ADIS DRUG EVALUATION

Ivacaftor: A Review of Its Use in Patients with Cystic Fibrosis

Emma D. Deeks

Published online: 13 September 2013

� Springer International Publishing Switzerland 2013

Abstract Ivacaftor (KalydecoTM) is a potentiator of the

cystic fibrosis transmembrane conductance regulator

(CFTR) and is the first drug that treats an underlying cause

of cystic fibrosis to be licensed for use. Ivacaftor increases

the open probability (i.e. gating) of CFTR channels with

the G551D mutation, thus enhancing chloride transport,

and is indicated in a number of countries for the treatment

of cystic fibrosis in patients aged C6 years who carry this

mutation. This review focuses on pharmacological, clinical

efficacy and tolerability data relevant to the use of ivacaftor

in this indication. In two 48-week, double-blind, phase III

trials in patients aged C12 (STRIVE) or 6–11 (ENVISION)

years with cystic fibrosis and the G551D mutation, oral

ivacaftor 150 mg every 12 h significantly improved lung

function relative to placebo, when used in combination

with standard care. Significant improvements in pulmonary

exacerbation risk (in STRIVE) as well as bodyweight and

some aspects of health-related quality of life (both studies)

were also seen with the drug versus placebo. Moreover, the

beneficial effects of ivacaftor on parameters such as lung

function and bodyweight were maintained over up to

96 weeks of treatment in an ongoing open-label extension

of these studies. Ivacaftor was generally well tolerated,

with headache, oropharyngeal pain, upper respiratory tract

infection and nasal congestion being among the most

common adverse events. Thus, ivacaftor expands the

current treatment options for patients with cystic fibrosis

who have the G551D mutation. Its potential for use in

patients with other CFTR mutations is also of interest.

Ivacaftor in cystic fibrosis: a summary

First drug that treats an underlying cause of cystic

fibrosis to be licensed for use

Increases the open probability (i.e. gating) of cystic

fibrosis transmembrane conductance regulator

channels with the G551D mutation, thus augmenting

chloride transport

Convenient oral administration

Improves lung function and bodyweight parameters

when used in combination with standard care in adults,

adolescents and children (aged C6 years) with cystic

fibrosis and the G551D mutation

Generally well tolerated

1 Introduction

Cystic fibrosis is a complex, life-limiting, genetic disorder

that can affect multiple organs throughout the body, lead-

ing to pulmonary disease (most cystic fibrosis-related

deaths are due to pulmonary insufficiency), reproductive,

hepatic, pancreatic and gastrointestinal dysfunction and

malnutrition [1, 2]. Cystic fibrosis results from mutations in

the gene encoding the cystic fibrosis transmembrane con-

ductance regulator (CFTR), a glycoprotein present in the

apical membrane of epithelial cells, where it functions as a

chloride channel predominantly, but also regulates trans-

port of sodium (via epithelial sodium channels) as well as

various other processes [2, 3]. It is largely accepted that

The manuscript was reviewed by: F. Becq, Institut de Physiologie

et Biologie Cellulaires, Universite de Poitiers, Poitiers, France; R.S.Pettit, Riley Hospital for Children, Indiana University Health,

Indianapolis, IN, USA.

E. D. Deeks (&)

Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay,

North Shore 0754, Auckland, New Zealand

e-mail: demail@springer.com

Drugs (2013) 73:1595–1604

DOI 10.1007/s40265-013-0115-2

defective ion transport caused by CFTR dysfunction leads

to depletion of airway surface liquid in the lungs of patients

with cystic fibrosis, which impairs ciliary function, result-

ing in mucus obstruction of the airways and consequently

infection and inflammation [4].

Cystic fibrosis is incurable at present [5]. Therapy can

involve a variety of different medications, including anti-

biotics (e.g. tobramycin) to treat lung infections, the DNase

dornase alfa to clear lung mucus, hypertonic saline to

improve mucociliary clearance, as well as anti-inflamma-

tory agents, bronchodilators and pancreatic enzymes [6, 7].

These therapies treat the downstream consequences of

CFTR dysfunction, rather than the underlying abnormality,

and although their aggressive use has helped to increase the

life expectancy of patients with cystic fibrosis [2], most

deaths still occur in early adulthood [8].

Understanding of the molecular biology of the CFTR

protein has increased over the last two decades and[1,500

CFTR mutations have now been identified [3]. Mutations

can be classified on the basis of their functional conse-

quences, which include CFTR protein that is truncated and

fails to reach the cell surface (class I) [e.g. R1162X]; is

misfolded, improperly processed and defective, little of

which reaches the cell surface (class II) [e.g. F508del]; is

unable to open and transport chloride properly (class III)

[e.g. G551D] or has reduced chloride conductance due to

channel narrowing (class IV) [e.g. R117H] but reaches the

cell surface; or transports chloride effectively but reaches

the cell surface in reduced amounts due to defective tran-

script splicing (class V) [e.g. 3120?1G?A] [1, 3]. As a

result of this knowledge, therapies specifically targeting

known CFTR defects have been a focus of drug develop-

ment for cystic fibrosis in recent years.

Ivacaftor (KalydecoTM) is the first drug to treat an

underlying cause of cystic fibrosis to be licensed for use in

the EU [9] and USA [10]. The drug potentiates the open

probability (i.e. gating) of the CFTR channel, thus

enhancing its transport of chloride, and is indicated for the

treatment of patients with cystic fibrosis aged C6 years

who carry the CFTR gating mutation G551D [9, 10]. This

narrative review focuses on pharmacological, clinical

efficacy and tolerability data relevant to the use of ivacaftor

in this indication.

2 Pharmacodynamic Properties

This section provides an overview of the pharmacody-

namic properties of ivacaftor. Data are from in vitro [11–

16] and ex vivo [17] studies, as well as from double-blind

[18–21] or single-blind [22], placebo-controlled trials in

patients with cystic fibrosis and the G551D mutation

(n = 8–167). Some data are available from the US

manufacturer’s prescribing information [10], the European

public assessment report (EPAR) [5] or abstracts [14, 17,

18, 22, 23]; further data from some clinical trials [19–21]

are discussed in Sect. 4.

2.1 In Vitro Studies

Ivacaftor (Fig. 1) is a CFTR potentiator that acts by

increasing the open probability of the CFTR channel, thus

enhancing its transport of chloride [10]. Ivacaftor binds

selectively to, and acts directly on, CFTR [5, 11, 12],

displaying little or no measurable activity at other sodium,

calcium or potassium channels tested, with the exception of

CaV1.2 and KV1.5, which it inhibited with moderate

potency (half maximal inhibitory concentrations of 1.3 and

3.4 lmol/L, respectively) [5]. Although CaV1.2 and KV1.5

are key cardiac ion channels, no clinically significant QT

interval prolongation was seen with ivacaftor in healthy

volunteers (Sect. 2.2).

In vitro, ivacaftor increased transepithelial current (a

measure of chloride secretion) by approximately fourfold

in rodent cells expressing human G551D CFTR (half

maximal effective concentration [EC50] 100 nmol/L) and

by approximately tenfold in human bronchial epithelial

(HBE) cells isolated from a cystic fibrosis patient with both

the G551D and F508del mutations (EC50 236 nmol/L) [10,

12]. This property of ivacaftor was shown in the rodent

cells to be dependent on prior treatment with a cyclic

adenosine monophosphate (cAMP) agonist [12], which is

consistent with the knowledge that phosphorylation of

CFTR by cAMP-dependent protein kinase (PKA), together

with adenosine triphosphate (ATP) binding, is needed for

the channel to be activated.

In membrane patches excised from recombinant rodent

cells exposed to both PKA and ATP, the open probability

of human G551D CFTR and wildtype CFTR increased

approximately sixfold and twofold at ivacaftor concentra-

tions of 10 and 1 lmol/L, respectively [12]. However,

recent in vitro data suggest ivacaftor may potentiate the

opening of phosphorylated CFTR in an ATP-independent

Fig. 1 Chemical structure of ivacaftor

1596 E. D. Deeks

manner [11, 15]. Such ATP-independent potentiation may

help to explain the drug’s benefit in cystic fibrosis patients

with the G551D-CFTR mutation (see Sect. 4), which is

known to cause disruption of the CFTR binding site usually

responsible for ATP-dependent gating [11, 15].

Of the two main circulating ivacaftor metabolites, only

one (M1; see Sect. 3) is considered to be pharmacologi-

cally active, potentiating CFTR-mediated chloride trans-

port with a potency approximately sixfold lower than that

of the parent drug in HBE cells expressing G551D/F508del

CFTR [5].

Ivacaftor may potentiate CFTR channels with gating

mutations other than G551D, according to additional

in vitro data [13]. For example, in rodent cells expressing

G551D/S, G178R, S549N/R, G970R, G1244E, S1251N,

S1255P or G1349D CFTR, ivacaftor increased channel

open probability from B5 % of normal at baseline to

30–118 % of normal and increased chloride transport C16-

fold (EC50 124–594 nmol/L). Further in vitro data suggest

that other CFTR proteins with residual function may also

be potentiated by ivacaftor, including those with mutations

that affect conductance (e.g. R117H, D110H), mildly affect

CFTR processing (e.g. E56K, P67L) or have uncharacter-

ized effects (e.g. D110E, S1235R) [5, 16].

The in vitro effect of ivacaftor on CFTR mutant proteins

with minimal chloride transport, such as those with muta-

tions affecting CFTR synthesis (e.g. G542X) [5] or

severely affecting CFTR conductance (e.g. R334W) or

processing (e.g. F508del [13]) [5, 16], was minimal [5, 13]

or less than its effect on CFTR proteins with mild con-

ductance or processing defects [16]. In another in vitro

study, transepithelial current was increased with ivacaftor

in HBE cultures from three of six patients homozygous for

the F508del mutation, although this effect was of lesser

magnitude than in HBE cells carrying both the F508del and

G551D mutation [12]. Notably, the affinity of the drug for

F508del CFTR may be higher than for G551D CFTR, as

the EC50 of ivacaftor was approximately tenfold lower in

homozygous than in heterozygous cells (22 vs. 236 nmol/

L) [12].

By potentiating CFTR-mediated chloride secretion,

ivacaftor may rescue the function of airway epithelial cells.

For example, the excessive absorption of sodium in HBE

cells expressing G551D/F508del CFTR was reduced with

ivacaftor, with a resultant increase in both apical surface

fluid and the beat frequency of cilia [12]. Augmentation of

cilia beat frequency also occurred with ivacaftor in primary

cultures of human sinonasal epithelia [14].

2.2 Studies in Humans

Improvements in CFTR function, as measured by the

concentration of chloride in sweat, were seen with oral

ivacaftor 150 mg every 12 h in patients with cystic fibrosis

and the G551D mutation. Ivacaftor significantly reduced

sweat chloride concentration relative to placebo through

week 24 of treatment in adults and adolescents aged

C12 years (mean adjusted change from baseline of -48.7

vs. -0.8 mmol/L; p \ 0.0001) [20] and children aged

6–11 years (-55.5 vs. -1.2 mmol/L; p \ 0.0001) [21] in

phase III trials, with this benefit being sustained through

48 weeks’ therapy in these populations [20, 21]; overall

mean values at baseline were 100 and &104 mmol/L in the

respective trials. Sweat chloride concentration was also

significantly (p B 0.02) reduced with this dosage of iva-

caftor versus placebo in phase II studies of up to 28 days’

duration in patients aged C18 [19] or C6 [18] years,

although the change from baseline in nasal potential dif-

ference (another measure of CFTR function) did not sig-

nificantly differ between the treatment groups [19].

Notably, reductions in sweat chloride did not correlate

directly with improvements in lung function (as measured

by forced expiratory volume in 1 s [FEV1]) in phase III

trials [10].

Treatment with ivacaftor 150 mg every 12 h for 28 days

generally led to significant (p \ 0.01) reductions in total

ventilation defects (assessed by hyperpolarized gas mag-

netic resonance imaging) [22] and ventilation inhomoge-

neity (measured by lung clearance index) [18] in patients

with cystic fibrosis and the G551D mutation in placebo-

controlled, phase II trials. Improvements in percent pre-

dicted FEV1 were also seen with ivacaftor in these studies

[18, 22]; at baseline, FEV1 was [90 % of predicted (i.e.

lung disease was mild) [18] or [40 % of predicted [22].

Neutrophil activity is dysregulated in cystic fibrosis and,

as a result, pathogens are not eliminated effectively, lead-

ing to lung infections [17, 24]. In an ex vivo study, the

impaired degranulation of secondary and tertiary neutro-

phil granules in patients with cystic fibrosis and the G551D

mutation was corrected following 1 year of treatment with

ivacaftor (dosage not specified), with levels of degranula-

tion significantly (p \ 0.05) increasing (by 130 %) to reach

those seen in healthy controls [17].

The Fridericia-corrected QT interval was not prolonged

to any clinically relevant extent with therapeutic (150 mg

every 12 h) or supratherapeutic (450 mg every 12 h) dos-

ages of ivacaftor relative to placebo over 5 days in a

moxifloxacin-controlled crossover study in 72 healthy

subjects [23].

3 Pharmacokinetic Properties

This section provides an overview of the pharmacokinetic

properties of ivacaftor. Data were obtained predominantly

from the US [10] and EU [9] prescribing information; some

Ivacaftor: A Review 1597

data are available from the EPAR [5] or as abstracts [25–

27].

Ivacaftor displays generally linear pharmacokinetics

with respect to time and across doses of 25–250 mg [9].

The mean maximum plasma concentration (Cmax) of the

drug (768 ng/mL) was reached within &4 h and the mean

area under the plasma concentration-time curve (AUC) was

10,600 ng � h/mL, following administration of a single oral

150 mg dose in healthy volunteers in a fed state [9, 10].

Steady-state ivacaftor plasma concentrations were attained

after 3–5 days of administering the drug every 12 h; the

accumulation ratio was 2.2–2.9 [9, 10]. The pharmacoki-

netic profile of ivacaftor in patients with cystic fibrosis is

similar to that in healthy adults [9, 10]; ivacaftor exposure

parameters in phase II and III trials are summarized in

Table 1 [9].

Administration of ivacaftor with fat-containing food

increased exposure to the drug approximately twofold to

fourfold; ivacaftor should be taken with fat-containing

foods, such as those prepared with oil or butter or con-

taining cheese, whole milk, eggs, nuts or meat [9, 10].

Exposure to ivacaftor appears to be related to FEV1 [9,

26] and sweat chloride [26] responses in patients with

cystic fibrosis and the G551D mutation, according to

population pharmacokinetic/pharmacodynamic modelling

of data from phase IIa and III trials. The concentration

leading to 90 % maximal response (EC90) was 405 ng/mL,

where specified, with the median minimal plasma drug

concentration at EC90 being the pharmacokinetic parameter

that was chosen as a target for efficacy [9].

Ivacaftor does not bind to human erythrocytes and is

highly plasma protein bound (&99 %), with albumin and

a1-acid glycoprotein contributing the most to binding [9,

10]. The mean apparent volume of distribution of ivacaftor

was 353 L in healthy volunteers who received oral iva-

caftor 150 mg every 12 h in the fed state for 7 days [9, 10].

Metabolism of ivacaftor in humans is extensive and

involves oxidation, reduction, dehydration, as well as sul-

fate and glucuronide conjugation [9, 10, 25]. Metabolism

occurs predominantly via the cytochrome P450 (CYP)

enzyme CYP3A4, with CYP3A5 probably contributing to

some extent [5], producing two major metabolites, M1 and

M6 [9, 10]. Of these metabolites, only M1 is considered to

be pharmacologically active, although is less potent than

the parent drug [9, 10] (see Sect. 2.1).

Elimination of ivacaftor after oral administration of a

radiolabelled dose in healthy volunteers was predominantly

via the faeces (87.8 %), with only 6.6 % being excreted via

the urine [25]. Of the drug that is eliminated, most

(&65 %) is the M1 or M6 metabolite; very little of an

administered dose is excreted unchanged (2.5 % via the

faeces; \0.01 % via the urine) [9, 10, 25]. The mean

apparent clearance of ivacaftor at steady state was 17.3 L/h

in healthy subjects receiving the 150 mg dose [9]. The

apparent terminal elimination half-life of the drug after a

single dose is &12 h in the fed state [9].

3.1 Special Patient Groups

The rate of ivacaftor absorption in children is similar to

that in adults, although the predicted total body clearance

of the drug in children is lower (e.g. 10 L/h in a 20 kg

child vs. 18.9 L/h in a 70 kg adult) according to a pop-

ulation pharmacokinetic analysis, which may explain why

exposure to ivacaftor was higher in children than in adults

in phase II and III studies (Table 1) [9]. The pharmaco-

kinetic profile of ivacaftor is consistent among adoles-

cents (aged [12 years) and adults [5]. The dosage of

ivacaftor does not require adjustment on the basis of

gender [9, 10].

In patients with moderate hepatic impairment (Child

Pugh class B), exposure to ivacaftor (as measured by the

AUC from time zero to infinity) was increased approxi-

mately twofold relative to healthy volunteers following a

single 150 mg dose, although the Cmax was similar; thus, a

reduction in dosage to 150 mg once daily is recommended

in these patients [9, 10]. What impact severe or mild

hepatic impairment may have on ivacaftor pharmacoki-

netics has not yet been studied. Exposure to ivacaftor is

expected to be increased substantially more by severe than

moderate impairment and, as a result, the drug is not rec-

ommended in patients with severe hepatic impairment in

the EU [9]; however, if the benefits outweigh the risks,

ivacaftor may be used (with caution [10]) at a reduced

dosage (150 mg once daily or less frequently in the USA

[10]; starting dosage of 150 mg every other day in the EU

[9]). Dosage adjustment is not considered necessary in

patients with mild hepatic impairment [9, 10].

The pharmacokinetics of ivacaftor have not been

studied in patients with renal impairment, although as

renal excretion of the drug is minimal, no dosage

adjustments are required in those with mild or moderate

impairment; however, ivacaftor should be used with

caution in patients with severe renal impairment (creati-

nine clearance B30 mL/min [B1.8 L/h]) or end-stage

renal disease [9, 10].

Table 1 Exposure parameters for ivacaftor 150 mg every 12 h;

values are means based on data from phase II and III trials [9]

Population Cmin (ng/mL) AUC (ng � h/mL)

Children (aged 6–11 years) 1,180 18,200

Adolescents (aged 12–17 years) 556 8,536

Adults 774 9,508

AUC area under the plasma drug concentration-time curve, Cmin

minimum plasma drug concentration

1598 E. D. Deeks

3.2 Potential Drug Interactions

Exposure to ivacaftor may be increased upon coadminis-

tration with agents that inhibit CYP3A enzymes either

strongly (e.g. ketoconazole, itraconazole, telithromycin,

clarithromycin) or moderately (e.g. fluconazole, erythro-

mycin) [9, 10, 27]; thus, the dosage of ivacaftor may need to

be reduced [9, 10]. Grapefruit juice may also increase iva-

caftor exposure via inhibition of CYP3A; grapefruit- and

Seville orange-containing foods should be avoided [9, 10].

Coadministering ivacaftor with agents that strongly

induce CYP3A (e.g. rifampin [rifampicin], rifabutin, car-

bamazepine, phenobarbital, phenytoin, hypericum [St

John’s Wort]) may reduce ivacaftor exposure (and thus

efficacy) [9, 10, 27], and is therefore not recommended [9,

10]. Exposure to ivacaftor may also be reduced by agents

that induce CYP3A weakly to moderately (e.g. dexa-

methasone, high-dose prednisone) [9].

Both CYP3A and permeability glycoprotein (p-gp) may

be inhibited by ivacaftor and its active metabolite M1 [9,

10]. Consequently, systemic exposure to drugs that are

CYP3A and/or p-gp substrates may be increased upon

coadministration with ivacaftor, which may increase/pro-

long not only their efficacy but also the adverse events

associated with their use. As a result, coadministration of

ivacaftor with midazolam, diazepam, alprazolam or tria-

zolam requires caution and monitoring for adverse events,

with similar recommendations applying to other substrates

of CYP3A and/or p-gp, including digoxin, tacrolimus and

cyclosporin [9, 10].

CYP2C9 may be inhibited by ivacaftor, necessitating

monitoring of the international normalized ratio if the drug

is coadministered with the CYP2C9 substrate warfarin [9,

10]. However, ivacaftor did not significantly affect expo-

sure to rosiglitazone (a CYP2C8 substrate), desipramine (a

CYP2D6 substrate) or an estrogen/progesterone oral con-

traceptive upon coadministration; thus, dosage adjustment

is not necessary for these [10] or other [9] CYP2C8 or

CYP2D6 substrates or for oral contraceptives [9, 10].

4 Therapeutic Efficacy

The potential for oral ivacaftor to be used in the treatment

of patients with cystic fibrosis who have a G551D mutation

in the CFTR gene was evaluated in a randomized, double-

blind, placebo-controlled, dose-ranging (25–250 mg every

12 h) trial (n = 39) [19]. On the basis of this multicentre

phase II study, an ivacaftor dosage of 150 mg every 12 h

was selected for subsequent trials.

This section focuses on the findings of two randomized,

double-blind, placebo-controlled trials, known as STRIVE

(n = 167 randomized) [20, 28] and ENVISION (n = 52)

[21, 29]. These multicentre, phase III studies were con-

ducted to evaluate the clinical efficacy of ivacaftor 150 mg

every 12 h in treating cystic fibrosis when used in addition

to existing therapy (the exception being inhaled hypertonic

saline) in adults and adolescents (aged C12 years; Sect.

4.1) [20, 28] and children (aged 6–11 years; Sect. 4.2) [21,

29] with the G551D mutation.

Patients eligible for these trials had confirmed cystic

fibrosis and the G551D mutation in at least one CFTR

allele [28, 29] and were required to have an FEV1 40–90 %

of predicted in STRIVE [28] and 40–105 % of predicted in

ENVISION [29]. Among the exclusion criteria of both

studies were pulmonary exacerbation, acute respiratory

infection, Mycobacterium abscessus, Burkholderia ceno-

cepacia or Burkholderia dolosa in sputum and changes in

pulmonary disease therapy in the last 4 weeks [10, 28, 29].

The primary endpoint of each trial was the absolute change

from baseline in percent predicted FEV1 through week 24

of treatment. Where specified, efficacy endpoint data were

adjusted for baseline parameters such as age, percent pre-

dicted FEV1, sweat chloride and/or Cystic Fibrosis Ques-

tionnaire-Revised (CFQ-R) domain score [28, 29].

Patients who completed STRIVE or ENVISION were

eligible to receive ivacaftor 150 mg every 12 h in addition

to their existing therapy (inhaled hypertonic saline per-

mitted [9]) in an open-label extension study, known as

PERSIST [30] (144 and 48 patients enrolled; the percent

predicted FEV1 was 29–127 % at extension baseline [9]);

data from a pre-specified interim analysis of PERSIST are

available. Some data in this section were obtained from

abstracts [30, 31] or the EU prescribing information [9].

4.1 In Adults and Adolescents

Most patients participating in STRIVE were aged

C18 years (78 % of patients) [range 12–53 years], had an

FEV1 \70 % predicted (58 % of patients) and had the

F508del mutation in the second CFTR allele (75.8 % of

patients); one patient randomized to placebo was found to

be homozygous for the F508del CFTR allele upon confir-

matory genotyping, although data from the patient were

still included [9, 20]. Of note, certain medicinal products,

including dornase alfa, tobramycin, salbutamol (albuterol)

and salmeterol/fluticasone, were being used by 8–13 %

fewer patients in the ivacaftor than in the placebo group at

the start of the study [9].

Oral ivacaftor 150 mg every 12 h improved lung func-

tion when used in combination with standard care in adults

and adolescents with cystic fibrosis and the G551D CFTR

mutation. Relative to placebo, ivacaftor significantly

increased the percent predicted FEV1 from baseline

through week 24 of treatment (primary endpoint), and

sustained this benefit through week 48 (Table 2) [20].

Ivacaftor: A Review 1599

Moreover, predefined subgroup analyses indicated that

ivacaftor was associated with significant (p B 0.008) ben-

efit over placebo in terms of this parameter regardless of

age (\18 or C18 years), sex, percent predicted FEV1 at

baseline (\70 or C70 %) or geographic region [20].

Through both 24 and 48 weeks of therapy, between-group

differences significantly (p \ 0.0001) favouring ivacaftor

were seen in mean changes from baseline in FEV1 (Table 2)

[20]. Improvements in FEV1 occurred rapidly with ivacaftor,

with a significant (p \ 0.001) treatment effect of 9.3 % evi-

dent by day 15 of treatment [20].

Ivacaftor significantly (p \ 0.002) reduced the risk of

pulmonary exacerbation relative to placebo by 60 % at

24 weeks [9] and by 55 % at 48 weeks [20] (adjusted data),

with 67 % of ivacaftor and 41 % of placebo recipients being

free from pulmonary exacerbations at the latter timepoint

[20]. There were significantly fewer pulmonary exacerba-

tions (47 vs. 99; p = 0.0003) and days with pulmonary

exacerbations (13.5 vs. 36.7 mean days; p = 0.0007) with

ivacaftor than with placebo over 48 weeks [20]. Although

the number of exacerbations that resulted in hospitalization

did not significantly differ between the treatment groups,

the mean number of days spent hospitalized for pulmonary

exacerbation was significantly lower among ivacaftor than

placebo recipients (3.9 vs. 4.2; p = 0.0275).

Bodyweight parameters also improved with ivacaftor.

Compared with placebo recipients, ivacaftor recipients

experienced significantly (p \ 0.0001) greater gains in

bodyweight after 24 (mean adjusted changes from baseline

of 3.0 vs. 0.2 kg) and 48 (3.1 vs. 0.4 kg) weeks of therapy,

with this benefit plateauing after 16 weeks; mean baseline

bodyweight was 61.7 and 61.2 kg in the ivacaftor and

placebo groups [20]. Consistent with these findings, sig-

nificant (p \ 0.05) improvements in body mass index

(BMI) and z-scores (weight-for-age and BMI-for-age

z-scores in patients aged \20 years) were also seen with

ivacaftor versus placebo [9].

Ivacaftor improved some aspects of health-related

quality of life (HR-QOL), as measured by the CFQ-R.

Compared with placebo, ivacaftor was associated with

significant (p \ 0.05) improvements in the scores for

respiratory symptoms after 24 and 48 weeks of therapy

(Table 2) [9, 20], as well as physical functioning, social

functioning, eating disturbances and treatment burden at

48 weeks [31]; however, no significant between-group

differences were evident for emotion, body image or

digestive scale scores [31]. The mean rate of adherence to

study drug during the trial was high in both ivacaftor

(91 %) and placebo (89 %) recipients [20].

4.1.1 Longer-Term Findings

The beneficial effects of ivacaftor on lung function,

respiratory symptoms and bodyweight in adults and

Table 2 Effect of oral ivacaftor 150 mg every 12 h, in addition to standard care, on lung function and respiratory symptoms in patients with

cystic fibrosis and the G551D mutation in the CFTR gene. Data are mean values from two 48-week phase III trials

Endpoint Week of

eval

STRIVE (pts aged C12 years) [20]a ENVISION (pts aged 6–11 years) [21]

IVA

(n = 83)bPL

(n = 78)bBetween-group diff

(95 % CI)

IVA

(n = 26)bPL

(n = 26)bBetween-group diff

(95 % CI)

Abs changec from baselined in %

predicted FEV1 (%)

24 10.4e -0.2e 10.6 (8.6–12.6)** 12.6e 0.1e 12.5 (6.6 to 18.3)**

48 10.1 -0.4 10.5 (8.5–12.5)** 10.7 0.7 10.0 (4.5 to 15.5)*

Abs change from baseline in FEV1 (L) 24 0.4 0.0 0.4 (0.3–0.4)** 0.30 0.07 0.24 (0.12 to 0.35)**

48 0.4 0.0 0.4 (0.3–0.4)** 0.33 0.13 0.20 (0.09 to 0.31)*

Abs changec from baselinef in CFQ-R

resp domain scoreg24 NR NR 8.1 (4.7–11.4)**h 6.3 0.3 6.1 (-1.4 to 13.5)

48 5.9 -2.7 8.6 (5.3–11.9)**h 6.1 1.0 5.1 (-1.6 to 11.8)

Abs absolute, CFQ-R Cystic Fibrosis Questionnaire-Revised, CFTR cystic fibrosis transmembrane conductance regulator, diff difference, eval

evaluation, FEV1 forced expiratory volume in 1 s, IVA ivacaftor, NR not reported, PL placebo, pts patients, resp respiratory

* p \ 0.001, ** p B 0.0001 vs. PL groupa With the exception of CFQ-R scores, data were sourced from the supplementary appendix of Ramsey et al. [20]. The mean absolute change from

baseline in FEV1 through week 24 reported in Ramsey et al. was 0.367 and 0.006 L in IVA and PL recipientsb Number of randomized pts who received C1 dose of study drugc Data were adjusted for baseline parameters [28, 29], such as age (in STRIVE [28]), % predicted FEV1 and/or CFQ-R domain scored Baseline FEV1 in IVA and PL groups was 63.5 and 63.7 % of predicted in STRIVE and 84.7 and 83.7 % of predicted in ENVISIONe Primary endpointf Where reported, baseline CFQ-R resp domain scores were 78 and 80 in the IVA and PL groups [21]g For the CFQ-R resp domain, 4 points is considered the minimal clinically important difference in pts with stable disease; higher scores indicate

better health-related quality of life. Data presented for ENVISION are from the child version of the CFQ-Rh Data were sourced from the EU prescribing information

1600 E. D. Deeks

adolescents were maintained during longer-term treatment,

according to a 48-week interim analysis of the extension

study PERSIST [30]. For example, among patients who

received 48 weeks’ treatment with ivacaftor in STRIVE

and continued to receive the drug in PERSIST (n = 73),

the mean absolute change from STRIVE baseline in per-

cent predicted FEV1 was 9.5 % after a total of 96 weeks’

therapy versus 9.4 % at the start of the extension [9].

Patients who had received placebo in STRIVE and were

switched to ivacaftor for the extension (n = 63) had a

corresponding improvement in this parameter of 9.4 %

48 weeks after switching [9].

4.2 In Children

At baseline, patients participating in ENVISION had a

mean age of 9 years, most had the F508del mutation in the

second CFTR allele (80.8 %) and 15 % of those in the

ivacaftor group versus 31 % of those in the placebo group

had an FEV1 \70 % of predicted, although the between-

group difference was not significant [9, 21].

Oral ivacaftor 150 mg every 12 h, in combination with

standard care, was effective in improving lung function in

children aged 6–11 years with cystic fibrosis and the

G551D CFTR mutation, according to primary endpoint

analysis. Percent predicted FEV1 increased from baseline

to a significantly greater extent with ivacaftor than with

placebo through week 24 of treatment (primary endpoint;

Table 2), with the between-group difference favouring

ivacaftor from day 15 of therapy and remaining significant

through week 48 (Table 2) [21]. Predefined subgroup

analyses suggested this measure was significantly

improved with ivacaftor relative to placebo among patients

who had an FEV1 B90 % of predicted at baseline, were

female or were participating at a European centre [21].

Ivacaftor also provided benefit over placebo in terms of

other lung function endpoints, including the mean absolute

change from baseline in FEV1 through 24 and 48 weeks’

treatment (Table 2) [21]. Pulmonary exacerbations, as

defined in the trial protocol, were uncommon (four

occurred with ivacaftor, three with placebo) [21].

Ivacaftor had beneficial effects on bodyweight parame-

ters. Significant bodyweight gain occurred with ivacaftor

relative to placebo after 24 weeks of therapy (mean adjus-

ted changes from baseline of 3.7 vs. 1.8 kg; p = 0.0004)

and was maintained through week 48 (treatment difference

of 2.8 kg; p = 0.0002); mean baseline bodyweight was

31.8 and 30.0 kg in the respective groups [21]. Similarly,

mean changes from baseline in BMI and both BMI-for-age

and weight-for-age z-scores also significantly (p \ 0.001)

favoured ivacaftor over placebo at 48 weeks [9].

Unlike placebo recipients, ivacaftor recipients had

clinically relevant improvements from baseline in

respiratory symptoms, as measured by the child version of

the CFQ-R respiratory domain, although the difference

between the treatment groups was not statistically signifi-

cant through 24 or 48 weeks’ therapy (Table 2) [21]. There

were also no significant between-group differences for

other CFQ-R domain scores [31]. However, in the parent/

caregiver CFQ-R, scores for respiratory symptoms

(through week 24) [21] as well as body image and body-

weight (through week 48) [31] significantly (p = 0.033

where reported [21]) favoured ivacaftor over placebo.

Compliance with study drug was high (mean rate C94 %)

in both treatment groups [21].

4.2.1 Longer-Term Findings

Ivacaftor provided beneficial effects on parameters such as

lung function and bodyweight for up to 72 weeks,

according to an interim analysis of the extension study

PERSIST [30]. For instance, among patients who received

ivacaftor for 48 weeks in ENVISION and received the drug

for a further 24 weeks in PERSIST (n = 26), the mean

absolute change from ENVISION baseline in percent pre-

dicted FEV1 was 10.1 % after a total of 72 weeks’ therapy

versus 10.2 % at the start of the extension [9]. Patients who

had received placebo in ENVISION experienced a corre-

sponding mean improvement in this measure of 8.1 %

24 weeks after switching to ivacaftor for the extension

(n = 22) [9].

5 Tolerability

Tolerability data concerning the use of oral ivacaftor in

patients aged C6 years with cystic fibrosis who have the

G551D CFTR mutation are available from the clinical

studies discussed in Sect. 4. Some data, including a pooled

analysis of the two pivotal phase III trials that compared

ivacaftor 150 mg every 12 h with placebo in adults and

adolescents (STRIVE) or children (ENVISION), are

available from the US [10] and EU [9] prescribing

information.

Treatment with ivacaftor 150 mg every 12 h for up to

48 weeks was generally well tolerated in adults [20],

adolescents [20] and children [21] with cystic fibrosis and

the G551D CFTR mutation participating in the STRIVE

[20] and ENVISION [21] trials. In each of these studies,

adverse events occurred in the vast majority (C96 %) of

ivacaftor and placebo recipients, although the incidence of

those considered to be serious was numerically lower with

ivacaftor than with placebo (19 vs. 23 % [21] and 24 vs.

42 % [20]).

Serious adverse events reported (more than once [21])

with ivacaftor or placebo included pulmonary exacerbation

Ivacaftor: A Review 1601

(two vs. three patients) and productive cough (one patient

per group) in ENVISION [21] and pulmonary exacerba-

tions (13 vs. 33 % of patients), haemoptysis (1 vs. 5 %)

and hypoglycaemia (2 vs. 0 %) in STRIVE [20]. Among

the two ivacaftor recipients who had hypoglycaemia, one

was receiving insulin for diabetes mellitus and the other

had had symptoms suggestive of hypoglycaemia previously

[20]. No patients died in either study [20, 21].

In the trial in adults and adolescents, adverse events led

to interruption of study drug in 13 % of ivacaftor and 6 %

of placebo recipients and discontinuation of study drug in 1

and 5 %, with the reason for discontinuation in the iva-

caftor group being increased levels of hepatic enzymes

[20]. In ENVISION, threefold fewer ivacaftor than placebo

recipients had their study drug interrupted because of

adverse events (3.8 vs. 11.5 %) and no children receiving

ivacaftor discontinued therapy permanently because of

adverse events (vs. 3.8 % of placebo recipients) [21].

In a pooled analysis, the adverse events that occurred

most frequently and with at least a 3 % greater incidence

with ivacaftor than with placebo among patients aged

C6 years with cystic fibrosis and the G551D CFTR

mutation included headache, oropharyngeal pain, upper

respiratory tract infection (URTI), nasal congestion,

abdominal pain, nasopharyngitis, diarrhoea, rash and diz-

ziness (Fig. 2) [10]. All headaches, rashes and dizziness

events and most respiratory tract reactions (i.e. URTI, nasal

or sinus congestion, oropharyngeal pain, rhinitis, naso-

pharyngitis and pharyngeal erythema) were of mild to

moderate severity and none were serious or led to treatment

discontinuation; one ivacaftor recipient experienced seri-

ous abdominal pain [9].

Some differences in the adverse event profile of iva-

caftor were observed among children (aged 6–11 years)

[n = 23] and adolescents (aged 12–17 years) [n = 22]

participating in the two pivotal 48-week phase III trials [9].

For example, dizziness was very common (incidence

C10 %) among adolescents but was not seen in children,

whereas diarrhoea, pharyngeal erythema and tympanic

membrane hyperaemia were common (incidence C1 to

\10 %) or very common (incidence C10 %) among chil-

dren but were not observed in adolescents.

Ivacaftor did not appear to have any clinically important

effect on vital signs, ECGs, physical examination mea-

surements or clinical laboratory tests in adults and ado-

lescents [20] or children [21] in STRIVE and ENVISION.

However, clinical studies have reported transaminase ele-

vations more frequently with ivacaftor than with placebo in

patients with a history of such elevations (see Sect. 5.1 for

details).

Longer term, interim data from a clinical trial extension

study [30] indicated that the tolerability profile of ivacaftor

over up to 96 weeks of therapy in patients with cystic

fibrosis was generally consistent with that seen during the

initial 48-week trials [20, 21], with no new safety signals of

any clinical importance identified. Serious adverse events

occurred in 20.1 % of adults/adolescents and 8.4 % of

children, and two patients (one in each age cohort) dis-

continued the extension because of an adverse event. The

most common adverse events were respiratory in nature.

5.1 Transaminase Elevations

Patients with cystic fibrosis often have moderate elevations

in levels of AST or ALT [9]. Some ivacaftor and placebo

recipients had maximum elevations in transaminase levels

of[8 (1.8 vs. 1.5 % of patients),[5 (2.7 vs. 2.3 %) or[3

(6.3 vs. 8.4 %) times the upper limit of normal (ULN) in

48-week cystic fibrosis phase IIb/III trials; these elevations

were serious in two patients (both were ivacaftor

recipients).

Although transaminase elevations have, overall, occur-

red with similar incidence with ivacaftor as with placebo in

clinical studies, they have been documented more fre-

quently with ivacaftor than with placebo in patients with a

history of such elevations [9]. Thus, it is recommended that

AST and ALT [10] or hepatic function [9] be assessed

before starting treatment with ivacaftor, every 3 months

during the initial year of therapy and then once every year

thereafter. If transaminase levels increase during treatment,

patients should be monitored closely until the abnormali-

ties resolve [9, 10], and if AST or ALT levels reach [59

ULN, ivacaftor therapy should be interrupted [10]; before

resuming treatment with ivacaftor, the benefits and risks

require consideration [9, 10].

0 5 10 15 20 25 30

Dizziness

Rash

Diarrhoea

Nasopharyngitis

Abdominal pain

Nasal congestion

URTI

Oropharyngeal pain

Headache

% of patients

Ivacaftor

Placebo

Fig. 2 Tolerability of oral ivacaftor 150 mg every 12 h in patients

(aged 6–53 years) with cystic fibrosis and the G551D CFTR mutation.

The most frequent adverse events (incidence C8 %) that occurred in

C3 % more ivacaftor (n = 109) than placebo (n = 104) recipients in

a pooled analysis of the 48-week phase III trials, STRIVE and

ENVISION [10]. Patients also received standard care (see Sect. 4 for

details). URTI upper respiratory infection

1602 E. D. Deeks

6 Dosage and Administration

For the treatment of patients with cystic fibrosis and the

G551D CFTR mutation, the recommended dosage of iva-

caftor in the USA [10] and EU [9] is 150 mg every 12 h, taken

orally with fat-containing food. Patients with an unknown

genotype should have the presence of the G551D mutation

confirmed before being treated with ivacaftor. Local pre-

scribing information should be consulted for suggested dos-

age modifications in special patient populations and patients

receiving concomitant CYP3A4 inhibitor therapy and for

information regarding contraindications, drug interactions,

and other warnings and precautions.

7 Current Status of Ivacaftor in Cystic Fibrosis

Oral ivacaftor is indicated in a number of countries, including

the USA [10] and those of the EU [9], for the treatment of

cystic fibrosis in patients aged C6 years who have the G551D

CFTR mutation and its use is strongly recommended in this

patient population in the most recent guidelines of the Pul-

monary Clinical Practice Guidelines Committee (established

by the Cystic Fibrosis Foundation) [7]. In two well-designed,

48-week trials in patients aged 6–11 years (ENVISION) or

C12 years (STRIVE) with cystic fibrosis and this mutation,

ivacaftor 150 mg every 12 h significantly improved lung

function relative to placebo when used in combination with

standard care. Significant improvements in other measures

such as pulmonary exacerbation risk (in STRIVE) and

bodyweight (in both studies) were also seen with the drug

versus placebo. In an ongoing extension of these trials, ben-

eficial effects of ivacaftor were maintained for up to 96 weeks

of therapy, although longer-term data in this setting would be

beneficial given that cystic fibrosis is a life-long condition.

Ivacaftor was generally well tolerated and adherence/com-

pliance to the drug was high at [90 %, which compares

favourably with adherence rates reported for some other cystic

fibrosis therapies, such as inhaled antibiotics (31–53 % [32]).

Whether use of ivacaftor could enable some standard care

medications to be discontinued remains to be determined [1].

The G551D mutation is present in &3 % of patients with

cystic fibrosis, making it the third most common mutation

of the CFTR gene [3]. The efficacy demonstrated by iva-

caftor in patients with this gating (i.e. class III) mutation has

prompted investigation into the potential use of the drug in

patients with other CFTR gating mutations, and such trials,

including one in younger patients aged 2–5 years, are cur-

rently ongoing or recruiting participants [33].

In addition to gating mutations, the efficacy and safety of

ivacaftor has also been evaluated in patients homozygous for

the class II mutation F508del [34], the most common CFTR

mutation in those with cystic fibrosis (accounting for around

two-thirds of alleles) [35]. In a randomized, double-blind,

phase II trial in this patient population, which was powered to

assess safety rather than efficacy [34], treatment with ivacaftor

150 mg every 12 h (n = 112) was generally well tolerated but

did not significantly improve lung function relative to placebo

(n = 28), as measured by the change from baseline in percent

predicted FEV1 through week 16 (primary efficacy endpoint).

As discussed in Sect. 1, class II mutations result in CFTR

that is misfolded and improperly processed, and only a small

amount of the defective protein (if any) reaches the cell sur-

face [1], which may in part explain the lack of benefit

observed with ivacaftor in the trial discussed above. One

potential solution may be to use a CFTR potentiator, such as

ivacaftor, in combination with a CFTR corrector, i.e. a

compound that enhances the processing and maturation of

class II mutant CFTR proteins such as F508del, with the idea

being that the amount of CFTR reaching the cell surface will

be increased by the corrector and the function of the channels

reaching the membrane will be increased by the potentiator

[1]. Indeed, small (n B 82) phase II studies assessing iva-

caftor in combination with the investigational corrector lu-

macaftor in patients homozygous for the F508del mutation

have been promising [36, 37], and phase III trials in this

setting have been initiated [33]. A phase III ivacaftor trial in

patients with the class IV CFTR mutation, R117H, is also

recruiting participants [33]. Results of these studies are

awaited with interest.

Data selection sources: Relevant medical literature (including

published and unpublished data) on ivacaftor was identified by

searching databases including MEDLINE (from 1946) and EM-

BASE (from 1996) [searches last updated 23 August 2013],

bibliographies from published literature, clinical trial registries/

databases and websites. Additional information was also

requested from the company developing the drug.

Search terms: Ivacaftor, kalydeco, vx-770, vx770, vrt-813077,

vrt813077.

Study selection: Studies in patients with cystic fibrosis who

received ivacaftor. When available, large, well-designed, com-

parative trials with appropriate statistical methodology were

preferred. Relevant pharmacodynamic and pharmacokinetic data

are also included. All data included are publically available.

Disclosure The preparation of this review was not supported by any

external funding. During the peer review process, the manufacturer of

the agent under review was offered an opportunity to comment on this

article. Changes resulting from comments received were made by the

author on the basis of scientific and editorial merit.

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1604 E. D. Deeks