Arnuity Ellipta - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Arnuity Ellipta - Scientific Information

Manufacture: GlaxoSmithKline
Country: Canada
Condition: Asthma, Maintenance
Class: Inhaled corticosteroids
Form: Inhaler
Ingredients: Fluticasone Furoate, Lactose Monohydrate

Pharmaceutical Information

Drug Substance

Proper name: fluticasone furoate
Chemical name: (6α,11β,16α,17α)-6,9-difluoro-17-{[(fluoro-methyl)thio]carbonyl}-11-hydroxy-16-methyl-3-oxoandrosta-1,4-dien-17-yl 2-furancarboxylate
Molecular formula and molecular mass: C27H29F3O6S  538.6
Structural formula:
Physicochemical properties: fluticasone furoate is a white powder. It is practically insoluble in water.

Clinical Trials

Trial Design and Demographics

The efficacy of ARNUITY ELLIPTA 100 mcg and 200 mcg in the treatment of asthma has been evaluated in four randomized, double blind, parallel-group clinical trials of between 12 and 24 weeks in duration (FFA112059, HZA106827, FFA114496 and HZA106829) in patients aged 12 years and older with persistent asthma. These pivotal trials were designed to evaluate the efficacy of ARNUITY ELLIPTA 100 mcg and 200 mcg, given once-daily in the evening, on lung function in subjects who were not controlled on their current treatments of inhaled corticosteroids, or combination therapy consisting of an inhaled corticosteroid plus a long-acting beta2-adrenergic agonist (LABA).

Two of these studies (FFA112059 and HZA106829) included a comparator group in order to compare the relative benefits of ARNUITY ELLIPTA with the established inhaled corticosteroid fluticasone propionate.

Study treatments were delivered as inhalation powders. The primary endpoint in all pivotal trials was change from baseline in evening trough FEV1 measured approximately 24 hours after the final dose of study medication. Trough FEV1 (assessed at approximately 24 hours after the previous dose) was also assessed at clinic visits throughout the trials. Studies HZA106827 and HZA106829 had a co-primary endpoint of change from baseline in weighted mean serial FEV1 measured after the final dose of study medication at 5, 15, and 30 minutes and 1, 2, 3, 4, 5, 12, 16, 20, 23, and 24 hours post-dose in a subset of patients. Details of the design and patient demographics of the pivotal trials are described in Table 1

Table 1 - Summary of Trial Design and Patient Demographics for Pivotal Trials
Study # Trial Design, Route of Administration and Study Duration Treatment and Dosage Study Subjects
Mean Age (Range)
Gender (%)
Primary Efficacy Endpoint(s)
FFA112059 24 week, multicenter, randomized,placebo-controlled (with rescue medication) double-blind, double-dummy,parallel group study to evaluate the efficacy and safety of FF 100 mcg administered once-daily in the evening in adolescent and adult subjects 12 years of age and older with persistent bronchial asthma. FF 100 mcg OD
FP 250 mcg BD
Placebo
Total:343
40.6 years (12-84)
Male: 41%
Female: 59%
Trough FEV1 at Week 24
HZA106827 12 week, multicenter, stratified,randomized, double-blind, placebo-controlled (with rescue medication),parallel group study to compare the efficacy and safety of FF/VI 100/25 mcg and FF 100 mcg both administered once-daily in the evening in adolescent and adult subjects 12 years of age and older with persistent bronchial asthma. FF 100 mcg OD
FF/VI 100/25 mcg OD
Placebo
Total: 609
39.7 years (12-84)
Male: 42%
Female: 58%
Trough FEV1 at Week 12
Weighted mean FEV1 (0-24 hours) at Week 12
FFA114496 24 week, multicenter, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of inhaled FF 100 mcg and 200 mcg administered once-daily in the evening in adolescent and adult subjects 12 years of age and older with persistent asthma.
FF 100 mcg OD
FF 200 mcg OD
Total: 238
45.9 years (12-76)
Male: 33%
Female: 67%
Trough FEV1 at Week 24
HZA106829 24 week, multicenter, stratified,randomized, double-blind, double-dummy,parallel group, active controlled study to compare the efficacy and safety of FF/VI 200/25 mcg administered once-daily each evening to FF 200 mcg administered alone once-daily each evening in adolescent and adult subjects 12 years of age and older with persistent bronchial asthma. FF 200 mcg OD
FF/VI 200/25 mcg OD
FP 500 mcg BD
Total: 586
46.2 years (12-76)
Male: 41%
Female: 59%
Trough FEV1 at Week 24*
.Weighted mean FEV1 (0-24 hours) at Week 24

Notes:

FF: fluticasone furoate; FP: fluticasone propionate; VI: vilanterol; OD: once-daily; BD: twice-daily

*FF vs. FP comparison was performed only for Trough FEV1

Study Results

FFA112059 evaluated the efficacy of ARNUITY ELLIPTA 100 mcg once-daily and fluticasone propionate 250 mcg twice-daily on lung function in subjects with asthma compared to placebo. The trial included a 4-week run-in period during which subjects were symptomatic while taking their usual low to mid-dose inhaled corticosteroid therapy (i.e. fluticasone propionate 100 mcg to 500 mcg daily or equivalent). Mean baseline percent predicted FEV1 was approximately 73% overall and was similar across the 3 treatment groups. Thirty-five percent of subjects on placebo and 19% of subjects on ARNUITY ELLIPTA 100 mcg failed to complete the 24-week trial.

Compared with placebo, at Week 24, the change from baseline in trough FEV1 was significantly greater for ARNUITY ELLIPTA 100 mcg once-daily (146 mL) and for fluticasone propionate 250 mcg twice-daily (145 mL) (Table 2). Further, subjects receiving ARNUITY ELLIPTA 100 mcg once-daily had a statistically significantly greater improvement from baseline in percentage of 24-hour periods without the need of beta2-agonist rescue medication use than subjects receiving placebo (treatment difference 14.8%, 95% CI: 6.9, 22.7, p<0.001, which equates to an additional 1 day per week without need for rescue medication).

Table 2 - Statistical Analysis of Change from Baseline in Trough FEV1 (mL) at Week 24 (FFA112059, ITT Population)
Trough FEV1 (mL) at Week 24 Placebo
(n=113)
ARNUITY ELLIPTA
100 mcg OD
(n=111)
Fluticasone Propionate
250 mcg BD
(n=107)
Least Squares Mean 2,372 2,519 2,517
Least Squares Mean Change from Baseline (SE) 15 (39.4) 161 (39.8) 159 (40.6)
Comparison vs. Placebo
Difference 146 145
95% CI 36, 257 33, 257
p-value 0.009 0.011

Analysis performed using ANCOVA with covariates of baseline, region, sex, age and treatment

HZA106827 evaluated the efficacy of ARNUITY ELLIPTA 100 mcg once-daily in the evening on lung function in subjects with asthma compared with placebo. The combination of fluticasone furoate 100 mcg and vilanterol 25 mcg was also included as a treatment arm. The trial included a 4-week run-in period during which the subjects were symptomatic while taking their usual low to mid-dose inhaled corticosteroid, (i.e. fluticasone propionate 200 mcg/day to 500 mcg/day or equivalent). LABA use was discontinued during the run-in. Mean baseline percent predicted FEV1 was approximately 70% in both treatment groups. Twenty-six percent of subjects on placebo and 10% of subjects on ARNUITY ELLIPTA 100 mcg failed to complete the 12-week trial.

ARNUITY ELLIPTA 100 mcg once-daily had greater changes from baseline than placebo throughout the study. At Week 12, the change from baseline in trough FEV1 for ARNUITY ELLIPTA 100 mcg once-daily was significantly greater than placebo (136 mL, 95% CI: 51, 222, p=0.002). At Week 12, the change from baseline in weighted mean FEV1 (measured in a subset of patients (n=201)) was significantly greater for ARNUITY ELLIPTA 100 mcg compared with placebo (186 mL; 95% CI: 62, 310, p=0.003).

Lung function improvements were sustained over 24 hours (Figure 1).

Figure 1 Change from Baseline in Individual Serial FEV1 (mL) Assessments after 12 Weeks of Treatment (HZA106827)

 FFA114496 evaluated the relative efficacy of ARNUITY ELLIPTA in doses of 100 mcg and 200 mcg on lung function in patients with asthma. The trial included a 4-week run-in period during which the subjects were symptomatic while taking their usual mid- to high-dose inhaled corticosteroid therapy (i.e. fluticasone propionate 250 mcg/day to 1,000 mcg/day or equivalent). LABA use was discontinued during the run-in period. Mean baseline percent predicted FEV1 was approximately 68% overall and similar in the two treatment groups. About 16% of subjects on ARNUITY ELLIPTA 100 mcg and 13% of subjects on ARNUITY ELLIPTA 200 mcg failed to complete the 24-week trial.

The group receiving ARNUITY ELLIPTA 200 mcg had generally numerically greater changes from baseline than the group receiving ARNUITY ELLIPTA100 mcg throughout the study (Figure 2). At Week 24, the change from baseline in trough FEV1 was 208 mL for ARNUITY ELLIPTA 100 mcg and 284 mL for ARNUITY ELLIPTA 200 mcg, a difference of 77 mL (95% CI: -39, 192).

Figure 2 Change from Baseline in Trough FEV1 (mL) Over Time (FFA114496)

HZA106829 evaluated the efficacy of ARNUITY ELLIPTA 200 mcg once-daily in the evening, and fluticasone propionate 500 mcg twice-daily on lung function in subjects with asthma. The combination of fluticasone furoate 200 mcg and vilanterol 25 mcg was also included as a treatment arm. The trial included a 4-week run-in period during which the subjects were symptomatic while taking their usual mid- to high-dose inhaled corticosteroid (fluticasone propionate 500 mcg/day to 1,000 mcg/day or equivalent). LABA use was discontinued during the run-in period. Mean baseline percent predicted FEV1 was approximately 67% in both treatment groups.

Similar improvements from baseline in lung function were observed for both ARNUITY ELLIPTA 200 mcg once-daily and fluticasone propionate 500 mcg twice-daily. At Week 24, the change from baseline in trough FEV1 was 201 mL for ARNUITY ELLIPTA 200 mcg once-daily and 183 mL for fluticasone propionate 500 mcg twice-daily (treatment difference of 18 mL; 95% CI: -66, 102).

Lung function improvements were sustained over 24 hours as seen by change in weighted mean FEV1 (Figure 3). At Week 24, the change from baseline in weighted mean FEV1 (measured in a subset of patients (n=169)) was 328 mL for ARNUITY ELLIPTA 200 mcg once-daily and 258 mL for fluticasone propionate 500 twice-daily (treatment difference of 70 mL; 95% CI: -67, 208).

Figure 3 Change from Baseline in Individual Serial FEV1 (mL) Assessments after 24 Weeks of Treatment (HZA106829)



Detailed Pharmacology

Animal Pharmacology

Pharmacological and toxicological effects seen with fluticasone furoate in nonclinical studies were those typically associated with glucocorticoids.

Clinical Pharmacology

Dose-ranging trials

Eight doses of fluticasone furoate ranging from 25 to 800 mcg once daily were evaluated in 3 randomized, double-blind, placebo-controlled, 8-week trials in subjects with asthma (FFA109687, FFA109685, and FFA109684). Across the 3 trials, subjects were uncontrolled at baseline on treatments of short-acting beta2-agonist and/or non-inhaled corticosteroid controller medications (FFA109687), low-dose inhaled corticosteroid (FFA109685), or medium doses of inhaled corticosteroid (FFA109684). The trials in Figure 4were dose-ranging trials of ARNUITY ELLIPTA not designed to provide comparative effectiveness data and should not be interpreted as evidence of superiority/inferiority to fluticasone propionate. A dose-related increase in trough FEV1 at Week 8 was seen for doses from 25 to 200 mcg with no consistent additional benefit for doses above 200 mcg as seen in Figure 4.

Figure 4 Dose-Ranging Trials


FF = Fluticasone furoate

FP = Fluticasone propionate

OD = Once daily

BD = Twice daily

To evaluate dosing frequency, a separate trial (FFA112202) compared fluticasone furoate 200 mcg once daily, fluticasone furoate 100 mcg twice daily, fluticasone propionate 100 mcg twice daily, and fluticasone propionate 200 mcg once daily. The results of this trial supported the selection of the once-daily dosing frequency.

Toxicology

Fluticasone furoate (FF) has undergone a comprehensive toxicological evaluation, and the principal findings are summarized in Table 7 . In the majority of studies, fluticasone furoate was administered by the inhaled route which resulted in systemic exposure. The major findings were typically associated with systemic exposure to glucocorticoids, and are commonly reported for other marketed inhaled corticosteroids. In patients following repeated inhaled doses of 100 or 200 mcg/day plasma concentrations of fluticasone furoate were typically lower than those achieved in animal toxicology studies (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Table 3 - Summary of Principal Findings in Fluticasone Furoate Toxicology Studies
Study Type & Duration Route Species Dose
mcg/kg/day
(unless indicated)
Noteworthy Findings
Single Dose oral
intravenous
inhalation
mouse 1000, 1500, 2000(mg/kg)
18000, 30000
7100
Findings following high single doses included reduced body weight and lymphoid depletion.Gastric irritation was seen following high doseoral administration in rats
oral
intravenous
inhalation
rat 1000, 1500, 2000(mg/kg)
12000, 18000
4400
aRepeat Dose
4 weeks
inhalation rat 6.9, 17.6, 71.7
6.5, 19.5, 72.0
Findings following repeated inhalationadministration of FF included suppressedweight gain, lymphocytopaenia, reducedadrenal weight/cortical atrophy, decreasedcellularity of lymphoid tissues, andhypocellularity/prominent adipocytes in bonemarrow. In dogs, reduced plasma cortisol,increased hepatic glycogen and infectionsecondary to immunosuppression wereobserved, along with development ofCushingoid syndrome on chronic treatment.In all species, there was no evidence ofsignificant treatment related effects on therespiratory tract.
dog 10.6, 30.6, 105
9, 22, 74
13 weeks inhalation mouse 7.3, 18.6, 76.9
rat 4.3, 8.5, 24.3
dog 11.3, 33.0, 64.7
26 weeks inhalation rat 3.2, 8.3, 20.3
39 weeks inhalation dog 13.3, 30.1, 59.6
Repeat Dose
14 days
intranasal rat (male) 80, 160 (mcg/day) In intranasal studies, findings following administration of FF were similar to those seen following inhalation administration. In the 26 week dog study, local effects were confined to increased numbers of goblet cells in the nasal epithelium, considered an adaptive response to local administration of supratherapeutic levels of FF.
4 weeks intranasal dog 400, 1200 (mcg/day)
13/26 weeks intranasal dog 1200, 2400 (mcg/day)
Genotoxicity
AMES
Mouse lymphoma
In vitro NA* up to 1000 (mcg/plate)
up to 25 (mcg/mL
FF did not cause gene mutation in bacteria or chromosomal damage in mammalian cells in vitro.
Micronucleus (2 doses, 24 hours apart) intravenous rat 625, 1000
1000, 2000, 4000
10000, 20000, 40000
There was no evidence of genotoxicity in the in vivo micronucleus tests in rats.
Carcinogenicity
104 weeks
Inhalation mouse 2.2, 6.1, 18.8 There was no evidence of treatment-related increases in tumour incidence in two year inhalation studies in rats and mice.
rat 1.0, 3.2, 8.6
Reproductive Toxicity
Male fertility
69 to 73 days (from 28 days prior to co habitation)
inhalation rat 6.6, 12.9, 29.4 There were no effects on mating performance or fertility of male or female rats. Developmental toxicity in rats was confined to an increased incidence of incompletely ossified sternabrae in association with lower fetal weight. High doses in rabbits (46.6 mcg/kg/day) induced abortion. There were no major skeletal or visceral abnormalities in either rats or rabbits, and no effect on pre- or post-natal development in rats treated with FF during gestation and lactation.
FFEEEFD**
41 to 46 days (from 14 days prior to mating until Day 17 of pregnancy)
inhalation rat 11, 23, 91 The developmental NOAEL in female rats achieved systemic exposures approximately 4-fold greater than in patients with asthma receiving FF 200 mcg/dayb; this dose is similar to the NOAEL in the male fertility and PPN studies in which TK data were not collected; AUC data for the NOAEL could not be calculated for the rabbit EFD study, but, at NOAEL, Cmax was approximately 2-fold greater than in patients with asthma receiving FF, 200 mcg/dayb.
EFD***
13 days (from Days 8 to 20 of pregnancy)
inhalation rabbit 9.7, 46.6, 85.1
1.8, 3.2, 8.1
PPN****
35 days (from Days 6 to 20pc and Days 2 to 21pp)
inhalation rat 5.5, 15.7, 27.2
Juvenile*****
(up to 13 weeks)
inhalation rat 7.9, 27, 73
41.8
In juvenile rats and dogs findings were consistent with the corticosteroid effects of FF seen in adult animals. Although the majority of changes were also seen in inhalation toxicity studies in adult animals, some findings in kidney, eyes, bone, lungs and teeth associated with FF treatment, were only seen in juvenile dogs dosed for 13 weeks.
dog 9.8, 27, 73
59.9
14 days intranasal dog 800 (µg/day)
Local Tolerance
Dermal irritancy
4 hours
16 hours
topical rabbit 500 (mcg)
0.2 (mcg/mL)
FF was non-irritating following single dose application to the skin, and practically non- irritating following application of the intranasal clinical formulation to the eye.
Ocular irritancy Single dose topical rabbit 0.05% (w/w)
Other Toxicity
Respiratory hypersensitivity 5 days
inhalation guinea pig (male) 67.1 to 71.2 There was no evidence of respiratory hypersensitivity reactions following inhalation administration of FF.
Key:
*NA = Not applicable
**FFEEEFD =Female fertility, early embryonic and embryofoetal development
*** EFD =Embryofoetal development
**** PPN =Pre- and post-natal development
*****Juvenile At start of dosing juvenile rats were aged approximately 21 days and juvenile dogs were aged approximately 8 weeks.
pc =post-coitum
pp =post partum
a =In all species, corticosteroid-related findings in repeat-dose toxicity studies with FF occurred at all doses, thus, a NOEL/NOAEL was not identified
b =Estimated geometric mean systemic exposure following administration of 200 mcg FF single strip in subjects with asthma = 0.0551 ng/mL (Cmax) or 0.395 ng.h/mL (AUC)