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: Treatment of acute 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".)
TYPES OF CFTR MODULATORS AND THEIR TARGETED MUTATIONS — The different types of CFTR modulators and the targeted classes of CFTR mutations are summarized in the table (table 1).
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 elexacaftor-tezacaftor-ivacaftor (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].
PATIENT SELECTION — We recommend treatment with a CFTR modulator for most individuals with CF who are ≥6 years old and have responsive CFTR gene mutations, and we suggest CFTR modulator therapy for younger patients with CF 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, and the Medicines and Healthcare products Regulatory Agency in the United Kingdom.
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 majority of the available data are from studies of patients ≥6 years old. For younger patients, regulatory agencies usually 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. However, it is reassuring that studies in younger patients have found other indications of efficacy, such as reductions in sweat chloride and improvements in nutritional status similar to older patients [8-10].
Because of their relatively recent introduction into CF care, the long-term efficacy and safety of these modulators have not been clearly established. However, observational studies of up to five years' duration for ivacaftor, the earliest-approved modulator, have shown favorable risk/benefit profiles [11].
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.
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 elexacaftor-tezacaftor-ivacaftor [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 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.
F508del homozygotes
●Age ≥6 years – For patients who have two F508del mutations (homozygotes) and are ≥6 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 [12]. 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 [12,13]. 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 [14]; however, ivacaftor boosts the efficacy of the other corrector agents (lumacaftor, tezacaftor, and elexacaftor) when given in combination. (See 'Elexacaftor-tezacaftor-ivacaftor' below.)
●Age <6 years – For homozygotes, we suggest lumacaftor-ivacaftor for children ages 1 to <6 years because ETI is not approved for children under six years old. Patients should be transitioned to ETI when they reach the age of six years. Clinical trials are underway to test the safety and efficacy of ETI in younger patients (NCT05153317).
Lumacaftor-ivacaftor is approved for children as young as one year, based on limited safety data in this age group [15,16]. 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 ≥6 years – We recommend ETI for patients who have one F508del mutation (heterozygotes) and are ≥6 years old regardless of their second mutation [17]. 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 [18]. (See 'Elexacaftor-tezacaftor-ivacaftor' below.)
●Age <6 years – For F508del heterozygotes who are 4 months to <6 years old, we suggest treatment with ivacaftor if they have a second mutation that is responsive to this modulator (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 — For patients who do not have any mutation that is approved for one of the available CFTR modulators, we suggest limiting the use of CFTR therapy to the setting of a clinical trial. The psychological burden of being in the small minority of patients not eligible for highly effective modulator therapy, while most of the CF population qualify for such treatment, is considerable [19].
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 CF 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 [20]:
●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 [21]. 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 [22].
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) [23,24]; 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 [25]. (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 [17]. ETI has been approved in the United States, United Kingdom, European Union, and Canada [26-28]. 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 six years [29].
Indications — We recommend ETI for patients ≥6 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 [17]
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 <6 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:
●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 [17]. 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 manufacturer's prescribing information or the Lexicomp drug interactions database [17].
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 [30]. 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 [31].
ETI was approved in the United States for patients ≥12 years in 2019 [5,12]; the indication was extended to children ≥6 years in 2021 [17].
Pulmonary outcomes — The key clinical trials are:
●Homozygous F508del – A clinical trial in 107 subjects homozygous for F508del compared ETI with tezacaftor-ivacaftor after a four-week run-in period on tezacaftor-ivacaftor alone [12]. Percent predicted forced expiratory volume in one second (FEV1) at four weeks (primary endpoint) increased by 10.0 points (95% CI 7.4-12.6) and sweat chloride decreased by 45.1 mmol/L in the group receiving ETI compared with the group receiving tezacaftor-ivacaftor. Respiratory symptoms were significantly improved in the group on ETI, as measured by a standardized questionnaire.
A similarly designed placebo-controlled trial compared ETI with tezacaftor-ivacaftor but prolonged the duration of the study to 24 weeks [32]. Percent predicted FEV1 in the ETI group improved by 11.2 points, compared with 1.0 point in the group that remained on tezacaftor-ivacaftor. Respiratory symptom score improved substantially and sweat chloride level decreased in the ETI group, similarly to the aforementioned study.
A long-term prospective study has been following 487 patients who were enrolled and assessed prior to beginning commercial ETI and then periodically thereafter [7]. After one, three, and six months of ETI, improvement in FEV1 from baseline continued regardless of whether the patient had previously been taking lumacaftor-ivacaftor or tezacaftor-ivacaftor. A retrospective study using chest computed tomography (CT) imaging showed reduction in mucus plugging and airway thickening following initiation of ETI; participants included F508del homozygotes and heterozygotes [33].
Younger patients aged 6 to 11 years who were homozygous for F508del were evaluated in a 24-week open-label trial of ETI [34]. Mean percent predicted FEV1 increased by 10.2 points (95% CI 7.9-12.6), with secondary efficacy measures showing levels of improvement similar to those seen in older CF patients.
●F508del heterozygotes with a second minimal function CFTR mutation – A randomized, placebo-controlled trial enrolled 403 subjects age ≥12 years who were heterozygous for F508del and had a second minimal function mutation (ie, one that produced no CFTR protein or a protein unresponsive to ivacaftor or tezacaftor-ivacaftor (see 'Types of CFTR modulators and their targeted mutations' above)) [5]. Compared with placebo, triple combination therapy with ETI increased percent predicted FEV1 by 13.8 points (95% CI 12.1-15.4) after four weeks of treatment (primary endpoint) and by 14.3 points (95% CI 12.7-15.8) after 24 weeks. The number of pulmonary exacerbations decreased by 63 percent in the active drug group compared with placebo, and sweat chloride decreased by 41.8 mmol/L. Respiratory symptoms were significantly improved in the group treated with ETI, as measured by a standardized questionnaire.
Patients 6 to 11 years who were enrolled in a 24-week open-label prospective trial of ETI showed an increase in FEV1 percent predicted of 9.1 points (95% CI 6.3-11.9) [34]. A subsequent clinical trial using lung clearance index (LCI) as the primary endpoint enrolled 121 children aged 6 to 11 years who were randomized to ETI or placebo for 24 weeks [35]. The change from baseline in LCI in the ETI group was -2.26 units (95% CI -1.81 to -2.71) compared with placebo (where LCI reduction represents improvement); percent predicted FEV1 was 11.0 points higher (95% CI 6.9-15.1).
●F508del heterozygotes with a second gating or residual function CFTR mutation – A randomized trial in more than 250 F508del heterozygotes ≥12 years of age compared ETI to active control with either dual therapy (tezacaftor-ivacaftor; in patients with F508del-residual function genotypes [n = 81]) or monotherapy (ivacaftor; in patients with F508del-gating genotypes [n = 45]) [18]. ETI for eight weeks improved respiratory symptoms (change from baseline +10.3 points on a 100-point scale compared with +1.6 point for active control; between-group difference 8.7 points [95% CI 5.3-12.1]), as well as pulmonary function (change from baseline FEV1 3.7 percent versus 0.2 percent for active control; between-group difference 3.5 percent [95% CI 2.2-4.7]) and sweat chloride (change from baseline -22.3 mmol/L versus +0.7 mmol/L for active control). These findings support our recommendation for using ETI rather than dual therapy or monotherapy for patients who are eligible.
●Other mutations – In vitro studies of cells that have been genetically engineered to express the complementary deoxyribonucleic acid (cDNA) of rare CFTR gene mutations identified 177 mutations that were responsive to ETI. The combination increased chloride transport above baseline in each of these mutations by at least 10 percent of the transport measured in normal cells [17]. Because this level of improvement has been predictive of benefit in clinical trials of patients with more common mutations [36], the FDA agreed to approve ETI for these additional rare mutations, which 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 [37,38]. 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 [38] to understand the nature of the mutations and balance the likely benefits and cost/risk.
●Patients 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 [24]. 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 [39,40].
Of note, studies from France reported a 57 percent reduction in CF lung transplants in 2020 compared with the years immediately preceding ETI approval [24]. 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 [41]. 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 [42]. Sixty-one of these patients were removed from transplant consideration and remained off of the transplant list during the one-year follow-up.
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.
●Gastrointestinal disease – In the clinical trials described above, ETI improved body weight and body mass index compared with control groups [5,12,18,32] (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 25-hydroxyvitamin D, a fat-soluble vitamin that is frequently low in people with CF [35]. Reports on the effects of ETI on gastrointestinal symptoms such as abdominal pain and bloating have been mixed. For example, a prospective study of 270 patients age >6 years used three validated questionnaires to assess gastrointestinal symptoms at baseline and at six months following initiation of ETI [43]. ETI treatment was associated with modest improvement in gastrointestinal symptom scores that were inconsistent between males and females. However, a study of 107 people with CF at eight European CF centers reported significant improvements using a validated patient-reported symptom score [44].
●Liver disease – Hepatobiliary disease is a common manifestation of CF with advanced disease (cirrhosis), reported in 3.1 percent of patients in the CF Foundation Patient Registry [45]. (See "Cystic fibrosis: Hepatobiliary disease".)
The effectiveness of ETI on liver disease has yet to be reported, but there is reason to suspect that it will be beneficial, based on preliminary reports of improvement with lumacaftor-ivacaftor [46-48] and the fact that ETI improves CFTR function much better compared with lumacaftor-ivacaftor. The potential benefits of CFTR modulators on CF liver disease need to be balanced with their known propensity to elevate serum transaminases in some patients with CF. (See 'Adverse effects' below.)
●Pancreatic disease – Preliminary evidence suggests that CFTR modulators may be effective at preventing, delaying, or, possibly, reversing pancreatic insufficiency when begun in early childhood. For example, an open-label study of ivacaftor in infants and children with a gating mutation showed improvement in exocrine pancreatic function [10,49]. Increase in fecal elastase was also seen in older patients who were pancreatic sufficient at baseline [50].
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 [50]. (See 'Ivacaftor monotherapy' below.)
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'). The effects of CFTR modulators on acute pancreatitis risk are unclear: Theoretically, improving CFTR function in the pancreas could ameliorate pancreatitis by returning pancreatic secretions toward normal or, alternatively, worsen it by increasing the flow of pancreatic secretions through ducts partially obstructed from scarring. Published reports on the effects of modulators on patients with pancreatitis have had conflicting results: Two case series reported improvement [51,52], and another reported worsening [53].
●CF-related diabetes – One retrospective [54] and two prospective [55,56] studies of patients without diagnosed CF-related diabetes reported improvement in glycemic control following initiation of ETI. However, the studies had conflicting results regarding effects of ETI on glycemic control in patients who had been diagnosed with CF-related diabetes. In a small study of patients with CF-related diabetes, lumacaftor-ivacaftor, which improves CFTR function modestly compared with ETI, did not improve glycemic control [57]. (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 [58-61].
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 [32].
The safety of ETI in younger children was evaluated in a 24-week open-label study in children 6 to 11 years old who were homozygous for F508del or heterozygous for F508del with a second minimal function mutation (n = 66) [34]. The safety profile and pharmacokinetics were similar to those in older individuals, and patients experience improvement in percent predicted FEV1 (10.2 percentage points, 95% CI 7.9-12.6), respiratory symptoms, sweat chloride, and body weight. On the basis of this study, the drug combination was approved for this age group in June 2021.
Specific safety measures monitored 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 [17]. 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 levels of discontinuation for elevated transaminases were seen in long-term open-label trials of lumacaftor-ivacaftor [62,63] and tezacaftor-ivacaftor [64].
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 [65]. 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 [17,66]. Worsening of liver function, sometimes leading to liver failure, has been reported in patients with advanced liver disease, such as cirrhosis and portal hypertension [17].
●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 [17]. 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) [17]. 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 [54]. Postmarketing, a case series reported four patients who were started on antihypertensive treatment soon after beginning ETI [67].
●Mental health effects – The phase 3 clinical trials of ETI did not report significantly more psychiatric events in those receiving ETI compared with controls [5,12,18,32]. In fact, quality-of-life measures consistently showed large improvements in well-being that were three to four times more than the minimal clinically important difference for the measure. However, occasional adverse events of anxiety and/or depression were noted in both active drug and control subjects [18,32]. Postmarketing, there have been some reports of depression, anxiety, insomnia, and/or "fogginess" in patients taking ETI [68-70]. This is similar to the occasional case reports of psychiatric consequences of lumacaftor-ivacaftor [69,71,72].
It is difficult to assess how often CFTR modulators cause psychiatric events, given the high background prevalence of anxiety and depression in patients with CF [73]. It is also relevant that ETI became commercially available just prior to the start of the COVID-19 pandemic, which likely has had an independent adverse effect on mental health. 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 a small case series suggested a dose reduction for patients with mental health changes that they perceive are related to ETI and who have a desire to retain its benefits [70].
Considerations for special populations
Pregnancy and lactation
●Effects on fertility – Following approval of ETI, the number of pregnancies per year among CF patients in the United States rose sharply from an average of 258 (2014 through 2016) to 618 in 2020 and 675 in 2021 [29,74]. 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 [17,75]. 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 [76-78]. 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 [79].
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 [80]. 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) [81].
●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 [82,83]. 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 [83]. 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 [17,75]. 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 [79].
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) [84]. 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 [85,86]. 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 [87].
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 [88]. 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 [89]. Subsequent clinical trials have shown that ivacaftor benefits patients with other CFTR gating mutations [90] 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 [91-95] (see 'Types of CFTR modulators and their targeted mutations' above). Subsequently, additional mutations have been approved for ivacaftor, based on results of in vitro studies and supporting clinical trials [36,89,91].
Indications — We suggest ivacaftor monotherapy for patients ≥4 months of age with eligible mutations (table 2) if the patient is not otherwise eligible for dual or triple therapy.
For patients who are eligible for triple combination therapy (elexacaftor-tezacaftor-ivacaftor [ETI]) or dual therapy (tezacaftor-ivacaftor) (table 2), we suggest using these combinations rather than ivacaftor 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 [89]:
●Patients 4 to <6 months and >5 kg body weight (and no hepatic impairment) – 25 mg packet taken orally every 12 hours
●Patients six months to five 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
●Patients ≥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 manufacturer's prescribing information or the Lexicomp drug interactions database [89]. 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 [96].
Efficacy
●G551D mutation – Clinical trials of ivacaftor in patients with a G551D mutation have demonstrated important benefits [97]:
•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 [98]. 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 [99].
•Patients with mild pulmonary disease and a G551D mutation also benefitted from ivacaftor, as demonstrated by improved lung clearance index (LCI) and FEV1 [100].
Long-term benefits of ivacaftor were shown in clinical studies of diverse designs including those that were open-label extensions [101], prospective observational [11,102,103], or registry based [104-106]. 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 [91,107]. 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 [108]. Based on these studies, the FDA expanded approval for ivacaftor beyond the G551D mutation to include other gating mutations that were responsive in vitro [89]. Subsequent clinical trials have provided supportive evidence of ivacaftor benefit for patients >6 years with either G551D or other CFTR gating mutations [90] 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 'Types of CFTR modulators and their targeted mutations' above) [91]. Evidence of clinical benefit has been reported for patients having one of several such mutations [92-95].
•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 [36]. 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 >4 months old [8-10,49]. 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 disease – Ivacaftor 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 [23]. 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 [109]. The CF Foundation clinical guideline for CFTR modulator use recommends ivacaftor for patients with advanced lung disease and an eligible genotype [110].
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 [89]. 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 [8-10,49].
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 that is slightly greater than what was reported for lumacaftor-ivacaftor and reduces the risk of pulmonary exacerbations [111,112]. 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 [113].
Indications — We recommend tezacaftor-ivacaftor for patients ≥6 years with one of five mutations that are approved for tezacaftor-ivacaftor but not triple therapy (table 2).
Most other genotypes that are eligible for tezacaftor-ivacaftor are also eligible for triple combination therapy (elexacaftor-tezacaftor-ivacaftor [ETI]). In these cases, we suggest ETI, based on evidence that it is more effective than dual therapy [18]. (See 'Elexacaftor-tezacaftor-ivacaftor' above.)
Dosing and administration — For patients six years and older, 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 Lexicomp drug interactions database or the manufacturer's prescribing information [113]. 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) [112]. 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 (LCI), a sensitive measure of airway obstruction in patients with mild lung disease [114]. 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 [115] or is a gating mutation [116]. (See 'Types of CFTR modulators and their targeted mutations' above.)
●Long-term outcomes – A 96-week open-label extension study that included both of the above populations reported sustained efficacy (including change in FEV1 from baseline and pulmonary exacerbations) and similar safety signals [64]. Among F508del homozygotes treated with tezacaftor-ivacaftor, the annualized rate of lung function decline was 61.5 percent lower than in untreated matched historical controls.
●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 [113]. 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) [117]. 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) [112]. 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 [118]. 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 [3,112]. 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 [117].
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) [3,112]. 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 [13,111]. 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 [14,119].
Indications — We suggest treatment with lumacaftor-ivacaftor for patients one to five years old who are homozygous for the F508del mutation (algorithm 1).
Lumacaftor-ivacaftor is approved by the US Food and Drug Administration (FDA) for CF patients age one year and older with homozygous F508del mutations [75]. However, for F508del homozygotes ≥6 to 11 years, we prefer triple combination therapy (elexacaftor-tezacaftor-ivacaftor [ETI]). This is because triple combination therapy 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 a greater improvement in forced expiratory volume in one second (FEV1) [111]. (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
●Children 2 to <6 years:
•If weight <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
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 (see the Lexicomp drug interactions database and manufacturer's prescribing information [75]).
Efficacy — Lumacaftor-ivacaftor is moderately effective for F508del homozygotes, as suggested by the following evidence:
●Age ≥12 years – Randomized, blinded clinical trials of F508del homozygous subjects age 12 years and older showed that the groups receiving the low and high doses of lumacaftor had modest but statistically significant improvements in percent predicted FEV1 of 3.3 and 2.8, respectively [13]. Small improvements in body mass index and a quality-of-life measure were reported. Compared with the placebo group, pulmonary exacerbations were significantly reduced by 30 and 39 percent in the groups receiving low and high doses of lumacaftor, respectively. The reduction in pulmonary exacerbations occurs irrespective of the change in FEV1 [6].
Sustained modest benefits in pulmonary outcomes were also shown in a 92-week open-label extension study (PROGRESS study) [120] and a postmarketing study in France [121]. Another smaller postmarketing study found no significant improvement in FEV1 but did detect improvement in multiple-breath washout test, a more sensitive measure of subtle changes in pulmonary disease [122].
●Age 1 to <12 years – A trial of 206 patients 6 to 11 years old reported that lumacaftor-ivacaftor caused significant improvement from baseline and compared with placebo group in lung clearance index (LCI), a sensitive measure of lung function change in patients with mild disease [123]. FEV1, a secondary endpoint, did not improve significantly from baseline but did relative to placebo, and there were significant improvements in body mass index and sweat chloride. In an open-label follow-up study, the improvements were maintained, with no new safety concerns [62]. Smaller studies in F508del homozygotes two to five years of age demonstrated an increase in growth parameters, sweat chloride, and biomarkers of pancreatic function and a safety profile that was similar to that of older children [15,63]. A small study in children 1 to <2 years had similar outcomes but no change in growth parameters [16].
For F508del heterozygotes, lumacaftor-ivacaftor did not improve FEV1 in a study of 126 patients [124]. Although significant reductions in sweat chloride and improvements in quality-of-life indices were seen, the changes were not sufficient to receive FDA approval in the absence of FEV1 improvement.
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 [13]. Although the frequency of discontinuation due to adverse events was 4 to 7 percent during lumacaftor-ivacaftor phase 3 clinical trials and extension studies [13,62,120], a postmarketing report from the manufacturer indicates that 15 percent of patients discontinued treatment within the first three months [125]. Other studies report discontinuation in more than 32 percent of patients with a percent-predicted FEV1 <40 at treatment initiation [25]. 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 [126]. 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 [127].
Worsening of liver function, sometimes leading to liver failure, has been reported in patients with advanced liver disease, such as cirrhosis and portal hypertension [75]. 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 ≥6 years – For patients with two F508del mutations (homozygotes) who are ≥6 years old and with any disease severity, we recommend triple therapy (elexacaftor-tezacaftor-ivacaftor [ETI]) rather than dual therapy (tezacaftor-ivacaftor or lumacaftor-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 six years old. (See 'F508del homozygotes' above and 'Elexacaftor-tezacaftor-ivacaftor' above.)
-Age 1 to <6 years – For F508del homozygotes who are 1 to <6 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 ≥6 years – For patients who have one F508del mutation (heterozygotes) (table 2) and are ≥6 years old and with any disease severity, we recommend ETI rather than no therapy (Grade 1B) and recommend ETI rather than dual therapy (tezacaftor-ivacaftor or lumacaftor-ivacaftor) or monotherapy (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 <6 years – For F508del heterozygotes who are <6 years old, we suggest treatment with tezacaftor-ivacaftor or ivacaftor if they have a second mutation that is responsive to these therapies (table 2) (Grade 2C). ETI has not been approved for patients who are <6 years old. For F508del heterozygotes who are <6 years old and who do not have a second mutation that is eligible for dual or monotherapy with a CFTR modulator, we initiate ETI when they reach six 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 – For patients who do not have any mutation that is approved for one of the available CFTR modulators, CFTR therapy should be limited to the setting of a clinical trial. In the United States, this represents approximately 8 percent of non-Hispanic White patients, 25 percent of Hispanic patients, and 30 percent of Black/African American patients with CF; this is an important source of health disparity. (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 Lexicomp drug interactions database. (See 'Dosing and administration' above.)
