Cystic fibrosis remains an incurable genetic disorder that impairs lung function and significantly reduces life expectancy. A new combination drug therapy that addresses the underlying defects of the disorder offers a promising new treatment approach. The use of this therapy had previously been limited to adolescents and adults. Designed to meet the highest standards of clinical practice, a study co-led by Charité – Universitätsmedizin Berlin has now confirmed that this combination therapy regimen is also beneficial for primary school-aged children. Earlier treatment means that the progression of the disease is likely to be slowed significantly. The researchers’ findings have been published in the American Journal of Respiratory and Critical Care Medicine.
Characterized by the accumulation of thick, sticky mucus, cystic fibrosis, also known as mucoviscidosis, is the most common fatal genetic disease in Germany. A defect in the CFTR ion channel (which is found on the surface of airway epithelial cells and transports salt and water) disrupts the normal fluid balance, resulting in highly viscous mucus. Cystic fibrosis primarily affects the lungs, which become clogged with this viscous mucus and are therefore less effective at removing pathogens. The result is chronic infection and inflammation of the airways, progressively impaired lung function and difficulty breathing. In severe cases, a lung transplant may be necessary. People affected by the disease used to die before reaching adulthood. Currently, the average life expectancy is about 55 years. These gains in life expectancy are mainly due to improved symptomatic treatment.
Drugs that target not only the symptoms of the disease but also its underlying molecular defects by improving the function of the CFTR channel, known as CFTR modulators, became available only a few years ago. In about 90 percent of cystic fibrosis patients, the underlying CFTR channel defect is caused by a specific error in the CFTR gene known as the F508del mutation. A triple therapy combining three CFTR modulators (elexacaftor, tezacaftor and ivacaftor) has been available in Europe since August 2020. In patients with one copy of the F508del mutation, this triple combination therapy can restore ion channel function to approximately half of the normal level, so producing notable improvements in lung function and quality of life. “It was a milestone in the treatment of cystic fibrosis,” explains the first author, Professor Dr. Marcus Mall, Head of the Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine at Charité and the Center for Cystic Fibrosis at Charité. He adds: “Unfortunately, until now this treatment was only available to patients aged 12 and over. This is because, traditionally, new drugs are tested first and then approved for use in adults. What we want to do, but is to administer this causal treatment as early as possible in the course of the disease in order to prevent irreversible lung damage. This, of course, is only possible if treatment begins in childhood. What we have been able to do now is demonstrate that this can be done safely and very effectively in primary school-aged children.”
Professor Mall and his international research partners studied the effects of this triple combination therapy in 121 children with cystic fibrosis. Participants were between 6 and 11 years of age and had at least one copy of the F508del mutation. The children were randomized to receive the triple combination regimen or placebo for a duration of approximately six months. The study, which was carried out at centers in ten different countries, was designed as a randomized controlled trial – the gold standard in clinical research. “This type of clinical study remains a rarity in pediatric drug development,” says Professor Mall, Einstein Professor at Charité and head of cystic fibrosis research at the German Lung Research Center (DZL). “The inclusion of control groups is often neglected in pediatric research. Instead, data from adults are used to extrapolate effects from adults to children. But children are not just small adults. Therefore, studies of high quality are crucial for the development of safe and effective drugs for children.”
Their recently published study showed that the treatment significantly improved the function of the CFTR channel, thereby improving the children’s lung function and quality of life. The treatment had a good overall safety profile and was well tolerated, with side effects comparable to those seen in older patients. “I was surprised and pleased to see that, even early in the course of the disease and despite the short duration of treatment, the children experienced remarkable improvements,” says Professor Mall. “These findings contributed to the European Medicines Agency’s decision to extend the marketing authorization for this triple combination regimen to include children aged 6 and over. This means we are now in a position to treat children of this age group. I hope that early initiation of treatment targeting the disease-causing defect will produce significant improvements in the long-term health of cystic fibrosis patients.”
As a next step, the research team plans to test whether the drug combination might be suitable for use in even younger children. Since cystic fibrosis is part of the newborn screening program, the disease can now be diagnosed within the first few weeks of life. “This would put us in a position to start a causal treatment for cystic fibrosis as early as early childhood, which we hope will prevent even early-stage damage to the lungs and possibly even other organs such as the pancreas. Very gradually, we are working our way closer to this goal. Currently, we are testing the safety and effectiveness of this triple combination therapy in children between 2 and 5 years old,” explains the Prof. Mal.
Source:
Charité – Medical University of Berlin
Journal reference:
10.1164/rccm.202202-0392OC