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 important 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]. Their indications and efficacy depend upon 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. Other aspects of care for patients with CF are discussed separately:

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

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

●(See "Cystic fibrosis: Treatment of acute pulmonary exacerbations".)

●(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".)

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

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

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

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

The benefits of these drugs have stimulated the search for additional CFTR modulators. A number of candidate drugs are being actively investigated, some of which have already entered clinical trials.

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 upon 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. Access to these drugs in the United Kingdom is progressing, as summarized by the Cystic Fibrosis Trust.

In clinical trials involving patients with a wide range of CF genotypes, CFTR modulators have been shown to improve forced expiratory volume in one second (FEV₁) and symptom-related quality of life (QoL) and reduce acute pulmonary exacerbations. Most of the available data are from patients ≥6 years old. These agents also appear to be safe and efficacious in younger children (<6 years), although the clinical benefits are harder to assess than in older patients (likely because younger children generally have milder disease and some children are unable to perform standard pulmonary function testing, which is the primary endpoint for studies in older populations). The long-term safety and efficacy of these agents have not been clearly established, because of their recent introduction into CF care. Selection of a specific CFTR modulator regimen depends on the individual's genotype and age. There are limited studies directly comparing one CFTR regimen with another, and, thus, many of our recommendations are based upon studies in which each regimen was tested independently rather than by direct comparison within a single study. These recommendations are likely to change as new evidence becomes available.

General approach — Our approach to patient 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 therapy > dual therapy > monotherapy) (table 1). If a child is not eligible for triple combination therapy due to age, we advance the therapy when the patient meets the age criterion that allows adding another modulator. If a patient develops a clinically significant adverse reaction when advancing to the next therapy (eg, skin rash following start of triple therapy), 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 triple therapy (elexacaftor-tezacaftor-ivacaftor) rather than dual therapy (tezacaftor-ivacaftor or lumacaftor-ivacaftor).

Both triple and dual therapies have demonstrated efficacy in this population, but in a four-week clinical trial, triple therapy achieved much greater improvements in FEV₁ and symptom-related QoL compared with tezacaftor-ivacaftor [2]. Monotherapy with ivacaftor is not effective in this population, given its mechanism of action [3]; however, ivacaftor boosts the efficacy of the other corrector agents (lumacaftor, tezacaftor, and elexacaftor) when given in combination. (See 'Elexacaftor-tezacaftor-ivacaftor (triple combination therapy)' below.)

●Age <6 years – For homozygotes, we suggest lumacaftor-ivacaftor for children ages 2 to <6 years. Triple combination therapy is not approved for children under six years old. Patients can be transitioned to triple therapy when they reach the age of six years.

Lumacaftor-ivacaftor is approved for children as young as two years, based on limited safety data in this age group [4]. 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 <2 years. (See 'Tezacaftor-ivacaftor' below and 'Lumacaftor-ivacaftor' below.)

F508del heterozygotes

●Age ≥6 years – We recommend triple therapy (elexacaftor-tezacaftor-ivacaftor) for patients who have one F508del mutation (heterozygotes) and are ≥6 years old regardless of their second mutation [5]. Although dual therapy with tezacaftor-ivacaftor is also approved for most of these patients (table 1), triple combination treatment appears to have superior efficacy [6]. (See 'Elexacaftor-tezacaftor-ivacaftor (triple combination therapy)' 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 therapy (table 1).

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 1). 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, triple therapy > 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. 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 [7]:

●Black or African American patients – 30 percent

●Hispanic patients – 25 percent

●Non-Hispanic White patients – 8 percent

The number of Black or Hispanic CF patients who are ineligible for modulator therapy may have been slightly reduced by the US Food and Drug Administration (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.

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, as outlined above. However, the data on efficacy and safety are more limited for this subgroup of patients since they were poorly represented in many of the randomized clinical trials.

Limited evidence suggests that treatment with the following drugs is safe and efficacious for this group of patients, selected by genotype (table 1 and algorithm 2) [8,9]; the available evidence for use of these drugs in patients with advanced lung disease is discussed in the linked sections:

●Elexacaftor-tezacaftor-ivacaftor (see 'Elexacaftor-tezacaftor-ivacaftor (triple combination therapy)' 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 [10]. (See 'Lumacaftor-ivacaftor' below.)

ELEXACAFTOR-TEZACAFTOR-IVACAFTOR (TRIPLE COMBINATION THERAPY) — The triple drug combination of elexacaftor-tezacaftor-ivacaftor 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 data [5]. The triple combination therapy was approved in the United Sates in 2019 and approved in England and the European Union in 2020 [11,12]. Approximately 92 percent of people with CF in the United States are eligible for this therapy [13].

Indications — We recommend triple combination therapy 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 triple therapy based on in vitro data; the responsive mutations are listed in the table (table 1) and in the manufacturer's prescribing information [5]

Some patients who have mutations approved for triple combination therapy 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, triple therapy > 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 triple therapy), we drop back to the prior treatment regimen.

If triple combination therapy 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 — Elexacaftor-tezacaftor-ivacaftor 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

The drug should be taken with fat-containing foods. 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, or fluconazole (see the Lexicomp drug interactions database or the manufacturer's prescribing information [5]).

Efficacy

Elexacaftor was identified by the same high-throughput screening strategy that identified other CFTR modulators. Elexacaftor, in combination 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 [14]. A 50 percent correction is approximately the same level that was achieved by ivacaftor in cells expressing the gating mutation G551D.

Phase III studies of elexacaftor-tezacaftor-ivacaftor in CF patients homozygous or heterozygous for F508del were completed in 2019 and led to the triple drug's approval in the United States for patients ≥12 years [2,15,16]; the indication was extended to children ≥6 years in 2021 [5].

The key clinical trials are:

●Homozygous F508del – A clinical trial enrolled subjects homozygous for F508del who received tezacaftor-ivacaftor for a four-week run-in period, after which 107 subjects were randomized to receive either elexacaftor or placebo while continuing the tezacaftor-ivacaftor [2]. Percent predicted 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 elexacaftor-tezacaftor-ivacaftor compared with the group receiving tezacaftor-ivacaftor. Respiratory symptoms were significantly improved in the group on triple combination therapy, as measured by a standardized questionnaire.

●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 mutation that produced no CFTR protein or a protein unresponsive to ivacaftor or tezacaftor-ivacaftor [15]. Compared with placebo, triple combination therapy with elexacaftor-tezacaftor-ivacaftor increased percent predicted forced expiratory volume in one second (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 triple combination therapy, as measured by a standardized questionnaire.

An open-label extension of these two randomized controlled trials for homozygous and heterozygous patients demonstrated continued efficacy during an additional 24 weeks of therapy [17]. Another open-label prospective trial reported similar levels of efficacy and safety in homozygous and heterozygous patients age 6 to <12 years [18].

●F508del heterozygotes with a second gating or residual function CFTR mutation: Triple therapy versus dual therapy or monotherapy – A randomized trial in more than 250 F508del heterozygotes ≥12 years of age compared triple therapy (elexacaftor-tezacaftor-ivacaftor) 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]) [6]. Triple therapy 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 suggestion for using triple therapy 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 rare CFTR gene mutations identified 177 mutations that were responsive to elexacaftor-tezacaftor-ivacaftor. The triple drug combination increased chloride transport above baseline in each of these mutations by at least 10 percent of the transport measured in normal cells [19]. Because this level of improvement is predictive of benefit in clinical trials of patients with more common mutations [20], the US Food and Drug Administration (FDA) agreed to approve triple therapy for these additional rare mutations.

●Advanced lung disease – In an observational study of 245 patients with advanced lung disease, treatment with elexacaftor-tezacaftor-ivacaftor for one to three months was associated with marked improvement in lung function (mean increase in 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 [9]. 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.

●Age ≥6 to <12 years – The safety of elexacaftor-tezacaftor-ivacaftor 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) [18]. 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.

Adverse effects — The triple combination therapy with elexacaftor-tezacaftor-ivacaftor was generally well tolerated. During the 24-week trial of subjects heterozygous for F508del, discontinuation of the study drug due to adverse events occurred in 1 percent of those receiving triple combination therapy and 0 percent of those receiving placebo [15]. Serious adverse events occurred less frequently in the group receiving triple combination therapy (13.9 percent) compared with placebo (20.9 percent). Adverse drug reactions that occurred more frequently in the triple combination therapy 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). The rate of adverse events was said to be similar in the subset of patients with advanced lung disease, but the underlying data were not reported.

Liver function tests are recommended prior to elexacaftor-tezacaftor-ivacaftor treatment, 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. Worsening of liver function, sometimes leading to liver failure, has been reported in patients with advanced liver disease, such as cirrhosis and portal hypertension [5].

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 1). (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 [21]. 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 [22]. Subsequent clinical trials have shown that ivacaftor benefits patients with other CFTR gating mutations 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 [23]. Subsequently, additional mutations have been approved for ivacaftor, based on results of in vitro studies [20].

Indications — We suggest ivacaftor monotherapy for patients ≥4 months of age with eligible mutations (table 1) if the patient is not otherwise eligible for dual or triple therapy.

For patients who are eligible for triple combination therapy (elexacaftor-tezacaftor-ivacaftor) or dual therapy (tezacaftor-ivacaftor) (table 1), 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 (triple combination therapy)' above and 'Tezacaftor-ivacaftor' below.)

Dosing and administration — Dosing for ivacaftor is as follows [22]:

●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, or fluconazole (see the Lexicomp drug interactions database or the manufacturer's prescribing information [22]). 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.

Efficacy

●G551D mutation – Clinical trials of ivacaftor in patients with a G551D mutation have demonstrated important benefits [24]:

•The initial phase III 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 [25]. 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.

•An open-label study demonstrated durable beneficial effects for at least three years of ivacaftor treatment [26]. After 36 months of treatment, the absolute change in FEV₁ was approximately 10 percentage points compared with baseline and patients also had improved body weight and a reduced rate of pulmonary exacerbations. Moreover, the decline in lung function over the three years of treatment was 50 percent slower than for a comparison group of patients with homozygous F508del mutations who were not treated with ivacaftor [27].

•In a post-approval study of ivacaftor, clinical and laboratory data confirmed rapid improvements in FEV₁, weight gain, reduction in the frequency of hospitalizations, and a decrease in the percent of subjects with at least one positive Pseudomonas aeruginosa culture [28,29].

•The long-term effects of ivacaftor have been evaluated using registry data from the United States and the United Kingdom. Compared with a matched control population, those in the United States on ivacaftor had lower risks of death (0.6 versus 1.6 percent), hospitalizations (27.5 versus 43.1 percent), and transplantations (0.2 versus 1.1 percent), and similar results were seen in the United Kingdom registry [30]. Another registry study from the United Kingdom reported lower prevalence of P. aeruginosa among patients treated with ivacaftor, with lower acquisition rates and higher clearance rates [31].

●Additional 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 [32]. A small randomized crossover trial in subjects with one of six in vitro-responsive mutations showed beneficial clinical results similar to those reported for patients with the G551D mutation [22,33]. Based on these studies, the FDA expanded approval for ivacaftor beyond the G551D mutation to include the other mutations that were responsive in vitro [22].

•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 [20]. As of December 2020, 97 mutations were approved for ivacaftor use.

●Young children – 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 [34-36]. Clinical efficacy in the younger cohorts is largely extrapolated from results in older patients and observation of similar reductions in sweat chloride. 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 [8]. The CF Foundation clinical guideline for CFTR modulator use recommends ivacaftor for patients with advanced lung disease and an eligible genotype [37].

Adverse effects — Elevations in serum hepatic enzyme levels were noted in a small number of subjects during clinical trials of ivacaftor. Studies done in juvenile rats found formation of cataracts at doses of ivacaftor above those recommended for humans. Furthermore, noncongenital lens opacities have been reported in children up to 12 years of age receiving ivacaftor [22]. 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 [38].

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 [16,39]. 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 [40].

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 1).

Most other genotypes that are eligible for tezacaftor-ivacaftor are also eligible for triple combination therapy (elexacaftor-tezacaftor-ivacaftor). In these cases, we suggest triple therapy, based on evidence that it is more effective than dual therapy [6]. (See 'Elexacaftor-tezacaftor-ivacaftor (triple combination therapy)' 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 is recommended before and during treatment with tezacaftor-ivacaftor, as it is for elexacaftor-tezacaftor-ivacaftor. 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, or clarithromycin). Details are available in the Lexicomp drug interactions database or the manufacturer's prescribing information [40]. 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) [39]. 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 (QoL) 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).

●F508del heterozygotes – A trial involving F508del heterozygotes with residual function mutations (EXPAND) enrolled 248 subjects 12 years and older with mild or moderate CF-related lung disease [41]. The subjects were randomized in a crossover study to tezacaftor-ivacaftor alone, ivacaftor monotherapy, or placebo. Treatment with tezacaftor-ivacaftor resulted in modest improvement in FEV₁ (absolute change 6.8 percentage points versus placebo), as did ivacaftor monotherapy (absolute change 4.7 percentage points versus placebo). The benefit of tezacaftor-ivacaftor compared with ivacaftor was slight but statistically significant (absolute change 2.1 percentage points). Tezacaftor-ivacaftor also resulted in clinically significant improvements in a disease-related QoL score (11.1 points versus placebo).

●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 [42]. 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 (NCT02565914).

●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 [40]. 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.

●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) [43]. 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 III trial (mean baseline percent predicted FEV₁ 91 compared with 60) [39]. Tolerability and adverse effects were similar to those for older children. These findings were the basis for the FDA's decision to extend the indication to this age group in June 2019.

Adverse effects — 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 [39,41]. In particular, there was no increase in chest discomfort, bronchospasm, dyspnea, or wheezing. Similar findings were reported for the open-label study in children 6 to 11 years old [43].

Taken together, these findings suggest that tezacaftor-ivacaftor has modest benefits on pulmonary outcomes that were sustained for the duration of the trial, with a good safety profile. For F508del homozygotes, the absolute improvements in FEV₁ during this 24-week trial are comparable with those achieved by inhaled dornase alfa (DNase) or hypertonic saline. The chest symptoms that have been noted to occur in some patients after initiating lumacaftor-ivacaftor were not reported for tezacaftor-ivacaftor. Also, the strong CYP3A4 induction by lumacaftor that speeds clearance of drugs frequently taken by CF patients has not been described for tezacaftor-ivacaftor.

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) [39,41]. 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 [16,44]. 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 [3,45].

Indications — We suggest treatment with lumacaftor-ivacaftor for patients 2 to 5 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 two years and older with homozygous F508del mutations [46]. However, for F508del homozygotes ≥6 to 11 years, we prefer triple combination therapy. 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) [16]. (See 'Elexacaftor-tezacaftor-ivacaftor (triple combination therapy)' above.)

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

●Children two to five 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 triple combination therapy, monitoring of liver function tests is recommended before and during treatment, similar to that recommended for elexacaftor-tezacaftor-ivacaftor. 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 [46]).

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 [44]. Small improvements in body mass index and a quality-of-life (QoL) 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 [47].

Longer-term outcomes were reported in a 92-week open-label extension study (PROGRESS study), which found ongoing modest benefits for patients who tolerate lumacaftor-ivacaftor [48]. For patients treated with lumacaftor-ivacaftor, there was a modest sustained increase in body mass index compared with baseline and a trend towards decreased rates of pulmonary exacerbations and hospitalization, which did not reach statistical significance.

●Age 2 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, a sensitive measure of lung function change in patients with mild disease [49]. 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 [50]. 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 [4,51].

In patients who are heterozygous for the F508del mutation, lumacaftor-ivacaftor does not appear to have clinically meaningful benefits. This is based on data from a small trial that included a variety of genotypes and does not exclude the possibility of benefit for certain genotypes [52].

Adverse effects — Soon after starting lumacaftor-ivacaftor, a subgroup of subjects developed chest discomfort and dyspnea, particularly those with worse baseline lung function [44]. Although the frequency of discontinuation due to adverse events was 4 to 7 percent during lumacaftor-ivacaftor phase III clinical trials and extension studies [44,48,50], a postmarketing report from the manufacturer indicates that 15 percent of patients discontinued treatment within the first three months [53]. Other studies report discontinuation in more than 32 percent of patients with a percent-predicted FEV₁ <40 at treatment initiation [10]. An 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 [54].

Worsening of liver function, sometimes leading to liver failure, has been reported in patients with advanced liver disease, such as cirrhosis and portal hypertension [55]. 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 5^th to 6^th 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 10^th to 12^th 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 (QoL) and reduce acute exacerbations. Most of the available data are in patients ≥6 years old and in patients with mild or moderate CF lung disease, but data are sufficient to 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 1).

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) rather than dual therapy (tezacaftor-ivacaftor or lumacaftor-ivacaftor) (Grade 1B). Compared with dual therapy, triple therapy considerably improves FEV₁ and QoL and the adverse effects are similar, based on short-term outcomes from a clinical trial. Triple combination therapy is not approved for children under six years old. (See 'F508del homozygotes' above and 'Elexacaftor-tezacaftor-ivacaftor (triple combination therapy)' above.)

-Age two to six years – For F508del homozygotes who are 2 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) or other eligible mutation based on in vitro data (table 1) and are ≥6 years old and with any disease severity, we recommend triple therapy (elexacaftor-tezacaftor-ivacaftor) rather than no therapy (Grade 1B) and suggest triple therapy 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 (triple combination therapy)' 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 1) (Grade 2C). Triple therapy (elexacaftor-tezacaftor-ivacaftor) 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 triple therapy 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 1). 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, triple therapy > 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 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, or fluconazole) or inducers (eg, rifampin, several antiseizure medications, and St. John's wort), as indicated by the Lexicomp drug interactions database. (See 'Dosing and administration' above.)