Treatments for cystic fibrosis are evolving. Here’s a look at new CFTR modulator therapies including the most recent approval-elexacaftor/tezacaftor/ivacaftor (Trikafta).
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
Lumacaftor/ivacaftor (Orkambi) is a combination therapy FDA-approved for individuals aged 2 years and older with 2 F508del copies. Approximately 44% of individuals with CF are homozygous for this mutation.1 Lumacaftor is known as a corrector therapy, working to increase the amount of CFTR protein that reaches the surface of cells. When used in conjunction with ivacaftor, there is significant improvement in the amount of chloride that can flow through the CFTR protein, which ultimately leads to clinical improvements in lung function (measured in percentage of predicted forced expiratory volume (ppFEV1), and a decrease in pulmonary exacerbations and need for intravenous antibiotic treatment, as well as improvements in nutritional status.8 Notably, respiratory adverse effects such as dyspnea and chest tightness have been reported with initiation of lumacaftor/ivacaftor, but it is generally well tolerated.9
Tezacaftor/ivacaftor (Symdeko) is an improved combination therapy FDA-approved for individuals aged 6 years and older with 2 copies of F508del or individuals with 1 of 26 other specified mutations. Tezacaftor/ivacaftor has been associated with improvements in lung function and lower rates of pulmonary exacerbations with a low rate of discontinuation attributed to adverse effects.10 Additionally, there are fewer drug-drug interactions than lumacaftor/ivacaftor, avoiding the need for temporary discontinuation due to other therapies, such as antifungals and oral contraceptives.
TRIPLE COMBINATION OR “NEXT-GENERATION” MODULATOR
Elexacaftor/tezacaftor/ivacaftor (Trikafta): Although CFTR modulator therapy has revolutionized CF care, individuals with certain heterozygous F508del genotypes were un able to receive these highly effective modulator therapies. In October 2019, the FDA approved the use of a triple-combination therapy for individuals aged 12 years and older with at least 1 F508del mutation. This twice-daily therapy, administered as 2 tablets in the morning and 1 in the evening, will allow nearly 90% of individuals with CF to benefit from highly effective CFTR modulator therapy that targets the underlying cause of disease.
Trikafta has been shown in clinical trials to result in dramatic improvement in key clinical disease measures. Individuals receiving Trikafta demonstrated a mean treatment difference of almost 14% in ppFEV1 at week 4 of therapy compared with placebo and an increase in 10% compared with treatment with tezacaftor/ivacaftor.11 Lung function improvement was sustained through 24 weeks of treatment. Individuals receiving Trikafta experienced a lower annualized rate of pulmonary exacerbations, including those requiring hospitalization or intravenous antibiotics, as well as sustained improvements in body mass index. Importantly, there was also a significant improvement in patient-reported quality of life, as measured by the Cystic Fibrosis Questionnaire-revised.12
Trikafta has been shown to be safe with potentially fewer adverse effects noted than with prior modulators. Notable drug-drug interactions include antifungal medications, certain antibiotics (such as rifampin or rifabutin), several seizure medications, and St. John’s wort. Similar to all CFTR modulators, Trikafta should be administered with fatty foods to help improve absorption. Quarterly monitoring of liver function testing in the first year of treatment and annual eye examinations are recommended to monitor for gastrointestinal (GI) complications, as well as the possibility of cataracts.
These CFTR modulators have heralded a new era of personalized medicine and life-prolonging therapies for an increased number of individuals with CF (Figure 2). Studies are now under way to assess the long-term effects of Trikafta as well as the possibility of simplifying daily treatment burden. As of the 2018 Cystic Fibrosis Foundation Patient Registry report, more than 50% of individuals living with CF are aged older than 18 years and the median life expectancy continues to rise.1
There is hope that CFTR modulators will help to continue to improve median life expectancy. Nevertheless, it is important to note that these therapies do not reverse existing disease, and approximately 10% of individuals presently do not qualify for any of the available CFTR modulator therapies based on their genotypes.1 The availability of mutation-specific modulators has brought new hope to individuals with CF and their families, but the search continues to find modulator therapies to benefit all individuals with all CFTR mutations.
Note from Dr. Lee:
The Cystic Fibrosis (CF) Foundation’s partnership with the pharmaceutical industry has significantly impacted patients with this lethal disorder by making CFTR-modifying drugs available. We look forward to the anticipated positive outcomes on morbidity and mortality for CF. Partnerships with pharma may serve as the way to accelerate the development of medicines for other disease where therapies are limited and/or less effective.
- Carlton Lee, PharmD, MPH, FASHP. FPPAG
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.