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, Dhooghe, Noel and Leal, 2012
). It involves a defect in a single gene, causing alterations in chloride secretion and sodium transport that ultimately lead to multiorgan complications (Davies, Alton and Bush, 2007
, Pettit and Fellner, 2014
). CF often causes symptomatic pulmonary disease, but the pancreas, gastrointestinal tract, liver, and reproductive tract can also be affected (Davies, Alton and Bush, 2007
, Spoonhower and Davis, 2016
). 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, Alton and Bush, 2007
, Lubamba, Dhooghe, Noel and Leal, 2012
). The percentage of CF patients over the age of 18years has increased from 29.2% in 1986 to 52.7% in 2016 (Cystic Fibrosis Foundation 2016
). In addition, the life expectancy has grown from just a few months in the 1950s to an average of 40years today (Elborn, 2016
, Spoonhower and Davis, 2016
).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, Alton and Bush, 2007
, Wright and Vera, 2017
). 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, 2016
, Farrell et al., 2017
). CF is diagnosed in almost 1,000 new patients in the US every year, and the median age at diagnosis is 4 months (Cystic Fibrosis Foundation 2016
, Pettit and Fellner, 2014
). 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 et al., 2006
).PATHOPHYSIOLOGY
Although CF can affect people of any ethnicity, it is most commonly diagnosed in White individuals with European ancestry (
Elborn, 2016
, Spoonhower and Davis, 2016
, Wright and Vera, 2017
). 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, 2016
, Pettit and Fellner, 2014
). The disease is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (Boucher, 2002
, Ong and Ramsey, 2016
). 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, Dhooghe, Noel and Leal, 2012
, Ong and Ramsey, 2016
, Rowe, Miller and Sorscher, 2005
). The primary function of this protein is ionic transport of chloride across the cellular membrane (Elborn, 2016
, Lubamba, Dhooghe, Noel and Leal, 2012
).There are approximately 2,000 known genetic mutations that can render this protein dysfunctional (
Ong and Ramsey, 2016
, Pettit and Fellner, 2014
). 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 and Fellner, 2014
). 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 and Ramsey, 2016
, Pettit and Fellner, 2014
, Rowe, Miller and Sorscher, 2005
).TABLE 1Classification of genetic mutation types in cystic fibrosis
Mutation class | Characteristics | Major genetic mutations | Percentage of patients |
---|---|---|---|
Class I | “Stop codon” prevents synthesis of CFTR proteins | G542X | 4.7 |
W1282X | 2.3 | ||
R553X | 1.8 | ||
Class II | Misfolded CFTR proteins are produced that are unable to reach apical surface | F508del | 86.4 |
N1303K | 2.4 | ||
I507del | 0.8 | ||
Class III | CFTR proteins exhibit abnormal chloride ion–channel opening | G551D | 4.4 |
Class IV | CFTR proteins do not conduct ions adequately | R117H | 3.0 |
D1152H | 0.9 | ||
R347P | 0.6 | ||
Class V | Overall production of CFTR proteins is reduced | 3849+10kbC>T | 1.5 |
2789+5G>A | 1.3 | ||
5T | 0.8 | ||
A455E | 0.6 | ||
Class VI | Rapid turnover of CFTR proteins induced by C-terminus mutations | 1811+1.6kbA>G | <0.5 |
Note. CFTR, cystic fibrosis transmembrane conductance regulator.
Data from
Cystic Fibrosis Foundation 2016
, Ong and Ramsey, 2016
, Pettit and Fellner, 2014
, Rowe, Miller and Sorscher, 2005
.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, 2016
, Lubamba, Dhooghe, Noel and Leal, 2012
, Pettit and Fellner, 2014
). Normally, the functioning CFTR protein regulates the electrochemical gradient at the surface of the cell to control liquid volume and mucus viscosity (Davies, Alton and Bush, 2007
, Elborn, 2016
). 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 and Fellner, 2014
, Wright and Vera, 2017
).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, Dhooghe, Noel and Leal, 2012
). The airways become inflamed, obstructed, and unable to clear bacteria effectively. Ultimately, this can cause persistent respiratory infections, respiratory failure, and potentially death (Davies, Alton and Bush, 2007
, Lubamba, Dhooghe, Noel and Leal, 2012
). Within the gastrointestinal tract, meconium ileus can occur in newborns. Also, pancreatic insufficiency can result in malabsorption, steatorrhea, and failure to thrive (Lubamba, Dhooghe, Noel and Leal, 2012
, Spoonhower and Davis, 2016
). Other consequences include cirrhosis, CF-related diabetes mellitus, CF-related bone disease, and infertility (Elborn, 2016
, Lubamba, Dhooghe, Noel and Leal, 2012
, Rowe, Miller and Sorscher, 2005
, Spoonhower and Davis, 2016
).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 (
Cystic Fibrosis Foundation et al., 2009
, Lahiri et al., 2016
). This includes both chest physiotherapy and mucolytic agents like dornase-α and hypertonic saline (Edmondson and Davies, 2016
, Lahiri et al., 2016
). 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 and Davies, 2016
, Elborn, 2016
). 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, Cannon and Pier, 2002
). In addition, pancreatic enzyme replacement is necessary in 80% of CF patients to prevent malnutrition and failure to thrive secondary to pancreatic insufficiency (Fieker, Philpott and Armand, 2011
).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, Sharma and Rowe, 2017
, Pettit and Fellner, 2014
). 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
Drug | Indication (FDA approved) | Dose | CYP enzyme dosage adjustments 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., 2017a, 2018a, 2018b. | Hepatic dysfunction dosage adjustments | Dosage formulations | Administration | Adverse effects |
---|---|---|---|---|---|---|---|
Ivacaftor | CF patients ≥ 1 year old with one mutation in CFTR gene that is responsive to ivacaftor potentiation | 1–5years 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, 150mg | Administer 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 + lumacaftor | CF patients ≥ 2years old homozygous for F508del mutation | 2–5years 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 dose | Severe: 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 + tezacaftor | CF 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 tablet | Administer 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. 2017a
, Vertex Pharmaceuticals, Inc. 2018a
, Vertex Pharmaceuticals, Inc. 2018b
.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. 2017a
). 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 et al., 2013
). 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. 2017a
).TABLE 3CFTR genetic mutations responsive to ivacaftor (percentage of patients with these mutations)
A455E (0.6%) | E193K | G1244E | R347H | S1251N |
A1067T | E831X | G1349D | R352Q | S1255P |
D110E | F1052V | K1060T | R1070Q | 711+3A>G |
D110H | F1074L | L206W (0.5%) | S549N | 2789+5G>A (1.3%) |
D579G | G178R | P67L | S549R | 3272-26A>G |
D1152H (0.9%) | G551D (4.4%) | R74W | S945L | 3849-10kbC>T (1.5%) |
D1270N | G551S | R117C | S977F | |
E56K | G1069R | R117H (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
Cystic Fibrosis Foundation 2016
, Vertex Pharmaceuticals, Inc. 2017a
.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 et al., 2013
). 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 et al., 2013
).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 et al., 2016
). 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.
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.
The Lancet Respiratory Medicine. 2016; 4: 107-115
Davies et al., 2016
). 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 (- 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.
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.
The Lancet Respiratory Medicine. 2016; 4: 107-115
Vertex Pharmaceuticals, Inc. 2017b
). Table 4 summarizes the other major trials that helped lead to the approval of ivacaftor for other mutations (Davies et al., 2013
, Davies et al., 2016
, - 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.
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.
The Lancet Respiratory Medicine. 2016; 4: 107-115
De Boeck et al., 2014
, Flume et al., 2012
, Moss et al., 2015
, Quittner et al., 2015
).- 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.
Health and Quality of Life Outcomes. 2015; 13: 93
TABLE 4Major clinical trials on ivacaftor
Authors | Patient population | Mutations evaluated | Results |
---|---|---|---|
Davies et al., 2013 | Patients 6–11years old | G551D | Treatment difference in mean absolute change in ppFEV1 from baseline through Week 24: 12.5% (p < .001) |
Davies et al., 2016
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. The Lancet Respiratory Medicine. 2016; 4: 107-115 | Patients 2–5years old | G178R, G551D, G551S, G970R, 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 et al., 2014 | Patients 6years and older | G178R, G551S, G970R, 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 et al., 2012 | Patients 12years and older | Homozygous for F508del | Treatment difference in mean absolute change from baseline in ppFEV1 through Week 16: 1.72% (p = .15) |
Moss et al., 2015 | Patients 6years and older | R117H | Treatment difference in mean absolute change in CFQ-R respiratory domain score from baseline through Week 24: 8.4 (p < .05) |
Quittner et al., 2015
Effect of ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutations: Patient-reported outcomes in the STRIVE randomized controlled trial. Health and Quality of Life Outcomes. 2015; 13: 93 | Patients 12years and older | G551D | Treatment difference in mean absolute change in ppFEV1 from baseline through Week 24: 10.6% (p < .0001) |
Vertex Pharmaceuticals, Inc. 2017a | Patients 12years and older | Heterozygous 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. 2018a
). 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 et al., 2014
). 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; - 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.
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 Lancet Respiratory Medicine. 2014; 2: 527-538
Vertex Pharmaceuticals, Inc. 2016a
, Vertex Pharmaceuticals, Inc. 2018a
).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. 2018a
).Lumacaftor/ivacaftor was first studied in patients aged 12years and older (
Wainwright et al., 2015
). 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 et al., 2015
).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 et al., 2017
). 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 et al., 2017
, Wainwright et al., 2015
). 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 et al., 2017
).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 et al., 2017
). 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.
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.
The Lancet Respiratory Medicine. 2017; 5: 557-567
Ratjen et al., 2017
).- 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.
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.
The Lancet Respiratory Medicine. 2017; 5: 557-567
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. 2018b
). 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 et al., 2017
, Vertex Pharmaceuticals, Inc. 2018b
). 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. 2018b
).TABLE 5CFTR genetic mutations responsive to tezacaftor/ivacaftor (percentage of patients with these mutations)
A455E (0.6%) | D1270N | F1074L | R347H | 2789+5G>A (1.3%) |
A1067T | E56K | K1060T | R352Q | 3272-26A>G |
D110E | E193K | L206W (0.5%) | R1070W | 3849+10kbC>T (1.5%) |
D110H | E831X | P67L | S945L | |
D579G | F508del (86.4%) | R74W | S977F | |
D1152H (0.9%) | F1052V | R117C | 711+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
Cystic Fibrosis Foundation 2016
, Vertex Pharmaceuticals, Inc. 2018b
.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 et al., 2017
). 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 et al., 2017
). 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 et al., 2017
). 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 et al., 2017
).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. 2016b
).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. 2018c
). 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, Wang, Pizzonero and Van der Plas, 2018
, Vertex Pharmaceuticals, Inc. 2018c
). 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, Wang, Pizzonero and Van der Plas, 2018
Vertex Pharmaceuticals, Inc. 2018c
). Vertex Pharmaceuticals has also initiated Phase 3 studies with VX-659, which will enroll patients 12years and older (Vertex Pharmaceuticals, Inc. 2018d
). If proven successful, a predicted 90% of patients with CF will have a treatment option with CFTR targeted therapy.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.
Article info
Footnotes
Conflicts of interest: None to report.
Identification
Copyright
Copyright © 2018 by the National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.