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
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.
6. Ramsey BW, Davies J, McElvaney G, et al; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-1672.
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.