Upload
others
View
1
Download
0
Embed Size (px)
Citation preview
Tezacaftor/Ivacaftor in Subjects with Cystic Fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR
Scott H. Donaldson1, Joseph M. Pilewski2, Matthias Griese3, Jon Cooke4, Lakshmi Viswanathan5, Elizabeth Tullis6, Jane C. Davies7, Julie A. Lekstrom-Himes8, and Linda T.
Wang8; on behalf of the VX11-661-101 Study Group
1University of North Carolina School of Medicine, Chapel Hill, NC, United States; 2University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; 3Ludwig-Maximilians-University, Dr. von Hauner Children’s Hospital, Department of Pediatric Pneumology, Munich, Germany;
4Formerly of Vertex Pharmaceuticals (Europe) Limited, London, United Kingdom; 5Vertex Pharmaceuticals Incorporated, Boston, MA, United States; 6St. Michael’s Hospital and Keenan
Research Centre of Li Ka Shing Knowledge Institute, University of Toronto, Toronto, ON, Canada; 7Paediatric Respiratory Medicine, Imperial College & Royal Brompton and Harefield
Foundation Trust, London, United Kingdom; 8Vertex Pharmaceuticals (Europe) Limited, London, United Kingdom
Corresponding author: Linda T. Wang50 Northern AvenueBoston, MA 02210Office: 617-961-5029Fax: 617-366-3918Email: [email protected]
Journal target: Am J Respir Crit Care Med
Author contributions: All authors were involved in data interpretation and the preparation, review, and approval of the manuscript.
Sources of support: This study was funded by Vertex Pharmaceuticals Incorporated.
Running title (50 characters max including spaces; current: 48): TEZ/IVA in Subjects with CF and F508del or G551D
Word count (max 3500): 3868
Descriptor number: 9.1 Adult Cystic Fibrosis
At a glance commentary (200 word max; current = 165):
Scientific Knowledge on the Subject: The most common mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is F508del, which causes independent defects in processing and trafficking that reduce the amount of protein on the cell membrane while also disrupting channel gating. In contrast, the G551D mutant protein trafficks, but does not gate normally. Ivacaftor is a CFTR potentiator that increases chloride transport and improves lung function in patients with CFTR gating mutations. Tezacaftor (formerly VX-661) is a novel corrector that increases processing and trafficking of CFTR to the cell membrane. In combination, tezacaftor and ivacaftor have been shown to enhance CFTR activity in human bronchial epithelial cells homozygous for F508del and compound heterozygous for F508del and G551D.
What This Study Adds to the Field: We show that in the first clinical trial evaluating tezacaftor combined with ivacaftor, the combination has an acceptable safety profile, reduces sweat chloride, and improves lung function in subjects homozygous for F508del or compound heterozygous for F508del and G551D.
This article has an online data supplement, which is accessible from this issue’s table of contents online at www.atsjournals.org.
Abstract:
Rationale: Tezacaftor (formerly VX-661) is an investigational small molecule that improves
processing and trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR)
in vitro, and improves CFTR function alone and in combination with ivacaftor.
Objectives: To evaluate safety and efficacy of tezacaftor monotherapy and
tezacaftor/ivacaftor combination therapy in subjects with CF homozygous for F508del or
compound heterozygous for F508del and G551D.
Methods: This was a randomized, placebo-controlled, double-blind, multicenter, phase 2 study
(NCT01531673). Subjects homozygous for F508del received tezacaftor (10 mg to 150 mg)
qday alone or in combination with ivacaftor 150 mg q12h in a dose escalation phase, as well
as in a dosage regimen testing phase. Subjects compound heterozygous for F508del and
G551D taking physician prescribed ivacaftor received tezacaftor 100 mg qday.
Measurements and Main Results: Primary endpoints were safety through day 56 and
change in sweat chloride from baseline through day 28. Secondary endpoints included change
in percent predicted FEV1 (ppFEV1) from baseline through day 28 and pharmacokinetics. The
incidence of adverse events was similar across treatment arms. Tezacaftor 100 mg
qday/ivacaftor 150 mg q12h resulted in a 6.04 mmol/L decrease in sweat chloride and 3.75
percentage point increase in ppFEV1 in subjects homozygous for F508del and a 7.02 mmol/L
decrease in sweat chloride and 4.60 percentage point increase in ppFEV1 in subjects
compound heterozygous for F508del and G551D from baseline through day 28 (P < 0.05 for
all).
Conclusions: These results support continued clinical development of tezacaftor 100 mg qday
in combination with ivacaftor 150 mg q12h in subjects with CF.
1
Clinical trial registered with www.ClinicalTrials.gov (NCT01531673).
Abstract word count (250 max): 255
Key words (3–5 [MeSH terms preferred]; do not use words from the title): Cystic fibrosis
transmembrane conductance regulator corrector; CFTR modulator; forced expiratory volume;
sweat chloride
Introduction
Cystic fibrosis (CF) affects an estimated 70,000 children and adults worldwide and is the most
common fatal genetic disease in persons of European descent (1). CF is caused by mutations
in the CF transmembrane conductance regulator (CFTR) gene that lead to a deficiency in the
amount and/or function of CFTR protein at the epithelial cell surface (2-4). Two complementary
approaches using CFTR modulators to increase CFTR-mediated chloride secretion in epithelia
have been studied (5). CFTR correctors modify the cellular processing and trafficking of the
CFTR protein to increase the amount of functional CFTR at the cell surface. CFTR potentiators
increase the channel gating activity of protein kinase A-activated CFTR at the cell surface to
enhance ion transport. Depending on the amount of residual CFTR channel activity in the
membrane and its functionality (reflecting the CFTR genotype of the patient and other factors),
both approaches may be required to effectively treat the clinical manifestations resulting from
defective CFTR-mediated chloride transport.
The most common CFTR mutation, F508del, is present on at least one allele in
approximately 87% of patients with CF who were entered into the US-based CF Foundation
Patient Registry and is on both alleles in approximately 46% (6). The F508del mutation causes
a processing and trafficking defect that reduces the amount of protein on the epithelial
membrane while also disrupting gating of the few channels that reach the surface; these
combined effects result in minimal CFTR-mediated chloride transport (7-10). Improving
chloride transport in patients homozygous for F508del requires combination therapy with both
a CFTR corrector, such as lumacaftor, and a CFTR potentiator (11-13).
3
Ivacaftor is an approved CFTR modulator for the treatment of patients with CF and at
least one of 33 CF- causing mutations (14), accounting for approximately 10% of all patients
with CF in the United States. It was first approved for patients with G551D (approximately 4%
of all patients with CF) or similar gating mutations (15-18) Most patients with G551D carry
F508del on their second allele. Both in vitro and clinical data support that the beneficial impact
of ivacaftor in those with a gating mutation is attributable to its effects on the gating allele (11).
Tezacaftor is a broad-acting CFTR corrector similar to lumacaftor that facilitates the cellular
processing and trafficking of normal CFTR and multiple mutant CFTR forms, including
F508del, thereby increasing the amount of CFTR protein at the cell surface, resulting in
increased chloride transport. The addition of a CFTR corrector to potentiator therapy provides
clinical benefit to those who carry processing and trafficking mutations such as F508del, the
most common CF-causing CFTR mutation (6). Additionally CFTR corrector and potentiator
combination therapy may provide benefit to patients who are compound heterozygous for
F508del and an ivacaftor-responsive mutation.
Tezacaftor is a new CFTR corrector currently being studied in clinical trials. Tezacaftor
in combination with ivacaftor has the potential to fill an important unmet need for CFTR
modulators, including improving the benefit-to-risk profile of CFTR modulation in patients
homozygous for F508del and enhancing the benefit of CFTR modulation for patients with
ivacaftor-responsive mutations. One of the important advantages of tezacaftor is that, unlike
lumacaftor, it is not an inducer of CYP3A4 enzymes (unpublished data) and does not interfere
with metabolism of ivacaftor or many other medications that are frequently used in CF,
reducing drug-drug interactions and dosing complexities (19). This phase 2, placebo-controlled
study evaluated the safety and efficacy of tezacaftor monotherapy and tezacaftor/ivacaftor
combination therapy in subjects with CF who were homozygous for F508del or compound
heterozygous for F508del and G551D.
Some of the results of these studies have been previously reported in the form of
abstracts (20-22).
Methods
Study Design
This was a randomized, placebo-controlled, double-blind, multicenter phase 2 study
(NCT01531673) using a multiple ascending dose and parallel-arm design that included a 28-
day treatment period followed by a 28-day post-treatment observation (washout) period. There
were 14 study arms as shown in the study schema (Figure 1). Because this was a proof-of-
concept study, each dose of tezacaftor was tested for tolerability as monotherapy before
testing in combination with ivacaftor during the dose escalation phase. Results across
treatment arms were assessed to evaluate dose response profiles and define dosing strategies
in subjects homozygous for F508del and to characterize safety and tolerability in subjects
homozygous for F508del or compound heterozygous for F508del and G551D.
Study Oversight
The protocol was reviewed and approved by the institutional review board or ethics committee
at each participating center before the study began. Written informed consent and participant
assent was obtained from each subject or caregiver as appropriate. An independent data
monitoring committee conducted safety reviews throughout the course of the trial.
Study Subjects
All eligible subjects were required to have a confirmed diagnosis of CF (23), defined as a
sweat chloride value greater than 60 mmol/L by quantitative pilocarpine iontophoresis or 2 CF-
causing mutations, and chronic sinopulmonary disease or gastrointestinal/nutritional
abnormalities; a forced expiratory volume in 1 second (FEV1) of 40-90% of the predicted value
for persons of their age, sex, race, and height (24); and a body weight of at least 40 kg and
body mass index of at least 18.5 kg/m2.
Eligible subjects in the dose escalation and alternate dosage regimen testing phases
were at least 18 years of age and homozygous for F508del. Eligible heterozygous subjects
were at least 12 years of age, were compound heterozygous for F508del and G551D, and
must have been taking physician-prescribed ivacaftor for at least 28 days at the time of
screening. Confirmation of genotype results was required before enrollment.
All subjects were randomly assigned in a 4:1 ratio to receive active drug or matched
placebo for 28 days, with an additional 28-day follow-up. Subjects who prematurely
discontinued treatment were required to complete the safety follow-up visit approximately 28
days after administration of the last dose of study drug. During the course of the study,
subjects were required to remain on their routine, stable medication regimen. In the dose
escalation phase, subjects received increasing doses by cohort. Subjects received tezacaftor
10 mg, 30 mg, 100 mg, or 150 mg qday alone or in combination with ivacaftor 150 mg q12h. In
the alternate dosage regimen testing phase, subjects received tezacaftor 100 mg
qday/ivacaftor 50 mg q12h or tezacaftor 50 mg q12h/ivacaftor 150 mg q12h. Subjects who
were compound heterozygous for F508del and G551D received tezacaftor 100 mg qday in
combination with physician-prescribed ivacaftor 150 mg q12h. Placebo subjects in this group
continued on physician-prescribed ivacaftor throughout the study.
Endpoints
The primary endpoints were safety through day 56, as determined by adverse events, clinical
laboratory values, standard digital electrocardiograms (ECGs), and vital signs, and change in
sweat chloride from baseline through day 28. Secondary endpoints included absolute and
relative changes in percent predicted FEV1 (ppFEV1) from baseline through day 28,
pharmacokinetic (PK) parameters, and change in Cystic Fibrosis Questionnaire-Revised
(CFQ-R) respiratory domain score from baseline to each visit up to day 28. Endpoints were
assessed every 7 days during the treatment and washout periods.
Statistical Analyses
Since this was a proof-of-concept study, no formal sample size determination was conducted.
Safety and efficacy were evaluated in all subjects who received at least one dose of study
drug. Independent comparisons of efficacy (eg, ppFEV1) and other clinical parameters were
performed in subjects homozygous for F508del and in those compound heterozygous for
F508del/G551D. Comparisons were made both within and between treatment groups. Change
in sweat chloride or ppFEV1 from baseline through day 28 was analyzed via a mixed-model for
repeated measures (MMRM). The average treatment effect across all post-baseline visits
obtained from the MMRM was used as the effect estimate for within and between group
comparisons. No alpha level adjustment for multiple comparisons was performed. Statistical
significance was defined as P < 0.05 and is only reported for the combination treatment of the
two higher doses of tezacaftor (100 mg qday and 150 mg qday).
Placebo subjects were pooled for between group comparisons in the dose escalation
and alternate dosage regimen testing phases. Subjects who received tezacaftor 100 mg
qday/ivacaftor 150 mg q12h in the dose escalation phase were included in the analyses with
the alternate dosage regimens.
Results
Results for baseline demographics, subject disposition, and safety were pooled into
monotherapy and combination therapy groups. Detailed results for each study arm are
presented in the supplemental appendix.
Study Population
The study was conducted from February 2012 through March 2014 at 37 CF centers in the
United States, Canada, Germany, and the United Kingdom. The screening, randomization, and
follow-up of subjects are shown in Figures 2 and E1. Overall, 185 of 190 subjects (97.4%)
completed the study and follow-up; 94.2% of subjects completed the full dosage regimen, with
a mean compliance (calculated as the number of tablets consumed relative to the number of
tablets administered) of 97.9%.
Baseline characteristics were well balanced among all study arms in subjects
homozygous for F508del (Tables 1; E1). Overall, the mean age was 30 years (SD 8.0), 44%
were female, the mean sweat chloride concentration was 95 mmol/L (SD 18.7), and the mean
ppFEV1 was 61 (SD 14.1). Baseline mean sweat chloride for subjects compound heterozygous
for F508del/G551D was 52.9 mmol/L (SD 19.6) in the active drug arm and 56.7 mmol/L (SD
22.1) in the placebo arm, consistent with the effects of ivacaftor (15,18).
Safety
The incidence of adverse events through day 56 was similar across study arms. Five subjects
homozygous for F508del discontinued the study (1 due to an adverse event, 1 due to
noncompliance, 1 was lost to follow-up, and 2 for other reasons, which were unspecified). Four
discontinuations occurred during the dose escalation phase (1 subject receiving tezacaftor 10
mg qday monotherapy, 1 receiving 100 mg qday monotherapy, 1 receiving 10 mg qday
combination therapy, and 1 receiving 30 mg qday combination therapy) and 1 during the
dosage regimen testing phase (tezacaftor 100 mg qday/ivacaftor 50 mg q12h). No subjects in
the F508del/G551D genotype cohort discontinued the study.
Tables 2 and E2 summarize the overall adverse events, serious adverse events, and
discontinuations that occurred through day 56. A total of 152 (88.4%) of 172 subjects
homozygous for F508del had at least 1 adverse event, with an incidence of 30 (90.9%)
subjects in the tezacaftor monotherapy arm, 92 (86.8%) subjects in the tezacaftor/ivacaftor
arm, and 30 (90.9%) subjects in the placebo arm. The majority (81.4%) of adverse events
were mild to moderate in nature. The most common adverse events by subject (≥15% in any
treatment group) were infective pulmonary exacerbation of CF, cough, increased sputum,
nausea, diarrhea, headache, and fatigue. Adverse events occurring in ≥15% of subjects in any
active drug arm are shown in Tables 3 and E3. Four adverse events, including cough, nausea,
fatigue, and increased sputum were more common in the tezacaftor monotherapy arm
compared with combination therapy (Table 3). However, the number of patients in the pooled
monotherapy arms was low (n=30), and examination of adverse events by cohort does not
suggest a dose relationship or dose-related increased intolerability. Serious adverse events
were reported in 15 subjects homozygous for F508del; ten of 139 subjects were in an active
drug arm (7%), and 5 of 33 subjects were in a placebo arm (15%). Fourteen of the 15 serious
adverse events were pulmonary exacerbations. One subject compound heterozygous for
F508del/G551D who received tezacaftor reported a serious adverse event of arthritis that was
considered not related to the study drug by the investigator. No deaths occurred during the
study.
Adverse events that occurred during the 28-day washout period were collected and
reported separately in Tables E4 and E5. During the washout period, a total of 120 (69.8%) of
172 subjects homozygous for F508del had at least 1 adverse event, with an incidence of 20
(60.6%) subjects in the tezacaftor monotherapy arm, 76 (71.7%) subjects in the
tezacaftor/ivacaftor arm, and 24 (72.7%) subjects in the placebo arm. The most common
adverse events by subject (≥15% in any treatment group) were infective pulmonary
exacerbation of CF, cough, headache, and nausea.
There were no clinically significant trends for laboratory tests, ECG parameters, vital
signs, weight, and body mass index.
Pharmacokinetics
Table E6 summarizes the PK of tezacaftor in all subjects. In subjects homozygous for
F508del, tezacaftor was rapidly absorbed following oral administration and reached steady
state by approximately 2 weeks. In the monotherapy arms, exposures of tezacaftor increased
in an approximately dose-proportional manner. Exposures of tezacaftor and its metabolites,
M1 and M2, were similar following tezacaftor monotherapy and tezacaftor/ivacaftor
combination therapy. In the dosage regimen testing phase, steady state area under the curve
(AUC) estimates of tezacaftor were similar when dosed at 50 mg q12h or 100 mg qday. The
geometric least squares mean ratios interval for tezacaftor exposures with combination therapy
(tezacaftor 100 mg qday/ivacaftor 150 mg q12h) relative to tezacaftor 100 mg qday
monotherapy were 0.998 (90% confidence interval [CI], 0.768, 1.30) for AUC and 1.07 (90%
CI, 0.844, 1.36) for Cmax. The mean accumulation ratios of tezacaftor based on AUC0-24h (day
28/day 1) were also similar following qday dosing of tezacaftor monotherapy and tezacaftor
100 mg qday/ivacaftor 150 mg q12h.
Table E7 summarizes the PK of ivacaftor in all subjects treated in the combination
therapy groups. Exposures of ivacaftor and its metabolites, M1 and M6, were also unaffected
by the co-administration with increasing doses of tezacaftor and were consistent with
previously observed exposures (25).
Tezacaftor 100 mg qday/ivacaftor 150 mg q12h in subjects compound heterozygous for
F508del/G551D yielded steady state exposures of tezacaftor and ivacaftor that were similar to
subjects homozygous for F508del (Tables E6 and E7).
Efficacy in the Dose Escalation Phase in Subjects Homozygous for F508del
In subjects homozygous for F508del, treatment resulted in mean within-group decreases in
sweat chloride from baseline through day 28 with the 2 higher doses of tezacaftor
monotherapy (100 mg qday and 150 mg qday) and with tezacaftor doses of 10 mg qday, 30
mg qday, and 100 mg qday given in combination with ivacaftor 150 mg q12h (P < 0.05 for 100
mg qday; Figure 3). Sweat chloride changes with tezacaftor 100 mg qday/ivacaftor 150 mg
q12h were also significant when compared with placebo through day 28 (P < 0.05; Table E8).
A clear dose response pattern was not observed in monotherapy or combination therapy
treatment arms. However the size of the treatment arms, particularly in the monotherapy
groups, was small. In all treatment arms, sweat chloride returned to near pretreatment levels
28 days after stopping treatment.
Treatment resulted in within-group improvements from baseline in ppFEV1 (absolute)
through day 28 with tezacaftor 10 mg qday monotherapy, while no treatment effect was
observed at the 3 higher doses. With combination therapy, within-group improvements from
baseline in ppFEV1 (absolute) were observed with tezacaftor doses of 30 mg qday, 100 mg
qday, and 150 mg qday in combination with ivacaftor 150 mg q12h (P < 0.05 for 100 mg qday
and 150 mg qday; Figure 3), in a pattern that suggested a dose-response relationship. The
absolute increase in ppFEV1 observed at the 2 higher doses of tezacaftor/ivacaftor was also
significant when compared with placebo through day 28 (P < 0.05 for both; Table E8). The
analyses of relative change in ppFEV1 were consistent with those of absolute change in
ppFEV1 (Table E8). In all treatment arms, ppFEV1 returned to near pretreatment levels 28 days
after stopping treatment (Figure 4).
The largest improvement in ppFEV1 (absolute) was observed in the tezacaftor 100 mg
qday/ivacaftor 150 mg q12h combination therapy arm (within-group increase from baseline of
3.75 percentage points [Figure 3]; treatment effect vs placebo: 3.89 percentage points; 95%
CI: 0.94, 6.83; P < 0.05 [Table E8]). The proportion of subjects experiencing an increase in
ppFEV1 from baseline through day 28 in this treatment arm was larger than that observed in
the placebo arm (Figure 4).
Combination therapy of tezacaftor 100 mg or 150 mg with ivacaftor 150 mg q12h
resulted in within-group increases from baseline in CFQ-R respiratory domain score through
day 28 of 5.15 points (P = 0.093)) and 7.62 points (P = 0.011), respectively. No significant
within-group changes in CFQ-R respiratory domain were observed in any other treatment
groups. No significant changes were observed when compared with placebo for any
monotherapy or combination therapy groups.
Efficacy in the Dosage Regimen Testing Phase in Subjects Homozygous for F508del
Tezacaftor 100 mg qday in combination with ivacaftor 150 mg q12h was selected during the
dose escalation phase as the most effective dose. During the dosage regimen testing phase,
alternate regimens, including a twice daily tezacaftor regimen (tezacaftor 50 mg q12h/ivacaftor
150 mg q12h) and a low dose ivacaftor regimen (tezacaftor 100 mg qday/ivacaftor 50 mg
q12h) were compared with responses to tezacaftor 100 mg qday with ivacaftor 150 q12h
observed during the dose escalation phase. All 3 dosage regimens resulted in within-group
decreases in sweat chloride from baseline through day 28 (Figure 5). Tezacaftor 50 mg
q12h/ivacaftor 150 mg q12h also resulted in a reduction in sweat chloride compared with
placebo (Table E9). However, treatment with the twice daily regimen or the low dose of
ivacaftor arm did not result in improvements (either within group, or vs placebo) in ppFEV1
(Figure 5; Table E9). Similarly, no changes (either within group or vs placebo) in CFQ-R
respiratory domain score were observed with either alternate regimen.
Efficacy in Subjects Compound Heterozygous for F508del and G551D
Subjects who were compound heterozygous for F508del and G551D received tezacaftor 100
mg qday or matched placebo while continuing to receive physician-prescribed ivacaftor 150
mg q12h. While the within-group decrease in sweat chloride from baseline through day 28 was
not significant (Figure 6), treatment resulted in a statistically significant mean absolute
decrease compared with placebo (treatment effect, −17.20, P < 0.05; Table E10). Treatment
also resulted in statistically significant mean absolute and relative within-group increases in
ppFEV1 from baseline through day 28 (4.60 and 7.29 percentage points, respectively, P < 0.05
for both; Figure 6 and data not shown). The treatment effect vs placebo, however, was not
significant for either absolute or relative change in ppFEV1 (Table E10). Concentrations of
sweat chloride and ppFEV1 values returned to near pretreatment levels 28 days after stopping
treatment (day 56) (Figure E2). Individual absolute change in ppFEV1 responses indicate that
12 of 14 (86%) subjects receiving tezacaftor in combination with ivacaftor experienced
increases in ppFEV1 from baseline through day 28 (Figure E2).
Combination of tezacaftor 100 mg qday with ivacaftor 150 mg q12h showed a mean
within-group increase in the CFQ-R respiratory domain score of 3.79 points (P = 0.1679) from
baseline through day 28. The treatment effect vs placebo was 6.81 points (P = 0.2451).
Discussion
This study is the first clinical trial of oral tezacaftor treatment in combination with ivacaftor in
subjects with CF homozygous for F508del and compound heterozygous for F508del/G551D.
Our results demonstrate that tezacaftor monotherapy and in combination with ivacaftor is well
tolerated, with low rates of discontinuation and similar incidences of adverse events in the
placebo, tezacaftor monotherapy, and tezacaftor/ivacaftor combination groups.
The most common adverse events were pulmonary or infectious in nature, which is
consistent with common manifestations of CF. The majority of adverse events were mild to
moderate in severity. The incidence of serious adverse events was lower in the tezacaftor
monotherapy and tezacaftor/ivacaftor combination groups than the placebo group, due largely
to the numerically lower number of pulmonary exacerbations. No other clinically significant
differences in safety profile were observed across any of the treatment groups.
In subjects homozygous for F508del, within-group and between-group decreases in
sweat chloride from baseline through day 28 were observed in the higher-dose tezacaftor
monotherapy groups (100 mg and 150 mg qday) and in most tezacaftor/ivacaftor combination
therapy groups. Changes in sweat chloride following tezacaftor monotherapy or
tezacaftor/ivacaftor combination therapy were not clearly dose dependent, suggesting that
there may be a threshold response among subjects homozygous for F508del. For absolute
and relative change in ppFEV1, within-group or compared with placebo, statistically significant
improvements were observed with tezacaftor/ivacaftor at the higher doses of tezacaftor (100
mg qday and 150 mg qday). The increases observed in the monotherapy groups were variable
and not dose dependent. By contrast, the increases in ppFEV1 in the combination therapy
groups showed dose dependency. Following discontinuation of treatment, sweat chloride and
lung function values returned to near pretreatment levels (day 28 to day 56), providing further
evidence that the effects observed during active dosing were treatment related.
The greatest improvements in both sweat chloride and lung function were observed in
the tezacaftor 100 mg qday/ivacaftor 150 mg q12h group during the dose escalation phase. In
the dosage regimen testing phase, lung function improvements were smaller when using a
twice-daily dosage regimen of tezacaftor (50 mg q12h) with ivacaftor 150 mg q12h or
tezacaftor 100 mg qday with a reduced dose of ivacaftor (50 mg q12h).
Improvements in lung function in patients homozygous for F508del were generally
comparable to or numerically greater than those observed in patients treated with
lumacaftor/ivacaftor in the phase 3, 24-week TRAFFIC/TRANSPORT studies (26). Treatment
initiation with lumacaftor/ivacaftor is sometimes associated with respiratory events and acute
lung function decline (26-30), which can restrict the number of patients willing to start
treatment. The improved benefit-to-risk profile makes tezacaftor/ivacaftor a potential treatment
option for a greater proportion of patients homozygous for F508del.
In subjects compound heterozygous for F508del and G551D, a numerical mean within-
group decrease in sweat chloride from baseline through day 28 was observed in the group
receiving tezacaftor 100 mg qday. Statistically significant within-group improvements from
baseline through day 28 were also observed in the tezacaftor group for the absolute and
relative change in ppFEV1. It is important to note that these subjects had been receiving
physician-prescribed ivacaftor for at least 28 days prior to initiation of tezacaftor treatment and
continued taking ivacaftor through the treatment and follow-up period; likewise, placebo
subjects were also taking ivacaftor during the study period. Therefore the treatment effects
observed with the addition of tezacaftor in these heterozygous subjects are greater than the
effect observed from ivacaftor alone, suggesting the potential to further enhance the benefit of
ivacaftor monotherapy in those who are compound heterozygous for F508del and an ivacaftor-
responsive mutation.
Lumacaftor/ivacaftor combination therapy is the only approved CFTR modulator
treatment for patients with CF homozygous for the F508del mutation. The combination of a
CFTR corrector and potentiator was a milestone treatment approach for CF (13) but is not
approved for patients with the F508del mutation who carry gating or other ivacaftor-responsive
mutations on their second allele. Tezacaftor in combination with ivacaftor may provide an
enhanced benefit-to-risk profile that could benefit a broader population of patients with CF than
either ivacaftor or lumacaftor/ivacaftor combination therapy.
Overall, these clinical trial results support the continued development of tezacaftor 100
mg qday in combination with ivacaftor 150 mg q12h in patients with CF. Based on these
results, this dosage regimen was chosen for phase 3 development. At the time this study was
initiated, ivacaftor was only approved for patients with the G551D gating mutation, therefore
patients with other gating mutations were not enrolled. Phase 3 studies are currently underway
to continue to evaluate tezacaftor/ivacaftor combination therapy in subjects heterozygous for
F508del and a gating mutation that has been shown to be clinically responsive to ivacaftor
(NCT02412111), in subjects homozygous for F508del (NCT02347657), and in subjects
heterozygous for F508del and a second mutation resulting in residual function
(NCT02392234).
Acknowledgements
Additional data review was performed by Kristin Stephan, PhD, an employee of Vertex
Pharmaceuticals Incorporated. Medical writing and editorial support were provided by
Stephanie Vadasz, PhD, and Dena McWain of Ashfield Healthcare Communications, which
received funding from Vertex Pharmaceuticals Incorporated. This project was supported in part
by the National Institutes of Health through grant numbers UL1RR024153 and UL1TR000005
(University of Pittsburgh) and the UK National Institute for Health Research (NIHR) Respiratory
Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation
Trust and Imperial College London. The views expressed in this publication are those of the
authors and not necessarily those of the National Health Service, NIHR, or the Department of
Health. The full list of investigators is provided in the online data supplement.
Disclosures
JC, JAL, LV, and LTW are employees of Vertex Pharmaceuticals Incorporated and may own
stock or stock options in that company. SHD has served as a consultant for AlgiPharma AS
and has received research funding from Vertex Pharmaceuticals Incorporated, Gilead
Sciences, Parion Sciences, N30 Pharmaceuticals, and Grifols. JMP has served on advisory
boards for Vertex Pharmaceuticals Incorporated. ET has received fees from Vertex
Pharmaceuticals Incorporated related to consultation, participation on advisory boards, and
speaking engagements and has served on advisory boards for Novartis and Proteostasis. JCD
has served on advisory boards for Novartis, Pharmaxis, Proteostasis, Pulmocide, and Vertex
Pharmaceuticals Incorporated, and has undertaken educational activities for Vertex
Pharmaceuticals Incorporated (the funder of the study), for which her institution, Imperial
College, has received payment. MG has served on advisory boards for Vertex
Pharmaceuticals Incorporated and PTC Therapeutics for which he has received payment.
References
1. Cutting GR. Cystic fibrosis genetics: from molecular understanding to clinical application.
Nat Rev Genet 2015;16:45-56.
2. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S,
Plavsic N, Chou JL, Drumm ML, Iannuzzi MC, Collins FS, Tsui LC. Identification of the cystic
fibrosis gene: cloning and characterization of complementary DNA. Science 1989;245:1066-
1073.
3. Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M,
Tsui LC. Identification of the cystic fibrosis gene: genetic analysis. Science 1989;245:1073-
1080.
4. Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole
JL, Kennedy D, Hidaka N, Zsiga M, Buchwald M, Riordan JR, Tsui LC, Collins FS.
Identification of the cystic fibrosis gene: chromosome walking and jumping. Science
1989;245:1059-1065.
5. Derichs N. Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator
modulators in cystic fibrosis. Eur Respir Rev 2013;22:58-65.
6. Cystic Fibrosis Foundation. Patient Registry 2014 Annual Data Report; 2015. [cited 2016
May 25]. Available from: www.cff.org/2014-Annual-Data-Report/.
7. Farinha CM, Amaral MD. Most F508del-CFTR is targeted to degradation at an early folding
checkpoint and independently of calnexin. Mol Cell Biol 2005;25:5242-5252.
8. Jensen TJ, Loo MA, Pind S, Williams DB, Goldberg AL, Riordan JR. Multiple proteolytic
systems, including the proteasome, contribute to CFTR processing. Cell 1995;83:129-135.
20
9. Lukacs GL, Chang XB, Bear C, Kartner N, Mohamed A, Riordan JR, Grinstein S. The delta
F508 mutation decreases the stability of cystic fibrosis transmembrane conductance regulator
in the plasma membrane. Determination of functional half-lives on transfected cells. J Biol
Chem 1993;268:21592-21598.
10. Sharma M, Benharouga M, Hu W, Lukacs GL. Conformational and temperature-sensitive
stability defects of the delta F508 cystic fibrosis transmembrane conductance regulator in post-
endoplasmic reticulum compartments. J Biol Chem 2001;276:8942-8950.
11. Flume PA, Liou TG, Borowitz DS, Li H, Yen K, Ordonez CL, Geller DE, V.X. Study Group.
Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation.
Chest 2012;142:718-724.
12. Clancy JP, Rowe SM, Accurso FJ, Aitken ML, Amin RS, Ashlock MA, Ballmann M, Boyle
MP, Bronsveld I, Campbell PW, De Boeck K, Donaldson SH, Dorkin HL, Dunitz JM, Durie PR,
Jain M, Leonard A, McCoy KS, Moss RB, Pilewski JM, Rosenbluth DB, Rubenstein RC,
Schechter MS, Botfield M, Ordonez CL, Spencer-Green GT, Vernillet L, Wisseh S, Yen K,
Konstan MW. 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.
13. Wainwright CE, Elborn JS, Ramsey BW. Lumacaftor-ivacaftor in patients with cystic
fibrosis homozygous for Phe508del CFTR. N Engl J Med 2015;373:1783-1784.
14. US Food and Drug Administration. FDA expands approved use of Kalydeco to treat
additional mutations of cystic fibrosis; 2017. [cited 2017 Jul 5]. Available from:
https://cysticfibrosisnewstoday.com/kalydeco-ivacaftor/.
15. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, Griese M, McKone
EF, Wainwright CE, Konstan MW, Moss R, Ratjen F, Sermet-Gaudelus I, Rowe SM, Dong Q,
Rodriguez S, Yen K, Ordonez C, Elborn JS, Group VXS. A CFTR potentiator in patients with
cystic fibrosis and the G551D mutation. N Engl J Med 2011;365:1663-1672.
16. De Boeck K, Munck A, Walker S, Faro A, Hiatt P, Gilmartin G, Higgins M. Efficacy and
safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst
Fibros 2014;13:674-680.
17. Moss RB, Flume PA, Elborn JS, Cooke J, Rowe SM, McColley SA, Rubenstein RC,
Higgins M, Group VXS. Efficacy and safety of ivacaftor in patients with cystic fibrosis who have
an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir Med
2015;3:524-533.
18. Davies JC, Wainwright CE, Canny GJ, Chilvers MA, Howenstine MS, Munck A, Mainz JG,
Rodriguez S, Li H, Yen K, Ordonez CL, Ahrens R, V. X. Study Group. Efficacy and safety of
ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J
Respir Crit Care Med 2013;187:1219-1225.
19. Orkambi [package insert]. Boston, MA: Vertex Pharmaceuticals Incorporated; 2016.
20. Donaldson S, Pilewski J, Cooke J, Lekstrom-Himes J. Addition of VX-661, an
investigational CFTR corrector, to ivacaftor, a CFTR potentiator, in patients with CF and
heterozygous for F508del/G551D-CFTR [abstract]. Pediatric Pulmonol 2014;49:S260.
21. Pilewski J, Donaldson S, Cooke J, Lekstrom-Himes J. Phase 2 studies reveal additive
effects of VX-661, and investigational CFTR corrector, and ivacaftor, a CFTR potentiator, in
patients with CF who carry the F508del-CFTR mutation [abstract]. Pediatric Pulmonol
2014;49:S10.14.
22. Pilewski JM, Cooke J, Lekstrom-Himes J, Donaldson S. VX-661 in combination with
ivacaftor in patients with cystic fibrosis and the F508del-CFTR mutation [abstract]. J Cyst
Fibros 2014;14:WS01.04.
23. Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. Cystic
Fibrosis Foundation Consensus Panel. J Pediatr 1998;132:589-595.
24. Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in the normal maximal
expiratory flow-volume curve with growth and aging. Am Rev Respir Dis 1983;127:725-734.
25. Kalydeco [package insert]. Boston, MA: Vertex Pharmaceuticals Incorporated; 2017.
26. Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, Colombo C,
Davies JC, De Boeck K, Flume PA, Konstan MW, McColley SA, McCoy K, McKone EF, Munck
A, Ratjen F, Rowe SM, Waltz D, Boyle MP. Lumacaftor-ivacaftor in patients with cystic fibrosis
homozygous for Phe508del CFTR. N Engl J Med 2015;373:220-231.
27. Hubert D, Chiron R, Camara B, Grenet D, Prevotat A, Bassinet L, Dominique S, Rault G,
Macey J, Honore I, Kanaan R, Leroy S, Desmazes Dufeu N, Burgel PR. Real-life initiation of
lumacaftor/ivacaftor combination in adults with cystic fibrosis homozygous for the Phe508del
CFTR mutation and severe lung disease. J Cyst Fibros 2017;16:388-391.
28. Jennings MT, Dezube R, Paranjape S, West NE, Hong G, Braun A, Grant J, Merlo CA,
Lechtzin N. An observational study of outcomes and tolerances in patients with cystic fibrosis
initiated on lumacaftor/ivacaftor. Ann Am Thorac Soc 2017 Apr 13 [Epub ahead of print].
29. Konstan MW, McKone EF, Moss RB, Marigowda G, Tian S, Waltz D, Huang X, Lubarsky
B, Rubin J, Millar SJ, Pasta DJ, Mayer-Hamblett N, Goss CH, Morgan W, Sawicki GS.
Assessment of safety and efficacy of long-term treatment with combination lumacaftor and
ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation
(PROGRESS): a phase 3, extension study. Lancet Respir Med 2017;5:107-118.
30. Labaste A, Ohlmann C, Mainguy C, Jubin V, Perceval M, Coutier L, Reix P. Real-life acute
lung function changes after lumacaftor/ivacaftor first administration in pediatric patients with
cystic fibrosis. J Cyst Fibros 2017 May 18 [Epub ahead of print].
Table 1. Baseline Characteristics
Subjects Homozygous for F508del
Subjects Compound Heterozygous for F508del and
G551DPooled
Tezacaftor Monotherapy
Pooled Tezacaftor
Combination Pooled Placebo
Active Combination
Drug
Placebo(Ivacaftor
Monotherapy)
Tezacaftor Dose10 mg qday-150 mg qday
10 mg qday-150 mg qday or 50
mg q12h NA 100 mg qday 100 mg qday
Ivacaftor Dose NA150 mg qday or
50 mg q12h NA 150 mg q12h NAN 33 106 33 14 4
Female, n (%) 14 (42.4) 47 (44.3) 13 (39.4) 6 (42.9) 3 (75.0)
Age, mean, y (SD) 30.8 (7.9) 29.5 (8.0) 30.7 (8.4) 26.6 (7.0) 34.5 (7.6)
BMI, mean, kg/m2 (SD) 22.4 (3.1) 22.5 (2.8) 21.8 (3.0) 24.6 (3.9) 22.9 (1.0)Sweat chloride, mean, mmol/L (SD) 101.8 (9.2) 99.0 (12.6) 98.4 (13.7) 52.9 (19.6) 56.7 (22.1)
FEV1, % predicted
Mean (SD) 61.1 (14.0) 61.5 (13.8) 58.0 (14.5) 59.1 (16.6) 62.6 (12.7)Range 35.6-89.0 34.2-90.7 35.2-89.9 31.1-79.4 52.6-80.9BMI=body mass index; FEV1=forced expiratory volume in 1 second; NA=not applicable; SD=standard deviation.
25
Table 2. Adverse Events in Subjects Homozygous for F508del Pooled Tezacaftor
MonotherapyPooled Tezacaftor
Combination Pooled PlaceboN 33 106 33Any AE, n (%) 30 (90.9) 92 (86.8) 30 (90.9)Any serious AE, n (%) 2 (6.1) 8 (7.5) 5 (15.2)Serious pulmonary exacerbation 2 (6.1) 7 (6.6) 5 (15.2)Discontinuation due to AE 1 (3.0) 4 (3.8) 0AE=adverse event.
Table 3. Adverse Events in Subjects Homozygous for F508del Occurring in ≥15% of Subjects in Any Active Drug Arm
Pooled Tezacaftor Monotherapy
Pooled Tezacaftor Combination
Pooled Placebo
N 33 106 33Adverse Event, n (%)Infective pulmonary exacerbation of CF 4 (12.1) 24 (22.6) 9 (27.3)Cough 10 (30.3) 17 (16.0) 6 (18.2)Headache 4 (12.1) 16 (15.1) 8 (24.2)Increased sputum 7 (21.2) 11 (10.4) 2 (6.1)Fatigue 7 (21.2) 7 (6.6) 3 (9.1)Nausea 8 (24.2) 11 (10.4) 1 (3.0)Diarrhea 5 (15.2) 6 (5.7) 2 (6.1)CF=cystic fibrosis.
FIGURE LEGENDS
Figure 1. Study Design aStudy arm analyzed in both the dose escalation and dosage regimen testing phases; bFive subjects counted in both pooled placebo groups.
Figure 2. Subject DispositionDisposition in subjects homozygous for F508del-pooled groups in the dose escalation phase (A), the alternate dosage regimen testing phase (B), and in subjects compound heterozygous for F508del and G551D (C). Figure E1 (available online) provides more detail on each study arm.aFive subjects were counted in both pooled placebo groups; bSeventeen subjects who received tezacaftor 100 mg qday/ivacaftor 150 mg q12h were counted in both the dose escalation and dosage regimen testing phases.
Figure 3. Efficacy in Subjects Homozygous for F508del in the Dose Escalation PhaseChange in sweat chloride (A) and absolute change in ppFEV1 (B) from baseline through day 28. Subjects in the combination therapy arms were treated with ivacaftor 150 mg q12h. Monotherapy arms are represented by solid bars. Combination therapy arms are presented by hatched bars. *P < 0.05 vs baseline within group; †P < 0.05 vs placebo; P values only reported for tezacaftor 100 mg qday and tezacaftor 150 mg qday/ivacaftor 150 mg q12h. CI=confidence interval; LS=least squares; ppFEV1=percent predicted forced expiratory volume in 1 second.
Figure 4. Efficacy in Combination Treatment in Subjects Homozygous for F508del in During the Dose Escalation PhaseMean absolute changes in ppFEV1 for the treatment and washout periods for tezacaftor + ivacaftor 150 mg q12h in the dose escalation phase (A) and individual subject absolute changes in ppFEV1 at day 28 for the tezacaftor 100 mg qday + ivacaftor 150 mg q12h (B) and placebo (C) cohorts. Analysis of change from baseline at all measurements up to day 28 was based on a mixed-effect model for repeated measures. For the washout period, summary statistics are shown. LS=least squares; ppFEV1=percent predicted forced expiratory volume in 1 second.
Figure 5. Efficacy in Subjects Homozygous for F508del in the Dosage Regimen Testing Phase Change in sweat chloride (A) and absolute change in ppFEV1 (B) from baseline through day 28. aSubjects also analyzed in the dose escalation phase; bComparison vs placebo not calculated.*P < 0.05 vs baseline within group; †P < 0.05 vs placebo through day 28; P values only reported for tezacaftor 100 mg qday and tezacaftor 150 mg qday/ivacaftor 150 mg q12h. CI=confidence interval; LS=least squares; ppFEV1=percent predicted forced expiratory volume in 1 second.
Figure 6. Efficacy in Subjects Compound Heterozygous for F508del and G551D Who Received Combination TherapyChange in sweat chloride (A) and absolute change in ppFEV1 (B) from baseline through day 28.*P < 0.05 vs baseline within group; †P < 0.05 vs placebo through day 28. CI=confidence interval; LS=least squares; ppFEV1=percent predicted forced expiratory volume in 1 second.
Tezacaftor/Ivacaftor in Subjects with Cystic Fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR
Scott Donaldson, Joseph M. Pilewski, Matthias Griese, Jon Cooke, Lakshmi Viswanathan, Elizabeth Tullis, Jane C. Davies, Julie A. Lekstrom-Himes, Linda T. Wang
Online Data Supplement
List of InvestigatorsThe VX-661-101 Study Group included: Steven Rowe, University of Alabama at Birmingham; John Clancy, Cincinnati Children’s Hospital Medical Center; Karen McCoy, Nationwide Children’s Hospital; Moira Aitken, University of Washington; Scott Donaldson, University of North Carolina School of Medicine; Joseph Pilewski, University of Pittsburgh; Theodore Liou, University of Utah; Philip Black, Children’s Mercy Hospital; Rubin Cohen, Hofstra University; Robert Vender, Pennsylvania State University; Allen Lapey, Massachusetts General Hospital; Manu Jain, Northwestern University Feinberg School of Medicine; Susan Millard, Helen DeVos Children’s Hospital CF Care Center; Gregory Shay, Kaiser Permanente; Henry Thompson, St. Luke’s CF Clinic; Robert Zanni, Monmouth Medical Center; Patrick Flume, Medical University of South Carolina; James Royall, University of Oklahoma Health Sciences Center; Laurie LeClair, University of Vermont College of Medicine; Elizabeth Tullis, St. Michael’s Hospital; Pearce Wilcox, Pacific Lung Research Centre; Roger Michael, Queen Elizabeth II Health Sciences Center; Harvey Rabin, University of Calgary; Yves Berthiaume, University of Montreal Hospital Research Centre; Burkhard Tuemmler, Hannover Medical School; Matthias Griese, Ludwig-Maximilians University; Jochen Mainz, Jena University Hospital; Theodor Zimmerman, University of Erlangen; Silke Van Koningsbruggen-Rietschel, University Hospital of Cologne; Manfred Ballmann, St. Josef-Hospital; Nico Derichs, Charite University Medicine Berlin; Wolfgang Gleiber, J.W. Goethe-University Hospital; Charles Haworth, Papworth Hospital; Ian Ketchell, University Hospital Llandough; Mary Carrol, Southampton General Hospital; Alex Horsley, University of Manchester.
Table E1. Baseline Characteristics Subjects Homozygous for F508del Subjects Compound
Heterozygous for F508del/G551DDose Escalation
Dosage Regimen Testing
Monotherapy Combination
Pooled Placeb
oa Active Drugb
Pooled Placeb
oa
ActiveCombination
Drug
Placebo(Ivacaftor
Monotherapy)
Tezacaftor Dose10 mg qday
30 mg qday
100 mg qday
150 mg qday
10 mg qday
30 mg qday
100 mg qdayb
150 mg qday NA
100 mg qday
50 mg q12h NA
100 mg qday NA
Ivacaftor Dose NA 150 mg q12h NA50 mg q12h
150 mg q12h NA 150 mg q12h NA
N 8 8 8 9 18 19 17 17 24 19 16 14 14 4Female, n
(%)4
(50.0)4
(50.0)3
(37.5)3
(33.3)6
(33.3)6
(31.6)11
(64.7)10
(58.8)8
(33.3)7
(36.8)7
(43.8)6
(42.9)6
(42.9)3
(75.0)
Age, mean, y (SD)
35.3(8.3)
30.8(6.6)
29.1(7.1)
28.2(8.6)
28.3(7.1)
29.2(6.4)
31.0(9.3)
28.2(6.5)
30.2(7.8)
27.9(5.6)
32.8(11.9)
31.4(9.1)
26.6(7.0)
34.5(7.6)
BMI, mean, kg/m2 (SD)
22.7(4.2)
23.6(3.6)
21.4(2.0)
22.2(2.3)
23.0(3.5)
22.3(2.6)
23.0(3.7)
22.0(2.3)
21.7(2.4)
21.9(2.5)
23.1(2.1)
22.2(4.0)
24.6(3.9)
22.9(1.0)
Sweat chloride, mean, mmol/L
(SD)
98.3(6.8)
102.7(8.8)
102.2(11.9)
103.7(9.3)
107.1(8.0)
102.3(10.5)
103.3(6.0)
101.2(6.3)
102.3(8.2)
79.2(9.5)
102.7(9.6)
92.5(16.9)
52.9(19.6)
56.7(22.1)
FEV1, % predicted
Mean (SD)
64.3(11.6)
61.4(19.2)
62.5(13.1)
56.9(12.8)
61.8(13.0)
62.0(13.6)
58.7(16.0)
59.8(16.0)
57.8(15.3)
62.6(14.6)
64.0(10.2)
58.7(14.8)
59.1(16.6)
62.6(12.7)
Range 50.0-80.4
35.6-89.0
43.8-86.5
37.8-77.1
42.1-86.7
40.6-87.5
36.4-90.5
34.2-90.7
35.2-89.9
39.3-84.5
44.3-77.1
39.9-84.3
31.1-79.4
52.6-80.9
aFive subjects counted in both pooled placebo groups; bSeventeen subjects counted in both the dose escalation and dosage regimen testing groups.BMI=body mass index;FEV1=forced expiratory volume in 1 second; NA=not applicable; SD, standard deviation.
Table E2. Summary of Adverse Events Subjects Homozygous for F508del Subjects Compound
Heterozygous for F508del/G551DDose Escalation
Dosage Regimen Testing
Pooled PlaceboMonotherapy Combination Active Druga
Active Combination
Drug
Placebo (Ivacaftor
Monotherapy)
Tezacaftor Dose10 mgqday
30 mgqday
100 mgqday
150 mgqday
10 mgqday
30 mg qday
100 mgqdaya
150 mgqday
100 mg qday
50 mg q12h NA
100 mgqday NA
Ivacaftor Dose NA150 mgq12h
50 mg q12h
150 mg q12h NA 150 mg q12h NA
N 8 8 8 9 18 19 17 17 19 16 33 14 4Any AE, n
(%)8
(100)7
(87.5)7
(87.5)8
(88.9)15
(83.3)18
(94.7)10
(58.8)17
(100)16
(84.2)16
(100)30
(90.9)12
(85.7)2
(50.0)
Any serious AE, n(%)
1(12.5)
1(12.5)
0 (0)
0(0)
1(5.6)
2(10.5)
2(11.8)
0(0)
1(5.3)
2(12.5)
5(15.2)
1(7.1)
0(0)
Serious pulmonary exacerbation, n
(%)
1(12.5)
1(12.5)
0(0)
0(0)
1(5.6)
1(5.3)
2(11.8)
0(0)
1(5.3)
2(12.5)
5(15.2)
0(0)
0(0)
Discontinuation due to AE, n
(%)
1(12.5)
0(0)
0(0)
0(0)
1(5.6)
0(0)
2(11.8)
1(5.9)
0(0)
0(0)
0(0)
0(0)
0(0)
aSeventeen subjects counted in both the dose escalation and dosage regimen testing groups.AE=adverse event.
Table E3. Adverse Events Occurring in ≥15% of Subjects in Any Active Drug Arm Subjects Homozygous for F508del Subjects Compound
Heterozygous for F508del/G551D
Dose Escalation
Dosage Regimen Testinga
Pooled PlaceboMonotherapy Combination
Active Combination
Drug
Placebo (Ivacaftor
Monotherapy)
Tezacaftor Dose10 mgqday
30 mgqday
100 mgqday
150 mgqday
10 mgqday
30 mgqday
100 mgqdaya
150 mgqday
100 mg qday
50 mg q12h NA
100 mgqday NA
Ivacaftor Dose NA150 mg
q12h50 mg q12h
150 mg q12h NA
150 mg q12h NA
N 8 8 8 9 18 19 17 17 19 16 33 14 4Adverse Event, n (%)Infective pulmonary exacerbation of CF 1 (12.5) 1 (12.5) 1 (12.5) 1 (11.1) 5 (27.8) 5 (26.3) 4 (23.5) 2 (11.8) 3 (15.8) 5 (31.3) 9 (27.3) 3 (21.4) 1 (25.0)
Cough 3 (37.5) 3 (37.5) 2 (25.0) 2 (22.2) 2 (11.1) 3 (15.8) 2 (11.8) 3 (17.6) 4 (21.1) 3 (18.8) 6 (18.2) 4 (28.6) 0 (0)
Headache 1 (12.5) 1 (12.5) 1 (12.5) 1 (11.1) 2 (11.1) 4 (21.1) 0 (0) 2 (11.8) 4 (21.1) 4 (25.0) 8 (24.2) 3 (21.4) 0 (0)
Increased sputum 2 (25.0) 2 (25.0) 1 (12.5) 2 (22.2) 2 (11.1) 1 (5.3) 2 (11.8) 1 (5.9) 2 (10.5) 3 (18.8) 2 (6.1) 0 (0) 0 (0)
Fatigue 4 (50.0) 1 (12.5) 1 (12.5) 1 (11.1) 1 (5.6) 3 (15.8) 0 (0) 2 (11.8) 0 (0) 1 (6.3) 3 (9.1) 1 (7.1) 0 (0)
Nausea 1 (12.5) 2 (25.0) 1 (12.5) 4 (44.4) 2 (11.1) 2 (10.5) 1 (5.9) 0 (0) 1 (5.3) 5 (31.3) 1 (3.0) 2 (14.3) 0 (0)
Diarrhea 2 (25.0) 1 (12.5) 1 (12.5) 1 (11.1) 2 (11.1) 1 (5.3) 0 (0) 1 (5.9) 0 (0) 2 (12.5) 2 (6.1) 0 (0) 0 (0)
Hemoptysis 2 (25.0) 0 (0) 2 (25.0) 0 (0) 0 (0) 2 (10.5) 1 (5.9) 1 (5.9) 0 (0) 1 (6.3) 2 (6.1) 1 (7.1) 0 (0)
Vomiting 0 (0) 1 (12.5) 1 (12.5) 2 (22.2) 1 (5.6) 2 (10.5) 0 (0) 1 (5.9) 0 (0) 1 (6.3) 1 (3.0) 1 (7.1) 0 (0)
Pyrexia 3 (37.5) 0 (0) 0 (0) 1 (11.1) 0 (0) 1 (5.3) 0 (0) 1 (5.9) 1 (5.3) 0 (0) 2 (6.1) 2 (14.3) 0 (0)
Rales 2 (25.0) 0 (0) 0 (0) 0 (0) 2 (11.1) 1 (5.3) 2 (11.8) 1 (5.9) 0 (0) 0 (0) 0 (0) 1 (7.1) 1 (25.0)
Nasopharyngitis 0 (0) 1 (12.5) 0 (0) 0 (0) 1 (5.6) 2 (10.5) 0 (0) 3 (17.6) 0 (0) 3 (18.8) 1 (3.0) 1 (7.1) 1 (25.0)Musculoskeletal chest pain 0 (0) 0 (0) 2 (25.0) 0 (0) 1 (5.6) 0 (0) 0 (0) 1 (5.9) 0 (0) 0 (0) 2 (6.1) 0 (0) 0 (0)
Nasal congestion 2 (25.0) 0 (0) 1 (12.5) 1 (11.1) 0 (0) 0 (0) 0 (0) 1 (5.9) 2 (10.5) 1 (6.3) 1 (3.0) 1 (7.1) 1 (25.0)
Sinusitis 2 (25.0) 0 (0) 0 (0) 0 (0) 1 (5.6) 0 (0) 0 (0) 1 (5.9) 0 (0) 0 (0) 3 (9.1) 1 (7.1) 0 (0)
Dizziness 0 (0) 3 (37.5) 0 (0) 1 (11.1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (6.3) 0 (0) 0 (0) 0 (0)
Gastroenteritis 2 (25.0) 0 (0) 0 (0) 1 (11.1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Flatulence 0 (0) 2 (25.0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (6.3) 0 (0) 0 (0) 0 (0)
Abdominal pain 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (5.3) 0 (0) 0 (0) 3 (15.8) 1 (6.3) 2 (6.1) 0 (0) 0 (0)aSeventeen subjects counted in both the dose escalation and dosage regimen testing groups.
CF=cystic fibrosis; NA=not applicable.
Table E4. Adverse Events in Subjects Homozygous for F508del Occurring in ≥15% of Subjects in Any Active Drug Arm During the 28-Day Washout
Pooled Tezacaftor Monotherapy
Pooled Tezacaftor Combination Pooled Placebo
N 33 106 33AE, n (%)Any AE 20 (60.6) 76 (71.7) 24 (72.7)
Infective pulmonary exacerbation of CF 1 (3.0) 21 (19.8) 5 (15.2)
Cough 5 (15.2) 8 (7.5) 3 (9.1)Headache 3 (18.8) 0 (0) 1 (3.0)Nausea 5 (15.2) 6 (5.7) 0 (0)
AE=adverse event; CF=cystic fibrosis.
Table E5. Adverse Events Occurring in ≥15% of Subjects in Any Active Drug Arm During the 28-Day WashoutSubjects Homozygous for F508del Subjects Compound
Heterozygous for F508del/G551D
Dose Escalation
Dosage Regimen Testinga
Pooled PlaceboMonotherapy Combination
Active Combination
Drug
Placebo (Ivacaftor
Monotherapy)
Tezacaftor Dose10 mgqday
30 mgqday
100 mgqday
150 mgqday
10 mgqday
30 mgqday
100 mgqdaya
150 mgqday
100 mg qday
50 mg q12h NA
100 mgqday NA
Ivacaftor Dose NA150 mg
q12h50 mg q12h
150 mg q12h NA
150 mg q12h NA
N 8 8 8 9 18 19 17 17 19 16 33 14 4AE, n (%)
Any AE 7 (87.5) 4 (50.0) 2 (25) 7 (77.8) 13 (72.2) 14 (73.7) 9 (52.9) 15 (88.2) 13 (68.4) 12 (75.0) 24
(72.7) 7 (50.0) 2 (50.0)
Infective pulmonary exacerbation of CF
0 (0) 0 (0) 0 (0) 1 (11.1) 5 (27.8) 5 (26.3) 4 (23.5) 2 (11.8) 2 (10.5) 3 (18.8) 5 (15.2) 2 (14.3) 1 (25.0)
Cough 1 (12.5) 2 (25.0) 0 (0) 2 (22.2) 1 (5.6) 0 (0) 1 (5.9) 1 (5.9) 3 (15.8) 2 (12.5) 3 (9.1) 2 (14.3) 0 (0)
Headache 0 (0) 0 (0) 0 (0) 0 (0) 1 (5.6) 1 (5.3) 0 (0) 0 (0) 0 (0) 3 (18.8) 1 (3.0) 1 (7.1) 0 (0)
Nausea 1 (12.5) 1 (12.5) 0 (0) 3 (33.3) 1 (5.6) 1 (5.3) 0 (0) 0 (0) 1 (5.3) 3 (18.8) 0 (0) 1 (7.1) 0 (0)
Diarrhea 2 (25.0) 0 (0) 0 (0) 1 (11.1) 1 (5.6) 1 (5.3) 0 (0) 1 (5.9) 0 1 (6.3) 1 (3.0) 0 (0) 0 (0)
Pyrexia 3 (37.5) 0 (0) 0 (0) 0 (0) 1 (5.6) 1 (5.3) 0 (0) 0 (0) 0 (0) 0 (0) 1 (3.0) 1 (7.1) 0 (0)aSeventeen subjects counted in both the dose escalation and dosage regimen testing groups.AE=adverse event; CF=cystic fibrosis; NA=not applicable.
Table E6. Pharmacokinetic Parameters of TezacaftorSubjects Homozygous for F508del Subjects Compound
Heterozygous for F508del/G551D
Dose Escalation
Dosage Regimen TestingaMonotherapy Combination
Active Combination Drug
Tezacaftor Dose10 mgqday
30 mgqday
100 mgqday
150 mgqday
10 mgqday
30 mgqday
100 mgqdaya
150 mgqday
100 mg qday
50 mg q12h
100 mgqday
Ivacaftor Dose NA150 mgq12h
50 mg q12h
150 mg q12h
150 mg q12h
Day 1N 8 8 8b 9 18c 16 15d 16 18e 16f 13g
tmax, median (range), h
3.86 (2.08-4.02)
2.50 (0.50-6.02)
3.52 (2.00-4.08)
2.98 (1.00-4.02)
3.00 (0.95-23.90)
2.06 (1.00-6.00)
3.30 (0.98-6.25)
2.47 (0.97-6.00)
3.40 (2.00-11.10)
2.59 (1.00-11.00)
3.07 (1.00-9.08)
Cmax, mean (CV%), ng*h/mL
479 (29)
1490 (43)
5530 (24)
7120 (24)
524 (30)
1360 (22)
5260 (29)
8200 (29)
4720 (20)
2270 (33)
5120 (23)
AUC0-24h, mean (CV%), ng*h/mL
4450 (28)
13200 (21)
57400 (38)
75000 (21)
4880 (23)
13000 (20)
51900 (30)
83900 (29)
49800 (16)
31400 (23)
57200 (20)
Day 28N 7h 8 8i 9 17j 13k 15l 16m 17n 16o 14p
tmax, median (range), h
3.18 (0.97-6.22)
2.48 (0.97-3.83)
4.08 (2.00-1.40)
3.98 (1.95-6.00)
2.02 (0.87-8.08)
2.05 (1.00-4.13)
4.00 (1.00-9.28)
2.97 (2.00-5.85)
2.85 (1.00-9.00)
3.45 (0.97-9.00)
3.28 (1.92-8.72)
Cmax, mean (CV%), ng*h/mL
563 (29)
1930 (26)
6250 (42)
7790 (13)
751 (24)
2240 (21)
6520 (28)
10200 (28)
6270 (25)
4300 (27)
6670 (30)
AUC0-24h, mean (CV%), ng*h/mL
6260 (42)
23000 (28)
88100 (58)
98900 (20)
8950 (27)
26300 (22)
82700 (28)
138000 (36)
77600 (23)
73300 (31)
90600 (34)
CLss/F, mean (CV%), L/h
1.84 (41)
1.43 (37)
1.34 (33)
1.58 (21)
1.20 (28)
1.19 (22)
1.31 (31)
1.25 (43)
1.37 (31)
1.46 (24)
1.26 (43)
t1/2, mean (CV%), h89.9 (43)
173 (26)
111 (26)
166 (26)
105 (64)
136 (31)
156 (34)
147 (24)
149 (38)
158 (37)
170 (29)
ARAUC0-24h,q mean (CV%), ng*h/mL
1.39 (15)
1.76 (22)
1.54 (23)
1.34 (16)
1.94 (20)
1.88 (23)
1.59 (20)
1.69 (23)
1.55 (16)
2.23 (20)
1.67 (31)
aSeventeen subjects counted in both the dose escalation and dosage regimen testing groups; bN=7 for AUC0-24h; cN=17 for AUC0-24h; dN=12 for AUC0-24h; eN=17 for AUC0-24h; fN=13 for AUC0-24h; gN=10 for AUC0-24h; hN= 6 for t1/2; iN=7 for t1/2 and ARAUC0-24h; jN=16 for AUC0-24h; kN=12 for t1/2 and N=10 for AUC0-24h; lN=14 for t1/2 and N=12 for ARAUC0-24h; mN=15 for ARAUC0-24h; nN=15 for ARAUC0-24h; oN=15 for AUC0-24h and CLssF/N; N=14 for t1/2; N=12 for ARAUC0-24h; pN=10 for ARAUC0-24h; qARAUC0-24h was calculated as day 28 tezacaftor AUC0-24h/day 1 tezacaftor AUC0-24h.AR=accumulation ratio; AUC=area under the concentration versus time curve; CLss/F=total systemic clearance; Cmax=maximum concentration; CV=coefficient of variation; NR=not reported; tmax=time of maximum concentration.
Table E7. Pharmacokinetic Parameters of IvacaftorSubjects Homozygous for F508del Subjects Compound
Heterozygous for F508del/G551Da
Dose Escalation
Dosage Regimen Testinga
Tezacaftor Dose10 mgqday
30 mgqday
100 mgqdayb
150 mgqday
100 mg qday
50 mg q12h
100 mgqday
Ivacaftor Dose150 mgq12h
50 mg q12h
150 mg q12h
150 mg q12h
Day 1N 18c 18c 17d 13e 19e 16f 13g
tmax, median (range), h
3.96(2.05-5.98)
4.00(2.98-9.17)
4.05(3.00-11.20)
4.00(1.83-12.00)
4.08(1.93-12.00)
5.08(2.00-11.03)
3.97(1.98-6.00)
Cmax, mean (CV%), ng*h/mL
660 (35)
681 (43)
699 (44)
872 (47)
207 (47)
687 (46)
1150 (46)
AUC0-12h, mean (CV%), ng*h/mL
4590 (38)
5370 (39)
4720 (32)
6530 (48)
1570 (34)
4450 (31)
8850 (37)
Day 28N 17h 11i 14j 13k 16l 15m 14tmax, median (range), h
3.17 (0.48-11.02)
4.13 (200-11.00)
4.00 (3.00-6.08)
4.02 (2.98-6.02)
4.01 (2.00-9.12)
3.77 (1.88-6.00)
4.04 (2.03-8.72)
Cmax, mean (CV%), ng*h/mL
1130 (37)
1280 (40)
1280 (35)
1720 (61)
395 (47)
1410 (42)
1350 (47)
AUC0-12h, mean (CV%), ng*h/mL
10100 (43%)
11800(42%)
10900 (36)
16000 (65)
3690 (40)
11800 (46)
12400 (50)
CLss/F, mean (CV%), L/h
17.1 (35)
15.3 (50)
15.7 (41)
14.0 (86)
16.1 (47)
14.9 (35)
16.7 (68)
t1/2, mean (CV%), h21.4 (62)
11.6 (42)
16.0 (152)
10.3 (24)
10.9 (39)
11.4 (60) NR
ARAUC0-12h,n mean (CV%), ng*h/mL
2.71 (84)
2.14 (47)
2.58 (29)
2.32 (32)
2.46 (46)
1.87 (30) NA
aIvacaftor levels were steady state on day 1; bSeventeen subjects counted in both the dose escalation and dosage regimen testing groups; cN=14 for AUC0-12h; dN=12 for AUC0-12h; eN=11 for AUC0-12h; fN=9 for AUC0-12h; gN=8 for AUC0-12h; hN=16 for AUC0-12h and CLss/F; N=15 for t1/2; N=12 for ARAUC0-12h; iN=9 for t1/2 and ARAUC0-12h; jN=13 for AUC0-12h, CLss/F, and t1/2; N=10 for ARAUC0-12h; kN=11 for ARAUC0-12h; lN=15 for AUC0-12h CLss/F; N=12 for t1/2; N=8 for ARAUC0-12h; mN=14 for AUC0-12h, CLss/F, and t1/2; N=7 for ARAUC0-12h; nARAUC0-12h was calculated as day 28 ivacaftor AUC0-12/day 1 ivacaftor AUC0-12h.AR=accumulation ratio; AUC0-24h=area under the concentration versus time curve; CLss/F=total systemic clearance; Cmax=maximum concentration; CV=coefficient of variation; NA=not applicable; NR=not reported; tmax=time of maximum concentration.
Table E8. Treatment Effects Compared with Placebo in the Dose Escalation Phase in Subjects Homozygous for F508del
Monotherapy CombinationPooled Placebo
Tezacaftor Dose
10 mg qday
30 mg qday
100 mg qday
150 mg qday
10 mg qday
30 mg qday
100 mg qday
150 mg qday NA
Ivacaftor Dose NA 150 mg q12h NAAbsolute change in sweat chloride from baseline through day 28a (mmol/L)Nb 8 6 8 9 18 18 17 17 24Treatment effectc
4.77 −3.91 −19.58 −9.60 −4.20 −5.14 −5.19 −1.77 NA
95% CI −0.30, 9.84 −9.50, 1.68 −24.57, −14.59
−14.38, −4.82
−8.10, −0.31
−9.03, −1.25
−9.16, −1.21
−5.71, 2.17 --
P value NR NR NR NR NR NR 0.0110* 0.3745 --
Absolute change in ppFEV1 from baseline through day 28a (percentage points)N 8 8 8 9 18 19 17 17 24Treatment effectc
3.63 1.76 1.74 2.68 1.44 3.03 3.89 3.75 NA
95% CI −0.16, 7.42 −1.99, 5.52 −2.01, 5.50 −0.92, 6.27 −1.43, 4.31 0.19, 5.88 0.94, 6.83 0.82, 6.68 --P value NR NR NR NR NR NR 0.0101* 0.0125* --
Relative change in ppFEV1 from baseline through day 28a (percentage points)N 8 8 8 9 18 19 17 17 24Treatment effectc
4.87 2.32 2.78 4.15 2.61 4.73 7.04 6.47 NA
95% CI −1.91, 11.65 −4.40, 9.03 −3.94, 9.50 −2.28, 10.59 −2.53, 7.75 −0.37, 9.82 1.77, 12.31 1.23,
11.71 --
P value NR NR NR NR NR NR 0.0093* 0.0160* --aObtained from mixed-effect model for repeated measures (MMRM) with dependent variable absolute change from baseline, fixed effects for treatment, categorical visit (day 7, day 14, day 21, and day 28), and treatment by visit interaction, with adjustment for continuous baseline values, using a compound symmetry covariance matrix;. bThree subjects did not have post-baseline sweat chloride assessments; cDifference between treatments for the least squares mean change from baseline and P value for between treatment comparison. *P < 0.05 vs placebo through day 28; P values only reported for tezacaftor 100 mg qday and tezacaftor 150 mg qday/ivacaftor 150 mg q12h.CI=confidence interval; LS=least squares; NA=not applicable; NR=not reported; ppFEV1=percent predicted forced expiratory volume in 1 second.
Table E9. Treatment Effects Compared with Placebo in the Dosage Regimen Testing Phase
Active Combination Drug Pooled PlaceboTezacaftor Dose 50 mg q12h 100 mg qday NAIvacaftor Dose 150 mg q12h 50 mg qday NAAbsolute change in sweat chloride from baseline through day 28a (mmol/L)Nb 16 18 14Treatment effectc −6.70 −4.89 NA95% CI −12.94, −0.46 −11.20, 1.42 --
Absolute change in ppFEV1 from baseline through day 28a (percentage points)Nc 16 18 14Treatment effectc 0.84 −0.53 NA95% CI −2.82, 4.51 −4.10, 3.04 --
Relative change in ppFEV1 from baseline through day 28a (percentage points)Nc 16 18 14Treatment effectc 1.02 −1.57 NA95% CI −6.04, 8.08 −8.44, 5.30 --
aObtained from mixed-effect model for repeated measures (MMRM) with dependent variable absolute change from baseline, fixed effects for treatment, categorical visit (day 7, day 14, day 21, and day 28), and treatment by visit interaction, with adjustment for continuous baseline values, using a compound symmetry covariance matrix; bOne subject did not have post-baseline assessments; cDifference between treatments for the least squares mean change from baseline and P value for between treatment comparison. CI=confidence interval; LS=least squares; NA=not applicable; ppFEV1=percent predicted forced expiratory volume in 1 second.
Tezacaftor 100 mg qday/Ivacaftor 150 mg q12h
Placebo/Ivacaftor 150 mg q12h
Absolute change in sweat chloride from baseline through day 28a (mmol/L)Nb 13 4Treatment effectc −17.20 NA95% CI −31.75, −2.65 --P value 0.0238* --
Absolute change in ppFEV1 from baseline through day 28a (percentage points)N 14 4Treatment effectc 3.20 NA95% CI −4.10, 10.51 --P value 0.3646 --Relative change in ppFEV1 from baseline through day 28a (percentage points)N 14 4Treatment effectc 3.72 NA95% CI −7.77, 15.21 --P value 0.5007 --Table E10. Treatment Effects Compared with Placebo in Subjects Compound Heterozygous for F508del and G551D Who Were Receiving Physician-Prescribed IvacaftoraObtained from mixed-effect model for repeated measures (MMRM) with dependent variable absolute change from baseline, fixed effects for treatment, categorical visit (day 7, day 14, day 21, and day 28), and treatment by visit interaction, with adjustment for continuous baseline values, using a compound symmetry covariance matrix; bOne subject did not have post-baseline sweat chloride assessments; cDifference between treatments for the least squares mean change from baseline and P value for between treatment comparison.*P < 0.05 vs placebo through day 28.CI=confidence interval; LS=least squares; NA=not applicable; ppFEV1=percent predicted forced expiratory volume in 1 second.
Figure E1. Subject Disposition Disposition for all subjects in the dose escalation phase (A), the dosage regimen testing phase (B), and in subjects compound heterozygous for F508del and G551D (C).aFive subjects were counted in both pooled placebo groups; bSeventeen subjects who received tezacaftor 100 mg qday/ivacaftor 150 mg q12h were counted in both the dose escalation and dosage regimen testing phases.
Figure E2. Efficacy in Subjects Compound Heterozygous for F508del and G551DMean absolute changes in ppFEV1 for the treatment and washout periods (A) and individual subject absolute changes in ppFEV1 at day 28 for the tezacaftor 100 mg qday + ivacaftor 150 mg q12h (B) and placebo (C) cohorts. Analysis of change from baseline at all measurements up to day 28 was based on a mixed-effect model for repeated measures. For the washout period, summary statistics are shown. LS=least squares; ppFEV1=percent predicted forced expiratory volume in 1 second.