A team of scientists has found that triple combination therapy may help reduce lung inflammation in patients with the hereditary disease cystic fibrosis (CF), and achieve positive, long lasting improvements in symptoms in many of the sufferers.
Two years ago, the German researchers, led by Charité-Universitätsmedizin Berlin and the Max Delbrück Centre, showed that combination therapy involving three drugs – elexacaftor, tezacaftor, and ivacaftor – was effective in a large portion of patients with cystic fibrosis, the treatment noticeably improving both lung function and quality of life.
Now, the team headed by Professor Marcus Mall, who has been the lead researcher in both studies, has investigated whether this form of treatment is also helpful in the long term, over a period of 12 months or more.
To examine this, the researchers took a closer look at the sputum, the secretions from patients’ respiratory tracts.
“In patients with cystic fibrosis, the mucus in the airways is very sticky because it doesn't contain enough water and the mucins, the molecules that form mucus, adhere too much due to their chemical properties.
“This results in thick, sticky mucus, which clogs the airways, making it harder for patients to breathe and leading to chronic bacterial infection and inflammation of the lungs,” said Mall, director of the Department of Paediatric Respiratory Medicine, Immunology and Critical Care Medicine and the Christiane Herzog Cystic Fibrosis Center at Charité.
In the current study, the researchers show that a combination of elexacaftor, tezacaftor, and ivacaftor results in less viscous respiratory secretions, decreasing inflammation and bacterial infection in the lungs of CF patients.
“What’s more, the effects lasted over the entire one-year study period. This is really important because previous medications caused a rebound in the bacterial load in the airways,” said Dr Simon Gräber, who also works in the Department of Paediatric Respiratory Medicine, Immunology and Critical Care Medicine at Charité and was one of the co-leaders of the study.
A total of 79 adolescents and adults with CF and chronic lung disease participated in the trial.
Major step in treatment
“This is a major step forward in treating CF,” said Mall. “At the same time, it would be premature to say patients have been normalised, let alone cured. Chronic lung changes arising over many years of living with the disease cannot be reversed, unfortunately.”
This means patients with advanced lung disease will still need to rely on established treatments involving inhaling mucus-thinning medications, taking antibiotics, and physical therapy.
“We plan to forge ahead with our research on how to make, even more effective, the treatments tackling cystic fibrosis via the molecular defects that cause the disease – like the triple medication combination studied here. This includes starting treatment in early childhood with the goal of preventing chronic lung changes wherever possible,” added Mall.
“Aside from that, this therapy is not available to about 10% of our patients right now due to their genetic conditions,” said Gräber. “That’s why we are also researching new molecular treatments so we can treat all people with CF effectively.”
They are also working to advance their understanding of mucus defects in cystic fibrosis and develop new mucolytics, drugs that thin and loosen the mucus. This research could also benefit patients with common chronic inflammatory lung diseases, such as asthma and COPD.
Cystic fibrosis
Cystic fibrosis is one of the most common fatal hereditary diseases worldwide, with as many as 8 000 children, teens, and adults afflicted by the disease in Germany. An imbalance in salt and water transport across mucosal surfaces of the body causes people with cystic fibrosis to produce thick, sticky secretions that harm organs such as the lungs, intestine and pancreas.
This leads to progressive loss of lung function and shortness of breath, which still significantly lowers life expectancy despite advances in treatment. Some 150 to 200 children are born with this rare disease in Germany each year.
A combination of elexacaftor, tezacaftor, and ivacaftor became available in Europe in August 2020. The therapy noticeably improves lung function and quality of life in patients with the most common genetic defect involved in CF, F508del. This means the treatment is an option for nearly 90% of those living with CF. The combination therapy was approved for children starting at the age of six years in early 2022.
Study details
Longitudinal Effects of Elexacaftor/Tezacaftor/Ivacaftor on Sputum Viscoelastic Properties, Airway Infection and Inflammation in Patients with Cystic Fibrosis.
Laura Schaupp, Simon Graeber, Marcus Mall, et al.
Published in the European Respiratory Journal Volume 62, 2023.
Abstract
Background
Recent studies demonstrated that the triple combination CFTR modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) improves lung function and reduces pulmonary exacerbations in CF patients with at least one F508del allele. However, effects of ETI on downstream consequences of CFTR dysfunction, i.e. abnormal viscoelastic properties of airway mucus, chronic airway infection and inflammation have not been studied. The aim of this study was, therefore, to determine the longitudinal effects of ETI on airway mucus rheology, microbiome and inflammation in CF patients with one or two F508del alleles aged 12 years and older throughout the first 12 months of therapy.
Methods
In this prospective observational study, we assessed sputum rheology, the microbiome, inflammation markers and proteome before and 1, 3 and 12 months after initiation of ETI.
Results
In total, 79 patients with CF and at least one F508del allele and 10 healthy controls were enrolled in this study. ETI improved the elastic modulus and viscous modulus of CF sputum at 3 and 12 months after initiation (all p<0.01). Further, ETI decreased the relative abundance of Pseudomonas aeruginosa in CF sputum at 3 months and increased the microbiome α-diversity at all timepoints. ETI also reduced IL-8 at 3 months (p<0.05) and free NE activity at all timepoints (all p<0.001), and shifted the CF sputum proteome towards healthy.
Conclusions
Our data demonstrate that restoration of CFTR function by ETI improves sputum viscoelastic properties, chronic airway infection and inflammation in CF patients with at least one F508del allele over the first 12 months of therapy, however, without reaching levels close to healthy.
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