Cystic fibrosis (CF) is an autosomal recessive genetic disorder characterized by chronic and progressive obstructive lung disease, sinusitis, pancreatic exocrine insufficiency leading to malabsorption and malnutrition, liver disease, and CF-related diabetes mellitus. The disease affects approximately 30,000 individuals in the United States and 70,000 persons worldwide.1 The care of individuals with CF has evolved significantly since it was first described in 1938.2 Earlier diagnosis through universal newborn screening, therapies to improve lung health and prevent exacerbations, a focus on optimization of nutritional status, aggressive treatment of chronic respiratory infections, and lung transplantation all have led to significant improvements in overall survival, with the current predicted median survival of 47.4 years.1
Cystic fibrosis results from deleterious genetic variants in the CFTR gene, which encodes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The CFTR gene was first discovered in 1989, and different mutations in the CFTR gene result in functional changes to the CFTR protein, grouped into 6 distinct classes3 (Figure 1). The different defects in CFTR protein lead to absent or malfunctioning chloride channels in apical membranes of the lung surface and glandular epithelium causing mucus to be thick and sticky, and resulting in chronic cough and lung infections, bronchiectasis, chronic sinusitis, pancreatic and liver dysfunction, as well as reduced fertility. Whereas there are more than 2000 different disease-causing mutations, approximately 90% of individuals with CF have at least 1 copy of F508del, the most common CFTR mutation.4,5
The ability to identify CFTR gene mutations has allowed for the development of therapies that target the basic genetic defects that cause the disease, known as CFTR modulator therapies. These therapies allow patients to receive treatments tailored to their individual mutations and have contributed greatly to improvements in quality of life, overall health, and survival. This article discusses the evolution of CFTR modulator therapies, with a focus on the most recently approved therapy—elexacaftor/tezacaftor/ivacaftor (Trikafta).
Current CF modulator therapies
Ivacaftor (Kalydeco): In 2012, the first modulator, ivacaftor, was approved by the US Food and Drug Administration (FDA) for the treatment of CF. Ivacaftor is known as a potentiator therapy because it binds to the defective CFTR protein at the cell surface and helps to keep chloride channels open so that chloride is better able to flow through the surface of the cell.6 It was initially approved exclusively for individuals with the G551D mutation, the third most common mutation (approximately 5% of the CF population). Through in vitro testing and clinical trials, the FDA has now expanded approval to 38 mutations, allowing individuals with lower prevalence mutations to benefit from modulator therapies. Ivacaftor is approved for use in individuals aged 6 months and older. Long-term studies have shown that ivacaftor use is associated with reduced mortality and rates of lung transplantation.7
1. Cystic Fibrosis Foundation Patient Registry. 2018 Patient Registry Annual Data Report. Bethesda, Maryland. Available at: https://www.cff.org/Research/Researcher-Resources/Patient-Registry/2018-Patient-Registry-Annual-Data-Report.pdf. Published August 2019. Accessed January 13, 2020.
2. Andersen DH. Cystic fibrosis of the pancreas and its relation to celiac disease. Am J Dis Child. 1938;56(2):344-399.
3. Kerem B, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989;245(4922):1073-1080.
4. US Cystic Fibrosis Foundation, Johns Hopkins University. CFTR2 website. Available at: http://cftr2.org/. Updated August 2016. Accessed January 13, 2020.
5. Dorfman R, for the CFMD/CFTR1 Team. Cystic fibrosis mutation database [Internet]. Available at: http://www.genet.sickkids.on.ca/StatisticsPage.html. Updated April 25, 2011. Accessed January 13, 2020.
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7. Bessonova L, Volkova N, Higgins M, et al. Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor. Thorax. 2018;73(8):731-740.
8. Wainwright CE, Elborn JS, Ramsey BW, et al; TRAFFIC Study Group; TRANSPORT Study Group. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe50del CFTR. N Engl J Med. 2015;373(3):220-231.
9. Jennings MT, Dezube R, Paranjape S, et al. An observational study of outcomes and tolerances in patients with cystic fibrosis initiated on lumacaftor/ivacaftor. Ann Am Thorac Soc. 2017;14(11):1662-1666.
10. Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med. 2017;377(21):2013-2023.
11. Middleton PG, Mall MA, Drevinek P, et al. Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with single Phe508del allele. N Engl J Med. 2019;381(19):1809-1819.
12. Quittner AL, Buu A, Messer MA, Modi AC, Watrous M. Development and validation of The Cystic Fibrosis Questionnaire in the United States: a health-related quality-of-life measure for cystic fibrosis. Chest. 2005;128(4):2347-2354.