Treatment, prognosis, and quality of life for people with cystic fibrosis (CF) have improved steadily since the initial description of the disease, but most dramatically in the past decade. In 2021, the median predicted survival increased to 53 years, compared with 17 years in 1970. The recent improvement in outcomes is attributable to the advent of cystic fibrosis transmembrane regulator (CFTR) modulators, small molecules that enhance the function of defective CFTR protein. The first CFTR modulator, ivacaftor, received Food and Drug Administration approval in 2011 to treat a single CFTR variant, comprising only 4% of those affected by CF. With the demonstration of efficacy, drug approval has been expanded to other variants. Multiple CFTR modulators used in combination with ivacaftor augment efficacy and increase the number of CFTR variants amenable to therapy. Approval of elexecaftor/tezecaftor/ivacaftor in 2019 increased the number of individuals who could benefit from highly effective modulator therapy (HEMT) to ∼90% of the CF population in the United States. HEMT has been dramatically effective, with overall improvements in lung function, quality of life, nutritional status, and, in women, increased fertility. HEMT may delay the onset of other CF-related comorbidities. Although off-target effects, including hepatotoxicity, drug-drug interactions, and putative mental health issues can complicate use, modulator therapy has been generally well tolerated. Ten percent of people with CF have variants that are not amenable to modulator treatment. HEMT, despite its great cost and limited global access, has brought legitimate hope and changed the lives of a significant majority of individuals and families affected by CF in North America.
Cystic fibrosis (CF), a disease named for the pathologic description of the pancreas on autopsy of small children who died of malnutrition and pneumonia in the 1930s, is the most common lethal genetic disease, with ∼1 in 37 in California being carriers of the autosomal recessive, inherited disease.1 Treatments focused on managing symptoms, treating infections, and later, early diagnosis with newborn screening had improved life expectancy from infancy to the mid-teenage years by the 1970s and early 30s by the 1990s.
However, the prognosis for persons with CF has dramatically improved further since 2011, especially in the context of a genetic variant amenable to cystic fibrosis transmembrane regulator (CFTR) protein modulator treatment. CFTR protein is an anion channel that permits the movement of chloride and bicarbonate, with enriched expression on epithelial surfaces. With 2 mutated copies of the CFTR gene, chloride and bicarbonate movement are compromised, and secretions on the epithelial surfaces are thickened. The lungs, with large epithelial surface area, are highly affected by thickened, tenacious, chronically infected secretions. Inflammation leads to progressive obstructive pulmonary disease, eventual respiratory failure, and death or lung transplantation. Disease often develops in epithelium-rich organs, including sinusitis, diabetes mellitus, and malnutrition. CFTR modulators, small molecules that improve CFTR protein function to rescue chloride conductance, have dramatically decreased CF-related morbidity and mortality.
CFTR Variants
The CFTR protein, encoded on chromosome 7, is composed of 1480 amino acids in 5 domains. Specific gene variants possess widely divergent protein effects. There are 5 classes of CFTR variants (Table 1) with distinct functional implications, with groupings designed to facilitate the development of therapeutic strategies.2 In class I variants, no functional CFTR protein is produced with a stop codon or large deletion. More focal variants result in insufficient protein production or compromised membrane trafficking. The most common CFTR variant is F508del, with a deletion of phenylalanine in the 508 amino acid position of the gene, leading to a folding error (class II) and CFTR protein degradation before reaching the cell surface. Class III and VI produce CFTR protein with specific deficiencies in function. Although the 5 separate classes possess utility relative to potential therapeutic response, many variants can rightfully be placed in more than a single class. More than 2000 variants in the CFTR gene have been described, with 804 annotated in the CFTR2 database,3 with only a minority recognized as disease-causing. Annotation includes clinical data (pulmonary function, sweat chloride, pancreatic status, and Pseudomonas aeruginosa infection rates), in vitro functional testing, and whether the variant causes disease.
CFTR Mutation Classes and Strategies for Therapeutics
| Wild Type . | Class I Protein production variant . | Class II Protein processing variant . | Class III Gating variant . | Class IV Conduction variant . | Class V Insufficient protein variant . |
|---|---|---|---|---|---|
| Protein production | — | + | + | + | +/− |
| Trafficked to cell membrane | — | — | + | + | + |
| Channel opening | n/a | n/a | — | +/− | + |
| Common variants | G542×, W128× | F508del, N1303K | G551D, V520F, R117H | R117H, R347P, D1152H | 3849 + 10kbC→T, 789 + 5G→A A455E |
| Therapeutic approach | Read through agents, gene therapy | Correctors, amplifiers | Potentiators, amplifiers | Potentiators, amplifiers | Potentiators, amplifiers |
| Wild Type . | Class I Protein production variant . | Class II Protein processing variant . | Class III Gating variant . | Class IV Conduction variant . | Class V Insufficient protein variant . |
|---|---|---|---|---|---|
| Protein production | — | + | + | + | +/− |
| Trafficked to cell membrane | — | — | + | + | + |
| Channel opening | n/a | n/a | — | +/− | + |
| Common variants | G542×, W128× | F508del, N1303K | G551D, V520F, R117H | R117H, R347P, D1152H | 3849 + 10kbC→T, 789 + 5G→A A455E |
| Therapeutic approach | Read through agents, gene therapy | Correctors, amplifiers | Potentiators, amplifiers | Potentiators, amplifiers | Potentiators, amplifiers |
n/a, not applicable; –, no channel opening; +/–, equivocal channel opening; +, channel opening.
Drug Discovery
In 1989, the CFTR gene was cloned and sequenced.4 Plans to rapidly translate the discovery into effective gene therapy were compromised by difficulties in delivery and inflammation in initial proof of concept trials5,6 and later the death of a research subject in a non-CF gene therapy trial.7 Increased insight into CFTR physiology and genotype-phenotype correlation motivated a focus on CFTR protein function and rescue. The Cystic Fibrosis Foundation (CFF) undertook “venture philanthropy,” partnering with biopharma to identify small molecules that improved in vitro chloride conductance in cells with mutated CFTR proteins.
The lead compound, ivacaftor, a CFTR potentiator, demonstrated in vitro efficacy in class III variants, characterized by preserved protein production and trafficking, but compromised opening. The 2012 phase III clinical trial was highly successful with rapid (within 2 weeks) and sustained (48 weeks) lung function improvement.8 Forced expiratory volume in 1 second, a marker of lung obstruction which is the most commonly studied pulmonary function outcome measure, increased by 10% in contrast to the historical 3% decline in lung function noted annually in adults. Sweat chloride production, the readout of the gold standard diagnostic test for CF, decreased in most and normalized in some individuals with CF.8 The trial only included persons with a G551D CFTR variant, a class III gating variant comprising only 4% of the people with CF in the United States. In 2017, based on in vitro studies alone, an unprecedented development, the Food and Drug Administration (FDA) expanded approval to 23 additional residual function variants (class III, IV, and V).9 Even with an expanded indication, ivacaftor availability was limited to 10% of persons with CF.
Ivacaftor provided proof-of-principle. Ongoing work was designed to develop CFTR modulator therapy for the F508del variant, affecting ∼90% of people with CF. The CFTR corrector, lumacaftor, reduced the F508del-associated protein folding error in vitro.10 Adding lumacaftor to ivacaftor restored ∼25% of CFTR function in vitro.10 In a phase III clinical trial in individuals homozygous for the F508del variant, although lung function and sweat tests did not substantially improve, there was a 39% decrease in pulmonary exacerbations, episodes of worsening pulmonary symptoms with decreased forced expiratory volume in 1 second, and need for treatment with antibiotics.11 The exacerbations often require prolonged hospitalization and intravenous antibiotics, which represents a significant care burden and cost, which motivated FDA approval for lumacaftor-ivacaftor in 2015.12,13 Unfortunately, favorable effects for individuals with CF with only 1 copy of the F508del variant were even more limited and did not warrant FDA approval.14 Lumacaftor was well tolerated, but significant drug-drug interactions as a CYP3A inducer proved problematic.15 A second combination tezacaftor-ivacaftor demonstrated similar efficacy to lumacaftor-ivacaftor but had fewer drug-drug interactions and was approved for use in persons with 2 copies of F508del in 2018 and began to replace lumacaftor-ivacaftor for those eligible.16
In a study in 2019, in people with CF heterozygous for F508del, triple-combination therapy with elexacaftor-tezacaftor-ivacaftor (ETI) improved lung function by 14% and decreased sweat chloride.17 In people homozygous for F508del, ETI improved lung function by 10% more in comparison with the group receiving dual therapy (lumacaftor-ivacaftor).18 The FDA approved ETI for people with CF >12 years of age in 2019. The CFF designated ivacaftor and ETI as HEMT but not lumacaftor-ivacaftor or tezacaftor-ivacaftor. Ivacaftor is now approved for 97 variants and for use in children with CF as young as 4 months of age. ETI approval has been expanded to 177 other variants and for use in children as young as 2 years of age with the most recent approval in May 2023.19
Effects of HEMT
The positive effects of ETI therapy were rapidly apparent. Lay media, blogs, and personal anecdotes describing marked improvements in QoL were prevalent, including improvements in cough, weight gain, sleep, and exercise capacity and decreased need for supplemental oxygen.20,21 Data revealing a decrease in pulmonary exacerbations from 31.5% in 2019 to 13.9% in 2020, with a further decrease to 12.1% in 2021 were supportive of the normative sentiment.22,23 Remarkably, for the first time ever, in 2021 lung function improved year-over-year in all birth cohorts included in the US CFF Registry.24
Lung transplantation in the United States has also significantly decreased, with 244 transplants in people with CF in 2019, 91 in 2020, and 54 in 2021.22–24 The 2021 CFF Registry report projects a median survival of 53 years for people with CF born between 2017 and 2021, whereas median survival was 33 years in 2011, the year before ivacaftor approval.24
With improved clinical status, monitoring and clinical trial design have changed. With HEMT, sputum production decreases substantially, with many unable to expectorate. Throat swabs, previously used only in pediatric clinics for microbial surveillance as a proxy for lower airway sampling, are increasingly used in adult clinics.25 Clinical trials for testing antimicrobial and anti-inflammatory agents can no longer reliably employ sputum biomarkers as outcome measures.25 Similarly, pulmonary exacerbation frequency is no longer a viable primary end point. Whether infection and inflammation have decreased is less clear as with ivacaftor initiation Pseudomonas aeruginosa sputum density decreased but returned to baseline levels within 12 months. Similarly, in a phase 4 study of HEMT in adults, CF pathogen sputum density decreased by 2 to 3 log-fold but cultures remained positive.26
With HEMT, weight and BMI have increased even after the stabilization of sweat chloride and pulmonary function.27,28 In some children with CF, HEMT treatment has been associated with improved pancreatic exocrine function, with increases in fecal elastase levels, an observation that is consistent with improving pancreatic exocrine function.29 As well, fat-soluble vitamin adsorption appears to be improved, with the authors of 1 study reporting increased vitamin D levels and the authors of another study reporting multiple patients with elevated vitamin A levels,30,31 which underscores the importance of monitoring fat-soluble vitamin levels after the initiation of HEMT. Early reports suggest that ivacaftor may improve insulin secretion32 and glucose tolerance, indicating the potential to delay the onset of CF-related diabetes.33 Radiographic evaluation reveals improvement in sinus disease after 1 year of ETI treatment.34 In addition, QoL measures reveal improvement after beginning ETI therapy.18,28
The pulmonary effects of ETI are more difficult to assess in younger children because early disease is difficult to detect given the relative insensitivity of chest radiographs and the difficulties that young children have in reliably performing spirometry. However, an intensive observational study conducted before the use of HEMT in Australia revealed that in people with CF, pulmonary disease is established early, with bronchiectasis (severe disease) detectable via computed tomography scan in children 1 year of age (8% to 30%) and 3 years of age (60% to 80%).35 New strategies to monitor lung function in infants and young children are being studied and provide insight into disease pathogenesis and can inform decisions about drug therapy initiation.36,37 Outcome metrics can include disease progression, QoL, and incidence of comorbid conditions.
HEMT in Fertility, Pregnancy, and Fetal Exposure
Until more recently, pregnancy in CF has been uncommon, likely because of poor nutrition, chronic inflammation, compromised lung function, and thickened cervical mucus.38 Since ETI approval, the number of women in North America with CF giving birth increased from 235 in 2019 to 675 in 2021.24 Many of these pregnancies were spontaneous and many unplanned, in comparison with times before HEMT, when most pregnancies required assistance, such as in vitro fertilization. Reasons underlying the increase in births likely include improved health, lung function, nutrition, and increased hope.39
Because pregnant women were excluded from phase III HEMT trials, the safety of CFTR modulator safety in pregnancy is unknown.40 Clinical decisions in pregnancy are based on animal studies of the ETI components, which revealed fetal levels but no teratogenicity.19,41 Early case series provide some evidence of safety because the women and infants treated with ETI have done well.42 The ongoing observational, multicenter, prospective MAYFLOWERS study follows maternal and fetal outcomes.39 Evidence of cataract formation in ivacaftor-exposed rat pups41 prompted guidance for regular eye examinations, with reports of 3 cases of bilateral congenital cataracts (small, non-visual-impairing) in infants exposed to ivacaftor.43
The safety and efficacy of treating fetuses with CF represents another layer of complexity. Three homozygous F508del infants born to mothers with CF treated with ETI had normal sweat tests and pancreatic function at birth. ETI is excreted in breastmilk, and these infants had normal sweat chloride, and pancreatic sufficiency was preserved until weaning.42 At least 2 women, pregnant with fetuses carrying 2 disease-causing variants (at least 1 being ETI-responsive) and evidence of meconium ileus, sought off-label use of ETI during pregnancy. In each case, meconium ileus resolved after the initiation of ETI at 23 weeks44 and 26 weeks.45 HEMTs are not currently approved for use in a pregnant person without CF carrying a fetus affected by CF. These case reports, as well as animal data revealing preserved pancreatic function and the delay of lung disease in HEMT-exposed CF-affected ferret pups,46 support seeking a pregnancy indication and offering HEMT to mothers with known CF pregnancies.
HEMT Intolerance and Drug-Drug Interactions
Ivacaftor, a component in all CFTR modulators, is metabolized in the liver. Elevated transaminases were reported in early trials resulting in interruption or cessation, typically with resolution after drug cessation.8,12,17 In the presence of preexisting liver disease, the modification of HEMT dosing may be needed and liver function carefully monitored.47 Drug-drug interactions occur, especially with antifungal azole agents and erythromycin, necessitating dosing modification owing to the ivacaftor component.19,41 Rifampin, rifabutin, several antiepileptics, and St. John’s Wort are contraindicated.19,41
Effects on mental health and cognition, including clouded thinking, anxiety, depression, and insomnia, have been reported with ETI use.48 Suicide attempts in teens shortly after the initiation of ETI have also been reported.49 In the context of ETI use, some individuals with CF have been treated with psychoactive medications, initiated therapy, or paused or even halted ETI as psychoactive or therapy is initiated. Whether the reports derive from an organic cause or the result of a dramatic change in circumstance with HEMT is unknown. Anticipating a life of >50 years, as is the case with HEMT, has markedly different financial, social, and professional implications than a life unlikely to extend beyond 30. There is potential that modulators directly affect the brain as CFTR is expressed in the brain and as ivacaftor binds to serotonin, norepinephrine, and dopamine receptors.50 The importance of mental health screening, added to CF care guidelines in 2016,51 is highlighted by the reports centered on mental health concerns after ETI initiation.
Those Left Behind
A significant number of people with CF, ∼10%, mostly those with rare or stop variants, are not benefiting from HEMT. Some rare variants have not been tested for HEMT responsiveness and, thus, are not FDA-approved. Stop variants will not benefit from HEMT. A disproportionate number of people with CF and stop codons are either Hispanic, Black, or Asian, populations that must contend with systemic racism, superimposed on more severe CF. Additionally, ETI is not available in many countries because it is either not approved or not paid for by the health care system, again limiting access. Thus, the advent of HEMT may be exacerbating disparities in outcomes because people ineligible for modulator treatment and with limited access may already be receiving less-than-optimal CF care.52 Additionally, this population has not been well-represented in clinical trials.53 Because the presence of significant comorbidities was an exclusion criterion for modulator trials, access for these individuals with CF remains limited. The issue is particularly relevant for those with CF-related liver disease because ivacaftor is metabolized by, and toxic to, the liver. Insight into the putative therapeutic benefit of HEMT for CF-related liver disease is needed.
The search for therapies to treat individuals with stop codons is ongoing. Clinical trials of agents designed to permit “read through” are underway.54 Adeno-associated virus gene delivery has reemerged as a strategy to cure CF. Clinical trials using inhaled mRNA to deliver full CFTR mRNA to the airway epithelial are planned to start in the spring of 2023.55
Financial Implications
The cost structure for modulator therapy places a high financial burden on families and payers. The annual cost for ivacaftor, the first HEMT approved, was in excess of $300 000.56 The costs for ETI, approved in 2019, are similar. In addition to posing a substantial burden on families and third-party payers, governmental agencies are challenged to cover the costs for the uninsured. Given that modulator therapy for CF is at the cutting edge of precision medicine, the societal approach to CF possesses meaningful implications for novel and remarkably costly therapies that are rapidly moving into the clinical arena. Moreover, there is a global consideration as in developing countries the prohibitive cost limits access for many people with CF to highly effective medications.
The Future
Therapy that modulates CFTR function has been life-changing for people and families with CF. Actuarial survival and QoL continue to improve. People with CF and access to HEMT are generally more well, better nourished, and less frequently hospitalized than ever before. The management of CF is increasingly outpatient and focused less on acute care and more on maintaining wellness. Although HEMT has improved the status of as many as 90% of people with CF, challenges remain, especially in discovering effective treatments for people with stop codons. The expense of the current small molecule therapeutics represents a barrier, especially in less-wealthy parts of the world. Future trials will need to address both the challenges and opportunities that come with HEMT.57
Dr Burgener performed the literature review and drafted the article; Dr Cornfield reviewed and revised the manuscript; and both authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: Funded by the National Institutes of Health (NIH) (R01 HL160018). Dr Burgener is funded by a Harry Schwachman Clinical Investigator Award from the Cystic Fibrosis Foundation. Dr Cornfield is supported by the NIH, Center for Excellence in Pulmonary Biology at Stanford University, and the Karam Family Innovation Fund.
CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no potential conflicts of interest relevant to this article to disclose.
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