Trelegy Ellipta (Page 8 of 10)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

TRELEGY ELLIPTA

No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with TRELEGY ELLIPTA; however, studies are available for the individual components, fluticasone furoate, umeclidinium, and vilanterol, as described below.

Fluticasone Furoate

Fluticasone furoate produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 9 and 19 mcg/kg/day, respectively (both approximately 0.5 times the MRHDID of 200 mcg for adults on a mcg/m2 basis).

Fluticasone furoate did not induce gene mutation in bacteria or chromosomal damage in a mammalian cell mutation test in mouse lymphoma L5178Y cells in vitro. There was also no evidence of genotoxicity in the in vivo micronucleus test in rats.

No evidence of impairment of fertility was observed in male and female rats at inhaled fluticasone furoate doses up to 29 and 91 mcg/kg/day, respectively (approximately 3 and 8 times, respectively, the MRHDID of 200 mcg for adults on an AUC basis).

Umeclidinium

Umeclidinium produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 137 and 295/200 mcg/kg/day (male/female), respectively (approximately 17 and 20/20 times, respectively, the MRHDID for adults on an AUC basis).

Umeclidinium tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro mouse lymphoma assay, and in vivo rat bone marrow micronucleus assay.

No evidence of impairment of fertility was observed in male and female rats at subcutaneous doses up to 180 mcg/kg/day and at inhaled doses up to 294 mcg/kg/day, respectively (approximately 60 and 40 times, respectively, the MRHDID for adults on an AUC basis).

Vilanterol

In a 2-year carcinogenicity study in mice, vilanterol caused a statistically significant increase in ovarian tubulostromal adenomas in females at an inhaled dose of 29,500 mcg/kg/day (approximately 9,920 times the MRHDID for adults on an AUC basis). No increase in tumors was seen at an inhaled dose of 615 mcg/kg/day (approximately 370 times the MRHDID for adults on an AUC basis).

In a 2-year carcinogenicity study in rats, vilanterol caused statistically significant increases in mesovarian leiomyomas in females and shortening of the latency of pituitary tumors at inhaled doses greater than or equal to 84.4 mcg/kg/day (greater than or equal to approximately 25 times the MRHDID for adults on an AUC basis). No tumors were seen at an inhalation dose of 10.5 mcg/kg/day (approximately equal to the MRHDID for adults on an AUC basis).

These tumor findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown.

Vilanterol tested negative in the following genotoxicity assays: the in vitro Ames assay, in vivo rat bone marrow micronucleus assay, in vivo rat unscheduled DNA synthesis (UDS) assay, and in vitro Syrian hamster embryo (SHE) cell assay. Vilanterol tested equivocal in the in vitro mouse lymphoma assay.

No evidence of impairment of fertility was observed in male and female rats at inhaled vilanterol doses up to 31,500 and 37,100 mcg/kg/day, respectively (both approximately 4,090 times the MRHDID based on AUC).

14 CLINICAL STUDIES

14.1 Chronic Obstructive Pulmonary Disease

The clinical efficacy of TRELEGY ELLIPTA has been evaluated in 3 clinical trials in subjects with COPD, including chronic bronchitis and/or emphysema: Trial 1 (NCT01957163), Trial 2 (NCT02119286), and Trial 3 (NCT02164513).

Trials 1 and 2 were multicenter, randomized, double-blind, parallel-group, 12-week treatment trials in subjects with COPD. Across both trials, a total of 412 subjects received coadministration of umeclidinium 62.5 mcg + fluticasone furoate/vilanterol 100/25 mcg, the components of TRELEGY ELLIPTA. Comparative in vitro data (drug delivery and aerodynamic particle size distribution) provide support for reliance on coadministration studies with umeclidinium 62.5 mcg + fluticasone furoate/vilanterol 100/25 mcg. These data demonstrated no pharmaceutical interactions and that each drug component (fluticasone furoate, umeclidinium, and vilanterol) was delivered in a comparable manner whether administered via a single ELLIPTA inhaler or from separate inhalers.

The population demographics for Trials 1 and 2 were: mean age of 64 years, 92% White, 66% male, and an average smoking history of 48 pack-years, with 50% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1 was 46% (range: 14% to 76%), the mean postbronchodilator FEV1 /FVC ratio was 0.48 (range: 0.21 to 0.70), and the mean percent reversibility was 13% (range: -24% to 86%).

Trial 3 was a randomized, multicenter, double-blind, parallel-group, 52-week treatment trial comparing the clinical efficacy of TRELEGY ELLIPTA 100/62.5/25 mcg with the fixed-dose combinations of fluticasone furoate/vilanterol 100/25 mcg and umeclidinium/vilanterol 62.5/25 mcg. A total of 10,355 subjects with COPD with a history of 1 or more moderate or severe exacerbations in the prior 12 months were randomized (2:2:1) to receive TRELEGY ELLIPTA, fluticasone furoate/vilanterol, or umeclidinium/vilanterol administered once daily.

The population demographics across all treatments were: mean age of 65 years, 77% White, 66% male, and an average smoking history of 46.6 pack-years, with 35% identified as current smokers. At study entry, the most common COPD medications were ICS + anticholinergic + LABA (34%), ICS + LABA (26%), anticholinergic + LABA (8%), and anticholinergic (7%); the mean postbronchodilator percent predicted FEV1 was 46% (SD: 15%), the mean postbronchodilator FEV1 /FVC ratio was 0.47 (SD: 0.12), and the mean percent reversibility was 10% (range: -59% to 125%).

Lung Function: In Trials 1 and 2, the primary endpoint was change from baseline in trough (predose) FEV1 at Day 85 (defined as the mean of the FEV1 values obtained at 23 and 24 hours after the previous dose on Day 84). For both COPD trials, umeclidinium + fluticasone furoate/vilanterol demonstrated a statistically significant increase relative to placebo + fluticasone furoate/vilanterol (Table 4); similar results were demonstrated for the secondary endpoint of the weighted mean FEV1 (0 to 6 hours postdose) on Day 84 (Table 4).

Table 4. Least Squares Mean Change from Baseline in Trough FEV1 and Weighted Mean FEV1 (0-6 h) at Week 12 (Days 84/85)
FEV1 = Forced Expiratory Volume in 1 Second, FF/VI = Fluticasone Furoate/Vilanterol 100/25 mcg, UMEC = Umeclidinium 62.5 mcg.a At Day 85.b At Day 84.c For Placebo + FF/VI: Trial 1, n = 206; Trial 2, n = 206.

Treatment

n

Trough FEV1 (mL)a

Weighted Mean FEV1 (0-6 h) (mL)b

Difference from Placebo + FF/VI

(95% CI)

Difference from Placebo + FF/VI

(95% CI)

Trial 1

UMEC + FF/VI

206

124

153

(93, 154)

(118, 187)

Trial 2

UMEC + FF/VI

206

122

147

(91, 152)

(114, 179)

Greater least squares (LS) mean changes from baseline in FEV1 over time were demonstrated for the umeclidinium + fluticasone furoate/vilanterol treatment group compared with the placebo + fluticasone furoate/vilanterol treatment group starting at 15 minutes postdose on Day 1. For Trial 1, LS mean changes in FEV1 over time relative to baseline are displayed for Day 1 and Day 84 in Figures 5 and 6, respectively. Similar results were seen in Trial 2.

Figure 5. Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (mL) on Day 1

Figure 5. Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (mL) on Day 1
(click image for full-size original)

Figure 6. Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (mL) on Day 84

Figure 6. Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (mL) on Day 84
(click image for full-size original)

In Trial 3, treatment with TRELEGY ELLIPTA 100/62.5/25 mcg demonstrated a statistically significant improvement in lung function (mean change from baseline trough FEV1 at Week 52) compared with fluticasone furoate/vilanterol and umeclidinium/vilanterol. The mean change from baseline in trough (predose) FEV1 at Week 52 was 97 mL for TRELEGY ELLIPTA compared with fluticasone furoate/vilanterol (95% CI: 85, 109; P <0.001) and 54 mL for TRELEGY ELLIPTA compared with umeclidinium/vilanterol (95% CI: 39, 69; P <0.001). The effects on lung function (mean change from baseline trough FEV1 ) of TRELEGY ELLIPTA compared with fluticasone furoate/vilanterol and umeclidinium/vilanterol were observed at all timepoints over the course of the 52-week study (Figure 7).

Figure 7. Least Squares (LS) Mean Change from Baseline in Trough FEV1 (mL)

Figure 7. Least Squares (LS) Mean Change from Baseline in Trough FEV1 (mL)
(click image for full-size original)

Exacerbations: In Trial 3, the primary endpoint was annual rate of on-treatment moderate and severe exacerbations in subjects with COPD treated with TRELEGY ELLIPTA 100/62.5/25 mcg compared with fluticasone furoate/vilanterol and umeclidinium/vilanterol. Exacerbations were defined as worsening of 2 or more major symptoms (dyspnea, sputum volume, and sputum purulence) or worsening of any 1 major symptom together with any 1 of the following minor symptoms: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, and increased cough or wheeze for at least 2 consecutive days. Exacerbations were considered to be moderate severity if treatment with systemic corticosteroids and/or antibiotics was required and were considered to be severe if resulted in hospitalization or death.

Treatment with TRELEGY ELLIPTA statistically significantly reduced the on-treatment annual rate of moderate/severe exacerbations by 15% compared with fluticasone furoate/vilanterol and by 25% compared with umeclidinium/vilanterol (Table 5).

Table 5. Moderate and Severe Chronic Obstructive Pulmonary Disease Exacerbations (Trial 3)a
FF/VI = Fluticasone furoate/vilanterol 100/25 mcg, UMEC/VI = Umeclidinium/vilanterol 62.5/25 mcg.a On-treatment analyses excluded exacerbation data collected after discontinuation of study treatment.

Treatment

n

Mean Annual Rate

(exacerbations/y)

Rate Ratio vs. Comparator

(95% CI)

% Reduction in Exacerbation Rate

(95% CI)

P Value

TRELEGY ELLIPTA

4,145

0.91

FF/VI

4,133

1.07

0.85

(0.80, 0.90)

15

(10, 20)

P<0.001

UMEC/VI

2,069

1.21

0.75

(0.70, 0.81)

25

(19, 30)

P<0.001

Treatment with TRELEGY ELLIPTA statistically significantly decreased the risk of a moderate/severe COPD exacerbation as measured by time to first exacerbation when compared with fluticasone furoate/vilanterol (14.8%; 95% CI: 9.3, 19.9; P <0.001) and umeclidinium/vilanterol (16.0%; 95% CI: 9.4, 22.1; P <0.001).

Treatment with TRELEGY ELLIPTA reduced the on-treatment annual rate of severe COPD exacerbations (i.e., requiring hospitalization or resulting in death) by 13% compared with fluticasone furoate/vilanterol (95% CI: -1, 24; P = 0.064) which was not statistically significant. Treatment with TRELEGY ELLIPTA statistically significantly reduced the on-treatment annual rate of severe COPD exacerbations by 34% compared with umeclidinium/vilanterol (95% CI: 22, 44; P <0.001).

Health-Related Quality of Life: In all 3 trials, health-related quality of life was assessed using the St. George’s Respiratory Questionnaire for COPD patients (SGRQ-C), a disease-specific shorter version derived from the original St. George’s Respiratory Questionnaire (SGRQ). Results were transformed to the SGRQ for reporting purposes. In Trial 1, the on-treatment responder rate at Week 12 (response defined as a decrease in score from baseline of 4 or more) was 40% for umeclidinium +fluticasone furoate/vilanterol vs. 35% for placebo + fluticasone furoate/vilanterol [odds ratio (OR): 1.2; 95% CI: 0.8, 1.8]. In Trial 2, the on-treatment responder rate at Week 12 was 35% for umeclidinium + fluticasone furoate/vilanterol vs. 21% for placebo + fluticasone furoate/vilanterol (OR: 2.0; 95% CI: 1.3, 3.1). In Trial 3, the on-treatment responder rate at Week 52 was statistically significantly greater for subjects treated with TRELEGY ELLIPTA (42%) compared with fluticasone furoate/vilanterol (34%; OR: 1.41; 95% CI: 1.29, 1.55; P <0.001) and compared with umeclidinium/vilanterol (34%; OR: 1.41; 95% CI: 1.26, 1.57; P <0.001).

Other Endpoints: In Trials 1 and 2, subjects treated with umeclidinium + fluticasone furoate/vilanterol on average used less rescue medication compared with subjects treated with placebo + fluticasone furoate/vilanterol over Weeks 1 to 12. In Trial 3, subjects treated with TRELEGY ELLIPTA on average used less rescue medication (mean number of uses per day and percentage of rescue-free 24-hour periods) compared with subjects treated with fluticasone furoate/vilanterol or umeclidinium/vilanterol over the course of the 52-week study.

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