach (MUPPITS-2). The NIAID-funded Inner City Asthma Consortium conducted the study under the direction of Daniel J. Jackson, MD, William W. Busse, MD, and Matthew C. Altman, MD, M.Phil. Dr. Jackson is a Professor of Pediatrics and Medicine and Dr. Busse is an Honorary Fellow of the University of Wisconsin-Madison School of Medicine and Public Health. Dr. Altman is an associate professor in the Department of Medicine at the University of Washington School of Medicine and a research associate at the Benaroya Research Institute at Virginia Mason in Seattle. GlaxoSmithKline donated mepolizumab for the trial.
Asthma is caused by chronic inflammation of the airways. During an asthma attack, the lining of the airways swells, the muscles around the airways tighten, and the airways produce more mucus, which greatly reduces the space for air to get in and out. come out of the lungs. According to the Centers for Disease Control and Prevention, approximately 2.3 million American children and adolescents suffered an asthma attack in 2019.
Black and Hispanic children who live in low-income urban environments in the United States are at particularly high risk for attack-prone asthma. These children often have many allergies and are exposed to both high levels of indoor allergens and traffic-related pollution, which can make their asthma even more difficult to control.
In an earlier study(link is external), MUPPITS-1, researchers have identified several functionally linked gene networks that are activated together and are associated with asthma attacks in children and adolescents who live in low-income urban settings. Some of these genetic networks are specifically associated with cells called eosinophils.
Many people with untreated asthma have high levels of eosinophils in their blood and airways. These cells are thought to increase inflammation in the airways, which in turn leads to tissue damage, making it harder to breathe.
Mepolizumab, marketed by GlaxoSmithKline as Nucala, is approved by the Food and Drug Administration to treat people age 6 and older with eosinophilic asthma and has been shown to reduce blood levels of eosinophils . Researchers hypothesized that mepolizumab would suppress eosinophil-specific gene networks associated with asthma attacks in urban black and Hispanic youth with eosinophilic asthma, thereby reducing the number of asthma attacks in this population. . The researchers further hypothesized that by analyzing gene networks associated with asthma during treatment, they would identify certain networks associated with stronger or weaker responses to mepolizumab. The MUPPITS-2 trial was designed to test these hypotheses.
The MUPPITS-2 study team recruited 290 children aged 6 to 17 years whose asthma was difficult to control, prone to attacks and characterized by high blood levels of eosinophils. Seventy percent of participants were black, 25% were Hispanic, and all lived in low-income neighborhoods in nine US cities. The children were randomly assigned to receive an injection of mepolizumab or a placebo once every four weeks for 12 months. No one knew who had received which type of injection until the end of the trial. All participants also received asthma care based on guidelines developed under the auspices of the National Heart, Lung, and Blood Institute, which is part of the NIH.
The study team collected nasal secretions from the children before they started receiving injections and after one year. RNA, a form of genetic material, has been extracted from nasal secretion cells and has been sequenced and analyzed to determine the activity of various gene networks. The study team also collected blood samples from participants at the start and end of the trial and a few times in between.
Asthma control improved in all study participants whether they received mepolizumab or a placebo. This suggests that by participating in the trial, the children benefited from frequent clinic visits and maintained better adherence to hand-held devices called asthma inhalers, which deliver standard medications to the lungs to relieve asthma symptoms. ‘asthma.
As expected, scientists found that mepolizumab safely and substantially reduced blood levels of eosinophils in children and adolescents after one year of treatment. However, this reduction translated into a relatively modest 27% decrease in the rate of asthma attacks compared to the placebo group.
To understand this result and explain why this effect is significantly weaker than what has been reported in adults(link is external) in other studies, researchers examined the activity levels of gene networks identified during MUPPITS-1 as associated with asthma attacks. They compared these activity levels between the mepolizumab and placebo groups and between the start and end of treatment. The researchers found that although mepolizumab significantly reduced the activity of three gene networks related to eosinophils, it did not reduce the activity of five gene networks related to tissue inflammation or one related to both to the activation of eosinophils and the overproduction of mucus.
These results partly explain why treatment with mepolizumab slightly reduced the risk of asthma attacks in the population of the MUPPITS-2 study. The results also identify potential future targets to further reduce asthma attacks in these children and adolescents. Importantly, by clearly illustrating how a variety of gene networks associated with airway inflammation play a role in asthma attacks in low-income urban youth, the MUPPITS-2 trial opens up the path to using gene activation patterns to monitor new asthma therapies in future clinical trials. in this population.
Additional information about the trial is available on ClinicalTrials.gov under study ID NCT03292588.
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DJ Jackson, et al. Mepolizumab for urban children with exacerbation-prone eosinophilic asthma in the United States (MUPPITS-2): a randomized, double-blind, placebo-controlled, parallel-group trial. The Lancet DOI: 10.1016/PIIS0140-6736(22)01198-9 (2022).