“Woe to that child which when kissed on the forehead tastes salty. He is bewitched and soon must die.” This old midwife’s adage was still being used in the early 20th century. The excessively salty sweat is caused by cystic fibrosis, Germany’s most common fatal genetic disorder. In this disease, a defective ion channel in the mucosal cells means the transport of salt and water via the surfaces of the mucous membranes does not function properly, which results in overly viscous secretions. In the lungs, this causes the respiratory tract to become blocked with thick mucus, leading to chronic infection and inflammation with progressive deterioration of lung function. But other organs are also affected, including the pancreas, the intestine, the liver, the male sex organs, and the skin’s sweat glands. About one in every 2,500 to 3,500 children born in the Western world is affected by CF.
Cystic fibrosis was long a childhood disease
“In the past, cystic fibrosis was typically treated by a pediatrician, because most patients died before they reached adulthood,” explains Professor Marcus Mall, head of the Department of Pediatrics, Division of Pneumology, Immunology, and Critical Care Medicine, and of the Christiane Herzog Cystic Fibrosis Center at the Charité. “However, life expectancy is still significantly shorter and many suffer from an enormous disease burden.”
Current therapy primarily targets the symptoms of the disease: Special physiotherapy and inhalation therapy helps patients to cough up the viscous mucus from their lungs, antibiotics prevent infections, missing digestive enzymes are administered by medication, and a particularly high-fat diet counteracts malnutrition. So far, attempts to use gene therapy to introduce the correct gene into the cells of those affected have been unsuccessful.
Discovery of the gene defect enables targeted treatment
Thirty years ago, U.S. researchers led by Francis Collins, the current director of the National Institutes of Health (NIH), discovered the disease-causing gene (called the CFTR gene). They were able to show that the disease can be caused by over 2,000 different errors in the CFTR gene, but that most patients with cystic fibrosis are affected by one particular defect – the so-called F508del mutation. This common mutation leads to serious malfunction and a particularly severe disease progression. In recent years, new drugs have been developed with the aim of correcting the malfunction of the CFTR channel (so-called CFTR modulators). “However, such correctional therapy was particularly difficult for the main mutation, F508del, because it causes several different molecular changes that could not be effectively targeted with a single drug,” explains Marcus Mall, lead author of the recently published study.
Triple combination may significantly help 90 percent of all sufferers
By combining three active substances (elexacaftor, tezacaftor, and ivacaftor), a way has now been found to effectively influence the various molecular defects. The study, which involved 403 participants at over 80 study centers in North America, Europe, and Australia, showed this triple combination therapy led to a noticeable and sustained improvement in the health of the patients treated. A major advantage of this new triple therapy is that the presence of only one F508del mutation is sufficient to achieve significant therapeutic success. In the study, for example, patients with only one F508del mutation experienced a significant and sustained improvement of lung function, a decrease in so-called pulmonary exacerbations, and a noticeably higher quality of life. The sweat test was so positive that the authors assume the CFTR channel of these treated patients reaches about 50 percent of normal function. The study showed this triple therapy to be safe and well tolerated. Undesirable side effects leading to treatment discontinuation were observed in 1 percent of the patients treated.
"The results of the study suggest that in the future, we will be able to use this new triple therapy to treat up to 90 percent of all CF patients,” explains Mall. “This is a breakthrough in the treatment of this genetic disorder, which has so far usually resulted in early death.” Professor Francis Collins, co-discoverer of the CFTR gene and director of the NIH, provides an accompanying editorial in The New England Journal of Medicine where he describes the results of the study as “realizing the dream of molecularly targeted therapies for cystic fibrosis.”
From a fatal to a treatable disease
The U.S. Food and Drug Administration (FDA) approved the new triple combination therapy in the United States for patients 12 years or older with cystic fibrosis who have at least one F508del mutation in the CTFR gene. It granted the application both Fast Track and Breakthrough Therapy Designation to speed up the approval process. An important task in coming years will be to make the therapy available, especially to young CF patients. “We see a big opportunity in using a preventative therapy, ideally in infancy, to significantly delay or even prevent the onset of the lung disease, thus transforming cystic fibrosis from a fatal to a treatable disease,” says Marcus Mall. “We also have to develop just as effective therapies for the some 10 percent of CF patients whose mutations don’t respond to the new triple combination therapy, so that in the future all people with the disease can be treated successfully.”
*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