Efficacy and safety of the CFTR potentiator icenticaftor
(QBW251) in COPD: Results from a phase 2 randomized trial
Steven M. Rowe1, Ieuan Jones2, Mark T. Dransfield1, Nazmul
Haque2, Stephen Gleason2, Katy A. Hayes2, Kenneth Kulmatycki2,
Denise P. Yates2, Henry Danahay3, Martin Gosling3,4 David J.
Rowlands2, Sarah S. Grant2
1University of Alabama at Birmingham, Department of Medicine,
Birmingham, AL, USA
2Novartis Institutes for BioMedical Research, Cambridge, MA,
USA
3Enterprise Therapeutics, Brighton, United Kingdom
4Sussex Drug Discovery Centre, University of Sussex, Brighton,
United Kingdom.
Supplementary material
List of participating study centres and principal
investigators
Principal investigator
Study centre
Piotr Kuna
SPZOZ Uniwersytecki Szpital
Kliniczny nr 1 im. Norberta Barlickiego
Lodz 90-153
Poland
Dr. Mark Dransfield
UAB Lung Health Center
Birmingham AL 25394
USA
Dr. Leonard Dunn
Clinical Research of West Florida, Inc.
Clearwater FL 33765
USA
Dr. Charles Fogarty
Spartanburg Medical Reserach
Spartanburg SC 29303
USA
Dr. Stephen Watson
Carolina Research Center, Inc.
Shelby NC 28150
USA
Dr. Edward Kerwin
Clinical Research Institute of Southern
Oregon, PC
Medford OR 97504
USA
Dr. James Pearle
California Research Medical Group
Fullerton CA 92835
USA
Dr. Krishna Pudi
Upstate Pharmaceutical Research
Greenville SC 29615
USA
Dr. Dareen Siri
Sneeze, Wheeze, & Itch Associates,
LLC
Normal IL 61761
USA
Dr. Alexander White
Progressive Medical Research
Port Orange FL 32127
USA
Dr. Joseph Boscia III
CU Pharmaceutical Research
Union SC 29379
USA
Dr. Asha Stern
Research Carolina of Huntersville
Huntersville NC 28078
USA
Methods
Study design and participants
During the entire study duration, patients were maintained on
their baseline COPD therapy (short-acting beta-2 agonist [SABA],
long-acting beta-2 agonist [LABA], long-acting muscarinic
antagonist [LAMA], and/or inhaled corticosteroids [ICS]).
Prohibited medications included theophylline, chronic daily
steroids or PDE4 inhibitors within four weeks of screening. In
addition, as icenticaftor is a potential CYP1A2 inhibitor and
CYP3A4 inducer, drugs with potential increased exposure due to
CYP1A2 inhibition or decreased exposure with CYP3A4 induction were
prohibited, including ciprofloxacin and verapamil (CYP1A2), and
cyclosporine, sirolimus, tacrolimus, and fentanyl (CYP3A4).
Medications to be withheld between 24 and 6 hours before study
visits included SABAs, SAMAs, LABAs and LAMAs. Subjects with a COPD
exacerbation during the treatment period or placebo follow-up
period, defined as worsening of pulmonary symptoms requiring
hospitalization, systemic steroids, systemic antibiotics or more
than six uses of rescue inhalers or nebulizer treatments within a
24-hour period on two consecutive days, were required to
discontinue. Subjects who discontinued the study for any reason
completed a final clinic visit where final safety assessments were
collected.
Key inclusion and exclusion criteria are listed below (Table
E1).
Table E1. Patient key inclusion and exclusion criteria
Inclusion criteria
Exclusion criteria
· Age: ≥35 and ≤75 years
· COPD exacerbation or respiratory tract infection in the 6
weeks before screening, during the screening period, or during the
run-in period
· Diagnosis of COPD according to GOLD criteria:
post-bronchodilator FEV1/FVC ratio ≤0.7 and FEV1 between 30–79%
predicted (1)
· Baseline CT scan demonstrated significant radiographic
emphysema (>25% whole lung) or with a diagnosis of severe
bronchiectasis or another concomitant pulmonary disease
· Smoking history (current or former): ≥10 pack-years
· Unchanged underlying COPD treatment regimen for ≥4 weeks prior
to screening and during the placebo run-in period
· Symptoms of chronic bronchitis (cough and sputum production on
most days for a minimum of 3 months during the last year)
· Evidence of global air trapping (≥15%) on a baseline
end-expiratory computed tomography (CT) scan
· Lung clearance index 2.5 (LCI) ≥8 at screening, adapted from
trials in CF patients (LCI >8 indicates small airway
dysfunction)
FEV1, forced expiratory volume in 1 second; FVC, forced vital
capacity
Randomization and masking
On Day 1, eligible patients were randomized using an interactive
response technology system to treatment with either 300 mg b.i.d.
icenticaftor or placebo (2:1) orally. Two patients received 450 mg
b.i.d. icenticaftor before protocol amendment reducing the dose to
300 mg b.i.d. icenticaftor. Subjects were stratified according to
smoking status (smoker or ex-smoker). The placebo run-in and
placebo follow-up periods were single-blinded, with only the
patients being blinded, while the treatment period with
icenticaftor or placebo was double-blinded, with patients,
investigator staff, persons performing the assessments, and data
analysts blinded to the identity of study treatments. Novartis was
unblinded to completed subjects data at the time of the interim
analysis and at the end of study (EOS).
Procedures and outcomes
Spirometry, in accordance with American Thoracic
Society/European Respiratory Society guidelines, was performed with
the patient in a sitting position. National Health and Nutrition
Examination Survey III reference ranges (NHANES III) were used.
Spirometry and all pulmonary function assessments performed at all
sites were reviewed centrally. Spirometry was performed in the
following order: pre-bronchodilator spirometry, post-bronchodilator
spirometry (assessed 15 minutes after 200 ug of
salbutamol/albuterol), diffusing capacity of the lungs for carbon
monoxide (DLCO), slow vital capacity, multiple breath nitrogen
washout (MBNW).
Spontaneous sputum was used to quantify colony forming units
(CFUs) as a potential efficacy marker. The data on following key
respiratory pathogens was collected: Haemophilus parainfluenza, H.
influenza, Pseudomonas aeruginosa, Moraxella catarrhalis, and
Streptococcus pneumonia.
An expiratory HRCT was performed at Screening and on Day 29 to
assess the change from baseline in quantitative air trapping.
Centralized review of the HRCT image data was performed by MedQIA,
Los Angeles, California. Historical HRCT scans were also used at
the Screening visit for assessing (i) extent of emphysema if
acquired within 6 months prior to Screening visit (ii) air trapping
if acquired within 3 months of the Screening visit (only applicable
to patient who were re-screened). HRCT scans, regardless of origin
(at Screening or historical) must have exhibited <25% total lung
emphysema extent and <15% total lung air trapping. The total
radiation exposure for a single patient completing the study did
not exceed 10 millisievert (mSv) which was less than the annual
limits allowed in the EU and US, 20 and 50 mSv, respectively.
Proposed revision for HRCT section:
A central imaging CRO, MedQIA, Los Angeles, CA provided HRCT
accreditation, site-specific imaging protocols and centralized
imaging review for the inclusion criteria and exploratory efficacy
analysis of quantitative air trapping. Briefly, all clinical
centers performed as part of the quality assessment COPD Gene
phantom imaging at all time points (screening and Day 29). At the
screening visit, thin section volumetric chest CT was performed at
Total Lung Capacity (TLC) and Residual Volume (RV) was used for
evaluation of the inclusion criteria and at Day 29, the RV scan to
assess the change from baseline in quantitative air trapping. The
total radiation exposure for a single patient completing the study
did not exceed 10 millisievert (mSv) which was less than the annual
limits allowed in the EU and US, 20 and 50 mSv, respectively.
The independent (blinded and de-identified) imaging analysis
included semi-automated evaluation of lung and lobar volumes which
were then subject to a CAD-based quantitative assessment to
determine percent total lung and lobar regions with pixel intensity
thresholds of less than −950 HU (TLC) and −856 HU (RV) for
emphysema and air trapping extent, respectively. To satisfy HRCT
inclusion, TLC must have exhibited <25% total lung emphysema
extent and RV > 15% total lung air trapping. Change from
baseline statistical analysis was performed on the RV derived whole
lung and lobar percentages of air trapping that were evaluated with
the same CAD based quantitative analysis. Exploratory 3D renderings
were constructed to further visualize regional patterns of
response.
Pharmacokinetic assessments
Plasma samples were obtained from all patients and
pharmacokinetics were evaluated in all patients who received
icenticaftor. Icenticaftor was analyzed by a validated liquid
chromatography tandem mass spectrometry (LC-MS/MS) method with a
lower limit of quantification (LLOQ) of 1 ng/mL. Concentrations
below the LLOQ were reported as “0” (zero) and missing data was
labeled as such in the Bioanalytical Data Report. The following PK
parameters were calculated: Cmax, Clast, Tmax, Tlast, and AUClast
on Day 1 and on Day 28.
Patient-reported outcomes (PRO)
The PRO measurements included St. George’s Respiratory
Questionnaire (SGRQ) and Baseline/Transition Dyspnea Index
(BDI/TDI) in the same order.
The SGRQ is a disease-specific instrument designed to measure
the impact on overall health, daily life, and perceived well-being
in patients with obstructive airways disease. It contains 51 items
divided into 3 components: “Symptoms” concerned with respiratory
symptoms, their frequency and severity; “Activity” concerned with
activities that cause or are limited by breathlessness; and
“Impacts” which covered a range of aspects concerned with social
functioning and psychological disturbances resulting from airway
disease.
The TDI is an 8-point scale PRO designed to measure functional
impairment, magnitude of task and magnitude of effort. It was
administered to the patient by investigator staff during interview.
Patients were interviewed by an assessor experienced in the use of
such questionnaires. Every attempt was made to ensure that it was
the same assessor that completed all the TDI assessments for an
individual patient. BDI/TDI was conducted after the SGRQ
assessment.
Statistical analysis
Sample size and power
A sample size of approximately 90 patients was required for the
study (icenticaftor, n=60; placebo, n=30) in order to appropriately
power for both LCI and FEV1. For LCI, assuming the true effect was
2 over placebo (SD: 3.8), an analysis had 80% power for declaring
statistically important effect at Day 29. For pre-bronchodilator
FEV1, assuming the true effect at Week 4 was 0.1 L over placebo
(SD: 0.2 L), a Bayesian analysis utilizing a weakly informative
prior had 90% power for declaring a statistically important effect.
The expected placebo response was evaluated by summarizing 1200
subjects from similar historical Novartis COPD trials. A
meta-analytic predictive prior was used to quantify the placebo in
the new trial.(2) It was believed to be normally distributed with a
mean change of 0.02 L worse (SD of 0.05 L). This approach allows
for uncertainty in the belief about placebo due to trial-to-trial
variability by discounting the prior and allowed Novartis to reduce
the sample size by 14 placebo subjects. The Bayesian sample size
calculations were performed using the freely available software
(3).
The study also assessed additional spirometric parameters
including forced expiratory flow (FEF25–75), forced expiratory
volume in 6 seconds (FEV6), inspiratory capacity (IC) and residual
volume (RV); however, the study was not appropriately powered for
these assessments.
Interim analysis
A total of 3 interim analyses (IAs) were performed during the
study. The IA, unblinded to the study statistician, included data
from 28 patients with FEV1, and was used to assess LCI and FEV1
variability to confirm sample size assumptions. The second
unblinded IA included data from 42 patients, and was used to assess
the probability of futility for LCI and FEV1. Futility criteria
(≥60% posterior probability that the treatment effect was worse
than placebo) were not met and the study continued as planned. The
third IA included data from 63 patients, and was used to support
internal decision-making evaluation for further development.
Population sets
Efficacy data were analyzed in patients who received any
treatment and had available pharmacodynamic data with no major
relevant protocol deviations. Patients were excluded from the PD
analysis if they did not complete the 28 day treatment period
(withdrawal of consent, AEs, PDs related to inclusion/exclusion),
if >2 days elapsed between the last dose of icenticaftor and the
Day 29 assessments, or if a COPD exacerbation occurred in the
2-weeks before or after the Day 29 visit. CFU analysis population
also required ≥1 pathogen isolated at baseline and ≥1
post-randomization assessment available. The percentage of
eradication at EOS was compared between treatments using a Bayesian
logistic model with non-informative priors.
For safety analysis, all AE data were displayed by treatment,
dose and patient. Absolute values and change from baseline values
for HRCT were listed by treatment, time point and patient.
Results
Table E2. Change from baseline for spirometry and lung volume
measurements on Day 29 (Bayesian analysis)
Raw
Posterior distribution
Posterior distribution of treatment difference versus Placebo
(Icenticaftor–placebo)
Parameter
Treatment
N
Mean ± SD
Mean ± SD
Mean ± SD
90% CrI
Probability (icenticaftor better than placebo
FVC pre (L)
Placebo
23
0.01 ± 0.36
0.01 ± 0.08
0.06 ± 0.09
−0.09, 0.21
0.73
Icenticaftor
51
0.07 ± 0.35
0.07 ± 0.05
FVC post (L)
Placebo
24
0.00 ± 0.22
0.01 ± 0.05
0.02 ± 0.07
−0.09, 0.12
0.62
Icenticaftor
51
0.03 ± 0.28
0.03 ± 0.04
FEV6 pre
(L)
Placebo
23
−0.00 ± 0.31
0.01 ± 0.06
0.06 ± 0.08
−0.08, 0.18
0.78
Icenticaftor
51
0.06 ± 0.30
0.07 ± 0.04
FEV6 post
(L)
Placebo
24
−0.03 ± 0.19
−0.02 ± 0.05
0.05 ± 0.06
−0.05, 0.15
0.82
Icenticaftor
51
0.04 ± 0.26
0.04 ± 0.04
FEF25–75% pre (L/s)
Placebo
23
−0.02 ± 0.15
−0.02 ± 0.03
0.05 ± 0.04
−0.02, 0.11
0.88
Icenticaftor
51
0.03 ± 0.16
0.03 ± 0.02
FEF25–75% post (L/s)
Placebo
24
−0.02 ± 0.16
−0.02 ± 0.04
0.06 ± 0.05
−0.02, 0.14
0.91
Icenticaftor
51
0.05 ± 0.21
0.04 ± 0.03
RV (L)
Placebo
24
−0.03 ± 0.44
−0.02 ± 0.10
0.05 ± 0.12
−0.15, 0.25
0.34
Icenticaftor
48
0.01 ± 0.51
0.03 ± 0.07
IC (L)
Placebo
24
−0.06 ± 0.16
−0.05 ± 0.06
0.05 ± 0.07
−0.06, 0.16
0.78
Icenticaftor
50
0.00 ± 0.31
0.00 ± 0.04
b.i.d, twice daily; CrI, credible interval; FEF, forced
expiratory flow; FEV, forced expiratory volume; FVC, forced vital
capacity; IC, inspiratory capacity; LS, least squares; RV, residual
volume
Table E3. Summary of sputum microbiology (pharmacodynamic
analysis set)
Type of organism
Isolate
Visit
Placebo
Icenticaftor
Haemophilus influenzae
1
Baseline
1419285.7 (1725636.85)
419652.2 (461411.15)
Day 29
432550.0 (496992.31)
767260.0 (1290194.99)
EOS
771692.3 (1592153.85)
1450024.3 (1777665.15)
Pseudomonas aeruginosa
Biotype 2 – dry
1
Baseline
-
12000.0 (11313.71)
Day 29
1400.0 (-)
17000.0 (18384.78)
EOS
-
40000.0 (-)
Pseudomonas aeruginosa
Small colony variant
1
Baseline
-
2400.0 (-)
Table E4. Incidence of adverse events (AEs) by preferred term,
arranged by frequency in the total column (safety set)
Parameter
PlaceboN=28, n (%)
IcenticaftorN=64, n (%)
TotalN=92, n (%)
Patients with AEs
11 (39.3)
26 (40.6)
37 (40.2)
Chronic obstructive pulmonary disease
2 (7.1)
4 (6.3)
6 (6.5)
Diarrhea
2 (7.1)
2 (3.1)
4 (4.3)
Dyspnea
1 (3.6)
2 (3.1)
3 (3.3)
Nasopharyngitis
1 (3.6)
2 (3.1)
3 (3.3)
Nausea
2 (7.1)
1 (1.6)
3 (3.3)
Constipation
1 (3.6)
1 (1.6)
2 (2.2)
Cough
0
2 (3.1)
2 (2.2)
Non-cardiac chest pain
0
2 (3.1)
2 (2.2)
Productive cough
0
2 (3.1)
2 (2.2)
Vomiting
0
2 (3.1)
2 (2.2)
AEs that occurred in >2% of study population are
presented
AE, adverse events; b.i.d., twice daily
Figure E1. Radar plot demonstrating probability of a positive
effect with icenticaftor for 6 different endpoints at Day 29*
Data presented as mean (90% credible interval). For CFU, data
presented as odds of response (90% credible interval)
*For CFU, data presented were at EOS
BD, bronchodilator; CFU, colony forming units; EOS, end of
study; FEV1, forced expiratory volume in 1 second; LCI, lung
clearance index
Pharmacokinetics
After single and multiple oral doses of icenticaftor 300 mg
b.i.d. to COPD patients, absorption of icenticaftor was rapid with
median Tmax at 1.27 hr and 1.98 hr, respectively, as shown in Table
E5. Although AUClast was only calculated to 8 hours, icenticaftor
exposure (Cmax and AUC) increased after multiple-dose
administration to less than 2-fold on Day 28. The mean plasma
concentration-time profiles of icenticaftor following single and
multiple doses is shown in Figure E2.
Table E5. Pharmacokinetic parameters following single and
multiple oral doses of icenticaftor 300 mg twice daily
Day
Statistic
AUClast(hr*ng/mL)
Clast(ng/mL)
Cmax(ng/mL)
Tlast(hr)
Tmax(hr)
Day 1
N
57
57
57
57
57
Mean (SD)
3830 (3280)
241 (445)
1250 (840)
CV% mean
85.6
185
67.2
Geo-mean
3040
142
969
CV% geo-mean
80.0
97.3
96.7
Median
3070
124
1080
8.00
1.27
min-max
312-24000
37.2-2570
52.9-4660
7.77-8.08
0.983-8.03
Day 28
N
53
53
53
53
53
Mean (SD)
6840 (4490)
552 (569)
1640 (916)
CV% mean
65.7
103.0
56.0
Geo-mean
5710
394
1380
CV% geo-mean
65.4
92.7
67.1
Median
5350
390
1480
8.00
1.98
min-max
1820-22400
88.3-3380
372-3640
7.73-8.08
0.933-7.97
AUClast, area under the plasma concentration-time curve
calculated to the last quantifiable concentration; Clast, last
observed quantifiable concentration; Cmax, observed maximum
concentration; Tlast, time point corresponding to the last
quantifiable concentration; Tmax, time to reach maximum
concentration
Figure E2. Arithmetic mean (SD) concentration-time profiles of
icenticaftor after administration of single and multiple oral doses
of 300 mg twice daily
After single and multiple oral doses of icenticaftor 450 mg
b.i.d. to COPD patients, absorption was rapid with median Tmax
ranging from 2 to 4 hours. The AUClast, Cmax and Clast was
calculated from two patients on Day 1 and for one patient on Day 28
is presented in Table E6. The plasma concentration-time profiles of
icenticaftor 450 mg following single and multiple oral doses is
shown in Figure E3.
Table E6. Pharmacokinetic parameters for two subjects after a
single and one subject after multiple oral doses of icenticaftor
450 mg twice daily
Day
AUClast(hr*ng/mL)
Clast(ng/mL)
Cmax(ng/mL)
Tlast(hr)
Tmax(hr)
1
16800
1850
2900
8.05
2.03
1
17600
2100
3040
8.02
4.00
28
44700
5640
6460
7.95
4.03
AUClast, area under the plasma concentration-time curve
calculated to the last quantifiable concentration; Clast=last
observed quantifiable concentration; Cmax, observed maximum
concentration; Tlast, time point corresponding to the last
quantifiable concentration; Tmax, time to reach maximum
concentration
Figure E3. Concentration-time profiles of icenticaftor after
administration of single and multiple oral doses of 450 mg twice
daily
Patient-reported outcomes
Baseline Dyspnea Index and Transition Dyspnea Index
An increase in mean change from baseline TDI scores is
considered improvement. On Day 29, the mean TDI scores of
functional impairment, magnitude of task, magnitude of effort and
adjusted total score for icenticaftor (placebo) were 0.10 (0.42),
0.18 (0.58), 0.06 (0.33) and 0.32 (1.33), respectively. The mean
scores increased in both placebo and icenticaftor groups as
compared with baseline, but relative to placebo, there was no
improvement noted with icenticaftor. On Day 29, the estimated mean
difference (icenticaftor to placebo) in change from baseline TDI
was − 1.00 (90% CI: − 1.81, − 0.19), suggesting no improvement with
icenticaftor as compared with placebo.
St. George’s Respiratory Questionnaire
A decrease in scores from baseline is considered improvement,
with a 4-point change representing a clinically meaningful
improvement. The estimated mean difference (icenticaftor to
placebo) in change from baseline for the SGRQ total score did not
suggest improvement with icenticaftor as compared with placebo. For
the SGRQ-Symptoms and SGRQ-Impacts domains, the estimated mean
difference (icenticaftor to placebo) in change from baseline
suggests a numerical trend for improvement with icenticaftor as
compared with placebo.
Activity of icenticaftor on WT CFTR
Authors: Giles Pergl-Wilson, Henry Danahay and Martin
Gosling
Methods:
Cell culture:
Human bronchial epithelial cells from wt or homozygous F508del
CFTR donors were cultured using a modification of the method
described by Gray and colleagues (4). Briefly, cells (1 x 106) were
seeded in plastic T-162 flasks and were grown in bronchial
epithelial cell growth medium (BEGM; Lonza) supplemented with
bovine pituitary extract (52 μg/mL), hydrocortisone (0.5 μg/mL),
human recombinant epidermal growth factor (0.5 ng/mL), epinephrine
(0.5 μg/mL), transferrin (10 μg/mL), insulin (5 μg/mL), retinoic
acid (0.1 μg/mL), triiodothyronine (6.5 μg/mL), gentamicin (50
μg/mL), and amphotericin B (50 ng/mL). Cells were seeded onto
collagen-coated polyester inserts (Transwell and Snapwell; Costar)
in differentiation media containing 50% DMEM in BEGM with the same
supplements as above but without triiodothyronine and a final
retinoic acid concentration of 50 nM (all-trans retinoic acid).
Cells were maintained submerged for the first 7 days in culture.
After 7 days submerged, the cells were exposed to air liquid
interface (ALI) for the remainder of the culture period. Cells were
used between days 14 and 28 after establishment of the ALI. At all
stages of culture, cells were maintained at 37°C in 5% CO2 in an
air incubator unless otherwise stated.
Short-circuit current (ISC) measurements:
Snapwell inserts were mounted in Vertical Diffusion Chambers
(Harvard Apparatus), bathed with continuously gassed physiological
salt solution (5% CO2 in O2; pH 7.4) maintained at 37°C. Cells were
voltage clamped to 0 mV and transepithelial resistance measured.
Sequentially, amiloride (10 μM) followed by FSK EC20 and then
cumulative concentrations of icenticaftor (or vehicle) were added
to both the apical and basolateral chambers. At the end of the
experiment, CFTRinh172 (30 μM apical) was added to inhibit all CFTR
mediated anion transport.
Results:
CFTR mutation
EC50 (uM)
N
None
0.072 ± 0.045
13
F508del/F508del
0.032 ± 0.0151
18
EC50 values are expressed as mean ± standard deviation (SD).
EC20 values for FSK were calculated to cause and increase in ISC
equivalent to 20% of the maximum IFSK value as determined by the
sigmoidal curve fit of the FSK concentration response
References
1. Global Initiative for Chronic Obstructive Lung Disease.
Global Strategy for the diagnosis, management, and prevention of
chronic obstructive pulmonary disease (2013 report). . 2013.
2. Neuenschwander B, Capkun-Niggli G, Branson M, Spiegelhalter
DJ. Summarizing historical information on controls in clinical
trials. Clin Trials 2010; 7: 5-18.
3. Fisch R, Jones I, Jones J, Kerman J, Rosenkranz GK, Schmidli
H. Bayesian Design of Proof-of-Concept Trials. Therapeutic
Innovation & Regulatory Science 2015; 49: 155-162.
4. Gray TE, Guzman K, Davis CW, Abdullah LH, Nettesheim P.
Mucociliary differentiation of serially passaged normal human
tracheobronchial epithelial cells. Am J Respir Cell Mol Biol 1996;
14: 104-112.
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