Triple combination therapy shows promise in long-term treatment of cystic fibrosis

Mucus in the airways is not as sticky, inflammation in the lungs is significantly reduced: triple therapy can produce these positive and lasting effects in patients with cystic fibrosis (CF). Researchers from Charité – Universitätsmedizin Berlin and the Max Delbrück Center have just published their findings in the European Respiratory Journal. According to their research, this form of the drug improves the symptoms of cystic fibrosis in many patients.

Two years ago, a research group led by Charité showed that a combination therapy involving three drugs – elexacaftor, tezacaftor and ivacaftor – is effective in a large proportion of patients with cystic fibrosis, an inherited disease, which means that treatment significantly improves both lung function and quality of life. Now the team led by Professor Marcus Mall, who was the principal investigator in both studies, has investigated for the first time whether this form of treatment is also useful in the long term, i.e. over a period of 12 months or more. To examine this, the researchers took a closer look at sputum, the secretions from the patients’ airways. “In patients with cystic fibrosis, the mucus in the airways is very sticky because it does not contain enough water and mucins, the molecules that form mucus, adhere too much due to their chemical properties. This results in mucus thick and sticky, which clogs the airways, making it harder for patients to breathe and leading to chronic bacterial infection and inflammation of the lungs,” says Mall, director of the Department of Pediatric Respiratory Medicine, Immunology and Medicine at intensive care and the Christiane Herzog cystic fibrosis center at Charité.

In the current study, researchers show that a combination of elexacaftor, tezacaftor, and ivacaftor results in less viscous respiratory secretions and decreased inflammation and bacterial infection in the lungs of patients with cystic fibrosis. “Furthermore, the effects lasted throughout the one-year study period. This is really important because the previous drugs caused a rebound in the bacterial load in the airways,” says Dr. Simon Gräber, who also works in the Department of Pediatric Respirology. Medicine, Immunology and Critical Care Medicine at Charité and was one of the co-leaders of the study. 79 adolescents and adults with cystic fibrosis and chronic lung disease participated in the trial.

A major step in the treatment of cystic fibrosis, important additional research

“This is a major breakthrough in the treatment of cystic fibrosis,” Mall said. “At the same time, it would be premature to say that patients have been normalized, let alone cured. The chronic lung changes that occur over many years of living with the disease unfortunately cannot be reversed.” This means that patients with advanced lung disease will still have to rely on established treatments involving inhaled antimucosal medications, antibiotics, and physical therapy.

“We plan to move forward with our research into how to make treatments that treat cystic fibrosis via the molecular defects that cause the disease – like the triple drug combination studied here – even more effective. This includes the initiation of treatment in infancy with the goal of preventing chronic lung changes whenever possible,” Mall notes. “Other than that, this therapy is currently not available to about ten percent of our patients due of their genetic conditions,” adds Gräber. “That is why we are also working hard on research involving new molecular treatments in order to be able to effectively treat all people with cystic fibrosis.”

Researchers are also working to advance their understanding of mucus defects in cystic fibrosis and to develop new mucolytics, drugs that thin and loosen 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 inherited diseases in the world. Up to 8,000 children, adolescents and adults live with the disease in Germany today. An imbalance in the transport of salt and water across the mucous surfaces of the body causes people with cystic fibrosis to produce thick, sticky secretions that damage organs such as the lungs, intestine, and pancreas. This leads to a progressive loss of lung function and shortness of breath, which further significantly reduces life expectancy despite advances in treatment. Some 150 to 200 children are born each year with this rare disease in Germany.

About triple therapy

A combination of three drugs – elexacaftor, tezacaftor and ivacaftor – became available in Europe in August 2020. The therapy significantly improves lung function and quality of life in patients with the most common genetic abnormality implicated in cystic fibrosis, F508del. This means that treatment is an option for almost 90% of people with cystic fibrosis. The combination therapy was approved for children from the age of six in early 2022.