ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Cystic fibrosis: Treatment with CFTR modulators

Cystic fibrosis: Treatment with CFTR modulators
Literature review current through: Jan 2024.
This topic last updated: Nov 09, 2023.

INTRODUCTION — Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are a class of drugs that act by improving production, intracellular processing, and/or function of the defective CFTR protein. These drugs represent an extraordinary advance in management of cystic fibrosis (CF) because they target the production or function of the mutant CFTR protein rather than its downstream consequences [1]. The most widely used approved modulator is the triple combination elexacaftor-tezacaftor-ivacaftor (ETI). Other approved modulators include ivacaftor monotherapy and the dual combinations tezacaftor-ivacaftor and lumacaftor-ivacaftor. Their indications and efficacy depend on the CFTR gene mutations in an individual patient.

The CFTR modulators that have been approved in the United States are discussed in this topic review. CF-associated lung disease is discussed in the following topic reviews:

(See "Cystic fibrosis: Clinical manifestations of pulmonary disease".)

(See "Cystic fibrosis: Overview of the treatment of lung disease".)

(See "Cystic fibrosis: Management of pulmonary exacerbations".)

(See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection".)

(See "Cystic fibrosis: Management of advanced lung disease".)

The diagnosis and pathophysiology of CF and its manifestations in other organ systems are also discussed separately:

(See "Cystic fibrosis: Clinical manifestations and diagnosis".)

(See "Cystic fibrosis: Genetics and pathogenesis".)

(See "Cystic fibrosis-related diabetes mellitus".)

(See "Cystic fibrosis: Overview of gastrointestinal disease".)

(See "Cystic fibrosis: Assessment and management of pancreatic insufficiency".)

(See "Cystic fibrosis: Nutritional issues".)

(See "Cystic fibrosis: Hepatobiliary disease".)

DEFINITIONS

Types of CFTR modulators and their targeted mutations — The different types of CFTR modulators (potentiators, correctors, amplifiers, and stabilizers) and the targeted classes of CFTR mutations are summarized in the table (table 1).

"Highly effective modulator therapy" (HEMT) refers to elexacaftor-tezacaftor-ivacaftor (ETI) when used by those with at least one copy of F508del, or ivacaftor when used by those with at least one copy of a CFTR gating mutation. In contrast, lumacaftor-ivacaftor and tezacaftor-ivacaftor have more modest effects for those who are F508del homozygous.

Other terms — In addition to their historical classifications, CFTR mutations have also been categorized by the severity of disease they cause and by their responsivity to existing CFTR modulators:

Residual function mutations – Mutations that retain some CFTR function and are often associated with a milder CFTR phenotype [2]. Patients with at least one residual function mutation are more likely to be pancreatic sufficient and may have later onset of disease manifestations. They usually respond to potentiators.

Clinical trials of CFTR modulators often enroll patients based on the functional activity of their mutations and their responsivity to approved modulators. For example, a clinical trial of tezacaftor-ivacaftor [3] enrolled patients with residual function mutations that they defined as associated with patients having, on average, a sweat chloride <86 mEq/L (1 standard deviation below the mean of F508del homozygotes) and an incidence of pancreatic insufficiency of <50 percent, based on information from publications or available databases [4]. Mutations also qualified as having residual function if in vitro testing showed an increase in chloride transport of >10 percent above the baseline level of normal cells following exposure to ivacaftor.

Minimal function mutations – Mutations that have negligible function at baseline and do not respond to approved CFTR modulators. For example, in a clinical trial of triple combination ETI, a minimal function mutation was defined as one that produces no full-length CFTR protein (production mutation) or has a baseline chloride transport that is <10 percent of normal CFTR and increases <10 percent following incubation with tezacaftor, ivacaftor, or tezacaftor-ivacaftor [5].

Theratype – A classification of mutations based on their pattern of response to CFTR modulators usually determined using model cell culture systems that measure the quantity, maturation, and/or function of CFTR protein. Theratype classes include mutations responsive to potentiators (ivacaftor), correctors (lumacaftor, tezacaftor, elexacaftor), and none of the modulators.

PATIENT SELECTION — We recommend treatment with elexacaftor-tezacaftor-ivacaftor (ETI) for most individuals with CF who are ≥2 years old and have responsive CFTR gene mutations. We suggest lumacaftor-ivacaftor for patients 1 to <2 years old and ivacaftor monotherapy for patients as young as one month with responsive mutations. The indications and efficacy of these drugs depend on the CFTR mutations in the individual patient. Therefore, all CF patients should undergo CFTR genotyping to determine if they carry a mutation that makes them eligible for CFTR modulator therapy. If screening against a panel of CFTR mutations fails to identify two disease-causing mutations, more extensive testing such as CFTR sequencing should be used to ensure that all modulator-responsive mutations will be identified. (see "Gene test interpretation: CFTR", section on 'CF-specific caveats')

Regulatory approvals — Our recommendations for drug selection are based primarily on regulatory approvals because these determine drug availability. Insurance companies will generally not cover the extremely high cost of modulators for off-label use. For patients who are eligible for more than one approved drug, we provide guidance about the optimal drug selection, as discussed in the following sections. The modulators that have received US Food and Drug Administration (FDA) approval in the United States have also been approved by Health Canada, the European Medicines Agency, the Medicines and Healthcare products Regulatory Agency in the United Kingdom, and the Australian Therapeutic Goods Administration, although the approved age ranges and eligible mutations may differ.

It should be noted that regulatory approvals are typically based on a few specific short-term outcomes and thus may not reflect the full range of clinical effects. In clinical trials involving patients with a wide range of CF genotypes, regulatory approvals for CFTR modulators are primarily based on improvements in forced expiratory volume in one second (FEV1), symptom-related quality of life, and reduced frequency of acute pulmonary exacerbations. Of note, in clinical trials of CFTR modulators, the frequency of pulmonary exacerbations was reduced irrespective of the change in FEV1 [6]. Likewise, the correlation between reduction in sweat chloride and improvement in FEV1 is statistically significant but quantitively small [7]. The FDA has approved additional mutations based solely on an in vitro assay showing that a particular CFTR modulator increases chloride flux in a cell line or tissue organoid that was genetically engineered to express a particular mutant CFTR protein [8].

The majority of the randomized controlled clinical trials have been performed in patients ≥6 years old. For younger patients, regulatory agencies always require demonstration of safety but are willing to accept evidence of efficacy by extrapolating from experience in older patients. Of note, many patients younger than six years have difficulty performing FEV1 measurements, the primary endpoint used for approval of modulators in older patients, but studies using lung clearance index, a more sensitive measure of CF-related pulmonary disease, show concordant results. It is also reassuring that studies in younger patients have found reductions in sweat chloride and improvement in nutritional status similar to older patients [9-17].

Because of their relatively recent introduction into CF care, the long-term efficacy and safety of these modulators for a population that may need to take them for decades have not been fully established. However, observational studies lasting up to five years for ivacaftor, 4.1 years for tezacaftor-ivacaftor, and 2.8 years for ETI have shown continuing clinical benefit and no new safety concerns [18-20].

General approach — Our approach to modulator selection depends on the patient's age and genotype, as summarized in the algorithms (algorithm 1 and algorithm 2) and outlined below. The data supporting this approach are summarized in the subsequent sections focused on each drug or combination. Standards of care for use of CFTR modulators have been published by the United States Cystic Fibrosis Foundation and the European Cystic Fibrosis Society [21,22].

If a patient has a genotype that is eligible for more than one therapy, we suggest starting on the regimen that has the greatest number of modulators that are approved for the patient's age group (ie, triple combination therapy with ETI > dual therapy > monotherapy) (table 2). If a child is not eligible for a preferred therapy due to age, we advance to that therapy when the patient meets the minimum required age. If a patient develops a clinically significant adverse reaction that prevents advancing to the next therapy (eg, severe skin rash following start of ETI), we drop back to the prior treatment regimen.

The beneficial effects of highly effective modulator therapy (HEMT; ie, ETI for individuals with at least one copy of F508del or ivacaftor for those with a CFTR gating mutation) occur within days of their initiation and appear to be quite durable (see 'Elexacaftor-tezacaftor-ivacaftor' below and 'Ivacaftor monotherapy' below). However, their effects wane quite quickly when HEMT is stopped, with sweat chloride and FEV1 returning to their pretreatment levels within days [23]. Severe pulmonary exacerbations that occur shortly after stopping HEMT have been reported in a small number of patients [24-26].

F508del homozygotes

Age ≥2 years – For patients who have two F508del mutations (homozygotes) and are ≥2 years old, we recommend ETI rather than dual therapy (tezacaftor-ivacaftor or lumacaftor-ivacaftor).

Both ETI and dual therapies have demonstrated efficacy in this population, but, in a four-week clinical trial, ETI achieved much greater improvements in FEV1 and symptom-related quality of life compared with tezacaftor-ivacaftor [27]. Although there are no randomized clinical trials directly comparing lumacaftor-ivacaftor with ETI, results of separate trials of patients with similar clinical characteristics strongly support the use of ETI over lumacaftor-ivacaftor [27,28]. Also, a prospective observational study of ETI reported that patients switching from lumacaftor-ivacaftor to ETI showed clinical improvement [7]. Monotherapy with ivacaftor is not effective in this population, given its mechanism of action [29]; however, ivacaftor boosts the efficacy of the other corrector agents (lumacaftor, tezacaftor, and elexacaftor) when given in combination. (See 'Elexacaftor-tezacaftor-ivacaftor' below.)

Age <2 years – For homozygotes, we suggest lumacaftor-ivacaftor for children between one and two years of age because ETI and tezacaftor-ivacaftor are not approved for children under two years. Patients should be transitioned to ETI when they reach the age of two years.

Lumacaftor-ivacaftor is approved for children as young as one year, based on two randomized trials [16,30] and a few observational open-label studies [12,13,15,31]. Although tezacaftor-ivacaftor has considerably fewer drug interactions than lumacaftor-ivacaftor and may be preferred for this reason, there are no available data on the safety and efficacy of tezacaftor-ivacaftor in children <6 years old and it is not approved for that age group. Neither agent is approved for children <1 year. (See 'Tezacaftor-ivacaftor' below and 'Lumacaftor-ivacaftor' below.)

F508del heterozygotes

Age ≥2 years – We recommend ETI for people with CF who have one F508del mutation (heterozygotes) and are ≥2 years old, regardless of their second mutation [32]. Although ivacaftor and/or tezacaftor-ivacaftor are also approved for some patients based on their second mutation being responsive (table 2), ETI has superior efficacy [33]. (See 'Elexacaftor-tezacaftor-ivacaftor' below.)

Age <2 years – For F508del heterozygotes who are ≥1 month to <2 years old, we suggest treatment with ivacaftor but only if they have a second ivacaftor-responsive mutation (table 2).

Other eligible mutations — More than 180 CFTR gene mutations have been approved for treatment with one or more CFTR modulators, based on clinical and/or in vitro sensitivity testing (table 2). If a patient has a genotype that is eligible for more than one therapy, we suggest starting on the maximal therapy available for their age group (ie, ETI > dual therapy > monotherapy).

Patients with no eligible mutations — Approximately 6 to 10 percent of people with CF in the United States have no mutations that are FDA approved for modulator therapy. Mutations with no approved CFTR modulator include canonical splice site variants, frameshifts, exon duplications/deletions, and nonsense mutations. The psychological burden of being in the small minority of patients not eligible for HEMT, while most of the CF population qualify for such treatment, is considerable [34,35].

Certain definable subgroups of CF patients based on race and ethnicity are more likely to have no mutations approved for modulator therapy. As an example, a study of CFTR mutations recorded in the Cystic Fibrosis Foundation Patient Registry reported that genotypes that are ineligible for CFTR modulator therapy are substantially more common among Black or Hispanic CF patients in the United States [36]:

Black or African American patients – 30 percent

Hispanic patients – 25 percent

Non-Hispanic White patients – 8 percent

For people with Asian ancestry, genotypes that are ineligible for CFTR modulator therapy are even more common. In a study from the United States, Canada, and the United Kingdom, ineligible CFTR genotypes were present in 40 to 50 percent of people with South Asian ancestry and 20 to 40 percent of those with other Asian ancestry, primarily due to lower frequency of the F508del variant [37]. The number of CF patients who are ineligible for modulator therapy may have been slightly reduced by the FDA approval of an expanded list of mutations in 2021. Nonetheless, these differences continue to be a substantial source of health care disparity and call for continued efforts toward new drug development to address a broad range of CFTR defects including those that are not amenable to CFTR modulator therapies [38].

Evidence is accumulating that some patients with mutations that have not received regulatory approval may in fact be responsive to modulator therapy. However, the high cost of modulator therapy makes third-party payors reluctant to reimburse for off-label use. There are several strategies for building the evidence needed to support modulator use in these patients:

Theratyping using genetically modified cells – The FDA has approved more than 175 mutations for ETI therapy based on changes in chloride flux in cells in culture; a response is defined as baseline CFTR functional activity <10 percent of normal but an increase of >10 percent of normal activity when exposed to ETI [32]. A separate study using the same cell culture system identified an additional 152 mutations that are responsive to ETI but are not yet approved by the FDA [39].

Individualized cell culture theratyping – Another approach to identifying patients whose mutations may be responsive to HEMT is to harvest their epithelial cells from nasal or rectal mucosa and test the effects of modulators on their cells in culture either as monolayers or organoids [40]. To standardize this approach and make testing widely available, the Cystic Fibrosis Foundation is supporting a laboratory to perform testing with the expressed purpose to use the data to encourage health insurers to cover this off-label use on a case-by-case basis [41,42].

Medication trials – A different innovative approach has been implemented in France, where patients with advanced lung disease and no F508del mutation (which is required for ETI prescription in France) were given a trial of ETI under a compassionate use program and evaluated for clinical response [43]. A centralized adjudication committee identified responders based on their change in symptoms, need for supplemental oxygen or noninvasive ventilation, sweat chloride concentrations, and FEV1. Responders were offered long-term ETI therapy that was fully reimbursed by the French national health care system. Of the first 84 patients in the program, 45 were responders and therefore qualified for continued ETI therapy. Of note, 19 of them had no mutation that is on the FDA eligibility list for an HEMT. There is no similar program in the United States.

Patients with advanced lung disease — Patients with advanced lung disease (FEV1 <40 percent predicted) should generally be treated with a CFTR modulator as indicated for their genotype and age, as outlined above (table 2 and algorithm 2) [44,45]; the available evidence for use of these drugs in patients with advanced lung disease is discussed in the linked sections:

ETI (see 'Elexacaftor-tezacaftor-ivacaftor' below)

Ivacaftor (see 'Ivacaftor monotherapy' below)

Tezacaftor-ivacaftor (see 'Tezacaftor-ivacaftor' below)

By contrast, lumacaftor-ivacaftor is associated with high rates of adverse events in this group of patients [46]. (See 'Lumacaftor-ivacaftor' below.)

ELEXACAFTOR-TEZACAFTOR-IVACAFTOR — The triple drug combination of elexacaftor-tezacaftor-ivacaftor (ETI) is an important therapy for individuals who have at least one F508del mutation and for those with any other CFTR gene mutation that is responsive, based on in vitro and/or clinical trial data. ETI has been approved in the United States and many other countries, including the United Kingdom, European Union, Canada, and Australia [47-49]. Approximately 92 percent of people with CF in the United States have a CFTR genotype that makes them eligible for this therapy once they reach the US Food and Drug Administration (FDA) approval age of two years [50].

Indications — We recommend ETI for patients ≥2 years with any of the following genotypes:

Two copies of F508del mutation (homozygotes)

One copy of F508del mutation (heterozygotes) regardless of what is present on their second CFTR allele

A CFTR mutation that is responsive to ETI based on in vitro data; the responsive mutations are listed in the table (table 2) and in the manufacturer's prescribing information [32]

Some patients who have mutations approved for ETI also meet the eligibility criteria for other CFTR modulators. If a patient has a genotype that is eligible for more than one therapy, we suggest starting on the maximal therapy available for the patient's age group (ie, ETI > dual therapy > monotherapy). We then advance the therapy when the patient meets the age criterion for each drug combination. If a patient develops a clinically significant adverse reaction when advancing to the next therapy (eg, skin rash following start of ETI), we drop back to the prior treatment regimen.

If ETI is not available (eg, for children <2 years), treatment options depend on the patient's age and genotype, as discussed below. (See 'Ivacaftor monotherapy' below and 'Tezacaftor-ivacaftor' below and 'Lumacaftor-ivacaftor' below.)

Dosing and administration — ETI is dosed as follows [32]:

Patients ≥2 to <6 years:

Weight <14 kg – One combination packet (containing elexacaftor 80 mg, tezacaftor 40 mg, and ivacaftor 60 mg) taken orally in the morning and one ivacaftor packet (containing ivacaftor 59.5 mg) taken orally in the evening

Weight ≥14 kg – One combination packet (containing elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg) taken orally in the morning and one ivacaftor packet (containing ivacaftor 75 mg) taken orally in the evening

Patients ≥6 to <12 years:

Weight <30 kg – Two combination tablets (each containing elexacaftor 50 mg, tezacaftor 25 mg, and ivacaftor 37.5 mg) taken orally in the morning and one ivacaftor tablet (containing ivacaftor 75 mg) taken orally in the evening

Weight ≥30 kg – Two combination tablets (each containing elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg) taken orally in the morning and one ivacaftor tablet (containing ivacaftor 150 mg) taken orally in the evening

Patients ≥12 years – Two combination tablets (each containing elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg) taken orally in the morning and one ivacaftor tablet (containing ivacaftor 150 mg) taken orally in the evening

ETI should be taken with fat-containing foods because it improves absorption 1.9- to 2.5-fold for elexacaftor and 2.5- to 4-fold for ivacaftor [32]. Foods containing grapefruit should be avoided due to its inhibition of cytochrome P450 3A (CYP3A), which would lead to excessive levels of modulator exposure. Dose reductions are needed for patients with hepatic impairment or those who are taking drugs that are inhibitors of CYP3A4 such as itraconazole, clarithromycin, fluconazole, or nirmatrelvir-ritonavir (an antiviral agent for coronavirus disease 2019 [COVID-19]). Elexacaftor may increase exposures to statins, glyburide, nateglinide, and repaglinide because it is an inhibitor of the organic anion-transporting polypeptide (OATP) 1B1 and 1B3. For details and guidance on drug interactions and dose reductions, refer to the drug interactions program, the drug monograph on elexacaftor-tezacaftor-ivacaftor, or the manufacturer's prescribing information [32].

Efficacy — Elexacaftor was identified by the same high-throughput screening strategy that identified other CFTR modulators. The combination of elexacaftor with tezacaftor-ivacaftor increased the level of chloride transport in human bronchial epithelial cells heterozygote for F508del to approximately 50 percent of normal and even higher in homozygous F508del cells [51]. ETI causes large increases in CFTR channel function in patients homozygous or heterozygous for F508del, as measured by changes in sweat chloride, nasal potential difference, and intestinal electrical current [52].

ETI was approved in the United States for patients ≥12 years in 2019 [5,27]; the indication was extended to children ≥6 years in 2021 and to children ≥2 years in 2023 [32].

Survival — The introduction of ETI has been associated with an abrupt, unprecedented increase in survival (figure 1). The Cystic Fibrosis Foundation Patient Registry reported that, in 2022, the median predicted age of survival of people with CF reached 68.2 years, an increase from 48.4 in 2019, which was the last year before widespread use of ETI in the United States [50]. The death rate declined from 1.2 deaths per 100 individuals in 2019 to 0.7 in 2022. The increased longevity has been accompanied by improved wellbeing in both pulmonary and nonpulmonary manifestations of the disease.

Pulmonary outcomes — The key clinical trials are:

Age >12 years with at least one F508del mutation – Multiple clinical trials have demonstrated substantial benefits of ETI for individuals with at least one F508del mutation. This includes trials in F508del homozygotes or heterozygotes with a second minimal function mutation, in which ETI improved forced expiratory volume in one second (FEV1) by 10 to 15 percentage points. There were associated improvements in respiratory symptoms, reductions in pulmonary exacerbation rates by 63 to 73 percent, reductions in sweat chloride concentrations by 42 to 46 mEq/L, and large increases in a quality-of-life index [5,27,53]. For individuals who are eligible for other CFTR modulators (ie, those with F508del and a second gating or residual function mutation), ETI treatment improved respiratory symptoms compared with active control (tezacaftor-ivacaftor or ivacaftor), with more modest improvement in FEV1 (3.5 percentage points compared with active control at eight weeks) [33]. These findings support our recommendation for using ETI rather than dual therapy or monotherapy for patients who are eligible.

In two years of follow-up including an open-label extension, participants treated with ETI experienced no loss in FEV1, in contrast with the FEV1 decline observed in an untreated control population [54]. An observational registry-based study following patients on ETI for two years likewise reported sustained improvement in FEV1 and reduction in pulmonary exacerbation rate [55]. Observational studies using chest computed tomography (CT) imaging before and after one year of treatment with ETI showed reduction in trapped air, mucus plugging, and bronchial wall thickening but not bronchiectasis scores [56,57]. Magnetic resonance imaging showed significant improvements from baseline in measures of bronchiectasis/wall thickening and mucus plugging after at least one month of ETI compared with a control group [58].

Use of ETI also effects the microbiome of airway secretions in people with CF. In a prospective study, one month of ETI reduced the density of bacterial pathogens in CF sputum, but most participants remained infected [59]. A small retrospective study reported that the frequency of positive cultures for nontuberculous mycobacteria obtained during the year after initiating ETI decreased compared with the rate during the preceding two years [60]. A majority of the patients (9 of 16) became culture negative, most of whom had been infected with Mycobacterium abscessus complex. ETI also reduced biomarkers of inflammation, which is thought to be an important contributor to the structural damage that occurs in CF airways [61].

With the marked improvement in respiratory status from highly effective modulator therapy (HEMT; ie, ETI for individuals with at least one copy of F508del or ivacaftor for those with a CFTR gating mutation), many patients and caregivers have asked whether any of the frequently prescribed pulmonary therapies can be discontinued without causing adverse effects. As a partial answer to this question, both prospective and retrospective studies have shown that withdrawal of inhaled dornase alfa (DNase) and/or hypertonic saline has no short-term adverse consequences [62,63]. (See "Cystic fibrosis: Overview of the treatment of lung disease".)

Younger children – Trials in younger children yielded similar outcomes. In children 6 to 11 years with at least one F508del mutation, ETI improved FEV1 by approximately 10 percentage points, with secondary efficacy measures showing levels of improvement similar to those seen in older CF patients [64,65], including associated improvement in lung clearance index (between-group difference -2.26 units, 95% CI -2.71 to -1.81) [65]. An extension of one of these studies showed continued efficacy over a mean of 94 weeks of treatment [20]. In a similar study in 75 children 2 to <6 years, treatment with ETI was associated with significant improvements in lung clearance index (-0.83 units, 95% CI -1.01 to -0.66) and decreases in sweat chloride [17]. The safety outcomes from these trials in young children were the basis for the FDA's approval of ETI for these age groups [32,66].

Other mutations – Many CFTR mutations are proven to be disease causing but are too rare to be studied in clinical trials of CFTR modulators. The FDA has agreed to approve ETI for 177 of these rare mutations based on its ability to improve chloride transport by >10 percent of the normal CFTR level using a specific cell culture system [8,32]. This expanded list of mutations made approximately 600 more people with CF in the United States eligible for modulators. However, there is concern that positive results from the in vitro tests may not consistently translate to clinical benefit for some of these mutations [67,68]. This is because the in vitro test that was used to expand eligibility is cDNA-based and would not detect the consequences of splicing defects that a few of the additional mutations are known to cause. For these uncommon mutations, it is prudent to consult a database such as CFTR2 [4] or a published description of the patient's mutations [68] to understand the nature of the mutations and balance the likely benefits and cost/risk.

People with advanced lung disease – In an observational study in France of 245 patients with advanced lung disease, treatment with ETI for one to three months was associated with marked improvement in lung function (mean increase in percent predicted FEV1 15.1); the number of patients requiring chronic oxygen therapy decreased by 50 percent and the number requiring noninvasive ventilation decreased by 30 percent [45]. Mean body weight increased by 4.2 kg, and the number of patients requiring enteral feeding decreased by 50 percent. In 45 patients, the rapid improvement in lung function was sufficient to remove them from lung transplant consideration during the study period. Similar levels of clinical improvement in patients with advanced lung disease were observed in two smaller retrospective studies performed in the United States and Ireland [69,70].

Of note, studies from France reported a 57 percent reduction in CF lung transplants in 2020 compared with the years immediately preceding ETI approval [45]. The timing and pattern of the decrease was most compatible with an ETI effect and not merely secondary to the COVID-19 pandemic, during which rates of lung transplantation fell off initially for all indications [71]. Among 65 patients who were deemed appropriate for lung transplantation, initiation of ETI was associated with a 13.4-point improvement in percent predicted FEV1 that then remained stable after a mean follow-up of one year [72]. Sixty-one of these patients were removed from transplant consideration and remained off of the transplant list during the one-year follow-up. Similar reduction in the rate of lung transplantation following initiation of ETI was seen in a registry-based study [55]. These observations have led the International Society for Heart and Lung Transplantation to recommend that assessment for lung transplant listing should await the outcome of a trial of ETI in individuals with eligible genotypes [73].

Nonpulmonary outcomes — The primary endpoint for the phase 3 clinical trials of CFTR modulators have been based on changes in pulmonary status, namely FEV1. However, some of the secondary endpoints and other data collected during these and subsequent studies address a variety of extrapulmonary effects of modulator therapy. The following discussion reviews these findings, with particular focus on ETI.

Quality of life – The pivotal studies of ETI used the respiratory domain of a quality-of-life questionnaire, Cystic Fibrosis Questionnaire-Revised (CFQ-R) [74], as a secondary efficacy endpoint and found striking improvements [5,27]. Further analysis of CFQ-R data has shown that the benefits extend to other quality-of-life domains such as overall physical and emotional functioning [75].

Gastrointestinal disease – In the clinical trials described above, ETI improved body weight and body mass index compared with control groups [5,27,33,53] (see "Cystic fibrosis: Overview of gastrointestinal disease"). Other evidence of improved gastrointestinal absorption can be inferred by the observation that ETI increased serum concentrations of vitamins A and D, fat-soluble vitamins that are frequently low in people with CF [65,76,77]. In fact, there have been reports of toxic vitamin A serum levels in patients who were taking high doses of vitamin A supplements before beginning ETI [78]. The effects of ETI on gastrointestinal symptoms such as abdominal pain and bloating have been mixed. In a prospective study of 438 patients age >12 years, ETI treatment for six months was associated with modest improvement in gastrointestinal symptom scores that were probably not clinically significant [79]. However, a study of 107 people with CF at eight European CF centers reported significant improvements using a validated patient-reported symptom score [80]. Improvement in gastroesophageal reflux symptoms has also been reported [81].

Liver disease – Hepatobiliary disease is a common manifestation of CF with advanced disease (cirrhosis), reported in 3 percent of patients in the Cystic Fibrosis Foundation Patient Registry [50]. Theoretically, ETI could reduce progression of CF-related liver disease by restoring CFTR function or could worsen it in those patients who develop increased concentrations of transaminases [82]. Fortunately, a study of 73 patients using elastography, an ultrasound-based technique that detects fibrosis, found no evidence of increased liver stiffness after a median of 21 months of ETI [83]. This is consistent with similar reports of improvement with lumacaftor-ivacaftor [84-86], but more studies are needed to accurately assess the long-term effects of ETI on the incidence and progression of CF-related liver disease. (See "Cystic fibrosis: Hepatobiliary disease".)

Pancreatic insufficiency – Preliminary evidence suggests that HEMT may be effective at preventing, delaying, or, possibly, reversing pancreatic insufficiency when begun in early childhood [87]. For example, an open-label study of ivacaftor in infants and children with a gating mutation showed improvement in exocrine pancreatic function [11,14]. Similar studies of the effects of ETI on pancreatic function in young children are not available.

By contrast, it is unlikely that modulators will reverse longstanding pancreatic insufficiency (see "Cystic fibrosis: Assessment and management of pancreatic insufficiency"). In fact, a small observational study reported no improvement in fecal elastase during ivacaftor treatment in adolescents and adults with a CFTR gating mutation despite the known benefits of ivacaftor on the lung disease in these patients [88] (see 'Ivacaftor monotherapy' below). A prospective study of patients 12 years and older showed a small but clinically insignificant increase in fecal elastase measured six months after starting ETI [79].

A survey of people with CF and their clinicians found that, following initiation of ETI, some patients decreased and occasionally discontinued their pancreatic enzyme replacement therapy [89]. One explanation is that, prior to ETI therapy, these patients had malabsorption due to poor hydration of the intestinal mucosa, which caused them to escalate enzyme doses beyond the level required for digestion. The ETI therapy restored mucosal hydration and absorption, thus permitting deescalation of the enzyme dose. Therefore, following initiation of ETI, we suggest that clinicians reassess enzyme doses to determine if reductions are appropriate.

Pancreatitis – Acute pancreatitis is a known complication of the subgroup of CF patients who have residual pancreatic function (see "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Pancreatitis'). Limited evidence from case series suggest variable effects of CFTR modulators on pancreatitis; most people with recurrent pancreatitis due to CF have an improved course after beginning CFTR modulators [87,90-92]. This is probably because these individuals had moderately impaired pancreatic function at baseline and modulator therapy improved pancreatic function sufficiently to put them out of the risk range for pancreatitis. Conversely, a few reports describe people with CF who first developed pancreatitis after starting CFTR modulators [93,94]. This is probably because they had pancreatic insufficiency at baseline and the modulator improved CFTR function sufficiently to move them into the risk range for pancreatitis. (See "Pancreatitis associated with genetic risk factors", section on 'CFTR modulator therapy'.)

CF-related diabetes – Observational studies of patients without diagnosed CF-related diabetes reported improvement in glycemic control following initiation of ETI, while another did not [95-99]. The studies had conflicting results regarding effects of ETI on glycemic control in patients who had been diagnosed with CF-related diabetes [100]. (See "Cystic fibrosis-related diabetes mellitus".)

Sinonasal disease – The majority of CF patients have symptoms of nasal congestion and sinusitis, often requiring chronic treatment and, occasionally, surgery. Initiation of ETI improves sinusitis symptoms, sense of smell, and CT manifestations of CF sinonasal disease [58,101-104].

Adverse effects — ETI was generally well tolerated during the clinical trials described above. In particular, discontinuation of study drug due to adverse events during a 24-week trial of subjects heterozygous for F508del occurred in 1 percent of those receiving ETI and 0 percent of those receiving placebo [5]. Serious adverse events occurred less frequently in the group receiving ETI (13.9 percent) compared with placebo (20.9 percent).

Adverse reactions that occurred more frequently in the ETI group compared with placebo included (reported here as percentages): abdominal pain (14 versus 9), diarrhea (13 versus 7), rash (10 versus 5), increased blood alanine aminotransferase (ALT; 10 versus 5) or aspartate aminotransferase (AST; 9 versus 2), increased blood creatine phosphokinase (9 versus 4), rhinorrhea (8 versus 3), and "influenza" (7 versus 1). These rates of adverse events are similar to those reported in other prospective placebo-controlled trials of ETI in patients homozygous for F508del [53].

The safety of ETI in younger children was evaluated in two 24-week open-label studies in children with at least one F508del mutation who were 6 to 11 years old (n = 66) or 2 to <6 years (n = 75) [17,64,65]. The safety profile and pharmacokinetics were similar to those in older individuals, with improvements in secondary efficacy measures (see 'Efficacy' above). On the basis of this study, the drug combination was approved by the FDA for these age groups [32].

Specific safety concerns include:

Transaminase elevations – Measurement of liver transaminases is recommended prior to all modulator treatments including ETI, with ongoing monitoring every three months for the first year and then annually thereafter. Dosing should be interrupted if the ALT or AST concentrations are more than five times the upper limit of normal or if ALT or AST is greater than three times the upper limit of normal with bilirubin greater than two times the upper limit of normal.

Increased ALT and/or AST occurred in 5 to 7 percent more subjects receiving ETI compared with placebo in the phase 3 clinical trial [32]. However, only approximately 0.6 percent of participants in the various placebo-controlled clinical trials had to permanently stop taking ETI due to transaminase elevations. Most were able to continue treatment or restart it following temporary interruption. Similar frequencies of discontinuation for elevated transaminases were seen in long-term open-label trials of lumacaftor-ivacaftor [15,31] and tezacaftor-ivacaftor [19]. Real-world experience found results similar to those reported in the clinical trials [105]. (See "Cystic fibrosis: Hepatobiliary disease", section on 'CFTR modulator-induced liver injury'.)

Determining the true rate of modulator-induced liver injury is confounded by the background prevalence of CF liver disease, which can cause transient transaminase elevations [82,106]. Although there were no episodes of severe acute liver failure during the controlled clinical trials, a small number of reports have described cases of severe liver injury that were temporally related to ETI treatment, including a patient who required liver transplantation [32,107]. Worsening of liver function, sometimes leading to liver failure, has been reported in patients with advanced liver disease, such as cirrhosis and portal hypertension [32].

Bilirubin elevations – Serum bilirubin measurement is recommended before initiating ETI, every three months during the first year, and then annually thereafter. Elevation of total bilirubin above two times the upper limit of normal in conjunction with elevation of ALT or AST above three times the upper limits of normal is a strong indication to interrupt ETI treatment [32]. In contrast, isolated elevations of total and indirect serum bilirubin are common in patients receiving ETI because elexacaftor is an inhibitor of OATP1B1 and OATP1B3, which facilitate uptake of unconjugated bilirubin from blood into hepatocytes. In the absence of concomitant elevations in transaminases or symptoms of liver injury, ETI does not need to be interrupted.

Blood pressure elevations – Mild increases in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were noted during controlled clinical trials in subjects randomized to ETI (SBP increased by 3.5 mmHg and DBP by 1.9 mmHg) compared with placebo (SBP increased by 0.9 mmHg and DBP by 0.5 mmHg) [32]. SBP elevations above 140 mmHg with an increase of at least 10 mmHg above baseline on two occasions occurred in 4 percent in the ETI group compared with 1 percent in the placebo group. Similar changes were found in a retrospective single-center study of 134 patients in whom initiation of ETI was associated with an increase of 4.8 mmHg in mean systolic blood pressure and 3.5 mmHg in diastolic [95]. Postmarketing, a case series reported four patients who were started on antihypertensive treatment soon after beginning ETI [108].

Mental health effects – The phase 3 clinical trials of ETI did not report increased adverse psychiatric events in those receiving ETI compared with controls [5,17,20,27,33,53,64,65]. A combined analysis of clinical trial results, postmarketing reports, and an ongoing registry-based safety study found no evidence indicating a causal association between ETI and depression [109]. In fact, quality-of-life measures performed during the studies consistently showed large improvements in wellbeing that were three to four times more than the minimal clinically important difference for the measure. This is consistent with a longitudinal study that showed overall improvement in the mean PHQ-9 (depression) and GAD-7 (anxiety) scores of 150 individuals who were monitored from 2016 to 2021 [110]. Importantly, following the widespread availability of ETI, there was no increase in prevalence of patients with higher levels of depression or anxiety (scores >15). However, in the postmarketing period, there have been an increasing number of case reports of depression, anxiety, insomnia, and/or "fogginess," which the authors attribute to ETI [111-114]. Similar reports have been published regarding psychiatric consequences of lumacaftor-ivacaftor [112,115,116].

It is difficult to determine if and how often CFTR modulators cause adverse psychiatric reactions, given the high background prevalence of anxiety and depression in people with CF [117]. A systematic review and meta-analysis of publications from 1989 to 2020 reported that the prevalence of depression and anxiety in people with CF was 27.2 and 28.4 percent, respectively, for adults and 18.7 and 26 percent, respectively, for adolescents [118]. Confounding an assessment is that ETI became commercially available just prior to the start of the COVID-19 pandemic, which is known to have had adverse effects on mental health in the general population [119]. Of 81 people with CF who were experiencing increased symptoms of depression and/or anxiety, 40 percent attributed their worsened symptoms to COVID-19 and 9 percent to ETI [120]. The mental health consequences of modulators need to be studied in well-constructed clinical trials of sufficient size to detect uncommon events. Meanwhile, authors of two small case series have suggested dose reduction strategies for patients with mental health changes that they perceive are related to ETI and who have a desire to retain its benefits [113,121].

Other adverse reactions – The package inserts for ETI list several additional adverse reactions. They include:

Cataracts – When cataracts were detected during preclinical studies of juvenile rats exposed to ivacaftor, a cataract warning was added to the package inserts of all CFTR modulators. Noncongenital cataracts have been reported postmarketing in pediatric patients, but some of them had other risk factors for developing cataracts, such as corticosteroid use. Of note, analysis of a large United States health insurance claims database performed before approval of ETI found that people with CF have a higher incidence of cataracts compared with the general population [122]. The package inserts recommend that pediatric patients undergo an ophthalmologic examination before and during treatment with ivacaftor-containing medications. The interval between starting medication and follow-up ophthalmologic examination is not stipulated in the package insert. Clinical trial protocols for ETI conducted the examination as long as 48 weeks after starting ETI (NCT04043806). A common clinical practice is to repeat examinations annually until age 18 years.

Creatine phosphokinase elevation – Routine safety monitoring during ETI clinical trials noted that episodic creatine phosphokinase elevations of greater than 10 times the upper limit of normal were seen more frequently in study participants receiving active drug (9 percent) than placebo (4 percent) [32]. Some, but not all, of the participants reported recent heavy exercise. ETI was occasionally interrupted because of these elevations, but no study participants permanently discontinued treatment. Routine monitoring does not appear to be indicated.

Considerations for special populations

Pregnancy and lactation

Effects on fertility – Following approval of ETI, the average number of pregnancies per year among CF patients in the United States rose sharply from 264 (2012 through 2019) to 644 (2020 through 2022) [50]. Possible explanations for this large increase are an ETI-induced improvement in overall health leading to a decision to become pregnant, the reversal of some of the abnormal properties of cervical mucus that were impairing sperm penetration and fertilization, and better overall heath leading to fewer anovulatory cycles.

Safety during pregnancy – All of the approved CFTR modulators cross the placenta. In preclinical studies in rats, there was no evidence of teratogenicity at clinically relevant doses [32,123]. Data from humans regarding modulator use during pregnancy are very limited, but small retrospective surveys and case reports have reported outcomes similar to that expected from CF pregnancies [124-126]. A study of three maternal-infant pairs reported that cord blood of babies born to CF mothers taking ETI had levels of each of the modulators similar to those measured in maternal blood [127].

Based on the observation of cataract formation in juvenile rats receiving ivacaftor (see 'Adverse effects' below), some CF centers are routinely performing ophthalmologic examinations on infants born to mothers who took ETI during pregnancy and nursing. A publication from two CF centers reported that, among 23 neonates born to mothers who took ETI during pregnancy and while nursing, bilateral cataracts were found in three [128]. Although the cataracts were described as mild, causing no significant visual impairment, and nonprogressive, this observation should be included in the discussion of women considering use of ETI during pregnancy and nursing.

A large prospective study of modulators in pregnancy is underway to assess the effects of CFTR modulators during and for two years following pregnancy (NCT04828382) [129].

Effects on newborn screening – Children with CF born to mothers taking ETI may have negative newborn screening tests for CF due to a beneficial effect of ETI exposure on pancreatic development/function [130-132]. In fact, a case report describes a mother and father without CF (both F508del heterozygotes) with a fetus diagnosed with CF by amniocentesis that developed ultrasound findings of meconium ileus in utero [131]. The mother was given off-label ETI, after which the ultrasound abnormalities resolved. The child was born healthy and had a negative newborn screening test for CF.

Safety during lactation – All of the approved CFTR modulators were detectable in the milk of lactating rats [32,123]. At present, minimal information is available regarding levels of ETI in human breast milk but, of note, the aforementioned study of three maternal-infant pairs reported detectable levels of ETI in breast milk [127].

Post-transplant

Lung transplant – Because donor lungs have normal CFTR function, CFTR modulator therapy would be expected to have no direct benefit for the transplanted lungs. However, ETI is increasingly prescribed to lung transplant recipients because of their beneficial effects on other organs (see 'Nonpulmonary outcomes' above). Thus, it is reasonable to offer CFTR modulators after lung transplantation for patients with burdensome nonpulmonary signs and symptoms, although this issue has not been addressed in clinical guidelines.

Experience with CFTR modulators after lung transplant is limited. In a case series of 94 patients who were prescribed ETI after lung transplantation, the predominant indications for the CFTR modulator were sinus disease (68 percent), gastrointestinal symptoms (39 percent), low body mass index (19 percent), and/or patient preference (45 percent) [133]. Little information was collected regarding benefits or adverse effects after initiating the CFTR modulator, but it was noted that body mass index did not change and that hemoglobin A1c decreased slightly. Of note, 42 percent of the patients discontinued modulator therapy after a median of 56 days, primarily due to gastrointestinal symptoms or no perceived benefit.

Smaller studies reported that ETI after lung transplantation was associated with slight improvement in body mass index, nonpulmonary symptoms, and fasting glucose level [134,135]. Sinus and gastrointestinal symptoms improved in the majority. Drug-drug interactions were reported to have caused minimal problems with immunosuppressive therapy.

Liver transplant – ETI has been prescribed for patients who have received liver transplants. Despite concern regarding possible drug-induced hepatotoxicity, a small case series found no liver problems and noted both pulmonary and extrapulmonary benefits [136]. (See "Cystic fibrosis: Hepatobiliary disease", section on 'Use of CFTR modulators post-liver transplant'.)

IVACAFTOR MONOTHERAPY — Ivacaftor is a small molecular weight oral drug that was specifically designed to treat patients who have a G551D mutation in at least one of their CFTR genes. The G551D mutation, which occurs in approximately 4.4 percent of CF patients, is called a "gating mutation" because it impairs the regulated opening of the ion channel that is formed by the CFTR protein. Its use has now been expanded to include many other mutations (table 2). (See "Cystic fibrosis: Genetics and pathogenesis", section on 'Class III mutations: Defective regulation'.)

Ivacaftor was developed using high-throughput screening of large chemical libraries, by which candidate molecules (called "potentiators") were identified that increased chloride ion flux in cultured cells expressing G551D CFTR [137]. From these candidate molecules, ivacaftor was developed and approved by the US Food and Drug Administration (FDA) in the United States for patients with this mutation [138]. Subsequent clinical trials have shown that ivacaftor benefits patients with other CFTR gating mutations [139] and with CFTR mutations of a type that allows a low level of CFTR function but not enough to prevent CF disease, known as "residual function" mutations [140-144] (see 'Other terms' above). Subsequently, additional mutations have been approved for ivacaftor, based on results of in vitro studies and supporting clinical trials [8,138,140].

Indications — The main clinical utility of ivacaftor is for children between one month and two years of age with ivacaftor-responsive mutations (table 2). Most such children can switch to elexacaftor-tezacaftor-ivacaftor (ETI) when they reach two years of age. For the few children with a mutation that is eligible for tezacaftor-ivacaftor but not ETI (eg, 3849+10kbC→T and no other ETI-eligible mutation), this means switching from ivacaftor to tezacaftor-ivacaftor when they reach six years of age.

This approach reflects our suggestion to treat with the maximum number of modulators that are approved for the patient's age group (triple therapy > dual therapy > monotherapy). This is based on indirect evidence that the combination therapies may be more effective than ivacaftor monotherapy and are well tolerated. (See 'Elexacaftor-tezacaftor-ivacaftor' above and 'Tezacaftor-ivacaftor' below.)

Dosing and administration — Dosing for ivacaftor is as follows [138]:

Infants <6 months:

Age ≥1 to <2 months and ≥3 kg body weight (and no hepatic impairment) – 5.8 mg packet taken orally every 12 hours

Age ≥2 to <4 months and ≥3 kg body weight (and no hepatic impairment) – 13.4 mg packet taken orally every 12 hours

Age ≥2 to <6 months and ≥5 kg body weight (and no hepatic impairment) – 25 mg packet taken orally every 12 hours

Age ≥6 months to <6 years:

5 kg to <7 kg body weight – 25 mg packet taken orally every 12 hours

7 kg to <14 kg body weight – 50 mg packet taken orally every 12 hours

≥14 kg body weight – 75 mg packet taken orally every 12 hours

Age ≥6 years – 150 mg tablet taken orally every 12 hours

Ivacaftor should be taken with fat-containing foods. If packets are used, the dose should be mixed with a small amount (1 teaspoon) of soft food or liquid.

Dose reductions are needed for patients with hepatic impairment or those who are taking drugs that are inhibitors of cytochrome P450 3A4 (CYP3A4) such as itraconazole, clarithromycin, fluconazole, or nirmatrelvir-ritonavir (an antiviral agent for COVID-19) or consuming foods containing grapefruit. For details and guidance on dose reductions, refer to the drug interactions program, the drug monograph on ivacaftor, or the manufacturer's prescribing information [138]. Coadministration of ivacaftor with CYP3A4 inducers such as rifampin, phenobarbital, carbamazepine, phenytoin, and St. John's wort is not recommended, because these drugs markedly decrease serum ivacaftor concentrations.

Liver function tests are recommended prior to ivacaftor treatment, every three months for the first year, and then annually thereafter. Dosing should be interrupted if the alanine aminotransferase (ALT) or aspartate aminotransferase (AST) concentrations are more than five times the upper limit of normal.

Of note, a study of patients taking the ivacaftor dose recommended by the manufacturer reported that serum and tissue levels concentrations were consistently higher than that needed to achieve maximal effect [145].

Efficacy

G551D mutation – Clinical trials of ivacaftor in patients with a G551D mutation have demonstrated important benefits [146]:

The initial phase 3 trial of ivacaftor in subjects 12 years of age or older with a G551D mutation showed a 10.4 improvement in mean percent predicted forced expiratory volume in one second (FEV1) compared with a decline by 0.2 percent in subjects receiving a placebo [147]. Ivacaftor also decreased sweat chloride values by 48.1 mmol/L, reduced the frequency of pulmonary exacerbations (55 percent reduction in risk), improved pulmonary symptoms, and resulted in a significant weight gain of 2.7 kg after 48 weeks of treatment.

Younger patients (age 6 to 11 years) had similar improvement in FEV1 compared with placebo in a randomized study of patients having at least one G551D-CFTR mutation [148].

Patients with mild pulmonary disease and a G551D mutation also benefitted from ivacaftor, as demonstrated by improved lung clearance index and FEV1 [149].

Long-term benefits of ivacaftor were shown in clinical studies of diverse designs including those that were open-label extensions [150], prospective observational [18,151,152], or registry based [153-155]. Collectively, they showed that the benefits of ivacaftor were maintained for up to five years and included a reduced rate of FEV1 decline following initial improvement, reduced rate of death and lung transplantation, increased body weight, reduced frequency of hospitalizations, and decreased frequency of having at least one positive Pseudomonas aeruginosa respiratory culture.

Non-G551D gating mutations

In vitro studies of cells genetically engineered to express various CFTR mutations showed that ivacaftor partially corrected chloride transport in a subset of them [140,156]. A small randomized crossover trial in subjects with one of six non-G551D gating mutations showed beneficial clinical results similar to those reported for patients with the G551D mutation [157]. Based on these studies, the FDA expanded approval for ivacaftor beyond the G551D mutation to include other gating mutations that were responsive in vitro [138]. Subsequent clinical trials have provided supportive evidence of ivacaftor benefit for patients >6 years with either G551D or other CFTR gating mutations [139] and for patients younger than six years (described below).

Other mutations

In vitro studies have shown that ivacaftor increases stimulated chloride flux for many mutations that allow limited CFTR function but not enough to prevent clinical disease, known as residual function mutations (see 'Other terms' above) [140]. Evidence of clinical benefit has been reported for patients having one of several such mutations [141-144].

Based on the concordance between in vitro demonstration of modulator-induced increase in chloride transport for a specific mutation and clinical benefit, the FDA subsequently approved many more mutations for treatment with ivacaftor [8]. As of December 2020, 97 mutations were approved for ivacaftor use.

Patients <6 years – Because lung disease in CF often begins in early childhood, studies have been performed to determine whether ivacaftor is safe for young children. A succession of small studies enrolling progressively younger children has led to FDA approval of ivacaftor for patients >1 month old [9-11,14]. Clinical efficacy in the younger cohorts is largely extrapolated from results in older patients and observation of similar reductions in sweat chloride and improvements in nutritional status and pancreatic function (fecal elastase). Inclusion of younger patients is further bolstered by the knowledge that the mode of action of modulators should be age independent.

Advanced lung diseaseIvacaftor appears to be reasonably safe and effective for patients with responsive mutations and advanced lung disease (FEV1 <40 percent predicted). Relatively few patients with FEV1<40 percent predicted at baseline were included in the randomized trials described above, but several observational studies reported benefits for this subgroup, with FEV1 improving between 3.9 and 11.5 percentage points, approximately a 50 percent reduction in exacerbations, and 2 to 3 kg in weight gain [44]. Data from an extended-access program available to patients with a G551D mutation and advanced lung disease showed improved lung function and no additional safety concerns [158]. The Cystic Fibrosis Foundation clinical guideline for CFTR modulator use recommends ivacaftor for patients with advanced lung disease and an eligible genotype [21].

Adverse effects — Elevations in serum hepatic enzyme levels were noted in a small number of subjects during clinical trials of ivacaftor.

A possible risk for cataract formation in young patients was raised by studies done in juvenile rats given ivacaftor at higher doses than those recommended for humans. Noncongenital lens opacities have also been reported in children up to 12 years of age receiving ivacaftor [138]. Although other risk factors for cataracts were often present (eg, glucocorticoid use), the FDA recommended that baseline and follow-up ophthalmologic examinations should be performed in pediatric patients receiving ivacaftor. Otherwise, the adverse events seen in younger patients are similar in frequency and type to those observed in older individuals [9-11,14,138].

Most of the other adverse events recorded during the placebo-controlled trials were similar to what many people with CF experience as part of their disease. However, of these, headache, nasopharyngeal pain, and upper respiratory tract infection were consistently reported more frequently in those receiving ivacaftor.

TEZACAFTOR-IVACAFTOR — For individuals who are homozygous for F508del mutations, treatment with the combination of tezacaftor and ivacaftor yields modest improvement in pulmonary function and reduces the risk of pulmonary exacerbations, and has fewer adverse effects than lumacaftor-ivacaftor [159,160]. The F508del mutation interferes with CFTR protein folding and channel gating activity. Tezacaftor partially corrects the CFTR misfolding, while ivacaftor improves the gating abnormality.

Tezacaftor-ivacaftor is approved by the US Food and Drug Administration (FDA) for individuals who are six years and older and have homozygous F508del mutations or ≥1 other mutations that are sensitive to tezacaftor-ivacaftor [161].

Indications — Tezacaftor-ivacaftor has very limited clinical utility where elexacaftor-tezacaftor-ivacaftor (ETI) is available. However, tezacaftor-ivacaftor is our drug of choice for patients ≥6 years with one of five mutations that are approved for tezacaftor-ivacaftor but not ETI, and who have no other ETI-eligible mutation (table 2). These patients can initiate therapy with ivacaftor at four months of age, then switch to tezacaftor-ivacaftor at six years of age.

Most other genotypes that are eligible for tezacaftor-ivacaftor are also eligible for triple combination therapy (ETI). In these cases, we suggest ETI, based on evidence that it is more effective than dual therapy [33]. (See 'Elexacaftor-tezacaftor-ivacaftor' above.)

Dosing and administration — Dosing for tezacaftor-ivacaftor is as follows:

Patients ≥6 years:

<30 kg – One combination tablet (containing tezacaftor 50 mg and ivacaftor 75 mg) orally in the morning and ivacaftor 75 mg orally in the evening

≥30 kg – One combination tablet (containing tezacaftor 100 mg and ivacaftor 150 mg) orally in the morning and ivacaftor 150 mg orally in the evening

Monitoring of liver function tests and bilirubin is recommended before and during treatment with tezacaftor-ivacaftor, as it is for ETI. Dose reduction is required for patients with significant hepatic impairment (Child-Pugh class B or C) or for patients taking cytochrome P450 3A4 (CYP3A4)-inhibiting drugs (eg, fluconazole, ketoconazole, clarithromycin, or nirmatrelvir-ritonavir [an antiviral agent for COVID-19]) or consuming foods containing grapefruit. Details are available in the drug interactions program, the drug monograph for tezacaftor-ivacaftor, or the manufacturer's prescribing information [161]. Conversely, coadministration with CYP3A4-inducing drugs (eg, rifampin, carbamazepine, or St. John's wort) reduces the efficacy of tezacaftor-ivacaftor and is not recommended.

Efficacy

F508del homozygotes – A trial involving F508del homozygotes (EVOLVE) enrolled 510 subjects 12 years and older with mild or moderate CF-related lung disease (forced expiratory volume in one second [FEV1] 40 to 90 percent predicted) [159]. The subjects were randomized to placebo or tezacaftor-ivacaftor for 24 weeks. Treatment with tezacaftor-ivacaftor resulted in modest improvement in FEV1 (absolute change 4 percentage points versus placebo) and modest improvement in a disease-related quality-of-life score (5.1 points versus placebo). The rate of pulmonary exacerbations was 35 percent lower in the treatment group compared with placebo (hazard ratio 0.64, 95% CI 0.46-0.88). Body mass index increased slightly during the 24-week study but was not significantly different between the study groups. In the subset of 27 patients with advanced lung disease (whose FEV1 dropped to <40 percent predicted between screening and baseline), treatment with tezacaftor-ivacaftor improved FEV1 by 3.5 points (95% CI 1.0-6.1). The absolute improvements in FEV1 are comparable to those achieved by inhaled dornase alfa (DNase) or hypertonic saline.

Subsequent studies have demonstrated similar levels of safety in younger patients and have provided supportive evidence of efficacy. For example, a randomized placebo-controlled trial of children 6 to 11 years old found that tezacaftor-ivacaftor improved lung clearance index, a sensitive measure of airway obstruction in patients with mild lung disease [162]. Safety assessment yielded results similar to that of the older patients.

F508del heterozygotes – For F508del heterozygotes, a benefit of tezacaftor-ivacaftor has been shown only if the second mutation has some residual function [3]. There appears to be no benefit for F508del heterozygotes whose second mutation has minimal function [163] or is a gating mutation beyond the benefit of ivacaftor alone [164]. (See 'Types of CFTR modulators and their targeted mutations' above.)

Long-term outcomes – Participants in a randomized controlled trial of tezacaftor-ivacaftor were eligible to roll over into an open-label extension that followed them for two consecutive 96-week periods. Efficacy as measured by change in FEV1 from baseline and pulmonary exacerbation was largely sustained, and no new safety signals were observed [19].

Other mutations – The main evidence for efficacy of tezacaftor-ivacaftor for CFTR residual function mutations in the absence of an accompanying F508del mutation comes from in vitro studies. In cells expressing residual function mutations, tezacaftor-ivacaftor caused similar or increased chloride transport compared with ivacaftor alone, as described in the manufacturer's package insert [161]. It is likely that this finding in part led the FDA to approve tezacaftor-ivacaftor for patients with the listed residual function mutations without requiring their second mutation to be F508del. (See 'Types of CFTR modulators and their targeted mutations' above.)

Younger children – Evidence for efficacy of tezacaftor-ivacaftor in children 6 to 11 years old is extrapolated from studies of older patients and from a 24-week open-label study in 70 children who are F508del homozygous or F508del heterozygous with a second residual function CFTR mutation. The study reported improved sweat chloride levels (mean change from baseline -14.5 mmol/L) and modest improvement in a survey measure of respiratory symptoms (CF questionnaire) [165]. No significant change in FEV1 or growth parameters were reported, but, of note, the patients had milder disease compared with those ≥12 years who participated in the earlier phase 3 trial (mean baseline percent predicted FEV1 91 compared with 60) [159]. Tolerability and adverse effects were similar to those for older children. A 96-week open-label extension of the trial found sustained reduction in sweat chloride, improvement in quality of life, and no additional safety concerns [166]. These findings were the basis for the FDA's decision to extend the indication to this age group in June 2019.

Adverse effects — Tezacaftor-ivacaftor is generally well tolerated and has a good safety profile. In the placebo-controlled trials described above, the most common adverse events were acute respiratory exacerbations and associated symptoms and there were slightly fewer adverse events among patients treated with tezacaftor-ivacaftor compared with placebo [3,159]. In particular, there was no increase in chest discomfort, bronchospasm, dyspnea, or wheezing (in contrast with the chest symptoms that some patients experience with lumacaftor-ivacaftor). Also, tezacaftor has few drug interactions (in contrast with lumacaftor, which is a strong inducer of CYP3A4, an enzyme that speeds clearance of drugs frequently taken by CF patients). Similar findings were reported for the open-label study in children 6 to 11 years old [165].

In clinical trials, elevations in serum aminotransferases were observed in similar percentages of patients treated with tezacaftor-ivacaftor compared with placebo (3.4 percent of each group experienced elevations more than three times the upper limit of normal) [3,159]. Nonetheless, periodic monitoring of aminotransferases is recommended during treatment with tezacaftor-ivacaftor.

LUMACAFTOR-IVACAFTOR — For individuals who are homozygous for the F508del mutation, treatment with the combination of lumacaftor and ivacaftor yields modest improvements in pulmonary function and reduces the risk of pulmonary exacerbations [28,160]. The F508del mutation interferes with CFTR protein folding and channel gating activity. Similar to tezacaftor, lumacaftor partially corrects the CFTR misfolding, while ivacaftor improves the gating abnormality. Neither lumacaftor nor ivacaftor is effective when used alone for F508del homozygotes [29,167].

Indications — We suggest treatment with lumacaftor-ivacaftor for children with homozygous F508del mutations who are 1 to <2 years of age (algorithm 1). Therapy should be switched to elexacaftor-tezacaftor-ivacaftor (ETI) when the child reaches two years of age.

For F508del homozygotes ≥2 years, we prefer ETI rather than lumacaftor-ivacaftor because ETI is approved for this age group and appears to have substantially fewer adverse effects (at least in adults), fewer drug-drug interactions compared with lumacaftor-ivacaftor, and considerably greater improvement in forced expiratory volume in one second (FEV1) [160]. (See 'Elexacaftor-tezacaftor-ivacaftor' above.)

Dosing and administration — Dosing for lumacaftor-ivacaftor is as follows:

Children 1 to <2 years:

If weight 7 to <9 kg – One packet of granules (containing lumacaftor 75 mg and ivacaftor 94 mg) taken orally every 12 hours

If weight 9 to <14 kg – One packet of granules (containing lumacaftor 100 mg and ivacaftor 125 mg) taken orally every 12 hours

If weight ≥14 kg – One packet of granules (containing lumacaftor 150 mg and ivacaftor 188 mg) taken orally every 12 hours

If lumacaftor is used after two years of age (although ETI is preferred), similar weight-based dosing is used.

Lumacaftor-ivacaftor should be taken with fat-containing foods. As for ivacaftor monotherapy and ETI, monitoring of liver function tests and bilirubin is recommended before and during treatment, similar to that recommended for ETI. Lower doses should be used for patients with moderate or severe hepatic impairment.

Coadministration of lumacaftor-ivacaftor with strong cytochrome P450 3A4 (CYP3A4) inducers is not recommended, due to reduced ivacaftor exposure. Lumacaftor-ivacaftor may decrease systemic exposure of other drugs that are CYP3A4 substrates, so coadministration must be carefully considered. In particular, lumacaftor-ivacaftor will reduce the effectiveness of the azole antifungal antibiotics (except fluconazole); coadministration is not advised. Likewise, lumacaftor-ivacaftor should not be used in patients needing the immunosuppressive drugs cyclosporine, everolimus, sirolimus, or tacrolimus. Because CYP3A4 induction may reduce the effectiveness of hormonal contraceptives, alternative methods of contraception will be needed. Some antidepressants, gastric acid blockers, and antiinflammatory drugs may need to have their doses increased to maintain effectiveness. For details, refer to the drug interactions program, the drug monograph on lumacaftor-ivacaftor, or the manufacturer's prescribing information [123].

Efficacy — Lumacaftor-ivacaftor is modestly effective for F508del homozygotes. Two randomized, blinded clinical trials of F508del homozygous subjects age 12 years and older showed a small but statistically significant improvement in percent predicted FEV1 of 3.3 that was sustained in a 96-week extension study [28,168]. Compared with the placebo group, pulmonary exacerbations were significantly reduced by 30 percent, a benefit that occurred in subjects irrespective of their change in FEV1 [6]. A smaller postmarketing study found no significant improvement in FEV1 but did detect improvement in lung clearance index, a more sensitive measure of subtle changes in pulmonary disease [169]. Similar levels of improvement were seen in studies of F508del homozygous children age 1 to <12 years [12,13,15,16,30,31]. An imaging study prospectively enrolled 31 children age 6 to 11 years who underwent CT scans prior to and annually for two years after beginning lumacaftor-ivacaftor [170]. Measurements of air trapping improved, but there was worsening bronchiectasis scores and no changes in mucus plugging.

Lumacaftor-ivacaftor did not improve FEV1 in a study of 126 adults who were heterozygous for F508del [171] and is therefore not approved by the US Food and Drug Administration (FDA) for use in any age group with less than two F508del mutations.

Adverse effects — Lumacaftor-ivacaftor is generally less well tolerated compared with tezacaftor-ivacaftor.

Soon after starting lumacaftor-ivacaftor, a subgroup of subjects developed chest discomfort and dyspnea, particularly those with worse baseline lung function [28]. Although the frequency of discontinuation due to adverse events was 4 to 7 percent during lumacaftor-ivacaftor phase 3 clinical trials and extension studies [28,31,168], a postmarketing report from the manufacturer indicates that 15 percent of patients discontinued treatment within the first three months [172]. Other studies report discontinuation in more than 32 percent of patients with a percent-predicted FEV1 <40 at treatment initiation [46]. The adverse respiratory events that lead to discontinuation of lumacaftor-ivacaftor appear to be due to the lumacaftor component. A study of 98 patients who had discontinued lumacaftor-ivacaftor for worsening respiratory symptoms were randomized to tezacaftor-ivacaftor or placebo [173]. The number of respiratory-related adverse events did not differ between groups. Of note, a separate open-label study in 46 patients with severe lung disease (FEV1 <40) reported fewer treatment discontinuations among patients who initiated treatment with a one-half dose for the first one to two weeks of treatment before increasing to the full dose [174].

Worsening of liver function, sometimes leading to liver failure, has been reported in patients with advanced liver disease, such as cirrhosis and portal hypertension [123]. We suggest avoiding this drug in patients with advanced liver disease.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cystic fibrosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Cystic fibrosis (The Basics)" and "Patient education: Bronchiectasis in children (The Basics)")

SUMMARY AND RECOMMENDATIONS

Overview – In clinical trials involving patients with a wide range of cystic fibrosis (CF) genotypes, CF transmembrane conductance regulator (CFTR) modulators have been shown to improve forced expiratory volume in one second (FEV1) and symptom-related quality of life and reduce acute exacerbations. Most of the available clinical trial data are in patients ≥6 years old and in patients with mild or moderate CF lung disease, but observational data support their use in patients with advanced lung disease.

Selection of CFTR modulator regimen – All patients with CF should undergo CFTR genotyping to determine if they carry one of the mutations approved for CFTR modulator therapy (table 2).

Selection of a specific CFTR modulator regimen depends on the individual's genotype and age. Our general approach is summarized in the algorithms (algorithm 1 and algorithm 2) and outlined below (see 'Patient selection' above):

F508del homozygotes:

-Age ≥2 years – For patients with two F508del mutations (homozygotes) who are ≥2 years old and with any disease severity, we recommend triple therapy (elexacaftor-tezacaftor-ivacaftor [ETI]) rather than dual therapy (tezacaftor-ivacaftor or lumacaftor-ivacaftor) or monotherapy (ivacaftor) (Grade 1B). Compared with dual therapy, ETI causes larger improvements in FEV1 and quality of life and the adverse effects are similar to tezacaftor-ivacaftor and less than lumacaftor-ivacaftor. ETI is not approved for children under two years old. (See 'F508del homozygotes' above and 'Elexacaftor-tezacaftor-ivacaftor' above.)

-Age 1 to <2 years – For F508del homozygotes who are 1 to <2 years old, we suggest lumacaftor-ivacaftor rather than no therapy (Grade 2C). Lumacaftor-ivacaftor is the only CFTR modulator that is approved for this genotype and age group. Clinical trials demonstrated modest but statistically significant improvements in FEV1. (See 'Lumacaftor-ivacaftor' above.)

F508del heterozygotes:

-Age ≥2 years – For patients who have one F508del mutation (heterozygotes) (table 2) and are ≥2 years old and with any disease severity, we recommend ETI rather than no therapy (Grade 1B) and recommend ETI rather than tezacaftor-ivacaftor or ivacaftor (Grade 2B). The latter recommendation is based on a short-term randomized trial and indirect comparisons from other trials. (See 'F508del heterozygotes' above and 'Elexacaftor-tezacaftor-ivacaftor' above.)

-Age <2 years – For F508del heterozygotes who are <2 years old, we suggest treatment with ivacaftor if they have a second mutation that is responsive to this therapy (table 2) (Grade 2C). ETI has not been approved for patients who are <2 years old. For F508del heterozygotes who are <2 years old and who do not have a second mutation that is eligible for ivacaftor, we initiate ETI when they reach two years of age or consider enrollment in a clinical trial if available. (See 'Ivacaftor monotherapy' above and 'Tezacaftor-ivacaftor' above.)

Other eligible mutations – More than 180 other CFTR gene mutations have been approved for treatment with one or more CFTR modulators, based on clinical and/or in vitro sensitivity testing (table 2). If a patient has a genotype that is eligible for more than one therapy, we suggest starting on the maximal therapy available for their age group (ie, ETI > dual therapy > monotherapy) (Grade 2C), based on indirect comparisons between different clinical trials. (See 'Other eligible mutations' above.)

Patients with no eligible mutations – In the United States, approximately 8 percent of non-Hispanic White patients, 25 percent of Hispanic patients, and 30 percent of Black/African American patients with CF have no mutations approved by the US Food and Drug Administration (FDA) for modulator therapy; this is an important source of health disparity. However, in vitro and a few limited clinical studies have identified additional mutations that appear to be responsive to modulator therapy. These approaches have the potential to provide information that may be useful when petitioning insurers to cover modulators for these select patients. (See 'Patients with no eligible mutations' above.)

Safety and monitoring – These drugs are generally well tolerated. Liver function tests and bilirubin should be monitored before and during treatment, and dose reductions are recommended for patients with significant hepatic impairment. Each of these drugs has multiple drug interactions, which include cytochrome P450 3A4 (CYP3A4) inhibitors (eg, itraconazole, clarithromycin, fluconazole, or nirmatrelvir-ritonavir [used for treatment of COVID-19]) or inducers (eg, rifampin, several antiseizure medications, and St. John's wort). Details on drug interactions are available in the drug interactions program included in UpToDate. (See 'Dosing and administration' above.)

  1. Middleton PG, Taylor-Cousar JL. Development of elexacaftor - tezacaftor - ivacaftor: Highly effective CFTR modulation for the majority of people with Cystic Fibrosis. Expert Rev Respir Med 2021; 15:723.
  2. Mei Zahav M, Orenti A, Jung A, et al. Disease severity of people with cystic fibrosis carrying residual function mutations: Data from the ECFS Patient Registry. J Cyst Fibros 2023; 22:234.
  3. Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis. N Engl J Med 2017; 377:2024.
  4. Clinical and Functional Translation of CFTR (CFTR2). Available at: https://cftr2.org/ (Accessed on August 24, 2023).
  5. Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med 2019; 381:1809.
  6. McColley SA, Konstan MW, Ramsey BW, et al. Lumacaftor/Ivacaftor reduces pulmonary exacerbations in patients irrespective of initial changes in FEV1. J Cyst Fibros 2019; 18:94.
  7. Nichols DP, Paynter AC, Heltshe SL, et al. Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in People with Cystic Fibrosis: A Clinical Trial. Am J Respir Crit Care Med 2022; 205:529.
  8. Durmowicz AG, Lim R, Rogers H, et al. The U.S. Food and Drug Administration's Experience with Ivacaftor in Cystic Fibrosis. Establishing Efficacy Using In Vitro Data in Lieu of a Clinical Trial. Ann Am Thorac Soc 2018; 15:1.
  9. Davies JC, Wainwright CE, Sawicki GS, et al. Ivacaftor in Infants Aged 4 to <12 Months with Cystic Fibrosis and a Gating Mutation. Results of a Two-Part Phase 3 Clinical Trial. Am J Respir Crit Care Med 2021; 203:585.
  10. Rosenfeld M, Cunningham S, Harris WT, et al. An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5 years (KLIMB). J Cyst Fibros 2019; 18:838.
  11. Davies JC, Cunningham S, Harris WT, et al. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study. Lancet Respir Med 2016; 4:107.
  12. McNamara JJ, McColley SA, Marigowda G, et al. Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2-5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study. Lancet Respir Med 2019; 7:325.
  13. Rayment JH, Asfour F, Rosenfeld M, et al. A Phase 3, Open-Label Study of Lumacaftor/Ivacaftor in Children 1 to Less Than 2 Years of Age with Cystic Fibrosis Homozygous for F508del-CFTR. Am J Respir Crit Care Med 2022; 206:1239.
  14. Rosenfeld M, Wainwright CE, Higgins M, et al. Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study. Lancet Respir Med 2018; 6:545.
  15. Hoppe JE, Chilvers M, Ratjen F, et al. Long-term safety of lumacaftor-ivacaftor in children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a multicentre, phase 3, open-label, extension study. Lancet Respir Med 2021; 9:977.
  16. Stahl M, Roehmel J, Eichinger M, et al. Effects of Lumacaftor/Ivacaftor on Cystic Fibrosis Disease Progression in Children 2 through 5 Years of Age Homozygous for F508del-CFTR: A Phase 2 Placebo-controlled Clinical Trial. Ann Am Thorac Soc 2023; 20:1144.
  17. Goralski JL, Hoppe JE, Mall MA, et al. Phase 3 Open-Label Clinical Trial of Elexacaftor/Tezacaftor/Ivacaftor in Children Aged 2-5 Years with Cystic Fibrosis and at Least One F508del Allele. Am J Respir Crit Care Med 2023; 208:59.
  18. Guimbellot JS, Baines A, Paynter A, et al. Long term clinical effectiveness of ivacaftor in people with the G551D CFTR mutation. J Cyst Fibros 2021; 20:213.
  19. Flume PA, Biner RF, Downey DG, et al. Long-term safety and efficacy of tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study. Lancet Respir Med 2021; 9:733.
  20. Wainwright C, McColley SA, McNally P, et al. Long-Term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in Children Aged ⩾6 Years with Cystic Fibrosis and at Least One F508del Allele: A Phase 3, Open-Label Clinical Trial. Am J Respir Crit Care Med 2023; 208:68.
  21. Ren CL, Morgan RL, Oermann C, et al. Cystic Fibrosis Foundation Pulmonary Guidelines. Use of Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy in Patients with Cystic Fibrosis. Ann Am Thorac Soc 2018; 15:271.
  22. Southern KW, Castellani C, Lammertyn E, et al. Standards of care for CFTR variant-specific therapy (including modulators) for people with cystic fibrosis. J Cyst Fibros 2023; 22:17.
  23. Accurso FJ, Ratjen F, Altes T, et al. Effect of withdrawal of ivacaftor therapy on CFTR channel activity and lung function in patients with cystic fibrosis. J Cyst Fibros 2013; 12:S62.
  24. Trimble AT, Donaldson SH. Ivacaftor withdrawal syndrome in cystic fibrosis patients with the G551D mutation. J Cyst Fibros 2018; 17:e13.
  25. Mitropoulou G, Balmpouzis Z, Plojoux J, et al. Effects of elexacaftor-tezacaftor-ivacaftor discontinuation in cystic fibrosis. Respir Med Res 2022; 82:100972.
  26. Uluer AZ, MacGregor G, Azevedo P, et al. Safety and efficacy of vanzacaftor-tezacaftor-deutivacaftor in adults with cystic fibrosis: randomised, double-blind, controlled, phase 2 trials. Lancet Respir Med 2023; 11:550.
  27. Heijerman HGM, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet 2019; 394:1940.
  28. Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med 2015; 373:220.
  29. Flume PA, Liou TG, Borowitz DS, et al. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest 2012; 142:718.
  30. Ratjen F, Hug C, Marigowda G, et al. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial. Lancet Respir Med 2017; 5:557.
  31. Chilvers MA, Davies JC, Milla C, et al. Long-term safety and efficacy of lumacaftor-ivacaftor therapy in children aged 6-11 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a phase 3, open-label, extension study. Lancet Respir Med 2021; 9:721.
  32. Manufacturer's prescribing information for TRIKAFTA (elexacaftor-tezacaftor-ivacaftor), 8/10/2023. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f354423a-85c2-41c3-a9db-0f3aee135d8d#table2 (Accessed on October 06, 2023).
  33. Barry PJ, Mall MA, Álvarez A, et al. Triple Therapy for Cystic Fibrosis Phe508del-Gating and -Residual Function Genotypes. N Engl J Med 2021; 385:815.
  34. Kramer-Golinkoff E, Camacho A, Kramer L, Taylor-Cousar JL. A survey: Understanding the health and perspectives of people with CF not benefiting from CFTR modulators. Pediatr Pulmonol 2022; 57:1253.
  35. Milo F, Ciciriello F, Alghisi F, Tabarini P. Lived experiences of people with cystic fibrosis that were not eligible for elexacaftor-tezacaftor-ivacaftor (ETI): A qualitative study. J Cyst Fibros 2023; 22:414.
  36. McGarry ME, McColley SA. Cystic fibrosis patients of minority race and ethnicity less likely eligible for CFTR modulators based on CFTR genotype. Pediatr Pulmonol 2021; 56:1496.
  37. Vaidyanathan S, Trumbull AM, Bar L, et al. CFTR genotype analysis of Asians in international registries highlights disparities in the diagnosis and treatment of Asian patients with cystic fibrosis. Genet Med 2022; 24:2180.
  38. Montemayor K, Jain R. Cystic Fibrosis: Highly Effective Targeted Therapeutics and the Impact on Sex and Racial Disparities. Med Clin North Am 2022; 106:1001.
  39. Bihler H, Sivachenko A, Millen L, et al. In Vitro Modulator Responsiveness of 655 CFTR Variants Found in People With CF. bioRxiv 2023.
  40. Ramalho AS, Amato F, Gentzsch M. Patient-derived cell models for personalized medicine approaches in cystic fibrosis. J Cyst Fibros 2023; 22 Suppl 1:S32.
  41. Cystic Fibrosis Foundation. Theratyping. Available at: https://www.cff.org/research-clinical-trials/theratyping (Accessed on October 14, 2023).
  42. Cincinnati Children's Research Foundation. Cincinnati Cystic Fibrosis Theratyping Research Center (CCFTRC). Available at: https://www.cincinnatichildrens.org/-/media/Cincinnati-Childrens/Home/service/c/clinical-trials/studies/cf-study-070819/cf-study-070819-pdf.pdf (Accessed on October 14, 2023).
  43. Burgel PR, Sermet-Gaudelus I, Durieu I, et al. The French Compassionate Program of elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis with advanced lung disease and no F508del CFTR variant. Eur Respir J 2023.
  44. Shteinberg M, Taylor-Cousar JL. Impact of CFTR modulator use on outcomes in people with severe cystic fibrosis lung disease. Eur Respir Rev 2020; 29.
  45. Burgel PR, Durieu I, Chiron R, et al. Rapid Improvement after Starting Elexacaftor-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and Advanced Pulmonary Disease. Am J Respir Crit Care Med 2021; 204:64.
  46. 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; 14:1662.
  47. European Medicines Agency. Kaftrio: ivacaftor/tezacaftor/elexacaftor. 2021. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/kaftrio (Accessed on March 20, 2021).
  48. Iacobucci G. Cystic fibrosis: NHS England strikes deal to offer triple combination treatment. BMJ 2020; 370:m2643.
  49. Government of Canada. Regulatory Decision Summary - Trikafta - Health Canada. 2021. Available at: https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00846 (Accessed on October 28, 2022).
  50. Cystic Fibrosis Foundation. 2022 Patient Registry Annual Data Report. 2023. Available at: https://www.cff.org/media/31216/download (Accessed on November 07, 2023).
  51. Keating D, Marigowda G, Burr L, et al. VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med 2018; 379:1612.
  52. Graeber SY, Vitzthum C, Pallenberg ST, et al. Effects of Elexacaftor/Tezacaftor/Ivacaftor Therapy on CFTR Function in Patients with Cystic Fibrosis and One or Two F508del Alleles. Am J Respir Crit Care Med 2022; 205:540.
  53. Sutharsan S, McKone EF, Downey DG, et al. Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial. Lancet Respir Med 2022; 10:267.
  54. Lee T, Sawicki GS, Altenburg J, et al. EFFECT OF ELEXACAFTOR/TEZACAFTOR/IVACAFTOR ON ANNUAL RATE OF LUNG FUNCTION DECLINE IN PEOPLE WITH CYSTIC FIBROSIS. J Cyst Fibros 2023; 22:402.
  55. Bower JK, Volkova N, Ahluwalia N, et al. Real-world safety and effectiveness of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: Interim results of a long-term registry-based study. J Cyst Fibros 2023; 22:730.
  56. Bec R, Reynaud-Gaubert M, Arnaud F, et al. Chest computed tomography improvement in patients with cystic fibrosis treated with elexacaftor-tezacaftor-ivacaftor: Early report. Eur J Radiol 2022; 154:110421.
  57. McNally P, Lester K, Stone G, et al. Improvement in Lung Clearance Index and Chest Computed Tomography Scores with Elexacaftor/Tezacaftor/Ivacaftor Treatment in People with Cystic Fibrosis Aged 12 Years and Older - The RECOVER Trial. Am J Respir Crit Care Med 2023; 208:917.
  58. Wucherpfennig L, Triphan SMF, Wege S, et al. Magnetic resonance imaging detects improvements of pulmonary and paranasal sinus abnormalities in response to elexacaftor/tezacaftor/ivacaftor therapy in adults with cystic fibrosis. J Cyst Fibros 2022; 21:1053.
  59. Nichols DP, Morgan SJ, Skalland M, et al. Pharmacologic improvement of CFTR function rapidly decreases sputum pathogen density, but lung infections generally persist. J Clin Invest 2023; 133.
  60. Wiesel V, Aviram M, Mei-Zahav M, et al. Eradication of Nontuberculous Mycobacteria in People with Cystic Fibrosis Treated with Elexacaftor/Tezacaftor/Ivacaftor: A Multicenter Cohort Study. J Cyst Fibros 2023.
  61. Schaupp L, Addante A, Völler M, et al. Longitudinal effects of elexacaftor/tezacaftor/ivacaftor on sputum viscoelastic properties, airway infection and inflammation in patients with cystic fibrosis. Eur Respir J 2023; 62.
  62. Mayer-Hamblett N, Ratjen F, Russell R, et al. Discontinuation versus continuation of hypertonic saline or dornase alfa in modulator treated people with cystic fibrosis (SIMPLIFY): results from two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials. Lancet Respir Med 2023; 11:329.
  63. Guenther EL, McCoy KS, Eisner M, et al. Impact of chronic medication de-escalation in patients with cystic fibrosis taking elexacaftor, tezacaftor, ivacaftor: A retrospective review. J Cyst Fibros 2023.
  64. Zemanick ET, Taylor-Cousar JL, Davies J, et al. A Phase 3 Open-Label Study of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 through 11 Years of Age with Cystic Fibrosis and at Least One F508del Allele. Am J Respir Crit Care Med 2021; 203:1522.
  65. Mall MA, Brugha R, Gartner S, et al. Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study. Am J Respir Crit Care Med 2022; 206:1361.
  66. Manufacturer's prescribing information for TRIKAFTA (elexacaftor-tezacaftor-ivacaftor), April 2023. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217660s000lbl.pdf (Accessed on May 04, 2023).
  67. Salvatore D, Pepe A, Carnovale V, et al. Elexacaftor/tezacaftor/ivacaftor for CFTR variants giving rise to diagnostic uncertainty: Personalised medicine or over-medicalisation? J Cyst Fibros 2022; 21:544.
  68. Raraigh KS, Lewis MH, Collaco JM, et al. Caution advised in the use of CFTR modulator treatment for individuals harboring specific CFTR variants. J Cyst Fibros 2022; 21:856.
  69. Djavid AR, Thompson AE, Irace AL, et al. Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in Advanced Cystic Fibrosis Lung Disease. Ann Am Thorac Soc 2021; 18:1924.
  70. O'Shea KM, O'Carroll OM, Carroll C, et al. Efficacy of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease. Eur Respir J 2021; 57.
  71. Martin C, Legeai C, Regard L, et al. Major Decrease in Lung Transplantation for Patients with Cystic Fibrosis in France. Am J Respir Crit Care Med 2022; 205:584.
  72. Martin C, Reynaud-Gaubert M, Hamidfar R, et al. Sustained effectiveness of elexacaftor-tezacaftor-ivacaftor in lung transplant candidates with cystic fibrosis. J Cyst Fibros 2022; 21:489.
  73. Leard LE, Holm AM, Valapour M, et al. Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2021; 40:1349.
  74. Quittner AL, Buu A, Messer MA, et al. Development and validation of The Cystic Fibrosis Questionnaire in the United States: a health-related quality-of-life measure for cystic fibrosis. Chest 2005; 128:2347.
  75. Fajac I, Daines C, Durieu I, et al. Non-respiratory health-related quality of life in people with cystic fibrosis receiving elexacaftor/tezacaftor/ivacaftor. J Cyst Fibros 2023; 22:119.
  76. Hergenroeder GE, Faino A, Bridges G, et al. The impact of elexacaftor/tezacaftor/ivacaftor on fat-soluble vitamin levels in people with cystic fibrosis. J Cyst Fibros 2023; 22:1048.
  77. Schembri L, Warraich S, Bentley S, et al. Impact of elexacaftor/tezacaftor/ivacaftor on fat-soluble vitamin levels in children with cystic fibrosis. J Cyst Fibros 2023; 22:843.
  78. Miller MJ, Foroozan R. Papilledema and hypervitaminosis A after elexacaftor/tezacaftor/ivacaftor for cystic fibrosis. Can J Ophthalmol 2022; 57:e6.
  79. Schwarzenberg SJ, Vu PT, Skalland M, et al. Elexacaftor/tezacaftor/ivacaftor and gastrointestinal outcomes in cystic fibrosis: Report of promise-GI. J Cyst Fibros 2023; 22:282.
  80. Mainz JG, Zagoya C, Polte L, et al. Elexacaftor-Tezacaftor-Ivacaftor Treatment Reduces Abdominal Symptoms in Cystic Fibrosis-Early results Obtained With the CF-Specific CFAbd-Score. Front Pharmacol 2022; 13:877118.
  81. Shakir S, Echevarria C, Doe S, et al. Elexacaftor-Tezacaftor-Ivacaftor improve Gastro-Oesophageal reflux and Sinonasal symptoms in advanced cystic fibrosis. J Cyst Fibros 2022; 21:807.
  82. Narkewicz MR. Cystic fibrosis liver disease in the post-modulator era. Curr Opin Pulm Med 2023; 29:621.
  83. Tewkesbury DH, Scott J, Barry PJ, et al. Effects of elexacaftor/tezacaftor/ivacaftor on liver fibrosis markers in adults with cystic fibrosis. J Cyst Fibros 2023.
  84. Levitte S, Sellers Z, Fuchs Y, Wise R. 212: Impact of lumacaftor/ivacaftor and tezacaftor/ivacaftor on pediatric liver health. J Cyst Fibros 2021; 20:S104.
  85. Paluck F, Power N, Lynch C, et al. Liver function tests in F508del homozygous paediatric patients with cystic fibrosis taking lumacaftor/ivacaftor combination therapy. Ir Med J 2021; 114:259.
  86. Drummond D, Dana J, Berteloot L, et al. Lumacaftor-ivacaftor effects on cystic fibrosis-related liver involvement in adolescents with homozygous F508 del-CFTR. J Cyst Fibros 2022; 21:212.
  87. Ramsey ML, Li SS, Lara LF, et al. Cystic fibrosis transmembrane conductance regulator modulators and the exocrine pancreas: A scoping review. J Cyst Fibros 2023; 22:193.
  88. Stallings VA, Sainath N, Oberle M, et al. Energy Balance and Mechanisms of Weight Gain with Ivacaftor Treatment of Cystic Fibrosis Gating Mutations. J Pediatr 2018; 201:229.
  89. Sathe M, Moshiree B, Aliaj E, et al. Need to study simplification of gastrointestinal medication regimen in cystic fibrosis in the era of highly effective modulators. Pediatr Pulmonol 2023; 58:811.
  90. Ramsey ML, Gokun Y, Sobotka LA, et al. Cystic Fibrosis Transmembrane Conductance Regulator Modulator Use Is Associated With Reduced Pancreatitis Hospitalizations in Patients With Cystic Fibrosis. Am J Gastroenterol 2021; 116:2446.
  91. Akshintala VS, Kamal A, Faghih M, et al. Cystic fibrosis transmembrane conductance regulator modulators reduce the risk of recurrent acute pancreatitis among adult patients with pancreas sufficient cystic fibrosis. Pancreatology 2019; 19:1023.
  92. Carrion A, Borowitz DS, Freedman SD, et al. Reduction of Recurrence Risk of Pancreatitis in Cystic Fibrosis With Ivacaftor: Case Series. J Pediatr Gastroenterol Nutr 2018; 66:451.
  93. Gould MJ, Smith H, Rayment JH, et al. CFTR modulators increase risk of acute pancreatitis in pancreatic insufficient patients with cystic fibrosis. J Cyst Fibros 2022; 21:600.
  94. Sadras I, Cohen-Cymberknoh M, Kerem E, et al. Acute pancreatitis in pancreatic-insufficient cystic fibrosis patients treated with CFTR modulators. J Cyst Fibros 2023; 22:777.
  95. Petersen MC, Begnel L, Wallendorf M, Litvin M. Effect of elexacaftor-tezacaftor-ivacaftor on body weight and metabolic parameters in adults with cystic fibrosis. J Cyst Fibros 2022; 21:265.
  96. Korten I, Kieninger E, Krueger L, et al. Short-Term Effects of Elexacaftor/Tezacaftor/Ivacaftor Combination on Glucose Tolerance in Young People With Cystic Fibrosis-An Observational Pilot Study. Front Pediatr 2022; 10:852551.
  97. Scully KJ, Marchetti P, Sawicki GS, et al. The effect of elexacaftor/tezacaftor/ivacaftor (ETI) on glycemia in adults with cystic fibrosis. J Cyst Fibros 2022; 21:258.
  98. Steinack C, Ernst M, Beuschlein F, et al. Improved glucose tolerance after initiation of Elexacaftor / Tezacaftor / Ivacaftor in adults with cystic fibrosis. J Cyst Fibros 2023; 22:722.
  99. Chan CL, Granados A, Moheet A, et al. Glycemia and β-cell function before and after elexacaftor/tezacaftor/ivacaftor in youth and adults with cystic fibrosis. J Clin Transl Endocrinol 2022; 30:100311.
  100. Salazar-Barragan M, Taub DR. The Effects of Elexacaftor, Tezacaftor, and Ivacaftor (ETI) on Blood Glucose in Patients With Cystic Fibrosis: A Systematic Review. Cureus 2023; 15:e41697.
  101. DiMango E, Overdevest J, Keating C, et al. Effect of highly effective modulator treatment on sinonasal symptoms in cystic fibrosis. J Cyst Fibros 2021; 20:460.
  102. Stapleton AL, Kimple AJ, Goralski JL, et al. Elexacaftor-Tezacaftor- Ivacaftor improves sinonasal outcomes in cystic fibrosis. J Cyst Fibros 2022; 21:792.
  103. Beswick DM, Humphries SM, Balkissoon CD, et al. Olfactory dysfunction in cystic fibrosis: Impact of CFTR modulator therapy. J Cyst Fibros 2022; 21:e141.
  104. Beswick DM, Humphries SM, Balkissoon CD, et al. Impact of Cystic Fibrosis Transmembrane Conductance Regulator Therapy on Chronic Rhinosinusitis and Health Status: Deep Learning CT Analysis and Patient-reported Outcomes. Ann Am Thorac Soc 2022; 19:12.
  105. Tewkesbury DH, Athwal V, Bright-Thomas RJ, et al. Longitudinal effects of elexacaftor/tezacaftor/ivacaftor on liver tests at a large single adult cystic fibrosis centre. J Cyst Fibros 2023; 22:256.
  106. Guimbellot JS, Taylor-Cousar JL. Combination CFTR modulator therapy in children and adults with cystic fibrosis. Lancet Respir Med 2021; 9:677.
  107. Lowry S, Mogayzel PJ, Oshima K, Karnsakul W. Drug-induced liver injury from elexacaftor/ivacaftor/tezacaftor. J Cyst Fibros 2022; 21:e99.
  108. Gramegna A, De Petro C, Leonardi G, et al. Onset of systemic arterial hypertension after initiation of elexacaftor/tezacaftor/ivacaftor in adults with cystic fibrosis: A case series. J Cyst Fibros 2022; 21:885.
  109. Ramsey B, Correll CU, DeMaso DR, et al. Elexacaftor/Tezacaftor/Ivacaftor Treatment and Depression-related Events. Am J Respir Crit Care Med 2023.
  110. Hjelm M, Hente E, Miller J, et al. Longitudinal mental health trends in cystic fibrosis. J Cyst Fibros 2023; 22:1093.
  111. Heo S, Young DC, Safirstein J, et al. Mental status changes during elexacaftor/tezacaftor / ivacaftor therapy. J Cyst Fibros 2022; 21:339.
  112. Dagenais RVE, Su VCH, Quon BS. Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review. J Clin Med 2020; 10.
  113. Spoletini G, Gillgrass L, Pollard K, et al. Dose adjustments of Elexacaftor/Tezacaftor/Ivacaftor in response to mental health side effects in adults with cystic fibrosis. J Cyst Fibros 2022; 21:1061.
  114. Baroud E, Chaudhary N, Georgiopoulos AM. Management of neuropsychiatric symptoms in adults treated with elexacaftor/tezacaftor/ivacaftor. Pediatr Pulmonol 2023; 58:1920.
  115. McKinzie CJ, Goralski JL, Noah TL, et al. Worsening anxiety and depression after initiation of lumacaftor/ivacaftor combination therapy in adolescent females with cystic fibrosis. J Cyst Fibros 2017; 16:525.
  116. Talwalkar JS, Koff JL, Lee HB, et al. Cystic Fibrosis Transmembrane Regulator Modulators: Implications for the Management of Depression and Anxiety in Cystic Fibrosis. Psychosomatics 2017; 58:343.
  117. Quittner AL, Goldbeck L, Abbott J, et al. Prevalence of depression and anxiety in patients with cystic fibrosis and parent caregivers: results of The International Depression Epidemiological Study across nine countries. Thorax 2014; 69:1090.
  118. Lord L, McKernon D, Grzeskowiak L, et al. Depression and anxiety prevalence in people with cystic fibrosis and their caregivers: a systematic review and meta-analysis. Soc Psychiatry Psychiatr Epidemiol 2023; 58:287.
  119. Jones SE, Ethier KA, Hertz M, et al. Mental Health, Suicidality, and Connectedness Among High School Students During the COVID-19 Pandemic - Adolescent Behaviors and Experiences Survey, United States, January-June 2021. MMWR Suppl 2022; 71:16.
  120. Sakon C, Vogt H, Brown CD, Tillman EM. A survey assessing the impact of COVID-19 and elexacaftor/tezacaftor/ifavacaftor on both physical and mental health in adults with cystic fibrosis. Pediatr Pulmonol 2023; 58:662.
  121. Ibrahim H, Danish H, Morrissey D, et al. Individualized approach to elexacaftor/tezacaftor/ivacaftor dosing in cystic fibrosis, in response to self-reported anxiety and neurocognitive adverse events: A case series. Front Pharmacol 2023; 14:1156621.
  122. Everage NJ, Bai Y, Loop B, et al. Diagnosed cataracts in patients with cystic fibrosis in a United States administrative database. Ophthalmic Genet 2017; 38:527.
  123. Manufacturer's prescribing information for Orkambi (lumacaftor/ivacaftor) tablets, 8/10/2023. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3fc1c40e-cfac-47a1-9e1a-61ead3570600 (Accessed on October 06, 2023).
  124. Taylor-Cousar JL, Jain R. Maternal and fetal outcomes following elexacaftor-tezacaftor-ivacaftor use during pregnancy and lactation. J Cyst Fibros 2021; 20:402.
  125. Nash EF, Middleton PG, Taylor-Cousar JL. Outcomes of pregnancy in women with cystic fibrosis (CF) taking CFTR modulators - an international survey. J Cyst Fibros 2020; 19:521.
  126. O'Connor KE, Goodwin DL, NeSmith A, et al. Elexacafator/tezacaftor/ivacaftor resolves subfertility in females with CF: A two center case series. J Cyst Fibros 2021; 20:399.
  127. Collins B, Fortner C, Cotey A, et al. Drug exposure to infants born to mothers taking Elexacaftor, Tezacaftor, and Ivacaftor. J Cyst Fibros 2022; 21:725.
  128. Jain R, Wolf A, Molad M, et al. Congenital bilateral cataracts in newborns exposed to elexacaftor-tezacaftor-ivacaftor in utero and while breast feeding. J Cyst Fibros 2022; 21:1074.
  129. Jain R, Magaret A, Vu PT, et al. Prospectively evaluating maternal and fetal outcomes in the era of CFTR modulators: the MAYFLOWERS observational clinical trial study design. BMJ Open Respir Res 2022; 9.
  130. Fortner CN, Seguin JM, Kay DM. Normal pancreatic function and false-negative CF newborn screen in a child born to a mother taking CFTR modulator therapy during pregnancy. J Cyst Fibros 2021; 20:835.
  131. Szentpetery S, Foil K, Hendrix S, et al. A case report of CFTR modulator administration via carrier mother to treat meconium ileus in a F508del homozygous fetus. J Cyst Fibros 2022; 21:721.
  132. Patel P, Yeley J, Brown C, et al. Immunoreactive Trypsinogen in Infants Born to Women with Cystic Fibrosis Taking Elexacaftor-Tezacaftor-Ivacaftor. Int J Neonatal Screen 2023; 9.
  133. Ramos KJ, Guimbellot JS, Valapour M, et al. Use of elexacaftor/tezacaftor/ivacaftor among cystic fibrosis lung transplant recipients. J Cyst Fibros 2022; 21:745.
  134. Benninger LA, Trillo C, Lascano J. CFTR modulator use in post lung transplant recipients. J Heart Lung Transplant 2021; 40:1498.
  135. Potter LM, Vargas B, Rotolo SM, et al. Elexacaftor/Ivacaftor/Tezacaftor in Lung Transplant Recipients: A Case Series. J Heart Lung Transplant 2021; 40:S375.
  136. Ragan H, Autry E, Bomersback T, et al. The use of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis postliver transplant: A case series. Pediatr Pulmonol 2022; 57:411.
  137. Van Goor F, Hadida S, Grootenhuis PD, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A 2009; 106:18825.
  138. Manufacturer's prescribing information for KALYDECO (iacaftor), revised 8/10/2023. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0ab0c9f8-3eee-4e0f-9f3f-c1e16aaffe25 (Accessed on October 06, 2023).
  139. Simmonds NJ, van der Ent CK, Colombo C, et al. VOCAL: An observational study of ivacaftor for people with cystic fibrosis and selected non-G551D-CFTR gating mutations. J Cyst Fibros 2023; 22:124.
  140. Van Goor F, Yu H, Burton B, Hoffman BJ. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros 2014; 13:29.
  141. Kerem E, Cohen-Cymberknoh M, Tsabari R, et al. Ivacaftor in People with Cystic Fibrosis and a 3849+10kb C→T or D1152H Residual Function Mutation. Ann Am Thorac Soc 2021; 18:433.
  142. Moss RB, Flume PA, Elborn JS, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir Med 2015; 3:524.
  143. Guigui S, Wang J, Cohen RI. The use of ivacaftor in CFTR mutations resulting in residual functioning protein. Respir Med Case Rep 2016; 19:193.
  144. Nick JA, St Clair C, Jones MC, et al. Ivacaftor in cystic fibrosis with residual function: Lung function results from an N-of-1 study. J Cyst Fibros 2020; 19:91.
  145. Guimbellot JS, Ryan KJ, Anderson JD, et al. Plasma and cellular ivacaftor concentrations in patients with cystic fibrosis. Pediatr Pulmonol 2022; 57:2745.
  146. Skilton M, Krishan A, Patel S, et al. Potentiators (specific therapies for class III and IV mutations) for cystic fibrosis. Cochrane Database Syst Rev 2019; 1:CD009841.
  147. Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365:1663.
  148. Davies JC, Wainwright CE, Canny GJ, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med 2013; 187:1219.
  149. Davies J, Sheridan H, Bell N, et al. Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial. Lancet Respir Med 2013; 1:630.
  150. McKone EF, Borowitz D, Drevinek P, et al. Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST). Lancet Respir Med 2014; 2:902.
  151. Rowe SM, Heltshe SL, Gonska T, et al. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med 2014; 190:175.
  152. Heltshe SL, Mayer-Hamblett N, Burns JL, et al. Pseudomonas aeruginosa in cystic fibrosis patients with G551D-CFTR treated with ivacaftor. Clin Infect Dis 2015; 60:703.
  153. Sawicki GS, McKone EF, Pasta DJ, et al. Sustained Benefit from ivacaftor demonstrated by combining clinical trial and cystic fibrosis patient registry data. Am J Respir Crit Care Med 2015; 192:836.
  154. 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; 73:731.
  155. Frost FJ, Nazareth DS, Charman SC, et al. Ivacaftor Is Associated with Reduced Lung Infection by Key Cystic Fibrosis Pathogens. A Cohort Study Using National Registry Data. Ann Am Thorac Soc 2019; 16:1375.
  156. Yu H, Burton B, Huang CJ, et al. Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros 2012; 11:237.
  157. De Boeck K, Munck A, Walker S, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros 2014; 13:674.
  158. Taylor-Cousar J, Niknian M, Gilmartin G, et al. Effect of ivacaftor in patients with advanced cystic fibrosis and a G551D-CFTR mutation: Safety and efficacy in an expanded access program in the United States. J Cyst Fibros 2016; 15:116.
  159. Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. N Engl J Med 2017; 377:2013.
  160. Heneghan M, Southern KW, Murphy J, et al. Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del). Cochrane Database Syst Rev 2023; 11:CD010966.
  161. Prescribing information for SYMDEKO, 8/10/2023. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=302ae804-37db-44fd-ac2f-3dbdeda9aa4b (Accessed on October 06, 2023).
  162. Davies JC, Sermet-Gaudelus I, Naehrlich L, et al. A phase 3, double-blind, parallel-group study to evaluate the efficacy and safety of tezacaftor in combination with ivacaftor in participants 6 through 11 years of age with cystic fibrosis homozygous for F508del or heterozygous for the F508del-CFTR mutation and a residual function mutation. J Cyst Fibros 2021; 20:68.
  163. Munck A, Kerem E, Ellemunter H, et al. Tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for minimal function CFTR mutations. J Cyst Fibros 2020; 19:962.
  164. McKone EF, DiMango EA, Sutharsan S, et al. A phase 3, randomized, double-blind, parallel-group study to evaluate tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for F508del-CFTR and a gating mutation. J Cyst Fibros 2021; 20:234.
  165. Walker S, Flume P, McNamara J, et al. A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 through 11 years with cystic fibrosis. J Cyst Fibros 2019; 18:708.
  166. Sawicki GS, Chilvers M, McNamara J, et al. A Phase 3, open-label, 96-week trial to study the safety, tolerability, and efficacy of tezacaftor/ivacaftor in children ≥ 6 years of age homozygous for F508del or heterozygous for F508del and a residual function CFTR variant. J Cyst Fibros 2022; 21:675.
  167. Clancy JP, Rowe SM, Accurso FJ, et al. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax 2012; 67:12.
  168. Konstan MW, McKone EF, Moss RB, et al. Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study. Lancet Respir Med 2017; 5:107.
  169. Sagel SD, Khan U, Heltshe SL, et al. Clinical Effectiveness of Lumacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for F508del-CFTR. A Clinical Trial. Ann Am Thorac Soc 2021; 18:75.
  170. McNally P, Linnane B, Williamson M, et al. The clinical impact of Lumacaftor-Ivacaftor on structural lung disease and lung function in children aged 6-11 with cystic fibrosis in a real-world setting. Respir Res 2023; 24:199.
  171. Rowe SM, McColley SA, Rietschel E, et al. Lumacaftor/Ivacaftor Treatment of Patients with Cystic Fibrosis Heterozygous for F508del-CFTR. Ann Am Thorac Soc 2017; 14:213.
  172. Vertex Pharmaceuticals. Press Release Details: Vertex Reports First Quarter 2016 Financial Results. 2016. Available at: http://investors.vrtx.com/releasedetail.cfm?ReleaseID=967156 (Accessed on April 30, 2016).
  173. Schwarz C, Sutharsan S, Epaud R, et al. Tezacaftor/ivacaftor in people with cystic fibrosis who stopped lumacaftor/ivacaftor due to respiratory adverse events. J Cyst Fibros 2021; 20:228.
  174. Taylor-Cousar JL, Jain M, Barto TL, et al. Lumacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease homozygous for F508del-CFTR. J Cyst Fibros 2018; 17:228.
Topic 118899 Version 45.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟