Annual Review of Medicine

Cystic Fibrosis Modulator

Therapies
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Shijing Jia1 and Jennifer L. Taylor-Cousar2

1
Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor,
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Michigan, USA; email: sjia@med.umich.edu

2
Divisions of Pulmonary Sciences and Critical Care Medicine and Pediatric Pulmonology,
National Jewish Health, Denver, Colorado, USA; email: Taylor-CousarJ@NJHealth.org

Annu. Rev. Med. 2023. 74:413–26 Keywords

First published as a Review in Advance on
cystic fibrosis, cystic fibrosis transmembrane conductance regulator, CFTR
August 16, 2022
modulators, modulator therapies
The Annual Review of Medicine is online at
med.annualreviews.org Abstract
https://doi.org/10.1146/annurev-med-042921-
Cystic fibrosis (CF) is an inherited multisystemic disease that can cause pro-
021447
gressive bronchiectasis, pancreatic endocrine and exocrine insufficiency, dis-
Copyright © 2023 by the author(s). This work is
tal intestinal obstruction syndrome, liver dysfunction, and other disorders.
licensed under a Creative Commons Attribution 4.0
International License, which permits unrestricted Traditional therapies focused on the treatment or prevention of damage to
use, distribution, and reproduction in any medium, each organ system with incremental modalities such as nebulized medica-
provided the original author and source are credited.
tions for the lungs, insulin for diabetes, and supplementation with pancreatic
See credit lines of images or other third-party
material in this article for license information. enzymes. However, the advent of highly effective modulator therapies that
target specific cystic fibrosis transmembrane conductance regulator protein
malformations resulting from individual genetic mutations has transformed
the lives and prognosis for persons with CF.

413
 CLINICAL MANIFESTATIONS
Cystic fibrosis (CF) is a genetic disease resulting from insufficient cystic fibrosis transmembrane
conductance regulator (CFTR) protein levels or function due to mutations in the CFTR gene on
chromosome 7 (1–3). As a result of defective or insufficient CFTR proteins in mucous membranes
throughout the body, salt and water dysregulation causes progressive damage within multiple
organ systems in which fluid transport is crucial to function. Thus, CF is a multisystem disease,
which most frequently affects the respiratory system (bronchiectasis, sinusitis), the pancreas
(CF-related diabetes in endocrine dysfunction, malabsorption in exocrine dysfunction), the
gastrointestinal tract (distal intestinal obstruction syndrome, biliary liver disease), the reproduc-
tive system (congenital absence of the vas deferens in men, decreased fertility in women), and
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electrolyte dysregulation (4, 5).

EPIDEMIOLOGY
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CF affects people of all races and ethnicities and is estimated to occur in ∼1:1,000 to ∼1:30,000 live
births depending on the genetic ancestry of the population (Figure 1) (6, 7). CF patient registries
in Europe and the United States include 82,000 people who have been diagnosed with CF (8,
9). The worldwide prevalence and incidence of undiagnosed disease are likely substantial due to
unrecorded cases in countries without robust diagnostic capabilities and patient registries, though
diagnosis rates are increasing with the expanded awareness of the disease in individuals who are
Black, Indigenous, or people of color (BIPOC). CF has been diagnosed with particularly increased
frequencies in Asia and Africa in recent years (10–12). Due to autosomal recessive inheritance,
significant portions of the world population (∼10 million in the United States) are asymptomatic
carriers of disease-causing CFTR mutations (8, 13).
The most common disease-causing mutation in CF individuals of European ancestry,
Phe508del (F508del, deletion of the phenylalanine at the 508 position of the protein), occurs in

Europe
1:1,300–25,000
North America
1:2,500–3,500 Asia
Middle East 1:4,000–35,000
1:2,500–16,000

Africa
~1:7,000

South America
1:3,500–8,500
Australia
1:2,900–3,200

Figure 1
Global prevalence of cystic fibrosis relative to live births. Estimations are based on data from References 1 and 2. Image of world map
from R-41, CC BY-SA 3.0, via Wikimedia Commons.

414 Jia • Taylor-Cousar

 >85% of the US CF population. It has been a major focus for drug development in the last several
decades due to the potential benefit to a large number of people with CF (8). However, BIPOC
individuals with CF are much less likely to have an F508del mutation and therefore are less likely
to be eligible for therapies directed at F508del (14, 15). Thus far, >2,000 mutations or variants
have been identified in the CFTR gene, including some known to cause disease and others with
uncertain clinical implications (16). New variants continue to be cataloged with increasing use of
genetic sequencing for diagnosis of disease.

PATHOPHYSIOLOGY
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The CFTR protein is a transmembrane ATPase [ATP-binding cassette (ABC)] that also functions
as an anion channel and is regulated by cAMP (cyclic adenosine monophosphate) and protein
kinase A phosphorylation (17, 18). Mutations may cause a variety of abnormalities in the CFTR
protein, ranging from protein folding defects (leading to mild decreases in ion transport efficiency
Annu. Rev. Med. 2023.74:413-426. Downloaded from www.annualreviews.org

at the cellular membrane) to complete absence of mature proteins due to the natural cellular
processing and degradation of aberrant proteins (5). CFTR ion channels are highly prevalent in
epithelial cells and serve as important ion and water regulators in multiple organ systems. Thus,
the severity of the protein defect often correlates with the severity of clinical disease (16).
To conceptualize and develop targeted therapies for the numerous genetic variants described
thus far, researchers have classified disease-causing mutations into six categories (19–21). Class I
mutations result from premature termination of transcription, as in the case of nonsense muta-
tions, some frameshift mutations, and some mRNA splice site mutations or deletions. As a result,
class I mutations cause severely decreased total CFTR protein levels and are typically associated
with severe disease. Class II mutations include the common F508del variant and thus account for a
large portion of clinical cases. These processing mutations cause misfolding of the CFTR protein,
which in turn leads to clearance of the abnormal products in the endoplasmic reticulum during
normal cellular processing and low amounts of mature CFTR protein being trafficked to the cell
surface. Furthermore, class II mutations probably cause additional folding abnormalities that de-
crease the function of any protein that is successfully trafficked to the cell membrane. Class III
mutations are termed gating mutations, which cause ineffective ion transport due to abnormali-
ties in the CFTR channel pore regulation. These mutations typically allow sufficient quantities
of CFTR protein at the cell surface. Class IV mutations are termed conduction mutations, with
reduced conductance across the ion channel. Like class III mutations, they result in decreased ion
transport across the channel despite preserved total surface protein. Class V mutations alter pro-
moter regions or splice sites and thus result in decreased total protein at the cell surface. Class VI
mutations lead to instability of the mature CFTR protein at the cell surface, resulting in increased
turnover of functional protein and decreased total ion transport in the cell.
While this classification system describes the broad categories of genetic defects, more recent
evidence suggests that many mutations exhibit features of more than one class (21). For exam-
ple, the well-studied F508del mutation is classified as a class II mutation but exhibits features of
class III and IV defects as well. This concept is confirmed clinically, since combination modulator
therapies designed to benefit multiple classes of mutations are more beneficial than single-agent
pharmacotherapy (22, 23). Thus, drugs that correct any CFTR defect may be beneficial for mul-
tiple classes of mutations.
Alternative classification systems have been employed as well. Residual function mutations
are those that enable enough CFTR protein expression at the cellular surface so that clinical
ramifications of disease are relatively mild, whereas minimal function mutations are those that
result in little to no functional protein. Although class II and III mutations are considered minimal

www.annualreviews.org • Cystic Fibrosis Modulator Therapies 415

 Cl–/HCO3–

Class IV
a S492F b
Class II Potentiator
ΔF508 Early Class III Restores or enhances
N1303K endosome channel gating
I-II II-VI Recycling
P67L Lysosome endosome
II-III-VI II-III
I-II-VI R117H
I-II- Class IV Stabilizer
I-II-III-VI W1282X
Class I I-V V
I-II-III Decreases surface
I-II-
V-VI I-III
Class III/IV protein turnover
I-II- TGN
I-V-VI I-II-III-V-VI III-V I-III-
I-VI G551D
V
G178R Corrector
I-II
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I-III-VI II-III- S549N Improves protein

V-VI II-III- Golgi
III-V
III-V-VI
V G551S Class II folding and
III-VI
II-V- G1244E ER trafficking
VI II-V S1251N CFTR
Class VI V-VI
S1255P Class I Read-through
G1349D Suppresses premature
Class V
stop codons
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Class V
Q1411X
Amplifier
Proteasome Stabilizes mRNA

Figure 2
(a) Mutations in CFTR account for complex protein expression defects spanning multiple classes. (b) Traditional classification of
protein defect classes and potential pharmacotherapeutics targeting each class of defect. Abbreviations: CFTR, cystic fibrosis
transmembrane conductance regulator; ER, endoplasmic reticulum; TGN, trans-Golgi network. Figure adapted from Reference 3 with
permission.

function mutations because of the lack of cell surface protein they cause, they do produce some
protein. In contrast, class I mutations, also considered minimal function mutations, are associated
with poor response to conventional modulator therapies. Because premature termination codons
(as well as frameshift and splice junction mutations) prevent translation of any protein to modulate,
CFTR modulator therapies are not an option for such mutations (Figure 2) (21).

PHARMACOLOGY OF DRUGS TARGETING MOLECULAR DEFECTS

CFTR modulators are small-molecule drugs that bind to the CFTR protein with specific site
affinity either during or after protein processing. There are several categories of therapies that
may ultimately increase the amount of CFTR protein available at the cell surface. These include
potentiators, correctors, read-through agents, amplifiers, and stabilizers (24). Potentiators and cor-
rectors are clinically available, while the development of the other categories of molecules is under
way. Potentiators enhance or restore ion channel activity and thereby improve chloride and bicar-
bonate transport across the CFTR protein. This class of drug is particularly effective for class III
and IV mutations, where the primary protein defect is related to ion channel dysregulation. Cor-
rectors bind to immature CFTR protein and assist in protein folding, processing, and trafficking
to the cellular membrane. This class of drug has so far shown effectiveness in specific mutations
such as F508del. Read-through agents target class I nonsense mutations by suppressing premature
stop codons. Amplifiers stabilize mRNA in order to increase immature CFTR protein production
and thus are postulated to work primarily in class V mutations but possibly could be a complemen-
tary part of combination therapy. Last, stabilizers theoretically improve the longevity of mature
protein at the cell membrane and counteract the impact of class VI mutations (Table 1).
Of these agents directed at improving available and functioning protein, drugs that work as
potentiators (e.g., ivacaftor) and/or correctors (e.g., lumacaftor, tezacaftor, elexacaftor) are now

416 Jia • Taylor-Cousar

 Table 1 CFTR mutation classes, examples, and potential pharmacotherapiesa
Class I Class II Class III Class IV Class V Class VI
Defect Protein synthesis Protein trafficking Channel gating Channel Reduced Plasma
conductance protein membrane
synthesis protein
stability
Example G542X F508del G551D R117H 3272–26A→G c. 120del123
mutation
Therapy Read-through, Corrector Potentiator Potentiator Amplifier Stabilizer
approach gene therapy
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Available None Elx/tez/iva Iva Iva None None

drug(s) Tez/iva
Lum/iva

a
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From Reference 24, Pharmacogenomics and Personalized Medicine 2022, 15:91–104, adapted and used with permission from Dove Medical Press Ltd.
Abbreviations: elx, elexacaftor; iva, ivacaftor; lum, lumacaftor; tez, tezacaftor.

commercially available and have transformed the lives of people with CF, dramatically improving
clinical outcomes (25–28). In the pre-modulator era of CF care, most therapeutic interventions
were aimed at decreasing the single-organ manifestations of CF. For example, inhaled hypertonic
saline and dornase alfa thinned sputum to improve airway clearance; antibiotics were frequently
used in repeated pulmonary exacerbations of bronchiectasis; pancreatic enzyme supplementation
was employed in those with exocrine pancreatic dysfunction; and insulin was increasingly required
as CF patients aged, due to progressive islet cell destruction related to pancreatic duct mucoid
plugging (29, 30). The discovery of modulators has led to a radical shift in the therapeutic approach
to CF because these drugs correct the CFTR protein dysfunction at the cellular level and thus have
the capacity to prevent the development of end organ damage related to ion and fluid imbalance
at the cellular level. The development, clinical results, and future directions of modulator therapy
and next-generation therapies are outlined chronologically below.

SINGLE-AGENT CFTR MODULATOR

Ivacaftor (VX-770) was approved by the US Food and Drug Administration (FDA) and European
Medicines Agency in 2012 for people with G551D mutations and became the first clinically avail-
able CFTR modulator (25). Ivacaftor is a potentiator that binds to the CFTR protein and increases
the time that the mature protein channel spends in the open configuration, thereby increasing ion
transport activity through the epithelial cell membrane (31–33). Due to its mechanism of action,
ivacaftor is highly effective in restoring the physiologic defect caused by gating, or class III, muta-
tions. However, the broad applicability of ivacaftor to a wide variety of CFTR protein defects was
rapidly recognized in subsequent preclinical and clinical studies (31, 34, 35). Indeed, ivacaftor in-
creased CFTR-dependent ion transport in G551D and F508del human bronchial epithelial cells
in vitro (35). Follow-up clinical trials showed remarkable clinical efficacy in people with G551D
mutations but not F508del mutations, likely due to the significant aberrations in F508del protein
processing that result in much lower quantities of mature CFTR protein at the cell surface (class II
and class VI features) (36–39).
In a phase III randomized controlled trial in people with at least one G551D gating mutation,
ivacaftor significantly improved pulmonary function as measured by percent predicted forced ex-
piratory volume in 1 sec (ppFEV1 ) (+10.6%, p < 0.001), respiratory symptom scores as measured
by the Cystic Fibrosis Questionnaire-revised (CFQ-R) (+8.6 points, p < 0.001, minimal clinically
important difference = 4.0), weight (+2.7 kg, p < 0.001), and decreased rates of exacerbations

www.annualreviews.org • Cystic Fibrosis Modulator Therapies 417

 (−55%, p < 0.001) (Table 1) (37, 40). Since regulatory approval based on this clinical trial for
people with G551D mutation, ivacaftor’s indications have been expanded in the United States to
other gating (class III) or conductance (class IV) mutations—or in other words, residual function
mutations—largely based on in vitro data (31, 41–44). The FDA has considered two key factors
that have allowed drug approval expansions without additional phase III clinical trials. First, in
vitro data assessment of modulator response per mutation has been highly predictive of clinical
outcomes (45). Second, due to the vast numbers of CFTR mutations in a relatively rare disease, it
would be infeasible to conduct clinical trials for additional mutations prior to clinical use, partic-
ularly for those mutations that occur in only a handful of people. This approach to drug develop-
ment and regulatory approval is transformative and speaks to the sense of urgency about bringing
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highly effective therapies to people with a life-limiting disease.

Unfortunately, in people homozygous for the F508del mutation, the use of a potentiator alone
did not improve CFTR function sufficiently to provide clinical benefit (38). As a class II mutation,
F508del results in several protein processing defects, including protein folding, trafficking, and cell
Annu. Rev. Med. 2023.74:413-426. Downloaded from www.annualreviews.org

surface turnover defects (39). While F508del seems to also cause conformational defects leading
to gating abnormalities, the singular effect of gating correction is not sufficient to restore function
to a clinically meaningful degree due to a scarcity of ion channels successfully transported to the
cellular membrane. The frequency of the F508del mutation varies across populations, but because
it is the most common mutation (with 84.7% of people with CF in the United States carrying at
least one copy), the focus of CFTR modulator development turned to correctors—drugs that
could increase the number of ion channels on the epithelial cell surface (46, 47).

DUAL COMBINATION CFTR MODULATORS

Although ivacaftor was a landmark success in CF care, much work remained, given the small num-
ber of people eligible for ivacaftor therapy. Gating and conductance mutations account for a small
fraction of the disease-causing mutations in people with CF. In 2014, only 7.0% of the US CF
population was eligible for ivacaftor (8). While this number increased with subsequent expansion
of indications by mutations, the number still remained small relative to the number of people
who were affected by a single mutation, F508del, which is estimated to affect 80–85% of the US
and European CF populations (8, 9). A primarily class II defect, F508del CFTR would require a
therapy that could improve trafficking of immature CFTR throughout the cell and functioning at
the cell membrane. High-throughput drug discovery techniques aided in identifying lumacaftor
(VX-809) as one of several eligible candidates for clinical testing (48, 49). Lumacaftor is a CFTR
corrector that works by improving the conformational stability within the first transmembrane
domain, thereby decreasing degradation of malformed CFTR protein in the endoplasmic reticu-
lum. Because F508del causes class III and IV defects in addition to class II processing abnormali-
ties in CFTR, combination drug therapy with lumacaftor-ivacaftor produces clinically meaningful
improvements compared to lumacaftor alone, which does not rescue protein dysfunction in a clin-
ically meaningful way in class III and IV defects (22, 50).
Phase III clinical trials showed that the dual combination corrector-potentiator CFTR mod-
ulator lumacaftor-ivacaftor significantly improved ppFEV1 (+2.6% to +4.0%, p < 0.001) and
decreased pulmonary exacerbations (−30% to −39%, p < 0.001) in people with CF homozygous
for F508del (23, 51). Lumacaftor-ivacaftor became the next CFTR modulator drug to achieve
regulatory approval for clinical use. It was approved by the FDA in 2015 for people with the ho-
mozygous F508del genotype, whereupon another 40–45% of CF individuals became eligible for
modulator therapy (8, 26). However, because these results were not as clinically robust as those
seen with ivacaftor for people with highly responsive gating and conductance mutations, the race

418 Jia • Taylor-Cousar

 to find a more effective treatment continued. Furthermore, as predicted by modest in vitro data,
lumacaftor-ivacaftor was not effective for people heterozygous for F508del and a minimal func-
tion mutation in a clinical study, leaving a large portion of the CF population without an available
modulator therapy (52).
Tezacaftor (VX-661) is a small molecule that has chemical similarities to lumacaftor and also
functions as a corrector by improving CFTR protein trafficking to the epithelial cell surface
(53). Tezacaftor has some advantages over lumacaftor, including fewer drug−drug interactions
(lumacaftor is a CYP3A4 enzyme inducer). Additionally, tezacaftor did not seem to be associated
with a clinical incidence of chest tightness, as was lumacaftor, which prompted some drug cessa-
tions of lumacaftor-ivacaftor in clinical practice (54).
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Two phase III studies of the dual combination tezacaftor-ivacaftor were conducted simulta-
neously. In people homozygous for F508del, tezacaftor-ivacaftor improved ppFEV1 (+4.0%, p <
0.001) and lowered the rate of pulmonary exacerbations (−35%, p = 0.005) compared to placebo
(55). In people who were heterozygous for F508del and a residual function mutation, including
Annu. Rev. Med. 2023.74:413-426. Downloaded from www.annualreviews.org

some people ineligible for ivacaftor at the time of the study, tezacaftor-ivacaftor improved ppFEV1
(+6.8%, p < 0.001) compared to placebo and (+2.1%, p < 0.001) compared to ivacaftor alone (44).
Based on these results, tezacaftor-ivacaftor was approved for clinical use in 2018 for any person
with CF having at least one F508del mutation or one of a subset of well-described residual func-
tion mutations. Expansions of mutation indications have followed, based on in vitro data (27).
These dual combination corrector-potentiator modulators confirmed the synergistic efficacy
of a multidrug approach to CFTR dysfunction, particularly due to the F508del mutation. Fur-
thermore, tezacaftor-ivacaftor allowed more people with CF to become eligible for modulator
therapy than lumacaftor-ivacaftor or ivacaftor alone. However, neither lumacaftor nor tezacaftor
is considered a highly effective modulator, given the modest clinical [ppFEV1, body mass index
(BMI), CFQ-R respiratory domain, sweat chloride, and pulmonary exacerbations] and preclinical
improvement in function in F508del patients compared to ivacaftor’s robust effect on gating and
conductance mutations. Furthermore, a significant portion (∼42%) of people with CF remained
ineligible for any modulator therapy (46, 52). Thus, the search continued for a highly effective
therapy that would impact most people with CF, particularly for a corrector synergistic with the
available dual combination modulators (Table 2).

TRIPLE COMBINATION CFTR MODULATOR

Elexacaftor (VX-445) is a corrector selected from several candidate small molecules evaluated in
preclinical and early clinical studies to determine clinical efficacy and side effect profiles (56–58).

Table 2 Summary of phase III clinical trials of CFTR modulators in people with CF age ≥12 yearsa
Modulator (reference) Mutation  ppFEV1 PEx RRR  Weight
Iva vs. placebo (37) G551D +10.6% 55% +2.8 kg
Lum/iva vs. placebo (23) F508del/F508del +2.8% 39% +0.24 kg/m2
Tez/iva vs. placebo (55) F508del/F508del +4.0% 35% +0.06 kg/m2
Tez/iva vs. placebo F508del/RF +6.8% 46%a +0.16 kg/m2b
Iva vs. placebo (44) +4.7% 54%a +0.29 kg/m2b
Elx/tez/iva vs. tez/iva (56) F508del/F508del +10.0% NDA NDA
Elx/tez/iva vs. placebo (57) F508del/MF +13.8% 62% +1.04 kg/m2

a
Data displayed are as compared to control group at the conclusion of each study.
b
Not statistically significant.
Abbreviations: elx, elexacaftor; iva, ivacaftor; lum, lumacaftor; NDA, no data available; PEx, pulmonary exacerbation; ppFEV1 , percent predicted forced
expiratory volume in 1 second; RRR, relative risk reduction; tez, tezacaftor.

www.annualreviews.org • Cystic Fibrosis Modulator Therapies 419

 When tested in triple combination, elexacaftor-tezacaftor-ivacaftor significantly improved CFTR
protein processing and trafficking in airway epithelial cells from people either homozygous for
the F508del mutation or heterozygous for the F508del mutation in combination with a minimal
function mutation. Tezacaftor was chosen over lumacaftor as the second corrector due to the
superior side effect and drug−drug interaction profiles.
The clinical availability of dual combination and single modulators made placebo-controlled
trials unethical for those already on approved therapy. Consequently, people with different classes
of mutations were enrolled in two separate phase III randomized controlled trials. In people with
CF ineligible for available modulator therapies, those heterozygous for a F508del and a minimal
function mutation, elexacaftor-tezacaftor-ivacaftor improved ppFEV1 (+14.3%, p < 0.001),
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respiratory symptom scores as measured by the CFQ-R (+20.2 points, p < 0.001), BMI
(+1.04 kg/m2 , p < 0.001), and decreased rates of pulmonary exacerbations (–63%, p < 0.001)
(59). These data show that the triple combination modulator was able to provide therapy to many
patients who had no available options at the time. Even more remarkably, when compared to
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dual combination tezacaftor-ivacaftor, the triple combination elexacaftor-tezacaftor-ivacaftor also

improved ppFEV1 (+10.0%, p < 0.0001) and CFQ-R respiratory symptom scores (+17.4 points,
p < 0.0001) in people homozygous for F508del (60). This degree of clinical response to the triple
combination drugs surpassed responses to ivacaftor in early clinical trials in people with CF with
the G551D mutation, sparking much enthusiasm in the CF community for a new, highly effective
modulator that would be available for the majority of people with CF.
Based on the results of these phase III studies, the triple combination CFTR modulator was
approved by the FDA through fast-track and orphan drug study status on October 21, 2019 (a
record 62 days after application), for people with at least one copy of F508del. With this approval,
therapy became available for an estimated 80–85% of individuals with CF (8, 28) (Figure 3). A
unique feature of these clinical trials was the efficiency within the design. Because of the thorough
understanding of CF disease, prior experience of modulator trials with 4-week ppFEV1 sustained
at 24- and 48-week extension studies, and the fact that blinded safety data could be obtained from
48-week extension study data in people heterozygous for F508del and minimal function mutations,
the clinical trial in homozygous F508del subjects was designed for a follow-up duration of only
4 weeks, an incredibly short period for a phase III clinical trial (23, 37, 55). This short duration
enabled rapid enrollment and more efficient use of resources including participant time and effort.
The successful conduct of an open-label clinical trial of elexacaftor-tezacaftor-ivacaftor in children
aged 6–11 years old demonstrated both safety and efficacy of the drug in this age group and led to
US CF patients eligible
for modulators (%)

80

60
Not prescribed
Total eligible
Prescribed
40

20

0
2011 2014 2016 2018 2020
Year
Figure 3
Proportions of the US cystic fibrosis (CF) population eligible for and prescribed modulator therapy in 2011,
2014, 2016, 2018, and 2020. Estimates are derived from data from the US CF Foundation patient registry (11).

420 Jia • Taylor-Cousar

 its approval in 2021 (61). Evaluation of elexacaftor-tezacaftor-ivacaftor in children aged 2–5 years
old is ongoing.

CLINICAL CONSIDERATIONS AND LONG-TERM OUTCOMES

Long-term outcomes are most abundantly available for ivacaftor in patients with residual function
mutations, due to the length of time since initial drug discovery and clinical availability. A 2-year
extension study of ivacaftor in subjects who were enrolled in the initial phase III trial showed
sustained benefit of the modulator (62, 63). Approximately 20% of subjects had adverse events
during the follow-up period, predominantly respiratory symptoms consistent with CF and occur-
ring at lower rates than in the placebo group. Liver function test abnormalities occurred at similar
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frequencies in the ivacaftor and placebo groups. However, due to the rates of elevated alanine
aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin, liver function testing is
recommended every 3 months during the first year of therapy with temporary cessation of drug
Annu. Rev. Med. 2023.74:413-426. Downloaded from www.annualreviews.org

if significant elevations are seen (25). Cataracts developed in juvenile rats receiving ivacaftor and
have been described in young children taking ivacaftor; thus, eye exams are recommended with
prescriptions to children taking ivacaftor or ivacaftor-containing modulators (i.e., all approved
modulator therapies) (25–28).
Subsequent real-world studies have highlighted the sustained benefit of highly effective mod-
ulator therapy with ivacaftor in those with responsive mutations, with a slower rate of pulmonary
function decline, fewer pulmonary exacerbations and hospitalizations, improved nutritional sta-
tus, and even some indication for lower rates of CF-related diabetes and restoration of pancreatic
exocrine function (64, 65). These data challenge prior notions that pulmonary and some extrapul-
monary tissue injury is nonreversible in CF and provide clues to the substantial long-term benefits
of highly effective modulator therapy.
While dual combination modulators lumacaftor-ivacaftor and tezacaftor-ivacaftor in F508del
homozygous populations did not perform as robustly as ivacaftor in individuals with highly
responsive mutations, long-term follow-up data showed a slower rate of pulmonary function
decline, a likely survival benefit over time (66–68). Since both drugs include ivacaftor, safety
concerns related to liver enzyme elevations and cataract development, particularly in youths,
apply (26, 27). Interestingly, study subjects experienced bronchospasm with lumacaftor-ivacaftor
leading to discontinuation, but not with tezacaftor-ivacaftor, a trend that continued post market
(23, 54). Lumacaftor is a strong inducer of CYP3A, a liver enzyme commonly involved in drug
metabolism (26). This creates complex drug–drug interactions with common agents such as
antifungal therapies and oral contraceptive drugs.
Due to the recency of clinical availability of the triple combination modulator elexacaftor-
tezacaftor-ivacaftor, long-term follow-up data on clinical efficacy and safety are not yet widely
available. The 24-week interim report of the extension trial showed sustained lung function
improvement, a continued increase in BMI, and continued increase in quality of life as mea-
sured by CFQ-R (69). Many investigations on the real-world outcomes in people prescribed
elexacaftor-tezacaftor-ivacaftor are also under way; topics of study include sinus disease, diabetes,
pregnancy, and the need for conventional therapies such as continued use of hypertonic saline
and dornase alfa (70–74). Most recent US registry data describe trends seen clinically across
many CF care centers (8). Over 80% of individuals were prescribed a modulator. Overall, people
with CF had a lower mortality rate, higher BMI, and higher ppFEV1 , and only 37% of the
volume of lung transplantations were performed in 2020 compared to 2019. In light of the
previously described experience with ivacaftor in people with highly responsive mutations, it is
tempting to speculate that dramatic long-term clinical benefits are likely to be observed with use
of elexacaftor-tezacaftor-ivacaftor (75).

www.annualreviews.org • Cystic Fibrosis Modulator Therapies 421

 The triple combination modulator has been associated with some intolerance, though most
side effects reported during the drug trial period were mild to moderate (59, 60). As in prior
modulator studies, almost all adverse events were equally reported between the intervention and
placebo groups. However, events with a higher occurrence in the elexacaftor-tezacaftor-ivacaftor
group included abdominal pain (14% in the triple combination group versus 9% in the placebo
group), diarrhea (13% versus 7%), rash (10% versus 5%), and increases in liver enzymes ALT,
AST, and bilirubin (5–10% versus 1–3%) (28). These trends appear consistent in clinical practice.
However, intolerance leading to drug cessation has been relatively rare, as was the case in clinical
trials.
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FUTURE DIRECTIONS
For the first time in history, according to US CF Foundation Patient Registry data, the median
predicted survival for an individual born with CF today is 50 years (8). Thus, what was once a
Annu. Rev. Med. 2023.74:413-426. Downloaded from www.annualreviews.org

disease of childhood will now require thoughtful management of complex disease in the setting of
an aging population. For example, consideration of cancer screening is now critical in a population
of patients who have, by the nature of their disease, been exposed to life-long immune function
dysregulation (76, 77). Additionally, while left-heart disease has been relatively rare in individuals
with CF to date, cardiac complications must now be considered and evaluated as people chronically
exposed to a high-fat diet for most of their lives begin to age (78). Finally, ∼30% of people with
CF have diabetes. To date, micro- and macrovascular complications have been rare, but their
incidence may increase with the increased longevity of people with CF (79, 80). On the other
hand, with the prospect of improved quality and quantity of life, the rate of pregnancies in women
with CF nearly doubled between 2019 and 2020, and an increasing number of CF individuals are
considering parenthood (8). Kazmerski and colleagues recently demonstrated that parenthood is
acutely associated with health decline in people with CF (81). Prospective studies designed to
assess potential areas of intervention for new parents with CF are needed.
Although the great strides we have made in the treatment of the majority of CF patients are
remarkable, our work is not yet done. First, based on CFTR mutation eligibility, the majority of
people with CF aged 6 years and older in the US are eligible for CFTR modulators, but BIPOC
individuals are overrepresented in the ∼10% of ineligible individuals, further contributing to
the many health inequities that exist for BIPOC individuals with CF (Figure 3) (15, 82). There
is variable response even to highly effective CFTR modulators, and some individuals cannot
tolerate their side effects (56, 59, 61). Additionally, infants and very young children who might
benefit the most from early initiation of highly effective CFTR modulators, with prevention
of disease complications, are not yet eligible for elexacaftor-tezacaftor-ivacaftor. Those who
are not eligible, those with suboptimal response, and those who cannot tolerate therapies rely
on continued development of the mainstays of CF therapy: agents that improve mucociliary
clearance, decrease inflammation and infection, and improve nutritional status (83).
Highly effective modulator therapy has conferred marked improvements in lung function, nu-
trition, quality of life, and pulmonary exacerbations that have changed the lives of many people
with CF. However, modulator therapy is not a cure for CF. For this reason, and to improve sur-
vival and daily life in those not benefiting from CFTR modulators, investigators are evaluating the
potential of nucleic acid therapies (84). Since the discovery of the CFTR gene in 1989, a number
of attempts to deliver a normal copy of the gene have failed. Yet, with improving technology, the
CF community is hopeful that renewed approaches will enable a definitive cure for everyone with
CF.

422 Jia • Taylor-Cousar

 DISCLOSURE STATEMENT
S.J. reports grants and clinical trial support from the Cystic Fibrosis Foundation (CFF), clinical
trial support from Insmed and Vertex Pharmaceuticals Inc., and honoraria from UpToDate. In
the last 12 months, J.L.T.-C. has received grants from Vertex Pharmaceuticals Inc. and Eloxx; has
received fees from Vertex Pharmaceuticals Inc. related to consultation on clinical research design,
participation on advisory boards, and speaking engagements; and has served on advisory boards
and/or provided consultation for Insmed, 4DMT, and AbbVie. She receives funding from the
CFF and serves on scientific advisory boards/grant review committees for the CFF and American
Thoracic Society.
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ACKNOWLEDGMENTS
The authors thank all of the individuals with CF and their families and care centers who have
contributed data and thus enabled the development of new therapies for people with CF.
Annu. Rev. Med. 2023.74:413-426. Downloaded from www.annualreviews.org

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Annual Review of
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Contents Volume 74, 2023

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COVID-19 and Kidney Disease

Maureen Brogan and Michael J. Ross p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
COVID-19 Thrombotic Complications and Therapeutic Strategies
Alexander C. Fanaroff and Renato D. Lopes p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p15
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COVID-19: Challenges of Viral Variants

Jana L. Jacobs, Ghady Haidar, and John W. Mellors p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p31
Post-COVID-19 Condition
Ani Nalbandian, Amar D. Desai, and Elaine Y. Wan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p55
SARS-CoV-2 Vaccination-Induced Thrombotic Thrombocytopenia:
A Rare but Serious Immunologic Complication
Charles S. Abrams and Geoffrey D. Barnes p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p65
Endocrine Disorders and COVID-19
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Cytomegalovirus Therapy: Role of Letermovir in Prophylaxis and
Treatment in Transplant Recipients
Jennifer L. Saullo and Rachel A. Miller p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p89
Gender-Affirming Care of Transgender and Gender-Diverse Youth:
Current Concepts
Janet Y. Lee and Stephen M. Rosenthal p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 107
Update in Adult Transgender Medicine
Alyxandra Ramsay and Joshua D. Safer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 117
New Frontiers in Obesity Treatment: GLP-1 and Nascent
Nutrient-Stimulated Hormone-Based Therapeutics
Ania M. Jastreboff and Robert F. Kushner p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 125
Advances and Applications of Polygenic Scores for Coronary
Artery Disease
Aniruddh P. Patel and Amit V. Khera p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 141
Valvular Heart Disease: New Concepts in Pathophysiology and
Therapeutic Approaches
Mackram F. Eleid, Vuyisile T. Nkomo, Sorin V. Pislaru, and Bernard J. Gersh p p p p p p p p p 155

v
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Myocardial Infarction with Nonobstructive Coronary Arteries

H.R. Reynolds and N.R. Smilowitz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 171
Lessons Learned from the ISCHEMIA Trial for the Management of
Patients with Stable Ischemic Heart Disease
William E. Boden and Peter H. Stone p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 189
Maternal Mortality in the United States: Trends and Opportunities
for Prevention
Siwen Wang, Kathryn M. Rexrode, Andrea A. Florio, Janet W. Rich-Edwards,
and Jorge E. Chavarro p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 199
Access provided by 2803:1800:5006:a0e2:199e:4f5:df7c:7e02 on 05/04/23. See copyright for approved use.

Primary Aldosteronism and the Role of Mineralocorticoid Receptor

Antagonists for the Heart and Kidneys
Jordana B. Cohen, Irina Bancos, Jenifer M. Brown, Harini Sarathy,
Annu. Rev. Med. 2023.74:413-426. Downloaded from www.annualreviews.org

Adina F. Turcu, and Debbie L. Cohen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 217

Adeno-Associated Virus Gene Therapy for Hemophilia
Benjamin J. Samelson-Jones and Lindsey A. George p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 231
Clonal Hematopoiesis and Its Impact on Human Health
Herra Ahmad, Nikolaus Jahn, and Siddhartha Jaiswal p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 249
Hepcidin and Iron in Health and Disease
Elizabeta Nemeth and Tomas Ganz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 261
Multispecific CAR T Cells Deprive Lymphomas of Escape
via Antigen Loss
Fateeha Furqan and Nirav N. Shah p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 279
FGFR2 Inhibition in Cholangiocarcinoma
Arndt Vogel, Oreste Segatto, Albrecht Stenzinger, and Anna Saborowski p p p p p p p p p p p p p p p p 293
Regulation of Erythropoiesis by the Hypoxia-Inducible Factor
Pathway: Effects of Genetic and Pharmacological Perturbations
Gregg L. Semenza p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 307
Cytokine Storm Syndrome
Randy Q. Cron, Gaurav Goyal, and W. Winn Chatham p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 321
Systemic Lupus Erythematosus: New Diagnostic and Therapeutic
Approaches
Stephanie Lazar and J. Michelle Kahlenberg p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 339
Genetics of Kidney Disease: The Unexpected Role of Rare Disorders
Mark D. Elliott, Hila Milo Rasouly, and Ali G. Gharavi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 353
SGLT2 Inhibitors: The Sweet Success for Kidneys
Atit Dharia, Abid Khan, Vikas S. Sridhar, and David Z.I. Cherney p p p p p p p p p p p p p p p p p p p p p 369

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ME74_FrontMatter ARjats.cls December 6, 2022 14:53

Use of Race in Kidney Function Estimation: Lessons Learned and the

Path Toward Health Justice
Dinushika Mohottige, Opeyemi Olabisi, and L. Ebony Boulware p p p p p p p p p p p p p p p p p p p p p p p p p 385
Origins of Racial and Ethnic Bias in Pulmonary Technologies
Michael W. Sjoding, Sardar Ansari, and Thomas S. Valley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 401
Cystic Fibrosis Modulator Therapies
Shijing Jia and Jennifer L. Taylor-Cousar p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 413
Club Cell Secretory Protein in Lung Disease: Emerging Concepts
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and Potential Therapeutics

Tereza Martinu, Jamie L. Todd, Andrew E. Gelman, Stefano Guerra,
and Scott M. Palmer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 427
Annu. Rev. Med. 2023.74:413-426. Downloaded from www.annualreviews.org

Chronic Neuromuscular Respiratory Failure and Home Assisted

Ventilation
Hugo Carmona, Andrew D. Graustein, and Joshua O. Benditt p p p p p p p p p p p p p p p p p p p p p p p p p p p 443
Biological Phenotyping in Sepsis and Acute Respiratory
Distress Syndrome
Pratik Sinha, Nuala J. Meyer, and Carolyn S. Calfee p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 457
Diverse Approaches to Gene Therapy of Sickle Cell Disease
Shanna L. White, Kevyn Hart, and Donald B. Kohn p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 473
Exome/Genome Sequencing in Undiagnosed Syndromes
Jennifer A. Sullivan, Kelly Schoch, Rebecca C. Spillmann, and Vandana Shashi p p p p p p p p 489
All the Tau We Cannot See
Bradley Hyman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 503

Indexes

Cumulative Index of Contributing Authors, Volumes 70–74 p p p p p p p p p p p p p p p p p p p p p p p p p p p 515

Cumulative Index of Article Titles, Volumes 70–74 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 519

Errata

An online log of corrections to Annual Review of Medicine articles may be found at

http://www.annualreviews.org/errata/med

Contents vii