Introduction
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators improve the function of the CFTR chloride channel in epithelial cells throughout the body, thereby decreasing sweat chloride, and improving lung function and growth parameters in many people with CF (pwCF). The number of pwCF eligible for modulators has continued to increase over the past several years due to the addition of compounds to the class. Ivacaftor (iva) is a potentiator that increases the flow of chloride ions through the CFTR protein channel. After the approval of iva for the G551D mutation in 2012, the expansion of this drug for the use of other gating mutations followed. In subsequent years, the cystic fibrosis (CF) community saw the addition of two drugs for people with CF (pwCF) homozygous for F508del, lumacaftor/ivacaftor (lum/iva) in 2015, currently available for pwCF ≥ 2 years old and tezacaftor/ivacator (tez/iva) in 2018, currently available for pwCF ≥ 6 years old. Most recently, in October 2019 elexacaftor/tezacaftor/ivacaftor (ETI) was approved by the FDA in the US for patients ≥ 12 years with at least one copy of F508del. During 2020, expansion has continued, with iva expanding to infants ≥ 4 months of age1 and to an additional 59 mutations, for a total of 97 mutations, based on both clinical data and in vitro cell data2. While iva mutations were expanded, tez/iva eligibility was also increased by 127 mutations for a total of 154 responsive mutations, and ETI was broadened to an additional 177 mutations beyond F508del2.
This review will focus on the literature related to CFTR modulators published in 2020. Topics include the use of CFTR modulators in pwCF with FEV1 percent predicted (FEV1pp) <40% or ≥90%; in prior studies often these groups of patients were excluded. CFTR modulator effects on alternative mutations, worldwide populations, gender differences, and fertility are reported. The effect of CFTR modulators on other outcomes is also evaluated, including intestinal organoids, pancreatic function, and diabetes. Real world experience through case reports of side effects, adherence, and current cost effectiveness are examined. Finally, next steps for clinical trials in an environment where modulators have been developed for ~90% of pwCF, but are not equally available, are highlighted. Research on other potential therapies is important so that all pwCF will have a highly effective therapy available to them.