You are here
CFTR Modulators for the Treatment of Cystic Fibrosis
Cystic fibrosis (CF) is an incurable, ultimately fatal inherited disorder that causes thick, sticky mucus to form in the lungs, pancreas, and other organs. In the lungs, thick mucus can damage tissue and block airways, making it difficult for patients to breathe and promoting lung infections.1 Although lung disease is responsible for more than 80% of CF-related deaths, CF has many other manifestations, including pancreatic insufficiency, gastrointestinal problems, endocrine disorders, and male infertility.1
CF was first recognized as a disease in the late 1930s, and the term cystic fibrosis was used to describe the characteristic cyst formation and scarring (fibrosis) observed in the pancreas of these patients.2 In 1949, Lowe and colleagues theorized that CF must be caused by a defect in a single gene, based on the disorder’s autosomal recessive pattern of inheritance.3 It wasn’t until 1989 that investigators identified a member of the adenosine triphosphate (ATP)–binding cassette (or traffic ATPase) gene family as the one involved in CF.4,5,6 Mutations in the CFTR gene result in defective cystic fibrosis transmembrane conductance regulator (CFTR) proteins, which in turn cause CF.7,8,9 Normally, CFTR proteins located on the surface of the epithelial membrane act as chloride channels that in turn regulate the ENaC (epithelial sodium channel) and other anion channels at the cell surface. The complex interplay of these channels regulates the electrochemical gradient that allows appropriate airway surface liquid depth and mucus viscosity.10,11 When these proteins are defective or missing, the body produces thick, viscous mucus.12
To date, more than 1,800 mutations of the CFTR gene have been identified.13CFTR mutations are divided into six classes, based on the mechanisms by which they cause disease (
More than 10 million Americans are asymptomatic carriers of a defective CFTR gene.16 To develop CF, an individual must inherit two defective genes—one from each parent. Each time two carriers of a CFTR gene mutation conceive, they have a 25% chance of passing CF to their child, a 50% chance that the child will only be a carrier of the defective gene, and a 25% chance that the child will not have the defective gene at all.16–19
In the U.S., approximately 30,000 children and adults have CF.13 The overall birth prevalence is one in 3,500, and an estimated 1,000 new cases are diagnosed each year.13 Most CF patients are diagnosed with the disease before they are 2 years old.13 In the 1950s, few children with CF lived to attend elementary school.20 In 2012, thanks to advances in medical treatment, the median predicted age of survival was 41.1 years.13
CF affects all racial and ethnic groups, but it is more common among Caucasians of Northern European descent.13,21 Approximately one in 2,500 Caucasians is diagnosed with CF, compared with one in 15,100 African-Americans and one in 13,500 Hispanics.16,22 About 72% of Caucasians have the F508del mutation, the most common gene mutation in CF.13,19 In contrast, only about 44% of African Americans and 54% of Hispanics carry this mutation. Moreover, CF is the most lethal genetic disease among Caucasians.17 Between 1999 and 2006, 3,708 people died of CF in the U.S.; 90% were white.16 The age-adjusted death rate among Caucasians is 0.22 per 100,000, compared with 0.04 and 0.05 per 100,000 among African-Americans and Hispanics, respectively.16
Until recently, medical therapies were unable to target the underlying genetic cause of CF and could only address symptoms. For example, airway clearance therapies are used daily to dislodge airway mucus, pancreatic enzyme replacement is taken with each meal to help digest food, and antibiotics are used to treat lung infections.1 Therefore, extensive research has focused on developing agents that can affect CF at the genetic level.23 Because CF is caused by defects in a single gene, it is considered an ideal candidate for mutation-targeted therapy.24
The study of CFTR modifier medications represents a major revolution in CF treatment because these agents target the basic defect as opposed to targeting the effects of the disease. Although ivacaftor is the only FDA-approved CFTR modifier, other medications are in development.
Studies of CFTR modifier medications use a variety of different outcome measures, including sweat chloride, nasal potential difference (NPD), and the Cystic Fibrosis Questionnaire– Revised (CFQ-R).15,25 The sweat chloride test measures the chloride content of the patient’s sweat as an indicator of CFTR function. A sweat chloride value of more than 60 mmol/L is diagnostic for CF.1 A decrease in sweat chloride to non-CF values may correlate with clinical changes, such as lung function. However, changes in which the sweat chloride value remains greater than 60 mmol/L have not been correlated with clinical outcomes. NPD testing is performed by running different solutions through the patient’s nose; voltage measurements from these solutions are used to detect changes in CFTR function. Increases in CFTR function may result in clinical changes in CF patients, although a direct correlation has not been established.25 CFQ-R is a measurement tool used to determine changes in health-related quality of life for CF patients. A clinically significant change in the CFQ-R score is defined as a change of 4 points.15
On January 31, 2012, the FDA approved ivacaftor (Kalydeco, Vertex Pharmaceuticals), a CFTR potentiator, for the treatment of CF patients 6 years of age and older with the G551D mutation, which represents about 4% of patients with CF.13,26 As a CFTR potentiator, ivacaftor increases the time the CFTR channel is open, allowing chloride ions to flow through the CFTR proteins on the surface of epithelial cells.27,28 Ivacaftor is the first FDA-approved treatment to target the basic defect in CF.
The approved dosage of ivacaftor is one 150-mg tablet taken orally every 12 hours (total daily dose, 300 mg) with fat-containing foods.27
Clinical Efficacy Data
Ivacaftor (25, 75, 150, and 250 mg twice daily) was initially studied against placebo in 39 adult patients with CF who had at least one copy of G551D. The study consisted of two parts. In part 1, two 14-day courses of two different ivacaftor doses were given with a washout period in between.15 Part 2 of the study examined the higher doses of ivacaftor (150 and 250 mg twice daily) against placebo for 28 days. The primary endpoint was safety and adverse event rates were similar between all groups.15
The sweat chloride test was used as an outcome. In the ivacaftor treatment group, sweat chloride decreased significantly from baseline (P < 0.001); however, this change was not statistically significant compared with placebo.15 NPD testing was also used to evaluate CFTR function; changes from baseline were statistically significant in the 75-mg, 150-mg and 250-mg groups (P = 0.03, 0.01, and 0.05, respectively) but not statistically significant compared with placebo. Forced expiratory volume in one second (FEV1) significantly increased from baseline at doses of at least 75 mg twice a day but did not change significantly compared with placebo.15 Although small, the study showed promising outcomes with ivacaftor, and the decision was made to proceed to phase 3 trials with ivacaftor 150 mg twice a day.
FDA approval of ivacaftor was based on results from two pivotal phase 3 trials (ENVISION and STRIVE).29,30 Eligible patients from these two studies were rolled over into an open-label extension study (PERSIST).31
In ENVISION, a randomized, double-blind, placebo- controlled trial of 52 patients ages 6 to 11 years, patients were treated with ivacaftor 150 mg every 12 hours for 48 weeks in addition to their prescribed CF therapies (
The mean absolute change from baseline in percent predicted FEV1 was 12.6% in the ivacaftor group versus 0.1% in the placebo group at 24 weeks (P < 0.001).29 This effect persisted through 48 weeks of treatment.29 Ivacaftor reduced sweat chloride to normal levels in some patients (P < 0.001) and showed a significant increase in body weight (P < 0.001) and a nonstatistically significant increase in CFQ-R scores of 6.1 points (P = 0.109).29
In the STRIVE trial, ivacaftor was evaluated in 161 CF patients ages 12 to 53 years.30 Treatment with ivacaftor resulted in a significant improvement in FEV1 compared with placebo (
The PERSIST trial was a 96-week, open-label extension of both the ENVISION and STRIVE studies (
The patients enrolled in the STRIVE and ENVISION studies had a wide range of FEV1, from 40% to 105%. In early lung-disease patients with a higher FEV1, FEV1 is an insensitive marker of disease and many not show a significant change despite a clinical effect.32 Lung clearance index (LCI) measures ventilation inhomogeneity using a multiple breath washout technique. LCI can detect mild lung-function abnormalities.32 A study evaluating LCI in patients being treated with ivacaftor showed significant improvements after 28 days of treatment (P < 0.001) (
The clinical trials of ivacaftor have excluded patients with FEV1 of less than 40%. To assess the impact of ivacaftor treatment in these patients with severe lung disease, a retrospective review of patients was completed (
Ivacaftor was also studied in patients who are homozygous for F508del, but it did not prove effective (
A phase 3 trial of ivacaftor monotherapy in CF patients with R117H showed a nonsignificant 2.1% increase in the mean absolute change from baseline in percent predicted FEV1 (P = 0.2).36 A subgroup analysis of patients at least 18 years old found a statistically significant 5% difference in the mean absolute change from baseline in percent predicted FEV1 (P = 0.01). Although ivacaftor did not meet its primary endpoint in patients with R117H, Vertex planned to discuss the finding with the FDA to determine future direction.36
Ivacaftor has shown efficacy in patients with a G551D mutation, one of the class III “gating” mutations, and initially received FDA approval for patients with this mutation. Ivacaftor use in non-G551D gating mutations was studied in patients older than 6 years of age in a randomized, placebo-controlled crossover study (
Ivacaftor was well tolerated in clinical trials. The most common adverse events included headache (24%), oropharyngeal pain (22%), upper respiratory tract infection (22%), nasal congestion (20%), abdominal pain (16%), nasopharyngitis (15%), diarrhea (13%), rash (13%), nausea (12%), and dizziness (9%).29,30 Serious adverse events included transaminase elevations (6%) above the upper limits of normal. Monitoring transaminases is recommended at baseline, every three months for the first year, and annually thereafter.27 Therapy should be discontinued in patients who experience transaminase elevations greater than five times the upper limit of normal. One safety concern that arose in animal studies was the development of cataracts in juvenile rats that were given doses at 10 mg/kg per day and higher.39 As a result, an ongoing study is assessing the ocular safety of ivacaftor in patients younger than 11 years old.40 Regular eye exams should be recommended in patients taking ivacaftor until more is known about ocular risk.
Metabolism of ivacaftor is primarily hepatic, and dose adjustments are recommended in patients with hepatic impairment. A dose decrease to 150 mg daily is recommended in patients with Child-Pugh class B impairment, and caution should be used when administering ivacaftor to patients with severe hepatic impairment (Child-Pugh class C).27 There is little renal elimination of ivacaftor, and dose adjustments in mild-to-moderate renal failure are not recommended; however, caution should be used in severe renal impairment.
Ivacaftor is a CYP3A substrate, but also has the potential to inhibit CYP3A and p-glycoprotein (P-gp). Ivacaftor is not recommended for administration with strong CYP3A inducers (i.e., rifampin, St. John’s wort). Avoiding grapefruit juice and Seville oranges is also recommended during ivacaftor therapy.27 If coadministered with strong CYP3A inhibitors (i.e., ketoconazole), the ivacaftor dose should be reduced to 150 mg twice a week. For moderate CYP3A inhibitors (i.e., fluconazole), ivacaftor should be reduced to 150 mg daily. Ivacaftor may increase the exposure to drugs that are CYP3A or P-gp substrates, including midazolam, digoxin, tacrolimus, and cyclosporine.
Note that ivacaftor was studied in combination with other CF therapies. It is important for patients to continue current treatment regimens until their reaction to ivacaftor can be assessed due to variability among patients. Because ivacaftor is an oral medication, adherence should be emphasized: Regular administration is required to see the benefits of the medication. In the phase 2 study, the benefit of ivacaftor therapy diminished shortly after therapy was withdrawn.15 A recent paper suggests that missing even a single dose of ivacaftor can decrease the medication’s effect on sweat chloride.41
Ivacaftor represents an important breakthrough in CF management, and has provided benefit for patients with CF who have a G551D mutation. A postapproval longitudinal cohort study showed improvement in lung function, weight, sweat chloride, and exacerbation rate in a broad patient population.44 Despite successful outcomes, several questions remain unanswered about ivacaftor. Foremost among these is whether the drug is safe for eventual use in infants and in children younger than 6 years of age. Because CF lung disease begins in infancy,45 it is important to start these therapies earlier than 6 years of age. Studies of ivacaftor in patients ages 2 to 5 with a G551D or a CFTR gating mutation are ongoing. These studies are evaluating dosing of 50 mg twice a day in patients who weigh less than 14 kg and 75 mg twice a day in patients who weigh 14 kg or more.46
Ivacaftor has successfully improved lung function and weight in patients with G551D and may soon benefit patients with other gating mutations and those younger than 6 years of age. The recent expansion of ivacaftor approval in February 2014 for other gating mutations will allow use of the drug in a larger patient population. Clinicians should continue to monitor ongoing research and literature to determine appropriate candidates for ivacaftor treatment.
The F508del mutation, a class II mutation, results in misfolded CFTR proteins in the endoplasmic reticulum of epithelial cells, which prevents the proteins from reaching the cell surface. Initial in vitro data showed that lumacaftor could facilitate the “trafficking” of CFTR proteins,47 thus allowing those proteins to reach the membrane and transport chloride.
In a subsequent phase 2a study, the safety and tolerability of lumacaftor were evaluated in 89 adult CF patients with homozygous F508del mutation (
The study’s pharmacokinetic findings supported a once-daily oral dosing regimen.48 However, more recent data have shown that lumacaftor 400 mg twice a day had a larger area under the curve than 600 mg daily.49 Due to the less-than-significant effects seen with lumacaftor or ivacaftor (
LUMACAFTOR PLUS IVACAFTOR
The rationale behind the combination of lumacaftor and ivacaftor is that lumacaftor will help with the trafficking of the CFTR protein to the epithelial surface, where ivacaftor will help the CFTR protein open and transport chloride. A phase 2 trial was initiated to evaluate the safety and efficacy of combining lumacaftor and ivacaftor in CF patients with the F508del mutation.50
In the first part of the phase 2 study, 62 adult patients homozygous for F508del were treated with lumacaftor (200 mg) or placebo once daily for 14 days, followed by once-daily lumacaftor (200 mg) in combination with twice-daily ivacaftor (150 mg or 250 mg every 12 hours) or placebo for seven days (
No clinically important differences in the frequency or types of adverse events were observed among the treatment groups, and no serious adverse events occurred during the study. Overall, 83% of patients receiving active treatment and 86% receiving placebo experienced an adverse event; approximately half of these events were respiratory in nature.50 The adverse-event profile observed during the seven days of treatment with lumacaftor and ivacaftor was similar to the profile observed during the prior 14 days of lumacaftor monotherapy. One patient receiving lumacaftor monotherapy discontinued therapy because of an increase in respiratory symptoms during the first seven days of the study.50 This study led to the conclusion to continue with the dose of ivacaftor 250 mg every 12 hours; however, it was felt that the lumacaftor dose might not be optimized at 200 mg daily.
A second phase 2 trial was conducted on adult CF patients with homozygous and heterozygous F508del (
Homozygous F508del patients receiving ivacaftor and the highest dose of lumacaftor (600 mg) experienced a mean absolute improvement in lung function of 6.7% compared with placebo (P = 0.002) and a 3.4% improvement within the group (P = 0.03).51 Patients treated with placebo experienced a mean absolute decline in lung function of 3.3% (P = 0.03) over the same period.
No decreases in sweat chloride were observed among patients receiving placebo on day 56. In homozygous patients treated with 600 mg of lumacaftor alone for four weeks, there was a statistically significant mean decrease in sweat chloride of 6.41 mmol/L compared with placebo (P = 0.01). An additional mean decrease in sweat chloride of 2.82 mmol/L was observed with combination treatment between days 28 and 56, but this difference was not statistically significant.51
The results in the heterozygous F508del group were not as significant as the homozygous groups. Heterozygous patients receiving lumacaftor (600 mg) and ivacaftor experienced a decline in absolute FEV1 from baseline of 1.3%. Patients in the placebo group had an even further decline in absolute FEV1 of 3.7%.51 Given these results, the F508del heterozygous patients will need a different combination of CFTR modulator therapy.
Two 24-week phase 3 studies are investigating fixed-dose combinations of lumacaftor and ivacaftor in CF patients who are homozygous for the F508del mutation.52,53,54 Both studies are being conducted in subjects ages 12 and older. These trials, TRAFFIC and TRANSPORT, are comparing lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) versus placebo over six months. An additional study is investigating the pharmacokinetics and safety of lumacaftor plus ivacaftor in children ages 6 to 11 with CF who are homozygous for the F508del mutation. The studies have been completed and patients are now in an open-label extension. Data from these studies are expected to support regulatory submissions in 2014.
VX-661 is another oral CFTR corrector similar to lumacaftor developed by Vertex Pharmaceuticals to treat CF. In vitro, a combination of VX-661 and ivacaftor resulted in greater CFTR activity compared with VX-661 alone.55
In February 2012, a phase 2, double-blind, placebo-controlled study of VX-661 was initiated in CF patients who were homozygous or heterozygous for the F508del mutation. The purpose of this trial is to evaluate the safety, efficacy, and pharmacokinetic and pharmacodynamic effects of VX-661 alone and when coadministered with ivacaftor.56 Interim results were reported on the 128 adults with CF who were randomly assigned to four weeks of treatment with varying daily doses of VX-661 (10, 30, 100, or 150 mg) either as monotherapy, in combination with ivacaftor (150 mg taken every 12 hours), or placebo.57 Interim results found decreases in sweat chloride with VX-661 alone and in combination with ivacaftor. A relative change in FEV1 compared with placebo was significant at 28 days with VX-661 100 mg (9%) and 150 mg (7.5%) in combination with ivacaftor (P = 0.01 and P = 0.02 respectively).57
Adverse effects were similar in the treatment groups and placebo group, with the most common being pulmonary exacerbations, headache, and increased sputum. Overall, VX-661 was well tolerated; however, there were five reported adverse effects that caused drug discontinuation in the treatment group compared with none in the placebo group.57 It is important to note that FEV1 returned to baseline during the washout period following treatment. Preliminary results indicate that VX-661 is a promising corrector that could benefit patients with CF after further study.
Ataluren has been developed by PTC Therapeutics as a first-in-class PTC suppressor that addresses class I CFTR gene mutations.58 Ataluren is structurally similar to the aminoglycoside antibiotic gentamicin in terms of its functional properties. The two compounds, however, are chemically distinct, and ataluren does not have the antibiotic characteristics or toxicity of an aminoglycoside.59,60
Ataluren targets nonsense mutations, which insert a termination codon in the middle of the CFTR gene. This premature “stop” signal (a class I mutation) prevents the cell from producing a full-length CFTR protein.61,62 Ataluren has the ability to override this signal, thereby allowing the synthesis of a functioning protein.63 Nonsense mutations in the CFTR gene are responsible for CF in approximately 10% of patients,12,47 or about 3,000 individuals in the U.S.13
Phase 2 Studies
In the first trial, the safety and activity of ataluren were evaluated in adults with CF with a class I CFTR mutation (
Ataluren was then studied in 30 children and adolescents (6 to 18 years old) with nonsense-mutation CF (
In another phase 2 study, three months of treatment with ataluren significantly improved chloride channel activity and CF-related cough and showed positive trends in lung function in 19 adults (19 to 57 years old) with nonsense-mutation CF (
The two ataluren dosing regimens were similarly active and improved chloride transport in 67% of the patients. The aggregate mean change in total chloride transport for all patients was −5.4 mV (P < 0.01). At three months (day 84), FEV1 and forced vital capacity (FVC) showed aggregate mean changes from baseline of 4.5% and 3.5%, respectively, for all patients. With the cessation of ataluren therapy, FEV1 and FVC values reverted toward baseline. The study was not powered to detect statistical significance in these outcome measures.65 As a secondary endpoint, CF-related cough was measured over a 24-hour period after each clinic visit. Ataluren was associated with a 23% aggregate mean reduction in the frequency of waking cough for all patients (P = 0.006).65 From the results of these phase 2 trials, a phase 3 study was designed with the higher dosing regimen of ataluren.
Phase 3 Study
A pivotal, long-term phase 3 trial was conducted to determine whether ataluren can improve physiological lung function, not just the nasal electrical gradient, in patients with nonsense-mutation CF. This study also evaluated the drug’s long-term safety as well as its effects on CF pulmonary exacerbations, health-related quality of life, antibiotic use for CF-related infections, and CF-related disruptions to daily living. A total of 238 patients 6 years of age and older were enrolled (
At the end of the study period, patients in the ataluren group had a decrease in FEV1 percent predicted of 2.5% compared with a decrease in the placebo group of 5.5%. The pulmonary exacerbation rate was lower in the ataluren group, but the difference was not statistically significant (P = 0.099).66
Patients were stratified in subgroups based on chronic inhaled tobramycin use. Inhaled tobramycin is a cornerstone of CF treatment, but it is structurally similar to ataluren. When patients on inhaled tobramycin were removed from the analysis, results improved, suggesting that inhaled tobramycin may interact with ataluren given their similar structure and competition for binding sites.66 Based on this interaction, PTC Therapeutics is moving to study ataluren in patients not on chronic inhaled tobramycin therapy.
Ataluren is not FDA approved but is currently produced for study in foil sachets that contain vanilla-flavored granules. These granules can be mixed with water, apple juice, or milk to form a suspension.64 This dosage form may not be palatable to all patients, but it makes administration easier in patients who cannot swallow pills. Ataluren is dosed three times a day, which may influence adherence to the medication regimen.
Inhaled tobramycin may impact the efficacy of ataluren, and use of inhaled tobramycin is not being allowed during the current phase 3 study.66 It may be difficult for some patients on chronic inhaled tobramycin to stop that therapy for treatment with ataluren. Ataluren will also have to be used with other chronic CF treatments. If approved, ataluren would be the first drug in its class; as with any new medication, it is important to watch for adverse effects. Ataluren reads through nonsense mutations; although it appears to be specific for premature stop codons, serious adverse effects could occur if ataluren reads through native stop codons. Patients on ataluren should be closely monitored for adverse effects if ataluren comes to market.
OTHER POTENTIAL CFTR MODULATORS
In addition to the handful of agents that have reached clinical development, numerous compounds are being evaluated for their ability to interact with defects in the synthesis and function of CFTR proteins, with varying results. More than 30 compounds have undergone preclinical investigation to determine their suitability for CFTR modulation.68 Three examples follow.
In vitro, sodium 4-phenylbutarate (4PBA), a short-chain fatty acid, restored chloride transport in CF epithelial cells containing the F508del mutation, although the compound’s mechanism of action was unclear.69 In a subsequent clinical study of 18 CF patients with the F508del mutation, oral 4PBA only partially restored CFTR activity in the nasal epithelium and had no effect on sweat chloride concentrations.70
Another study showed, however, that treatment with 20 mg of oral 4PBA could induce significant chloride transport in nasal epithelia compared with placebo in 19 adult CF patients with the F508del mutation.71 Additional evidence suggests that the combination of oral 4PBA with topical or aerosol flavonoids may restore CFTR function in CF airways.72,73
The pyrazole VRT-532 was found to be a CFTR potentiator in proteins bearing the F508del mutation in human CF airway cultures.74 Subsequent preclinical studies demonstrated that VRT-532 also functions as a CFTR corrector, rescuing the surface expression of proteins affected by F508del and G551D mutations.75–78 VRT-532 has shown an approximately fivefold greater affinity for F508del than for G551D.74
N6022 is a new injectable compound that has been shown to increase the amount of CFTR at the epithelial membrane and decrease the inflammation in the lungs.79 N6022 works by increasing the level of S-nitrosoglutathione (GSNO) by inhibiting GSNOR, an enzyme that breaks down GSNO.80 GSNO is a signaling molecule that decreases in people with CF. A phase 1b/2a clinical trial is studying the safety and pharmacokinetics of N6022 in adult CF patients with two copies of the F508del CFTR mutation.81
CFTR modulators for the treatment of cystic fibrosis are a growing area that is quickly changing. Ivacaftor, the first CFTR potentiator to receive FDA approval, has overall been well tolerated and produced dramatic results in CF patients with a G551D mutation. The benefit of ivacaftor has been expanded to eight other gating mutations. For patients with two copies of F508del, the most common CF mutation, a combination of lumacaftor and ivacaftor has shown promising results, and phase 3 studies are under way.
Ataluren was a promising treatment for patients with CF and class I mutations; despite initial phase 3 results, it is possible that concomitant inhaled tobramycin may have reduced the true impact of the medication. The developer is planning further clinical trials excluding patients who use inhaled tobramycin.
VX-661 and other potential CFTR modulator compounds are under investigation. These medications may also prove useful in other CFTR-related diseases, such as pancreatitis in patients with mild CFTR variants. In the future it is hoped that all patients with CF will have a CFTR modulator medication or combination that corrects the underlying defect of their particular disease.
Classification of Gene Mutations That Cause Cystic Fibrosis
|I||G542X||Presence of premature termination codons (PTCs) causes CFTR protein synthesis to be defective or absent.|
|II||F508del||Impaired processing: misfolded CFTR proteins; defective protein maturation; premature protein degradation; CFTR proteins do not reach apical cell surface.|
|III||G551D||Disordered regulation: Full-length CFTR proteins reach apical cell surface but are not activated by ATP or cAMP; proteins exhibit abnormal chloride-channel “gating” (i.e., open time is reduced)|
|IV||R334W||Impaired function: Full-length CFTR proteins reach apical cell surface, but transport of chloride ions is reduced.|
|V||R117H||Synthesis and surface expression of normal CFTR proteins are reduced because of promoter or splicing abnormalities.|
|VI||1811+1.6kbA>G||CFTR proteins reach apical cell surface, but C-terminus mutations result in accelerated turnover.|
ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate; CFTR= cystic fibrosis transmembrane conductance regulator
Ivacaftor Clinical Trials
||G551D||Age 12–53 years
N = 161
|IVA 150 mg b.i.d. or PBO b.i.d.
||G551D||Age 6–11 years
N = 52
|IVA 150 mg b.i.d. or PBO b.i.d.
||G551D||Age ≥ 6 years
Patients had completed 48 wks of either ENVISION or STRIVE
|IVA 150 mg b.i.d.
Absolute change in percent predicted FEV1:
Absolute change in weight (kg):
Absolute change in CFQ-R respiratory domain:
||G551D||Age > 6 years
N = 17
FEV1 > 90%
LCI > 7.4
|Sequence 1: PBO ➙ WO ➙ IVA 150 mg b.i.d. Sequence 2: IVA 150 mg b.i.d. ➙ WO ➙ PBO
||G551D||Age 20–31 in IVA group
N = 21
FEV1 < 40%
|IVA 150 mg b.i.d. (n = 21); matched controls (n = 35)
|De Boeck (2013)
||Non-G551D gating mutations G178R, G551S, S549N, S549R, G970R, G1244E, S1251N, S1255P, G1349D||Age ≥ 6 years
N = 39
FEV1 ≥ 40%
|Treatment sequence 1: IVA 150 mg b.i.d. ➙ WO ➙ PBO ➙ open-label Treatment sequence 2: PBO ➙ WO ➙ IVA 150 mg b.i.d. ➙ open- label
||Homozygous F508del||Age ≥ 12 years
Part 1: N = 140
Part 2: N = 33
42 patients were eligible for part 2 if change in FEV1 ≥ 10% or sweat chloride decreased by at least 15 mmol/L at day 15 and week 8
|Part 1: IVA 150 mg b.i.d. or PBO
b.i.d. = twice daily;
Lumacaftor Clinical Trials
||Homozygous F508del||Age 18–54 years
N = 89
FEV1 ≥ 40%
|LUM 25 mg q.d.
LUM 50 mg q.d.
LUM 100 mg q.d.
LUM 200 mg q.d.
Mean change in sweat chloride from baseline to day 28 compared with PBO:
Number of pulmonary exacerbations (
Mean change in FEV1 from baseline to 28 days (
CFQ-R change from baseline to 28 days:
||Homozygous F508del||Age > 18 years
N = 62
FEV1 ≥ 40%
|Part 1: LUM 200 mg q.d. or PBO
Change in FEV1 percentage from day 1 to day 14:
Change in FEV1 percentage from day 14 to day 21:
Mean change in sweat chloride from day 1 to day 14:
Mean change in sweat chloride from day 14 to day 28:
||Homozygous F508del||Age > 18 years
N = 82
|Period 1: LUM 200 mg, 400 mg, 600 mg q.d. or PBO
Change in absolute FEV1 percent predicted from baseline at 28 days of combination treatment (end of period 2):
Sweat chloride change compared to PBO in LUM 600-mg group:
|Heterozygous F508del||Age > 18 years
N = 27
|Period 1: LUM 600 mg q.d. or PBO
Change in absolute FEV1 percent predicted from baseline at 28 days of combination treatment (end of period 2):
b.i.d. = twice daily;
Ataluren (PTC124) Clinical Trials
||Nonsense mutation (class I mutations)||Age 18–56 years
Cycle 1: N = 23
Cycle 2: N = 21
FEV1 ≥ 40%
|Cycle 1: ATA 4 mg/kg at breakfast, 4 mg/kg at lunch, 8 mg/kg with dinner Cycle 2: ATA 10 mg/kg at breakfast, 10 mg/kg at lunch, 20 mg/kg with dinner
Patients with NPD within normal range:
Mean change in NPD chloride transport from baseline to day 14:
Weight change from baseline:
||Class I mutations||Age 6–18 years
N = 30
FEV1 ≥ 40%
|ATA 4 mg/kg at breakfast, 4 mg/kg at lunch, 8 mg/kg with dinner ATA 10 mg/kg at breakfast, 10 mg/kg at lunch, 20 mg/kg with dinner
Mean change in chloride transport from baseline to end of cycle 2:
Number of patients with NPD changes of at least −5 mV at the end of cycle 2:
||Class I mutations||Age 19–57 years
N = 19
FEV1 ≥ 40%
|ATA 4 mg/kg at breakfast, 4 mg/kg at lunch, 8 mg/kg with dinner
ATA 10 mg/kg at breakfast, 10 mg/kg at lunch, 20 mg/kg with dinner
Mean change in chloride transport from baseline to 12 wks:
Number of patients with NPD change of at least −5 mV at 12 wks:
||Class I mutations||Age ≥ 6 years
N = 238
|ATA 10 mg/kg at breakfast, 10 mg/kg at lunch, 20 mg/kg with dinner PBO
ATA = ataluren;
- O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet 2009;373:1991–2004.
- Andersen DH. Cystic fibrosis of the pancreas and its relation to celiac disease: a clinical and pathological study. Am J Dis Child 1938;56:344–399.
- Lowe CU, May CD, Reed SC. Fibrosis of the pancreas in infants and children: a statistical study of clinical and hereditary features. Am J Dis Child 1949;78:349–374.
- Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989;245:1066–1073.
- Kerem B, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989;245:1073–1080.
- Rommens JM, Zengerling-Lentes S, Kerem B, et al. Physical localization of two DNA markers closely linked to the cystic fibrosis locus by pulsed-field gel electrophoresis. Am J Hum Genet 1989;45:932–941.
- Kerem E, Corey M, Kerem B, et al. The relationship between genotype and phenotype in cystic fibrosis: analysis of the most common mutation (ΔF508). N Engl J Med 1991;323:1517–1522.
- Mohon RT, Wagener JS, Abman SH, et al. Relationship of genotype to early pulmonary function in infants with cystic fibrosis identified through neonatal screening. J Pediatr 1993;122:550–555.
- Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell 1993;73:1251–1254.
- Rich DP, Anderson MP, Gregory RJ, et al. Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells. Nature 1990;347:358–363.
- Bear CE, Li CH, Kartner N, et al. Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR). Cell 1992;68:809–818.
- Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med 2005;352:1992–2001.
- Patient Registry: Annual Data Report 2012 Bethesda, Md.: Cystic Fibrosis Foundation. 2013;Available at: http://www.cff.org/UploadedFiles/research/ClinicalResearch/PatientRegistryReport/2012-CFF-Patient-Registry.pdf. Accessed June 2, 2014
- Grasemann H, Ratjen F. Emerging therapies for cystic fibrosis lung disease. Exp Opin Emerg Drugs 2010;15:653–659.
- Accurso FJ, Rowe SM, Clancy JP, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med 2010;36:1991–2003.
- American Lung Association. Cystic fibrosis (CF). State of Lung Disease in Diverse Communities 2010 Washington, D.C.: American Lung Association. 2010;41–44.Available at: https://www.lung.org/assets/documents/publications/lung-diseasedata/solddc_2010.pdf. Accessed June 9, 2014
- Milavetz G. Cystic fibrosis. In: DiPiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: A Pathophysiologic Approach
7th ed.chapter 32New York, New York: McGraw Hill Medical. 2008;535–546.
- World Health Organization. Genes and human disease: monogenic diseases 2012;Available at: https://www.who.int/genomics/public/geneticdiseases/en/index2.html. Accessed March 8, 2012
- March of Dimes. Cystic fibrosis and pregnancy. Available at: https://www.marchofdimes.org/pregnancy/cystic-fibrosis-and-pregnancy.aspx. Accessed June 15, 2014
- Cystic Fibrosis Foundation. About cystic fibrosis Available at: http://www.cff.org/AboutCF/. Accessed June 2, 2014
- Kliegman RM, Stanton BMD, Geme JS, et al. Nelson’s Textbook of Pediatrics
19th edPhiladelphia, Pa: Elsevier Saunders. 2011;1481
- Centers for Disease Control and Prevention. ACCE review of CF/prenatal: clinical validity, version 2002.6 Available at: https://www.cdc.gov/genomics/gtesting/file/print/fbr/cfclival.pdf. Accessed June 15, 2014
- Anderson P. Emerging therapies in cystic fibrosis. Ther Adv Resp Dis 2010;4:177–185.
- Lee TWR, Matthews DA, Blair GE. Novel molecular approaches to cystic fibrosis therapy. Biochem J 2005;387:1–15.
- Kerem E, Hirawat S, Armoni S, et al. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet 2008;372:719–727.
- Food and Drug Administration. FDA approves Kalydeco to treat rare form of cystic fibrosis (January 31, 2012) Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm289633.htm. Accessed March 28, 2013
- Kalydeco (ivacaftor) tablets, prescribing information Cambridge, Massachusetts: Vertex Pharmaceuticals. August 2012;Available at: https://pi.vrtx.com/files/uspi_ivacaftor.pdf. Accessed March 28, 2013
- Van Goor F, Hadida S, Grootenhuis PDJ. Pharmacological rescue of mutant CFTR function for the treatment of cystic fibrosis. Top Med Chem 2008;3:91–120.
- Davies JC, Wainwright CE, Canny GJ, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with G551D mutation. Am J Respir Crit Care Med 2013;187:1219–1225.
- Ramsey BW, Davies J, McElvaney G, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365:1663–1672.
McKone E, Borowitz D, Drevinek P, et al. Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the G551D-CFTR mutation: response through 144 weeks of treatment (96 weeks of PERSIST). Poster presented as part of the North American Cystic Fibrosis Conference Salt Lake City, Utah October 1–19, 2013Abstract published in Pediatr Pulmonol2013;(suppl 36):287
- Davies J, Sheridan H, Bell N, et al. Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomized controlled trial. Lancet Respir Med 2013;1:630–638.
Elborn JS, Rodriguez S, Lubarsky B, et al. Effect of ivacaftor in patients with cystic fibrosis and the G551D-CFTR mutation who have baseline FEV1 > 90% of predicted. Poster presented as part of the North American Cystic Fibrosis Conference Salt Lake City, Utah October 1–19, 2013Abstract published in Pediatr Pulmonol2013(suppl 36):298
- Barry PJ, Plant BJ, Nair A, et al. Effects of ivacaftor in cystic fibrosis patients carrying the G551D mutation with severe lung disease. Chest 2014;[Epub ahead of print February 13]:1–48
- Flume PA, Liou TG, Borowitz DS, et al. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest 2012;142:718–724.
- Vertex Pharmaceuticals. Vertex announces results of phase 3 study of ivacaftor in people with CF who have the R117H mutation December
192013;Available at: https://investors.vrtx.com/news-releases/news-release-details/vertex-announces-results-phase-3-study-ivacaftor-people-cf-who?ReleaseID=814799. Accessed March 2, 2014 De Boeck K, Gilmartin G, Chen X, et al. Ivacaftor, a CFTR potentiator, in cystic fibrosis patients who have a non-G551D-CFTR gating mutation: phase 3, part 1 results. Poster presented as part of the North American Cystic Fibrosis Conference Salt Lake City, Utah October 17–19, 2013Abstract published in Pediatr Pulmonol2013(suppl 36):292
- Vertex Pharmaceuticals. U.S. Food and Drug Administration approves Kalydeco (ivacaftor) for use in eight additional mutations that cause cystic fibrosis February
212014;Available at: https://investors.vrtx.com/news-releases/news-release-details/us-food-and-drug-administration-approves-kalydecotm-ivacaftor?ReleaseID=827435. Accessed March 2, 2014
- Kalydeco [Product Monograph] Laval, Quebec: Vertex Pharmaceuticals (Canada) Inc.. 2012;
- National Institutes of Health. An ocular safety study of ivacaftor-treated pediatric patients 11 years of age or younger with cystic fibrosis May
222013;Available at: https://clinicaltrials.gov/ct2/show/NCT01863238. Accessed October 29, 2013
- Barry PJ, Jones AM, Webb AK, et al. Sweat chloride is not a useful marker of clinical response to ivacaftor. Thorax 2013;0:1–2.
- Red Book Online Ann Arbor, Michigan: Truven Health Analytics. Accessed May 28, 2014
- Gever J. FDA approves cystic fibrosis drug www.medpagetoday.com/Pulmonology/CysticFibrosis/30936. Accessed March 6, 2012
- Rowe SM, Heltshe SL, Gonska T, et al. Clinical mechanism of the CFTR potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med 2014;[Epub ahead of print June 13]:1–44
- Sly PD, Brennan S, Gangell C, et al. Lung disease at diagnosis in infants with cystic fibrosis detected by newborn screening. Am J Respir Crit Care Med 2009;180:146–152.
- National Institutes of Health. Study of ivacaftor in cystic fibrosis subjects 2 through 5 years of age with a CFTR gating mutation October
82012;Available at: https://clinicaltrials.gov/ct2/show/NCT01705145. Accessed October 29, 2013
- Van Goor F, Hadida S, Grootenhuis PD, et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci USA 2011;108:18843–18848.
- Clancy JP, Rowe SM, Accurso FJ, et al. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax 2012;67:12–18.
Boyle M, Bell S, Konstan M, et al. Lumacaftor, an investigational CFTR corrector, in combination with ivacaftor, a CFTR potentiator, in CF patients with the F508del-CFTR mutation. Presentation at European Cystic Fibrosis Conference Lisbon, Portugal June 12–15, 2013
- Boyle MP, Bell S, Konstan MW, et al. VX-809, an investigational CFTR corrector, in combination with VX-770, an investigational CFTR potentiator, in subjects with CF and homozygous for the F508DEL-CFTR mutation. Abstract published in
Pediatr Pulmonol2011;46;(suppl 34):287 Boyle MP, Bell S, Konstan MW, et al. The investigational CFTR corrector, VX-809 (lumacaftor) co-administered with the oral potentiator ivacaftor improved CFTR and lung function in F508Del homozygous patients: phase II study results. Poster presented as part of the North American Cystic Fibrosis Conference Orlando, Florida October 11–13, 2012Abstract published in Pediatr Pulmonol2012;(suppl 35):315
- Vertex Pharmaceuticals. Vertex announces initiation of pivotal phase 3 program of VX-809 in combination with ivacaftor for the treatment of people with cystic fibrosis who have two copies of the F508del mutation February
262013;Available at: https://investors.vrtx.com/news-releases/news-release-details/vertex-announces-initiation-pivotal-phase-3-program-vx-809?ReleaseID=743425. Accessed April 8, 2013
- National Institutes of Health. A study of lumacaftor in combination with ivacaftor in cystic fibrosis subjects aged 12 years and older who are homozygous for the F508del-CFTR mutation (TRAFFIC). Available at: https://clinicaltrials.gov/show/NCT01807923. Accessed June 9, 2014
- National Institutes of Health. A study of lumacaftor in combination with ivacaftor in cystic fibrosis subjects aged 12 years and older who are homozygous for the F508del-CFTR mutation (TRANSPORT). Available at: https://clinicaltrials.gov/show/NCT01807923. Accessed June 9, 2014
- Vertex Pharmaceuticals. Vertex and Cystic Fibrosis Foundation Therapeutics to collaborate on discovery and development of new medicines to treat the underlying cause of cystic fibrosis April
72011;Available at: https://investors.vrtx.com/news-releases/news-release-details/vertex-and-cystic-fibrosis-foundation-therapeutics-collaborate?releaseid=563453. Accessed March 29, 2013
- National Institutes of Health. Study of VX-661 alone and in combination with VX-770 in subjects homozygous to the F508del-CFTR mutation March
92012;Available at: https://clinicaltrials.gov/ct2/show/NCT01531673. Accessed March 29, 2013 Donaldson S, Pilewski J, Griese M, et al. VX-661, an investigational CFTR corrector, in combination with ivacaftor, a CFTR potentiator, in patients with CF homozygous for the F508del-CFTR mutation, interim analysis. Presentation at European Cystic Fibrosis Conference Lisbon, Portugal June 12–15, 2013
- Du M, Liu X, Welch EM, et al. PTC124 is an orally bioavailable compound that promotes suppression of the human CFTRG542X nonsense allele in a CF mouse model. Proc Natl Acad Sci USA 2008;105:2064–2069.
- Hamed SA. Drug evaluation: PTC-124: a potential treatment of cystic fibrosis and Duchenne muscular dystrophy. IDrugs 2006;9:783–789.
- Ratjen FA. Cystic fibrosis: Pathogenesis and future treatment strategies. Respir Care 2009;54:595–602.
- Welch E, Barton E, Zhuo J, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 2007;447:87–91.
- Hirawat S, Welch EM, Elfring GL, et al. Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. J Clin Pharmacol 2007;47:430–444.
- PTC Therapeutics. Ataluren for genetic disorders 2012;Available at: https://www.ptcbio.com/our-pipeline/areas-of-interest/ataluren/. Accessed March 29, 2013
- Sermet-Gaudelus I, De Boeck K, Casimir GJ, et al. Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis. Am J Respir Crit Care Med 2010;182:1262–1272.
- Wilschanski M, Miller LL, Shoseyov D, et al. Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis. Eur Respir J 2011;38:59–69.Erratum:
Eur Respir J2011;38:996
- Kerem E, Konstan MW, De Boeck K, et al. Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomized, double-blind, placebo-controlled phase 3 trial. Lancet Respir Med 2014;[Epub ahead of print, May 15]
- National Institutes of Health. Extension study of ataluren (PTC124) in cystic fibrosis August
162011;Available at: http://clinical-trials.gov/ct2/show/NCT01140451. Accessed March 30, 2013
- Exclusive Chemistry Ltd. CFTR modulators for treatment of cystic fibrosis–35 compounds Available at: https://exchemistry.com/chem-catalog/cftr-compounds/. Accessed April 5, 2013
- Rubenstein RC, Egan ME, Zeitlin PL. In vitro pharmacologic restoration of CFTR-mediated chloride transport with sodium 4-phenylbutyrate in cystic fibrosis epithelial cells containing F508-CFTR. J Clin Invest 1997;100:2457–2465.
- Rubenstein RC, Zeitlin PL. A pilot clinical trial of oral sodium 4-phenylbutyrate (buphenyl) in F508-homozygous cystic fibrosis patients: Partial restoration of nasal epithelial CFTR function. Am J Respir Crit Care Med 1998;157:484–490.
- Zeitlin PL, Diener-West M, Rubenstein RC, et al. Evidence of CFTR function in cystic fibrosis after systemic administration of 4-phenylbutyrate. Mol Ther 2002;6:119–126.
- Lim M, McKenzie K, Floyd AD, et al. Modulation of F508 cystic fibrosis transmembrane regulator trafficking and function with 4-phenylbutyrate and flavonoids. Am J Respir Cell Mol Biol 2004;31:351–357.
- Rubenstein RC, Propert KJ, Reenstra WW, Skotleski ML. A pilot trial of the combination of phenylbutyrate and genistein. Abstract published in
Pediatr Pulmonol2006;41;(suppl 29):248
- Van Goor F, Straley KS, Cao D, et al. Rescue of deltaF508 CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules. Am J Physiol Lung Cell Mol Physiol 2006;290:L1117–L1130.
- Wang Y, Bartlett MC, Loo TW, Clarke DM. Specific rescue of cystic fibrosis transmembrane conductance regulator processing mutants using pharmacological chaperones. Mol Pharmacol 2006;70:297–302.
- Wang Y, Loo TW, Bartlett MC, Clarke DM. Correctors promote maturation of cystic fibrosis transmembrane conductance regulator (CFTR)-processing mutants by binding to the protein. J Biol Chem 2007;282:33247–33251.
- Wellhauser L, Chiaw PK, Pasyk S, et al. A small-molecule modulator interacts directly with phe508-CFTR to modify its ATPase activity and conformational stability. Mol Pharmacol 2009;75:1430–1438.
- Pasyk S, Li C, Ramjeesingh M, Bear CE. Direct interaction of a small-molecule modulator with G551D-CFTR, a cystic fibrosis-causing mutation associated with severe disease. Biochem J 2009;418:185–190.
- N6022. Available at: http://www.cff.org/treatments/Pipeline/. Accessed March 2, 2014
- NS30 Pharma. N30 Pharmaceuticals announces first patient treated in clinical trial of N6022 in cystic fibrosis Available at: http://www.nivalis.com/docs/news/2013-03-12-6022-CF-First-Patient.pdf. Accessed June 9, 2014
- National Institutes of Health. Safety and pharmacokinetic study of N6022 in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation (SNO-2) December
62012;Available at: https://clinicaltrials.gov/show/NCT01746784. Accessed March 2, 2014