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A Review on the Use of Cystic Fibrosis Transmembrane Conductance Regulator Gene Modulators in Pediatric Patients

      Abstract

      The literature surrounding the use of cystic fibrosis transmembrane conductance regulator-targeted pharmacotherapies in pediatric patients continues to evolve. These therapies represent a departure from symptom management and infection prevention, which have been the mainstay of cystic fibrosis management in pediatrics, to targeting the genetic defect present within these patients. This article reviews the clinical studies evaluating the safety and efficacy of ivacaftor, ivacaftor/lumacaftor, and ivacaftor/tezacaftor. These medications were initially studied in adults and adolescents but have begun to be studied in younger populations. Further investigation into the use of these drugs with different CFTR mutations and in younger age groups will continue to expand the number of patients who can benefit from these therapies.

      Key words

      OBJECTIVES

      • 1.
        Describe the six major classes of mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
      • 2.
        Review the mechanisms of action of ivacaftor, lumacaftor/ivacaftor, and tezacaftor/ivacaftor.
      • 3.
        Compare the indications and efficacy among the three CFTR-modifying drugs.
      • 4.
        Identify the counseling points for the three CFTR-modifying drugs.

      EPIDEMIOLOGY

      Cystic fibrosis (CF) is an incurable, autosomal recessive diseaseaffecting over 80,000 people worldwide (
      • Lubamba B.
      • Dhooghe B.
      • Noel S.
      • Leal T.
      Cystic fibrosis: Insight into CFTR pathophysiology and pharmacotherapy.
      ). It involves a defect in a single gene, causing alterations in chloride secretion and sodium transport that ultimately lead to multiorgan complications (
      • Davies J.C.
      • Alton E.W.
      • Bush A.
      Cystic fibrosis.
      ,
      • Pettit R.S.
      • Fellner C.
      CFTR modulators for the treatment of cystic fibrosis.
      ). CF often causes symptomatic pulmonary disease, but the pancreas, gastrointestinal tract, liver, and reproductive tract can also be affected (
      • Davies J.C.
      • Alton E.W.
      • Bush A.
      Cystic fibrosis.
      ,
      • Spoonhower K.A.
      • Davis P.B.
      Epidemiology of cystic fibrosis.
      ). Originally considered to be primarily a disease of pediatrics, advances in supportive care and innovations in pharmacotherapy have significantly improved survival and increased the numbers of adults living with the disease (
      • Davies J.C.
      • Alton E.W.
      • Bush A.
      Cystic fibrosis.
      ,
      • Lubamba B.
      • Dhooghe B.
      • Noel S.
      • Leal T.
      Cystic fibrosis: Insight into CFTR pathophysiology and pharmacotherapy.
      ). The percentage of CF patients over the age of 18years has increased from 29.2% in 1986 to 52.7% in 2016 (). In addition, the life expectancy has grown from just a few months in the 1950s to an average of 40years today (
      • Elborn J.S.
      Cystic fibrosis.
      ,
      • Spoonhower K.A.
      • Davis P.B.
      Epidemiology of cystic fibrosis.
      ).
      Regardless, CF continues to affect nearly 1 in 3,500 White newborns in the US; the incidence is even higher in Europe, with 1 in 2,500 newborns affected in the United Kingdom (
      • Davies J.C.
      • Alton E.W.
      • Bush A.
      Cystic fibrosis.
      ,
      • Wright C.C.
      • Vera Y.Y.
      Chapter 29: Cystic fibrosis.
      ). All U.S. states are required to screen newborns for CF, and diagnosis involves the use of immunoreactive trypsinogen analysis, sweat chloride testing, and genetic sequencing (
      • Elborn J.S.
      Cystic fibrosis.
      ,
      • Farrell P.M.
      • White T.B.
      • Ren C.L.
      • Hempstead S.E.
      • Accurso F.
      • Derichs N.
      • Sosnay P.R.
      Diagnosis of cystic fibrosis: Consensus guidelines from the Cystic Fibrosis Foundation.
      ). CF is diagnosed in almost 1,000 new patients in the US every year, and the median age at diagnosis is 4 months (,
      • Pettit R.S.
      • Fellner C.
      CFTR modulators for the treatment of cystic fibrosis.
      ). Although improvements in the management of CF have occurred in recent years, children with this disease still face metabolic complications, infection risk, psychosocial consequences, and poor quality of life (
      • Arrington-Sanders R.
      • Yi M.S.
      • Tsevat J.
      • Wilmott R.W.
      • Mrus J.M.
      • Britto M.T.
      Gender differences in health-related quality of life of adolescents with cystic fibrosis.
      ).

      PATHOPHYSIOLOGY

      Although CF can affect people of any ethnicity, it is most commonly diagnosed in White individuals with European ancestry (
      • Elborn J.S.
      Cystic fibrosis.
      ,
      • Spoonhower K.A.
      • Davis P.B.
      Epidemiology of cystic fibrosis.
      ,
      • Wright C.C.
      • Vera Y.Y.
      Chapter 29: Cystic fibrosis.
      ). CF follows a classic Mendelian autosomal recessive genetic pattern, whereby two parents who are asymptomatic carriers have a 25% chance of having a child with CF (
      • Elborn J.S.
      Cystic fibrosis.
      ,
      • Pettit R.S.
      • Fellner C.
      CFTR modulators for the treatment of cystic fibrosis.
      ). The disease is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (
      • Boucher R.C.
      An overview of the pathogenesis of cystic fibrosis lung disease.
      ,
      • Ong T.
      • Ramsey B.W.
      New therapeutic approaches to modulate and correct cystic fibrosis transmembrane conductance regulator.
      ). This gene is found on Chromosome 7 and encodes the CFTR protein, which is located within the apical plasma membrane of epithelial cells in various organs (
      • Lubamba B.
      • Dhooghe B.
      • Noel S.
      • Leal T.
      Cystic fibrosis: Insight into CFTR pathophysiology and pharmacotherapy.
      ,
      • Ong T.
      • Ramsey B.W.
      New therapeutic approaches to modulate and correct cystic fibrosis transmembrane conductance regulator.
      ,
      • Rowe S.M.
      • Miller S.
      • Sorscher E.J.
      Cystic fibrosis.
      ). The primary function of this protein is ionic transport of chloride across the cellular membrane (
      • Elborn J.S.
      Cystic fibrosis.
      ,
      • Lubamba B.
      • Dhooghe B.
      • Noel S.
      • Leal T.
      Cystic fibrosis: Insight into CFTR pathophysiology and pharmacotherapy.
      ).
      There are approximately 2,000 known genetic mutations that can render this protein dysfunctional (
      • Ong T.
      • Ramsey B.W.
      New therapeutic approaches to modulate and correct cystic fibrosis transmembrane conductance regulator.
      ,
      • Pettit R.S.
      • Fellner C.
      CFTR modulators for the treatment of cystic fibrosis.
      ). The different mutations can be organized into six different classes based on their mechanism. Class I mutations inhibit synthesis of the CFTR protein altogether. Class II mutations produce misfolded versions of the protein. This includes the most common mutation, F508del, which affects over 70% of White individuals with CF (
      • Pettit R.S.
      • Fellner C.
      CFTR modulators for the treatment of cystic fibrosis.
      ). Class III mutations prevent the protein from opening properly, inhibiting normal flow of chloride ions out of the cell. Class IV mutations lead to poor conductance of chloride ions. Class V mutations produce normally functioning CFTR proteins but with reduced quantities. Finally, Class VI mutations increase degradation or turnover of the CFTR protein (Table 1;
      • Ong T.
      • Ramsey B.W.
      New therapeutic approaches to modulate and correct cystic fibrosis transmembrane conductance regulator.
      ,
      • Pettit R.S.
      • Fellner C.
      CFTR modulators for the treatment of cystic fibrosis.
      ,
      • Rowe S.M.
      • Miller S.
      • Sorscher E.J.
      Cystic fibrosis.
      ).
      TABLE 1Classification of genetic mutation types in cystic fibrosis
      Mutation classCharacteristicsMajor genetic mutationsPercentage of patients
      Class I“Stop codon” prevents synthesis of CFTR proteinsG542X4.7
      W1282X2.3
      R553X1.8
      Class IIMisfolded CFTR proteins are produced that are unable to reach apical surfaceF508del86.4
      N1303K2.4
      I507del0.8
      Class IIICFTR proteins exhibit abnormal chloride ion–channel openingG551D4.4
      Class IVCFTR proteins do not conduct ions adequatelyR117H3.0
      D1152H0.9
      R347P0.6
      Class VOverall production of CFTR proteins is reduced3849+10kbC>T1.5
      2789+5G>A1.3
      5T0.8
      A455E0.6
      Class VIRapid turnover of CFTR proteins induced by C-terminus mutations1811+1.6kbA>G<0.5
      Note. CFTR, cystic fibrosis transmembrane conductance regulator.
      Data from ,
      • Ong T.
      • Ramsey B.W.
      New therapeutic approaches to modulate and correct cystic fibrosis transmembrane conductance regulator.
      ,
      • Pettit R.S.
      • Fellner C.
      CFTR modulators for the treatment of cystic fibrosis.
      ,
      • Rowe S.M.
      • Miller S.
      • Sorscher E.J.
      Cystic fibrosis.
      .
      Regardless of the mutation class, defects in the CFTR protein promote irregular chloride transport across the cellular membrane. It is also known that dysfunction of the CFTR protein can cause aberrations of epithelial sodium, glutamate, and bicarbonate concentrations (
      • Elborn J.S.
      Cystic fibrosis.
      ,
      • Lubamba B.
      • Dhooghe B.
      • Noel S.
      • Leal T.
      Cystic fibrosis: Insight into CFTR pathophysiology and pharmacotherapy.
      ,
      • Pettit R.S.
      • Fellner C.
      CFTR modulators for the treatment of cystic fibrosis.
      ). Normally, the functioning CFTR protein regulates the electrochemical gradient at the surface of the cell to control liquid volume and mucus viscosity (
      • Davies J.C.
      • Alton E.W.
      • Bush A.
      Cystic fibrosis.
      ,
      • Elborn J.S.
      Cystic fibrosis.
      ). This regulates the components and characteristics of sweat, mucus, and digestive fluids. In the setting of CF, this protein is missing, poorly functioning, or completely nonfunctional, causing production of viscous fluid (
      • Pettit R.S.
      • Fellner C.
      CFTR modulators for the treatment of cystic fibrosis.
      ,
      • Wright C.C.
      • Vera Y.Y.
      Chapter 29: Cystic fibrosis.
      ).
      The most common organ affected by CF is the lungs. Impaired ion transport leads to dehydrated, viscous mucus within the airways, producing altered mucociliary clearance (
      • Lubamba B.
      • Dhooghe B.
      • Noel S.
      • Leal T.
      Cystic fibrosis: Insight into CFTR pathophysiology and pharmacotherapy.
      ). The airways become inflamed, obstructed, and unable to clear bacteria effectively. Ultimately, this can cause persistent respiratory infections, respiratory failure, and potentially death (
      • Davies J.C.
      • Alton E.W.
      • Bush A.
      Cystic fibrosis.
      ,
      • Lubamba B.
      • Dhooghe B.
      • Noel S.
      • Leal T.
      Cystic fibrosis: Insight into CFTR pathophysiology and pharmacotherapy.
      ). Within the gastrointestinal tract, meconium ileus can occur in newborns. Also, pancreatic insufficiency can result in malabsorption, steatorrhea, and failure to thrive (
      • Lubamba B.
      • Dhooghe B.
      • Noel S.
      • Leal T.
      Cystic fibrosis: Insight into CFTR pathophysiology and pharmacotherapy.
      ,
      • Spoonhower K.A.
      • Davis P.B.
      Epidemiology of cystic fibrosis.
      ). Other consequences include cirrhosis, CF-related diabetes mellitus, CF-related bone disease, and infertility (
      • Elborn J.S.
      Cystic fibrosis.
      ,
      • Lubamba B.
      • Dhooghe B.
      • Noel S.
      • Leal T.
      Cystic fibrosis: Insight into CFTR pathophysiology and pharmacotherapy.
      ,
      • Rowe S.M.
      • Miller S.
      • Sorscher E.J.
      Cystic fibrosis.
      ,
      • Spoonhower K.A.
      • Davis P.B.
      Epidemiology of cystic fibrosis.
      ).

      DRUG THERAPY

      Historically, treatment of children with CF has involved mostly symptom and infection control. Daily airway clearance therapy is recommended in all patients with CF (
      • Borowitz D.
      • Robinson K.A.
      • Rosenfeld M.
      • Davis S.D.
      • Sabadosa K.A.
      • Accurso F.J.
      Cystic Fibrosis Foundation
      Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis.
      ,
      • Lahiri T.
      • Hempstead S.E.
      • Brady C.
      • Cannon C.L.
      • Clark K.
      • Condren M.E.
      • Davis S.D.
      Clinical practice guidelines from the Cystic Fibrosis Foundation for preschoolers with cystic fibrosis.
      ). This includes both chest physiotherapy and mucolytic agents like dornase-α and hypertonic saline (
      • Edmondson C.
      • Davies J.C.
      Current and future treatment options for cystic fibrosis lung disease: Latest evidence and clinical implications.
      ,
      • Lahiri T.
      • Hempstead S.E.
      • Brady C.
      • Cannon C.L.
      • Clark K.
      • Condren M.E.
      • Davis S.D.
      Clinical practice guidelines from the Cystic Fibrosis Foundation for preschoolers with cystic fibrosis.
      ). Infection management is an important consideration in CF patients as well. The most common pathogens found in CF patients’ lungs change as they age, with Staphylococcus aureus being frequently isolated in infancy and Pseudomonas species becoming more common in adolescents (
      • Edmondson C.
      • Davies J.C.
      Current and future treatment options for cystic fibrosis lung disease: Latest evidence and clinical implications.
      ,
      • Elborn J.S.
      Cystic fibrosis.
      ). Patients will often develop chronic infections that necessitate the use of intermittent inhaled antibiotic therapy in 28-day cycles to prevent the development of resistance and reduce the likelihood of acute pulmonary exacerbations (
      • Lyczak J.B.
      • Cannon C.L.
      • Pier G.B.
      Lung infections associated with cystic fibrosis.
      ). In addition, pancreatic enzyme replacement is necessary in 80% of CF patients to prevent malnutrition and failure to thrive secondary to pancreatic insufficiency (
      • Fieker A.
      • Philpott J.
      • Armand M.
      Enzyme replacement therapy for pancreatic insufficiency: Present and future.
      ).
      Significant efforts have been made toward developing targeted therapy for CF. Research focusing on CFTR-modifying medications has represented a major step forward in precision medicine. These agents directly target the basic defect in CF as opposed to simply managing symptoms of the disease (
      • Guimbellot J.
      • Sharma J.
      • Rowe S.M.
      Toward inclusive therapy with CFTR modulators: Progress and challenges.
      ,
      • Pettit R.S.
      • Fellner C.
      CFTR modulators for the treatment of cystic fibrosis.
      ). Ivacaftor was the first of these therapies to receive U.S. Food and Drug Administration (FDA) approval, followed by ivacaftor/lumacaftor and ivacaftor/tezacaftor (Table 2). Patients should still continue supportive care measures while taking this CFTR modulator. The rest of this article will focus on the pharmacology and clinical outcomesof these medications in pediatric patients with CF.
      TABLE 2CFTR-targeted pharmacotherapies
      DrugIndication (FDA approved)DoseCYP enzyme dosage adjustments
      No specific recommendations for dosage adjustment exist for CYP3A4 inducers, but the manufacturers recommend against the use of these CFTR drugs with strong CYP3A4 inducers, and clinicians should implement close monitoring in patients receiving moderate CYP3A4 inducers. Data from Vertex Pharmaceuticals, Inc., 2017a, 2018a, 2018b.
      Hepatic dysfunction dosage adjustmentsDosage formulationsAdministrationAdverse effects
      IvacaftorCF patients ≥ 1 year old with one mutation in CFTR gene that is responsive to ivacaftor potentiation1–5years old and 7 to <14 kg: 50mg orally every 12 hours

      1–5years old and ≥14 kg: 75mg orally every 12 hours

      ≥6years old: 150mg orally every 12 hours

      Strong CYP3A4 inhibitors: Reduce to 1 tablet or 1 packet twice weekly

      Moderate CYP3A4 inhibitors: Reduce to 1 tablet or 1 packet once daily
      Severe: Use with caution at reduced dose of 1 tablet or 1 packet once daily or less frequently

      Moderate: Reduce to 1 tablet or 1 packet once daily
      50 mg, 75 mg, 150mgAdminister before or after high-fat foods

      Granules: mix with 5ml soft food or liquid

      Do not chew or crush tablet

      Headache, skin rash, abdominal pain, nausea, diarrhea, nasal congestion, nasopharyngitis, oropharyngeal pain, upper respiratory tract infections
      Ivacaftor + lumacaftorCF patients ≥ 2years old homozygous for F508del mutation2–5years old and <14 kg: 1 packet of granule (100mg lumacaftor/125mg ivacaftor) orally every 12 hours

      2–5years old and ≥14 kg: 1 packet of granule (150mg lumacaftor/188mg ivacaftor) orally every 12 hours

      6 to 11years old: 200mg lumacaftor/250mg ivacaftor orally every 12 hours

      ≥12 years old: 400mg lumacaftor/250mg ivacaftor orally every 12 hours
      Strong CYP3A4 inhibitors: Reduce to 1 tablet daily for 1st week, then recommended daily doseSevere: Use with caution at reduced dose of 1 tablet every 12 hours

      Moderate: Reduce to 2 tablets in the morning and 1 tablet in the evening
      100mg lumacaftor/125mg ivacaftor tablet and granules,

      150mg lumacaftor/ 188mg ivacaftor granules,

      200mg lumacaftor/125-mg ivacaftor tablet
      Administer with high-fat foods

      Do not chew or crush tablet
      Chest discomfort, nausea, diarrhea, increased AST/ALT, dyspnea, nasopharyngitis
      Ivacaftor + tezacaftorCF patients ≥ 12years old homozygous for F508del mutation or with one mutation in CFTR gene that is responsive to ivacaftor/tezacaftor≥12years old: 100mg tezacaftor/150mg ivacaftor orally in the morning + 150mg ivacaftor orally in the evening

      Strong CYP3A4 inhibitors: Reduce to 100mg tezacaftor/150mg ivacaftor twice weekly 3–4days apart

      Moderate CYP3A4 inhibitors: Alternate daily dosing between 100mg tezacaftor/150mg ivacaftor and 150mg ivacaftor
      Severe: Omit the evening ivacaftor 150 mg and consider dosing 100mg tezacaftor/150mg ivacaftor less frequently

      Moderate: Omit the evening ivacaftor 150-mg dose
      100mg tezacaftor/150mg lumacaftor tablet + 150mg ivacaftor tabletAdminister with high-fat foods

      Do not chew or crush tablet
      Headache, nausea, sinus congestion, dizziness
      Note. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; CYP, cytochrome P450; CYP3A4, cytochrome P450 3A4 enzyme; FDA, U.S. Food and Drug Administration.
      a No specific recommendations for dosage adjustment exist for CYP3A4 inducers, but the manufacturers recommend against the use of these CFTR drugs with strong CYP3A4 inducers, and clinicians should implement close monitoring in patients receiving moderate CYP3A4 inducers.Data from
      Vertex Pharmaceuticals, Inc
      Kalydeco® (ivacaftor) prescribing information.
      ,
      Vertex Pharmaceuticals, Inc
      Orkambi® (lumacaftor/ivacaftor) prescribing information.
      ,
      Vertex Pharmaceuticals, Inc
      SymdekoTM (tezacaftor and ivacaftor) prescribing information.
      .
      Significant efforts have been made toward developing targeted therapy for CF.

      Ivacaftor (Kalydeco)

      In January of 2012, the FDA approved ivacaftor (Kalydeco; Vertex Pharmaceuticals, Boston, MA) as the first CF treatment targeting CFTR mutations (
      Vertex Pharmaceuticals, Inc
      Kalydeco® (ivacaftor) prescribing information.
      ). Ivacaftor is a CFTR potentiator, which binds to and potentiates the opening of the CFTR protein on the surface of the cell, allowing it to remain open so that chloride and water can effectively be transported across the membrane (
      • Davies J.C.
      • Wainwright C.E.
      • Canny G.J.
      • Chilvers M.A.
      • Howenstine M.S.
      • Munck A.
      • Ahrens R.
      Efficacyand safety of ivacaftor in patients aged 6–11years old with cystic fibrosis with a G551D mutation.
      ). Ivacaftor is indicated only in patients with specific mutations in the CFTR gene. Since its discovery, ivacaftor has been approved for the treatment of 38 different CFTR genetic mutations based on the results of six clinical trials and in vitro research (Table 3). Because of its mechanism of action, ivacaftor is effective only in patients who have some degree of functioning CFTR protein production. Ivacaftor is not indicated in patients homozygous for the F508del mutation or in patients with other mutation classes that completely prevent the production of the CFTR protein. Ivacaftor's bioavailability is highly variable, with a 2.5- to 4-fold increase when given with high-fat meals. Dose adjustments are necessary if patients are receiving strong cytochrome P450 3A4 (CYP3A4) inhibitors because of its metabolism via the CYP3A4 pathways. Ivacaftor also should not be used with strong CYP3A4 inducers. Additionally, patients must be monitored frequently for increases in hepatic transaminase levels (
      Vertex Pharmaceuticals, Inc
      Kalydeco® (ivacaftor) prescribing information.
      ).
      TABLE 3CFTR genetic mutations responsive to ivacaftor (percentage of patients with these mutations)
      For those mutations that do not have a percentage value next to them, the prevalence is less than 0.5%. Data from Cystic Fibrosis Foundation, 2016; Vertex Pharmaceuticals, Inc., 2017a.
      A455E (0.6%)E193KG1244ER347HS1251N
      A1067TE831XG1349DR352QS1255P
      D110EF1052VK1060TR1070Q711+3A>G
      D110HF1074LL206W (0.5%)S549N2789+5G>A (1.3%)
      D579GG178RP67LS549R3272-26A>G
      D1152H (0.9%)G551D (4.4%)R74WS945L3849-10kbC>T (1.5%)
      D1270NG551SR117CS977F
      E56KG1069RR117H (3%)S1244E
      Note. CFTR, cystic fibrosis transmembrane conductance regulator.
      a For those mutations that do not have a percentage value next to them, the prevalence is less than 0.5%.Data from ,
      Vertex Pharmaceuticals, Inc
      Kalydeco® (ivacaftor) prescribing information.
      .
      Ivacaftor was approved based on the results of various studies, one of which specifically included patients 6 to 11years old. Patients 6years or older (n = 52) with CF and at least one G551D CFTR mutation were randomized to either ivacaftor 150mg every 12hours or placebo (
      • Davies J.C.
      • Wainwright C.E.
      • Canny G.J.
      • Chilvers M.A.
      • Howenstine M.S.
      • Munck A.
      • Ahrens R.
      Efficacyand safety of ivacaftor in patients aged 6–11years old with cystic fibrosis with a G551D mutation.
      ). After 24 weeks, ivacaftor resulted in a 12.6% increase from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) compared with a 0.1% increase observed in the placebo group, a treatment difference of 12.5 percentage points (p < .001). The effect of ivacaftor on ppFEV1 reached significance by Day 15 of treatment and continued through Week 48. Patients receiving ivacaftor experienced significantly more weight gain than the placebo group (3.7kg vs. 1.8kg at week 24, p < .001). The most common adverse events in the treatment arm included oropharyngeal pain, headache, nasopharyngitis, upper respiratory tract infection, otitis media, diarrhea, and increase in eosinophil count (
      • Davies J.C.
      • Wainwright C.E.
      • Canny G.J.
      • Chilvers M.A.
      • Howenstine M.S.
      • Munck A.
      • Ahrens R.
      Efficacyand safety of ivacaftor in patients aged 6–11years old with cystic fibrosis with a G551D mutation.
      ).
      Ivacaftor was later studied in a two-part study in patients 2 to 5years old (Part A, n = 9; Part B, n = 34) with CFTR gating mutations previously proven responsive to ivacaftor (G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, and G1349D;
      • Davies J.C.
      • Cunningham S.
      • Harris W.T.
      • Lapey A.
      • Regelmann W.E.
      • Sawicki G.S.
      KIWI Study Group
      Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2–5years with cystic fibrosis and a CFTR gating mutation (KIWI): An open-label, single-arm study.
      ). Patients received 50mg or 75mg of ivacaftor every 12hours based on body weight. In Part A, ivacaftor concentrations and area under the curve (AUC) compared among populations, including adults receiving 150mg of ivacaftor enrolled in previous trials, showed that the pharmacokinetics were similar among all populations (AUC concentrations = 9,840 and 10,200 ng × h/ml for children aged 2–5years receiving 50mg and 75mg, respectively, vs. 9,840 ng × h/ml in adults receiving on 150 mg). Because of these results, pediatric patients aged 2 to 5years should be treated with lower doses of ivacaftor according to their body weight. Additionally, safety analysis (Part B) showed a similar safety profile to that of adults, with the exception of increased incidence of liver function test elevations in pediatric patients than that seen in adult studies (
      • Davies J.C.
      • Cunningham S.
      • Harris W.T.
      • Lapey A.
      • Regelmann W.E.
      • Sawicki G.S.
      KIWI Study Group
      Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2–5years with cystic fibrosis and a CFTR gating mutation (KIWI): An open-label, single-arm study.
      ). Therefore, pediatric patients initiated on ivacaftor may require more frequent laboratory test monitoring, especially if other risk factors are present. Recently, ivacaftor was approved in patients as young as 12 months of age based on a Phase 3 study evaluating its safety, pharmacokinetics, and pharmacodynamics inthis population with a CFTR gating mutation (
      Vertex Pharmaceuticals, Inc
      A study to evaluate the safety of long-term ivacaftor treatment in subjects with cystic fibrosis who are less than 24 months of age at treatment initiation and have an approved ivacaftor-responsive mutation.
      ). Table 4 summarizes the other major trials that helped lead to the approval of ivacaftor for other mutations (
      • Davies J.C.
      • Wainwright C.E.
      • Canny G.J.
      • Chilvers M.A.
      • Howenstine M.S.
      • Munck A.
      • Ahrens R.
      Efficacyand safety of ivacaftor in patients aged 6–11years old with cystic fibrosis with a G551D mutation.
      ,
      • Davies J.C.
      • Cunningham S.
      • Harris W.T.
      • Lapey A.
      • Regelmann W.E.
      • Sawicki G.S.
      KIWI Study Group
      Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2–5years with cystic fibrosis and a CFTR gating mutation (KIWI): An open-label, single-arm study.
      ,
      • De Boeck K.
      • Munck A.
      • Walker S.
      • Faro A.
      • Hiatt P.
      • Gilmartin G.
      • Higgins M.
      Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation.
      ,
      • Flume P.A.
      • Liou T.G.
      • Borowitz D.S.
      • Li H.
      • Yen K.
      • Ordonez C.L.
      VX 08-770-104 Study Group
      Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation.
      ,
      • Moss R.B.
      • Flume P.A.
      • Elborn J.S.
      • Cooke J.
      • Rowe S.M.
      • McColley S.A.
      VX11-770-110(KONDUCT) Study Group
      Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: A double-blind, randomised controlled trial.
      ,
      • Quittner A.
      • Suthoff E.
      • Rendas-Baum R.
      • Bayliss M.S.
      • Sermet-Gaudelus I.
      • Castiglione B.
      • Vera-Llonch M.
      Effect of ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutations: Patient-reported outcomes in the STRIVE randomized controlled trial.
      ).
      TABLE 4Major clinical trials on ivacaftor
      AuthorsPatient populationMutations evaluatedResults
      • Davies J.C.
      • Wainwright C.E.
      • Canny G.J.
      • Chilvers M.A.
      • Howenstine M.S.
      • Munck A.
      • Ahrens R.
      Efficacyand safety of ivacaftor in patients aged 6–11years old with cystic fibrosis with a G551D mutation.
      Patients 6–11years oldG551DTreatment difference in mean absolute change in ppFEV1 from baseline through Week 24: 12.5% (p < .001)
      • Davies J.C.
      • Cunningham S.
      • Harris W.T.
      • Lapey A.
      • Regelmann W.E.
      • Sawicki G.S.
      KIWI Study Group
      Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2–5years with cystic fibrosis and a CFTR gating mutation (KIWI): An open-label, single-arm study.
      Ivacaftor versus placebo.
      Patients 2–5years oldG178R, G551D, G551S, G970R
      Efficacy has not been established for this mutation.
      , G1244E, G1349D, S549N, S549R, S1251N, and S1255P
      Similar exposure to drug across populations (AUC concentration = 10,200ng h/ml, 9,840mg h/ml, and 9,840ng h/ml for 75-mg dose, 50-mg dose, and 150-mg dose, respectively)
      Safety: cough (56%), vomiting (29%), nasal congestion (26%), upper respiratory tract infection (24%), rhinorrhea (21%), elevations in AST/ALT (15%)
      • De Boeck K.
      • Munck A.
      • Walker S.
      • Faro A.
      • Hiatt P.
      • Gilmartin G.
      • Higgins M.
      Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation.
      Ivacaftor versus placebo.
      Patients 6years and olderG178R, G551S, G970R
      Efficacy has not been established for this mutation.
      , G1244E, G1349D, S549N, S549R, S1251N, or S1255P
      Treatment difference in mean absolute change in ppFEV1 from baseline through Week 8: 10.7% (p < .0001)
      • Flume P.A.
      • Liou T.G.
      • Borowitz D.S.
      • Li H.
      • Yen K.
      • Ordonez C.L.
      VX 08-770-104 Study Group
      Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation.
      Ivacaftor versus placebo.
      Patients 12years and olderHomozygous for F508delTreatment difference in mean absolute change from baseline in ppFEV1 through Week 16: 1.72% (p = .15)
      • Moss R.B.
      • Flume P.A.
      • Elborn J.S.
      • Cooke J.
      • Rowe S.M.
      • McColley S.A.
      VX11-770-110(KONDUCT) Study Group
      Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: A double-blind, randomised controlled trial.
      Ivacaftor versus placebo.
      Patients 6years and olderR117HTreatment difference in mean absolute change in CFQ-R respiratory domain score from baseline through Week 24: 8.4 (p < .05)
      • Quittner A.
      • Suthoff E.
      • Rendas-Baum R.
      • Bayliss M.S.
      • Sermet-Gaudelus I.
      • Castiglione B.
      • Vera-Llonch M.
      Effect of ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutations: Patient-reported outcomes in the STRIVE randomized controlled trial.
      Ivacaftor versus placebo.
      Patients 12years and olderG551DTreatment difference in mean absolute change in ppFEV1 from baseline through Week 24: 10.6% (p < .0001)
      Vertex Pharmaceuticals, Inc
      Kalydeco® (ivacaftor) prescribing information.
      Ivacaftor versus placebo.
      Patients 12years and olderHeterozygous for F508del with second mutation predicted to be responsive to ivacaftor (A455E, D1152H, D579G, E831X, L206W, P67L, R1070W, R117C, R347H, R352Q, S945L, S977F, 711+3A>G, 2789+5G>A, 3272-26A>G, 3849+10kbC>T)Treatment difference in mean absolute change from baseline in ppFEV1 averaged at Weeks 4 and 8 of treatment: 4.7% (p < .0001)
      Note. ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUC, area under the curve; CFQ-R, Cystic Fibrosis Questionnaire–Revised; ppFEV1, percent predicted forced expiratory volume in 1 second.
      a Ivacaftor versus placebo.
      b Efficacy has not been established for this mutation.

      Lumacaftor/Ivacaftor (Orkambi)

      In July 2015, the FDA approved a combination CFTR modulator, lumacaftor/ivacaftor (Orkambi, Vertex Pharmaceuticals). As mentioned previously, ivacaftor is a CFTR potentiator that improves the function of already-produced CFTR protein (
      Vertex Pharmaceuticals, Inc
      Orkambi® (lumacaftor/ivacaftor) prescribing information.
      ). Lumacaftor, on the other hand, is a CFTR corrector. In patients with the F508del mutation, both a dysfunction in CFTR and a decrease in the CFTR protein can be observed. Lumacaftor complements ivacaftor by increasing the production and trafficking of CFTR to the cell surface. Lumacaftor/ivacaftor is approved for patients homozygous for the F508del mutation of the CFTR gene, but it is found to have reduced efficacy for heterozygotes (
      • Boyle M.P.
      • Bell S.C.
      • Konstan M.W.
      • McColley S.A.
      • Rowe S.M.
      • Rietschel E.
      VX09-809-102 study group
      A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: A phase 2 randomised controlled trial.
      ). The dosage is 400 mg/250mg (lumacaftor/ivacaftor) every 12hours for patients ages 12years and older. A dose reduction to 200 mg/250mg (lumacaftor/ivacaftor) twice daily is required for pediatric patients ages 6 to 11years. Lumacaftor/ivacaftor was recently approved for patients 2 to 5years old; their dosages are based on weight (Table 2;
      Vertex Pharmaceuticals, Inc
      Safety and pharmacokinetic study of lumacaftor/ivacaftor in subjects aged 2 through 5years with cystic fibrosis, homozygous for F508del.
      ,
      Vertex Pharmaceuticals, Inc
      Orkambi® (lumacaftor/ivacaftor) prescribing information.
      ).
      As with ivacaftor alone, lumacaftor/ivacaftor should be given with high-fat meals, and doses should be reduced in patients with hepatic impairment. In patients receiving concomitant CYP3A4 inhibitors, the dose of lumacaftor/ivacaftor should be reduced for the first week of treatment. Similar to ivacaftor alone, lumacaftor/ivacaftor should not be co-administered with strong CYP3A4 inducers. Lumacaftor/ivacaftor has been associated with a higher incidence of respiratory events (including chest discomfort and dyspnea), elevated blood pressure, and cataracts (
      Vertex Pharmaceuticals, Inc
      Orkambi® (lumacaftor/ivacaftor) prescribing information.
      ).
      Lumacaftor/ivacaftor was first studied in patients aged 12years and older (
      • Wainwright C.E.
      • Elborn J.S.
      • Ramsey B.W.
      • Marigowda G.
      • Huang X.
      • Cipolli M.
      TRANSPORT Study Group
      Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR.
      ). In this 24-week, Phase 3 randomized controlled trial, patients with cystic fibrosis (n = 1,108) homozygous for the F508del mutation were randomized to receive lumacaftor 600mg once daily or 400mg every 12hours along with ivacaftor 250mg every 12hours or placebo. The treatment difference in mean absolute change from baseline to Week 24 in ppFEV1 proved to be significant compared with placebo for both doses (2.6–4.0 percentage points, p < .001 for all comparisons). The rate of pulmonary exacerbations was reduced in the treatment groups compared with the placebo group (rate ratio of 0.57–0.72, p < .001). The most common adverse effects associated with treatment were respiratory effects (e.g., dyspnea and chest tightness;
      • Wainwright C.E.
      • Elborn J.S.
      • Ramsey B.W.
      • Marigowda G.
      • Huang X.
      • Cipolli M.
      TRANSPORT Study Group
      Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR.
      ).
      Although originally approved for treatment of patients 12years of age or older, subsequent analysis of lumacaftor/ivacaftor showed positive outcomes in patients 6 to 11years old as well. Lumacaftor/ivacaftor was evaluated in two separate trials in patients aged 6 to 11years. The first was a Phase 3 open-label safety study that was performed in patients 6 to 11years old (n = 58) and who were homozygous for the F508del mutation with a primary objective to analyze the safety of lumacaftor/ivacaftor via adverse events, laboratory data, and other measures of clinical safety (
      • Milla C.E.
      • Ratjen F.
      • Marigowda G.
      • Liu F.
      • Waltz D.
      • Rosenfeld M.
      VX13-809-011 Part B Investigator Group
      Lumacaftor/ivacaftor in patients aged 6–11years with cystic fibrosis and homozygous for F508del-CFTR.
      ). Patients received lumacaftor 200mg/ivacaftor 250mg every 12hours along with their maintenance CF therapies for 24 weeks. Despite a high incidence of adverse events (94.8%), the majority was classified as having mild or moderate severity, which was similar to that seen in trials with older patients. The most common adverse events reported were cough, nasal congestion, infective pulmonary exacerbation, and headache. The incidence of serious adverse events was low (6.9%), with one patient experiencing elevated liver transaminase levels that led to discontinuation of therapy. Because of the higher incidence of abnormal respiration and chest tightness seen in adult studies, respiratory adverse events were evaluated as a secondary outcome (
      • Milla C.E.
      • Ratjen F.
      • Marigowda G.
      • Liu F.
      • Waltz D.
      • Rosenfeld M.
      VX13-809-011 Part B Investigator Group
      Lumacaftor/ivacaftor in patients aged 6–11years with cystic fibrosis and homozygous for F508del-CFTR.
      ,
      • Wainwright C.E.
      • Elborn J.S.
      • Ramsey B.W.
      • Marigowda G.
      • Huang X.
      • Cipolli M.
      TRANSPORT Study Group
      Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR.
      ). Respiratory symptoms were very rare, with a reported four patients experiencing some symptom of abnormal respiration (e.g., dyspnea and wheezing). Analysis of sweat chloride levels in the study indicated that lumacaftor/ivacaftor effectively increased CFTR activity (least squares mean change = –24.8mmol/L at Week 24, p < .0001;
      • Milla C.E.
      • Ratjen F.
      • Marigowda G.
      • Liu F.
      • Waltz D.
      • Rosenfeld M.
      VX13-809-011 Part B Investigator Group
      Lumacaftor/ivacaftor in patients aged 6–11years with cystic fibrosis and homozygous for F508del-CFTR.
      ).
      The second study was a 24-week Phase 3 randomized efficacy and safety analysis of lumacaftor/ivacaftor in children aged 6–11years (n = 204) homozygous for the F508del mutation (
      • Ratjen F.
      • Hug C.
      • Marigowda G.
      • Tian S.
      • Huang X.
      • Stanojevic S.
      VX14-809-109 Investigator Group
      Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11years with cystic fibrosis homozygous for F508del-CFTR: A randomised, placebo-controlled phase 3 trial.
      ). Patients received lumacaftor 200mg/ivacaftor 250mg every 12hours or placebo. Analysis of the primary outcome showed a significant difference in mean absolute change in lung clearance index from baseline to each visit up to 24 weeks between the treatment groups (least squares mean difference of –1.09 units, p < .0001), favoring lumacaftor/ivacaftor over placebo. Although the change in ppFEV1 from baseline to Week 24 was not significant in either group, the between-group difference in absolute change in ppFEV1 through Week 24 was significantly improved in the treatment group compared with the placebo group (treatment difference = 2.4%, p = .0182). Safety data analyzed in this study were similar to those seen in the previous study, attesting acceptable tolerability in pediatric patients (
      • Ratjen F.
      • Hug C.
      • Marigowda G.
      • Tian S.
      • Huang X.
      • Stanojevic S.
      VX14-809-109 Investigator Group
      Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11years with cystic fibrosis homozygous for F508del-CFTR: A randomised, placebo-controlled phase 3 trial.
      ).

      Tezacaftor/Ivacaftor (Symdeko)

      The most recent CFTR drug therapy, approved in February 2018, is tezacaftor/ivacaftor (Symdeko, Vertex Pharmaceuticals). Unfortunately, tezacaftor/ivacaftor is currently approved only for patients 12years or older (
      Vertex Pharmaceuticals, Inc
      SymdekoTM (tezacaftor and ivacaftor) prescribing information.
      ). Like lumacaftor, tezacaftor is a CFTR corrector, allowing increased production and trafficking of CFTR to the cell surface. Tezacaftor has several advantages over lumacaftor, including a reduced incidence of respiratory symptoms and the ability to treat a larger number of CFTR gene mutations (
      • Taylor-Cousar J.L.
      • Munck A.
      • McKone E.F.
      • van der Ent C.K.
      • Moeller A.
      • Simard C.
      • Elborn J.S.
      Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del.
      ,
      Vertex Pharmaceuticals, Inc
      SymdekoTM (tezacaftor and ivacaftor) prescribing information.
      ). Tezacaftor/ivacaftor is indicated in patients homozygous for the F508del CFTR mutation or who have at least 1 of the 26 other CFTR gene mutations (Table 5). Tezacaftor is administered once daily (100 mg), whereas ivacaftor remains at twice daily (150mg every 12 hours). Dose adjustments remain for patients with hepatic impairment and patients taking concomitant CYP3A4 inhibitors. No specific recommendations for dosage adjustment exist for CYP3A4 inducers, but the manufacturer recommends against the use of tezacaftor/ivacaftor with strong CYP3A4 inducers, and clinicians should implement close monitoring in patients receiving moderate CYP3A4 inducers (
      Vertex Pharmaceuticals, Inc
      SymdekoTM (tezacaftor and ivacaftor) prescribing information.
      ).
      TABLE 5CFTR genetic mutations responsive to tezacaftor/ivacaftor (percentage of patients with these mutations)
      For those mutations that do not have a percentage value next to them, the prevalence is <0.5%.
      A455E (0.6%)D1270NF1074LR347H2789+5G>A (1.3%)
      A1067TE56KK1060TR352Q3272-26A>G
      D110EE193KL206W (0.5%)R1070W3849+10kbC>T (1.5%)
      D110HE831XP67LS945L
      D579GF508del
      Homozygous for F508del or F508del + another mutation listed in the table. Data from Cystic Fibrosis Foundation, 2016; Vertex Pharmaceuticals, Inc., 2018b.
      (86.4%)
      R74WS977F
      D1152H (0.9%)F1052VR117C711+3A>G
      Note. CFTR, cystic fibrosis transmembrane conductance regulator.
      a For those mutations that do not have a percentage value next to them, the prevalence is <0.5%.
      b Homozygous for F508del or F508del + another mutation listed in the table.Data from ,
      Vertex Pharmaceuticals, Inc
      SymdekoTM (tezacaftor and ivacaftor) prescribing information.
      .
      The most recent CFTR drug therapy, approved in February 2018, is tezacaftor/ivacaftor (Symdeko, Vertex Pharmaceuticals).
      Tezacaftor/ivacaftor has yielded promising data in the treatment of CF. Tezacaftor/ivacaftor was studied in patients 12years of age and older with CF (n = 504) and homozygous for the F508del mutation (
      • Taylor-Cousar J.L.
      • Munck A.
      • McKone E.F.
      • van der Ent C.K.
      • Moeller A.
      • Simard C.
      • Elborn J.S.
      Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del.
      ). In that study, patients received either tezacaftor 100mg once daily along with ivacaftor 150mg twice daily or placebo. A treatment difference in mean absolute change in ppFEV1 from baseline through Week 24 of 4% was observed when compared with placebo (p < .001). Tezacaftor/ivacaftor also reduced the number of pulmonary exacerbation events (78vs. 122 events, p = .005;
      • Taylor-Cousar J.L.
      • Munck A.
      • McKone E.F.
      • van der Ent C.K.
      • Moeller A.
      • Simard C.
      • Elborn J.S.
      Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del.
      ). Alternatively, tezacaftor/ivacaftor is the only CFTR therapy that has been studied against an active comparator group. When studied in patients (n = 234) heterozygous for the F508del mutation along with other mutations proven responsive to tezacaftor/ivacaftor in vitro, analysis was performed on treatment differences between tezacaftor/ivacaftor, ivacaftor alone, and placebo (
      • Rowe S.M.
      • Daines C.
      • Ringshausen F.C.
      • Kerem E.
      • Wilson J.
      • Tullis E.
      • Davies J.C.
      Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis.
      ). As expected, tezacaftor/ivacaftor significantly improved ppFEV1 compared with placebo (treatment difference of 4.7%, p < .001). In addition, tezacaftor/ivacaftor also proved to be significantly superior to ivacaftor alone at improving ppFEV1 (treatment difference of 2.1%, p < .001;
      • Rowe S.M.
      • Daines C.
      • Ringshausen F.C.
      • Kerem E.
      • Wilson J.
      • Tullis E.
      • Davies J.C.
      Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis.
      ).

      On the Horizon

      Despite showing positive data in the adolescent and adult population, there still remains a significant lack of data for CFTR treatment in the pediatric population. Ivacaftor and lumacaftor/ivacaftor are the only CFTR-targeted drug therapies approved for patients younger than 6years old, and there are not any medications currently approved for patients younger than 1year old. Many trials are ongoing to evaluate the approved therapies in pediatric patients of other age groups. For example, tezacaftor/ivacaftor is being evaluated in patients 6 to 11years old (
      Vertex Pharmaceuticals, Inc
      A study to evaluate the pharmacokinetics, safety, and tolerability of VX-661/ivacaftor in pediatric subjects with cystic fibrosis.
      ).
      Although development and improvement of the CFTR-targeted therapies throughout the years have broadened the patient population that qualifies for treatment, many patients still have mutations that do not respond to CFTR treatment. New triple drug combination therapies with next-generation CFTR correctors are being developed and tested for patients with only one F508del mutation (
      Vertex Pharmaceuticals, Inc
      Vertex selects two next-generation correctors, VX-659 and VX-445, to advance into phase 3 development as part of two different triple combination regimens for people with cystic fibrosis.
      ). In a Phase 2 study of VX-659 400mg daily combined with tezacaftor and ivacaftor for 4 weeks in patients (n = 63) with one F508del mutation and one minimal function mutation, a 13.3% improvement in ppFEV1 was observed compared with placebo (
      • Kym P.R.
      • Wang X.
      • Pizzonero M.
      • Van der Plas S.E.
      Recent progress in the discovery and development of small-molecule modulators of CFTR.
      ,
      Vertex Pharmaceuticals, Inc
      Vertex selects two next-generation correctors, VX-659 and VX-445, to advance into phase 3 development as part of two different triple combination regimens for people with cystic fibrosis.
      ). Similarly, in a Phase 2 study of VX-445 200mg daily combined with tezacaftor and ivacaftor in patients (n = 65) with one F508del mutation and one minimal function mutation, a 13.8% improvement in ppFEV1 was observed compared with placebo (
      • Kym P.R.
      • Wang X.
      • Pizzonero M.
      • Van der Plas S.E.
      Recent progress in the discovery and development of small-molecule modulators of CFTR.
      Vertex Pharmaceuticals, Inc
      Vertex selects two next-generation correctors, VX-659 and VX-445, to advance into phase 3 development as part of two different triple combination regimens for people with cystic fibrosis.
      ). Vertex Pharmaceuticals has also initiated Phase 3 studies with VX-659, which will enroll patients 12years and older (
      Vertex Pharmaceuticals, Inc
      A phase 3 study of VX-659 combination therapy in subjects with cystic fibrosis heterozygous for the F508del mutation and a minimal function mutation (F/MF).
      ). If proven successful, a predicted 90% of patients with CF will have a treatment option with CFTR targeted therapy.
      Many patients still have mutations that do not respond to CFTR treatment.

      CONCLUSION

      CF is an autosomal recessive disease affecting thousands of people worldwide. Advances in treatment have increased patients’ anticipated life expectancy. Treatment consists of supportive respiratory care, infection management, and pancreatic enzyme replacement. In the past 6years, three CFTR-targeted medications have been approved for the treatment of CF, allowing more patients as young as 1year old to receive such therapy targeting the underlying cause of their CF. Ivacaftor-containing drugs continue to be the mainstay of care for various CFTR gene mutations. Several clinical trials are aiming to expand the age range and mutations indicated for these medications. With continued advances in this field, more patients will likely qualify for CFTR modulators in the near future, especially if the drug cost of these therapies can be lower leading to coverage by more health insurance companies.

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      Biography

      Michael Bitonti, PGY1 pharmacy resident, Department of Pharmacy, Moses H. Cone Memorial Hospital, Greensboro, NC.
      Laura Fritts, PharmD candidate, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC.
      Tsz-Yin So, Pediatric Clinical Pharmacist, Department of Pharmacy, Moses H. Cone Memorial Hospital, Greensboro, NC.