Cystic fibrosis remains an incurable genetic disease that impairs lung function and significantly reduces life expectancy. A new combination drug therapy that addresses underlying disease defects offers a promising new therapeutic approach. The use of this therapy was previously 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 treatment regimen is also beneficial for children of primary school age. Earlier treatment means the progression of the disease is likely to be significantly slowed. The researchers’ findings were published in the American Journal of Respiratory and Critical Care Medicine.
Characterized by the buildup of thick, sticky mucus, cystic fibrosis, also known as cystic fibrosis, is the most common fatal genetic disease in Germany. A defect in the CFTR ion channel (which sits on the surface of airway epithelial cells and transports salt and water) disrupts the normal fluid balance, resulting in highly viscous mucus. Cystic fibrosis mainly damages the lungs, which become clogged with this viscous mucus and thus become less efficient in eliminating pathogens. The result is chronic infection and inflammation of the airways, progressive impairment of lung function and difficulty breathing. In severe cases, a lung transplant may become necessary. Those affected by the disease died before reaching adulthood. Today, the average life expectancy is around 55 years. These gains in life expectancy are mainly due to improved symptomatic treatments.
Drugs that target not only the symptoms of the disease, but also its underlying molecular defects by improving the function of CFTR channels – known as CFTR modulators – only became available a few years ago. In approximately 90% of CF patients, the underlying CFTR channel defect is caused by a specific defect 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 carrying one copy of the F508del mutation, this triple therapy can restore ion channel function to approximately half the normal level , producing notable improvements in lung function and quality of life. “This was an important step in the treatment of cystic fibrosis,” says 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 from the Charité. He adds: “Unfortunately, until now, this treatment was only accessible to patients aged 12 and over. Indeed, traditionally, new drugs are first tested and then authorized in adults. we want to do, however, is to administer this causal treatment as early as possible in the course of the disease in order to avoid irreversible lung damage.This is of course only possible if the treatment begins during childhood. What we have been able to do now is show that this can be done both safely and very effectively in children of primary school age.”
Professor Mall and his international research partners studied the effects of this triple therapy in 121 children with cystic fibrosis. The participants were between the ages of 6 and 11 and had at least one copy of the F508del mutation. The children were randomized to receive either the triple combination diet or a placebo for approximately six months. The study, which was conducted at centers in ten different countries, was designed as a randomized controlled trial – the gold standard of clinical research. “This type of clinical study remains too rare in pediatric drug development,” says Professor Mall, Einstein Professor at the Charité and head of cystic fibrosis research at the German Lung Research Center (DZL). “The inclusion of control groups is often overlooked in pediatric research. Instead, adult data are used to extrapolate effects from adults to children. But children are not just small adults. Studies of high quality are therefore crucial for the development of safe and effective medicines for children.”
Their recently published study showed that the treatment significantly improved CFTR channel function, improving 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 both surprised and delighted to see that, even so early in the disease trajectory and despite the short duration of treatment, the children experienced noticeable improvements,” says Professor Mall. “These findings contributed to the decision of the European Medicines Agency to extend the marketing authorization of this triple combination regimen to include children aged 6 years and over. This means that we are already able to treat children in this age group. I expect that earlier initiation of treatment targeting the causative disease defect will produce significant improvements in the long-term health of CF 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 in the first weeks of life. “This would put us in a position to start causative treatment for CF in early childhood, which would hopefully prevent even early-stage damage to the lungs and possibly even other organs like the pancreas. Very gradually “, we are working our way we are getting closer to this objective. Currently, we are testing the safety and effectiveness of this triple therapy in children aged 2 to 5 years, “explains Professor Mall.
Charity – Berlin University Medicine