On December 20, 2019, Beijing time, Science magazine unveiled its list of the Top 10 Breakthroughs of 2019, with the inclusion of drug therapy for treating a significant majority of cystic fibrosis cases.

Cystic fibrosis (CF) is a common fatal autosomal recessive genetic disorder among Caucasians, caused by mutations or genetic polymorphisms in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). This results in the formation of thick mucus in the lungs, digestive tract, and other parts of the body, leading to severe respiratory and digestive problems, as well as other complications such as infections and diabetes.

In 1938, the characteristic symptoms of CF were first discovered by American pathologist Dorothy Andersen during the autopsy of malnourished children. She observed cystic dilation of pancreatic ducts and extensive fibrosis in some of these children, which she described as "cystic fibrosis of the pancreas," thus giving cystic fibrosis its name and discovery. Prior to the recognition of cystic fibrosis as a medical condition, there existed an old superstition: "When kissing a child's forehead and sensing a salty taste, it was believed that the child had been cursed and would not live long." The increased sodium chloride content in sweat is a hallmark of this disease, and the method of testing skin sweat for salt content to detect CF in patients is still used today. The average chloride content in the sweat of normal infants is 30-40 mmol/L, with an average sodium content of approximately 60 mmol/L. In contrast, CF children have an average chloride content in their sweat as high as 105-125 mmol/L, and an average sodium content of approximately 120 mmol/L. This is due to mutations or polymorphisms in the CFTR gene, leading to the loss of function of the CFTR chloride ion transmembrane transport protein that it encodes.

The development of small molecule drugs targeting the cause of cystic fibrosis began with Aurora's screening of 230,000 compounds using advanced cellular assay platforms at the time. They discovered VX-770, a drug that can act on the G551D mutation site on the CFTR protein. VX-770 can reduce the frequency of respiratory infections and improve respiratory function in patients. In 2012, after just three months of review, the FDA approved the first drug developed specifically for the cause of cystic fibrosis, Kalydeco (ivacaftor, also known as VX-770), for the treatment of cystic fibrosis patients carrying the G551D gene mutation. In July 2015, the FDA approved the first combination therapy for cystic fibrosis, Orkambi (ivacaftor/lumacaftor), for the treatment of cystic fibrosis patients aged 6 and above who have two copies of the F508del mutation.

In October 2019, scientists celebrated a milestone achievement in gene therapy, which was also featured as one of the Top 10 Breakthroughs of the year by Science: the FDA approved the innovative therapy Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor) in less than three months for the treatment of cystic fibrosis patients aged 12 and older who carry at least one F508del gene mutation.

Trikafta incorporates a third drug into the mix, enhancing the effectiveness of the strategy. This triple combination targets CF patients with at least one copy of the F508del mutation, helping CFTR reach the cell membrane. In clinical trials, the drug increased lung function by 10% to 15% and delayed the onset of CF complications. The Trikafta triple-drug combination therapy can correct the most common mutation associated with lung disease. Trikafta has the potential to transform CF from a progressive disease into a more manageable chronic condition for patients.

Trikafta consists of three active ingredients. Among them, elexacaftor is a new-generation CFTR protein corrector that restores the function of CFTR proteins carrying the F508del mutation, thereby improving patients' respiratory function. Tezacaftor enhances the function of CFTR proteins by increasing their transport to the cell surface, while ivacaftor improves the function of defective CFTR proteins by prolonging the open time of CFTR proteins on the cell surface.

Since CF is a disease caused by the deletion or dysfunction of CFTR proteins due to mutations in the gene that encodes CFTR, leading to multi-organ damage, Trikafta triple therapy represents a groundbreaking treatment option for patients with cystic fibrosis carrying common gene mutations. However, for the complications often associated with CF, additional supportive drug therapy is also necessary. For instance, the primary causes of death among CF patients are chronic airway infections and respiratory failure, with the most common pathogens being Staphylococcus aureus, Pseudomonas aeruginosa, or other Gram-negative bacilli. Among these, Pseudomonas aeruginosa is the most commonly colonized bacterium in the airways and can cause the most severe symptoms. Tobramycin has been approved by the FDA for nebulized inhalation therapy to treat Pseudomonas aeruginosa infections in cystic fibrosis. Aztreonam has also been approved by the FDA to improve respiratory symptoms in cystic fibrosis patients infected with Pseudomonas aeruginosa. Additionally, other antibiotics such as macrolides, penicillins, cephalosporins, and quinolones are also used.

While Trikafta triple therapy is a significant advancement and a great boon for CF patients, there is also a shadow cast over this excitement. The price tag for Trikafta exceeds $300,000 per year, and it must be taken for life.

References:

[1] US. Food and Drug Administration, FDA approves new breakthrough therapy for cystic fibrosis, 21 October 2019

[2] What Medications are Used for Cystic Fibrosis? FDA Approves First Triple Therapy
https://new.qq.com/rain/a/20191030A0OBH3

[3] Just Now, Science Announces the Top 10 Scientific Breakthroughs of 2019!
https://mp.weixin.qq.com/s/JEoYF9WjFZNwfMdiw_gPkw

[4] H. Heijerman et al., "Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial," The Lancet, Vol. 394, p. 1940, 23 November 2019.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.