A deadly disease becomes treatable
A joint press release by Charité and the BIH
According to clinical trial results published by an international team of researchers co-led by Charité – Universitätsmedizin Berlin and the Berlin Institute of Health (BIH), a new triple combination therapy has been shown to be highly effective in the treatment of patients with cystic fibrosis. In patients with the most common causative genetic defect (F508del), the new treatment resulted in unprecedented improvements in both lung function and quality of life. As the treatment is not symptomatic but targeted at the underlying defect, its early use in children may be able to prevent the onset of lung disease. The research has been published in the New England Journal of Medicine*.
At the beginning of the 20th century, traditional midwife wisdom held that “a child whose brow tastes salty when kissed will soon die”. The characteristic salty taste was caused by Germany’s most common lethal hereditary disease, cystic fibrosis. The disease, caused by abnormalities in the way salt and fluid is transported across epithelial membranes, is characterized by excessively viscous mucus secretions. In addition to causing airway obstruction, these thick secretions also cause chronic lung infection and inflammation, as well as a progressive decline in lung function. The disease also impairs the function of other organs, such as the pancreas, bowel and liver, as well as the male reproductive organs and sweat glands in the skin. Approximately one in 2,500 to 3,000 newborn infants born in the Western world are affected by the disease. It is caused by a defect in the CFTR gene, which produces abnormalities in the function of a specific ion channel found in epithelial cells. So far, researchers have discovered more than 2,000 individual CFTR gene defects capable of causing cystic fibrosis. The most common defect, known as the F508del mutation, is found in approximately 90 percent of patients with cystic fibrosis.
“Cystic fibrosis was once a purely pediatric disease, as most patients died before they reached adulthood,” explains the study’s joint first author, BIH and Einstein Professor Dr. Marcus Mall, who is also the Director of the Department of Pediatrics, Division of Pneumonology, Immunology and Intensive Medicine and of Charité’s Christiane Herzog Cystic Fibrosis Center. He adds: “Thankfully, things have changed, and most patients will now live into adulthood. However, life expectancy remains significantly reduced and, for many patients, the disease burden is extremely high.”
Previous treatments had been primarily symptomatic in nature: special physiotherapy and inhaled therapies help patients to clear and cough up thick secretions from their lungs; antibiotics help to control infections; medications replace missing digestive enzymes; and a high fat diet helps to combat malnutrition. Researchers across the globe have also been striving to develop treatment strategies which address the underlying cause of the disease. Attempts to use gene therapy to deliver non-defective CFTR genes into the cells of patients have so far proved unsuccessful. A different approach, however, appears to have delivered rather promising results. The approach involves ‘CFTR modulators’, drugs capable of correcting the abnormal function of the CFTR channel. “Correcting this abnormality proved particularly difficult in patients with the F508del mutation, as this mutation results in several different molecular defects, which could not be corrected using a single drug,” explains Prof. Mall.
The combined use of three separate drugs (elexacaftor, tezacaftor and ivacaftor), has now been shown to be effective in influencing the various molecular defects involved. A total of 403 patients with at least one (of a possible two copies) of the F508del mutation took part in the study and were recruited from more than 100 study centers in North America, Europe and Australia. Use of the triple combination therapy resulted in a substantial and sustained improvement in patients’ health when compared with placebo. Based on the analysis of sweat salt concentration, the authors estimated that, in treated patients, CFTR channel function reached approximately 50% of the level found in healthy individuals. In addition to being shown to be safe, the triple combination therapy was also shown to be generally well tolerated by patients. Side effects resulting in treatment withdrawal were recorded in just one percent of treated patients.
Explaining the significance of the results, Prof. Mall says: “Study results suggest that this new triple combination therapy will be suitable for use in up to 90% of patients with cystic fibrosis. Among experts, this is being heralded as a breakthrough in the treatment of a previously fatal disease.” He adds: “The development a preventive treatment for cystic fibrosis, ideally one suitable for use from infancy, would represent a major opportunity to significantly delay – or even entirely prevent – the onset of cystic fibrosis lung disease, effectively turning a previously fatal disease into a treatable one. However, this will still leave approximately ten percent of patients for whom there is no similarly effective causal therapy. Our future research will therefore focus on finding an effective treatment option for this group of patients.”
The U.S. Food and Drug Administration (FDA) has approved the new triple combination therapy for patients 12 years and older with at least one F508del mutation in the CFTR gene. The approval was granted in a fast-track procedure following an expedited review. The application for a Europe-wide marketing authorization has been submitted.
*Middleton PG and Mall MA et al., Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Eng J Med. doi: 10.1056/NEJMoa1908639
Prof. Dr. Marcus Mall
Director of the Department of Pediatrics, Division of Pneumonology, Immunology and Intensive Medicine
Charité – Universitätsmedizin Berlin
Tel: +49 30 450 566 131
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