Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
Cystic fibrosis (CF), a genetic disease with autosomal-recessive inheritance, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.1 Abnormally thick, sticky mucus causes blockage in several organ systems, most commonly the airways and digestive tract.1,2 Complications of this disease include nutritional deficiencies, osteoporosis, infertility, and dehydration manifesting as low blood pressure, increased heart rate, and fatigue.3
CF has no known cure; however, the progress made in diagnosing the disease early, together with newly available treatments, has improved overall survival, and many patients with CF reach adulthood.3,4 CF is characterized by dysfunction in multiple organs, but the main cause of morbidity and mortality is lung disease.2 The goals of treatment in CF are to prevent and control lung infections, reduce and remove the thick mucus that builds up in the lungs and airways, prevent intestinal blockage, and provide calories and nutrients sufficient to ensure an adequate nutritional status.3
Several medications can be prescribed for a patient with CF. Antibiotics are used to prevent or treat lung infections, bronchodilators and mucus thinners to clear mucus from the lungs, and CFTR modulators to correct the underlying cause of CF.5
Inhaled therapies such as albuterol and levalbuterol hydrochloride are commonly prescribed for patients with CF to relax the muscles and open the airways.6 Bronchodilator therapy makes it easier for other drugs, such as mucus thinners and antibiotics, to reach the airways, and it facilitates airway clearance techniques. Bronchodilators are administered with specific devices that release controlled doses, and also with nebulizers and dry powder inhalers.6
Mucus thinners are typically administered after bronchodilators and facilitate the removal of mucus from the airways.7 The drug Pulmozyme® (dornase alfa) thins and loosens mucus in the airways to prevent lung infections.7,8 Other mucus thinners, such as hypertonic saline, hydrate the airways and break down mucus, with long-term beneficial effects on lung function in patients with CF.9,10
Read more about mucus thinners for cystic fibrosis
As thick mucus accumulates within the airways, removal becomes difficult. Therefore, susceptibility to infection increases because microorganisms are not eliminated.11,12 Pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus are isolated from patients with CF, and antibiotics such as penicillins, aminoglycosides, tetracyclines, and cephalosporins are commonly prescribed.13 Recommendations for the administration of antibiotics in CF include intermittent dosing (28 days on/28 days off) and switching between 2 inhaled antibiotics; these practices may benefit patients with severe disease.14
Read more about antibiotics used to treat cystic fibrosis
CFTR modulators are disease-modifying therapies targeting specific defects in the CFTR protein that are the underlying cause of CF. These drugs modulate the activity of CFTR protein so that normal chloride transport is restored.15
Currently, 4 CFTR modulators have been approved by the US Food and Drug Administration (FDA) for patients who have CF associated with specific mutations: Kalydeco® (ivacaftor), Orkambi® (lumacaftor/ivacaftor), Symdeko® (tezacaftor/ivacaftor), and Trikafta® (elexacaftor/tezacaftor/ivacaftor).15
CFTR modulators are classified as potentiators when they function to keep the CFTR channel open and allow chloride to flow through the cell membrane (eg, ivacaftor), and as correctors when they improve the trafficking of CFTR protein to the cell surface (eg, lumacaftor, elexacaftor, and tezacaftor).16 Ivacaftor was the first CFTR modulator to demonstrate efficacy in a phase 3 clinical trial.17 Like other CFTR potentiators, it was discovered after a high-throughput screening campaign.18 The subsequent development of the corrector lumacaftor and its combination with ivacaftor was a significant breakthrough in CF therapy that made it possible to target the p.Phe508del mutation, the most common CFTR mutation in CF.17
Read more about specific disease-modifying treatments for cystic fibrosis
Two additional groups of CFTR modulators have been identified: amplifiers and stabilizers. Amplifiers increase CFTR mRNA expression and consequently the expression of immature CFTR protein.16 The first molecule studied within this group was nesolicaftor (PTI-428, Proteostasis).16 Stabilizers increase the half-life of the CFTR channel and prevent its premature degradation. Cavosonstat (N91115, Nivalis Therapeutics) is one of the molecules that has been shown to stabilize the CFTR channel.16
Some side effects associated with the administration of CFTR modulators include headache, nasal congestion, upper respiratory tract infection, abdominal pain, dizziness, nasopharyngitis, and liver dysfunction.2
1. Cystic fibrosis. National Organization for Rare Disorders (NORD). Accessed January 24, 2022.
2. Jaques R, Shakeel A, Hoyle C. Novel therapeutic approaches for the management of cystic fibrosis. Multidiscip Respir Med. 2020;15(1):690. doi:10.4081/mrm.2020.690
3. Rafeeq MM, Murad HAS. Cystic fibrosis: current therapeutic targets and future approaches. J Transl Med. 2017;15(1):84. doi:10.1186/s12967-017-1193-9
4. De Boeck K. Cystic fibrosis in the year 2020: a disease with a new face. Acta Paediatr. 2020;109(5):893-899. doi:10.1111/apa.15155
5. Medications. Cystic Fibrosis Foundation. Accessed January 24, 2022.
6. Bronchodilators. Cystic Fibrosis Foundation. Accessed January 24, 2022.
7. Mucus thinners. Cystic Fibrosis Foundation. Accessed January 24, 2022.
8. PULMOZYME® (dornase alfa) inhalation solution. Prescribing information. Genentech; 2021.
9. Shteinberg M, Haq IJ, Polineni D, Davies JC. Cystic fibrosis. Lancet. 2021;397(10290):2195-2211. doi:10.1016/S0140-6736(20)32542-3
10. Elkins MR, Robinson M, Rose BR, et al, National Hypertonic Saline in Cystic Fibrosis (NHSCF) Study Group. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med. 2006;354(3):229-240. doi:10.1056/NEJMoa043900
11. Morrison CB, Markovetz MR, Ehre C. Mucus, mucins, and cystic fibrosis. Pediatr Pulmonol. 2019;54(Suppl 3):S84-S96. doi:10.1002/ppul.24530
12. Research into mucus. Cystic Fibrosis Foundation. Accessed January 24, 2022.
13. Antibiotics. Cystic Fibrosis Foundation. Accessed January 24, 2022.
14. Kapnadak SG, Dimango E, Hadjiliadis D, et al. Cystic Fibrosis Foundation consensus guidelines for the care of individuals with advanced cystic fibrosis lung disease. J Cyst Fibros. 2020;19(3):344-354. doi:10.1016/j.jcf.2020.02.015
15. CFTR modulator therapies. Cystic Fibrosis Foundation, Accessed January 24, 2022.
16. Gramegna A, Contarini M, Aliberti S, Casciaro R, Blasi F, Castellani C. From ivacaftor to triple combination: a systematic review of efficacy and safety of CFTR modulators in people with cystic fibrosis. Int J Mol Sci. 2020;21(16):5882. doi:10.3390/ijms21165882
17. Ramsey BW, Davies J, McElvaney NG, et al. CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-1672. doi:10.1056/NEJMoa1105185
18. Mall MA, Mayer-Hamblett N, Rowe SM. Cystic fibrosis: emergence of highly effective targeted therapeutics and potential clinical implications. Am J Respir Crit Care Med. 2020;201(10):1193-1208. doi: 0.1164/rccm.201910-1943SO
Reviewed by Debjyoti Talukdar, MD, on 1/25/2022.