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.