A monoclonal antibody, mepolizumab, cut asthma attacks by 27% in black and Hispanic children and adolescents with severe asthma living in low-income urban neighbourhoods, found a National Institutes of Health clinical trial, which said this population has been under-represented in previous clinical trials of asthma therapeutics.
The study investigators undertook an innovative exploratory analysis of gene activity in cells collected from study participants’ nasal secretions at the beginning and end of the trial to try to help explain how mepolizumab works and link this to its clinical effect.
The antibody tamped down the activity of three networks of genes associated with airway inflammation and asthma attacks in the study population but did not reduce the activity of six other such networks, reports MedicalXpress.
“Asthma exacts a heavy toll, especially on disadvantaged school-aged children of colour who live in urban areas,” said Dr Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health and sponsor of the trial, which was published in The Lancet. “This study’s results indicate that more research is needed to develop therapies that substantially reduce asthma attacks among these children.”
Asthma is caused by chronic inflammation of the airways. During an asthma attack, the airway lining swells, muscles around the airways contract, and the airways produce extra mucus, substantially narrowing the space for air to move in and out of the lungs. An estimated 2.3m US children and adolescents experienced an asthma attack in 2019, according to the US Centres for Disease Control and Prevention (CDC).
Black and Hispanic children who live in low-income urban environments in America are at particularly high risk for asthma that is prone to attacks. 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, MUPPITS-1, investigators identified multiple networks of functionally related genes that are activated together and linked to asthma attacks in children and adolescents living in low-income urban settings. Some of these genetic networks are specifically associated with cells called eosinophils.
Many people with untreated asthma have a high level of eosinophils in the blood and airways. These cells are thought to increase airway inflammation, which leads to tissue damage, making breathing more difficult.
Mepolizumab, marketed by GlaxoSmithKline as Nucala, is approved by the US Food and Drug Administration (FDA) to treat people ages six years and older with eosinophilic asthma and has been shown to reduce blood levels of eosinophils. The investigators hypothesised that mepolizumab would suppress the eosinophil-specific gene networks associated with asthma attacks in black and Hispanic urban youth with eosinophilic asthma, thereby reducing the number of asthma attacks in this population. They further hypothesised that by analysing asthma-associated gene networks 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 enrolled 290 children ages 6 to 17 whose asthma was difficult to control, prone to attacks, and characterised by high blood levels of eosinophils: 70% were black, 25% were Hispanic, and all lived in low-income areas in nine cities. They were assigned at random to receive an injection of either mepolizumab or a placebo every four weeks for 12 months. No one knew who 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, part of NIH.
The study team collected nasal secretions from the children before they began receiving injections and at the end of one year. RNA, a form of genetic material, was extracted from cells in the nasal secretions and sequenced and analysed to determine the activity of various gene networks. Blood samples were also taken at the start and end of the trial and a few times in between.
Asthma control improved in all study participants, regardless of whether they received mepolizumab or placebo. This suggests that by participating in the trial, the children benefited from frequent clinic visits and maintained better adherence to hand-held asthma inhalers, which deliver standard medication to the lungs to ease asthma symptoms.
As expected, the scientists found mepolizumab safely and substantially reduced blood levels of eosinophils among participants after a year of treatment. However, this translated into a relatively modest 27% decrease in the rate of asthma attacks compared with the placebo group.
To understand this result and explain why this effect is significantly lower than what has been reported in adults in other studies, the researchers examined activity levels of the networks of genes 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 investigators found that although mepolizumab significantly suppressed the activity of three eosinophil-related gene networks, it did not reduce the activity of five gene networks related to tissue inflammation nor of one related to both eosinophil activation and overproduction of mucus.
These findings partially explain why mepolizumab therapy modestly decreased the risk of asthma attacks in the MUPPITS-2 study population. The findings also identify potential future targets for further reducing asthma attacks among these children and adolescents. Importantly, by clearly illustrating how various gene networks associated with airway inflammation play a role in asthma attacks in low-income urban youth, the MUPPITS-2 trial paves the way for using gene activation patterns to monitor new asthma therapies in future clinical trials in this population.
Study details
Mepolizumab for urban children with exacerbation-prone eosinophilic asthma in the USA (MUPPITS-2): a randomised, double-blind, placebo-controlled, parallel-group trial.
Daniel Jackson, Leonard Bacharier, Peter Gergen, Lisa Gagalis, Agustin Calatroni,Stephanie Wellford, Michelle Gill, Jeffrey Stokes, Andrew Liu, Rebecca Gruchalla, Robyn Cohen, Melanie Makhija, Gurjit Khurana Hershey, George O'Connor, Jacqueline Pongracic, Michael Sherenian, Katherine Rivera-Spoljaric, Edward Zoratti, Stephen Teach, Meyer Kattan, Cullen Dutmer, Haejin Kim, Carin Lamm, William SheehanR Max SegnitzKimberly Dill-McFarland, Cynthia Visness, Patrice Becker, James Gern, Christine Sorkness, William Busse, Matthew Altman on behalf of the US National Institute of Allergy and Infectious Disease’s Inner City Asthma Consortium
Published in The Lancet on 13 August 2022
Summary
Background
Black and Hispanic children living in urban environments in the USA have an excess burden of morbidity and mortality from asthma. Therapies directed at the eosinophilic phenotype reduce asthma exacerbations in adults, but few data are available in children and diverse populations. Furthermore, the molecular mechanisms that underlie exacerbations either being prevented by, or persisting despite, immune-based therapies are not well understood. We aimed to determine whether mepolizumab, added to guidelines-based care, reduced the number of asthma exacerbations during a 52-week period compared with guidelines-based care alone.
Methods
This is a randomised, double-blind, placebo-controlled, parallel-group trial done at nine urban medical centres in the USA. Children and adolescents aged 6–17 years, who lived in socioeconomically disadvantaged neighbourhoods and had exacerbation-prone asthma (defined as ≥two exacerbations in the previous year) and blood eosinophils of at least 150 cells per μL were randomly assigned 1:1 to mepolizumab (6–11 years: 40 mg; 12–17 years: 100 mg) or placebo injections once every 4 weeks, plus guideline-based care, for 52 weeks. Randomisation was done using a validated automated system. Participants, investigators, and the research staff who collected outcome measures remained masked to group assignments. The primary outcome was the number of asthma exacerbations that were treated with systemic corticosteroids during 52 weeks in the intention-to-treat population. The mechanisms of treatment response were assessed by study investigators using nasal transcriptomic modular analysis. Safety was assessed in the intention-to-treat population.
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Findings
Between 1 November 2017, and 12 March 2020, we recruited 585 children and adolescents. We screened 390 individuals, of whom 335 met the inclusion criteria and were enrolled: 290 met the randomisation criteria, were randomly assigned to mepolizumab (n=146) or placebo (n=144), and were included in the intention-to-treat analysis. 248 completed the study. The mean number of asthma exacerbations within the 52-week study period was 0·96 (95% CI 0·78–1·17) with mepolizumab and 1·30 (1·08–1·57) with placebo (rate ratio 0·73; 0·56–0·96; p=0·027). Treatment-emergent adverse events occurred in 42 (29%) of 146 participants in the mepolizumab group versus 16 (11%) of 144 participants in the placebo group. No deaths were attributed to mepolizumab.
Interpretation
Phenotype-directed therapy with mepolizumab in urban children with exacerbation-prone eosinophilic asthma reduced the number of exacerbations.
MedicalXpress article – Monoclonal antibody reduces asthma attacks in urban youth (Open access)
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