Anoro Ellipta (Page 5 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

ANORO ELLIPTA

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

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 20 and 25/20 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 100 and 50 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 7,800 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 210 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 20 times the MRHDID for adults on an AUC basis). No tumors were seen at an inhaled 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 5,490 times the MRHDID based on AUC).

14 CLINICAL STUDIES

The safety and effectiveness of ANORO ELLIPTA were evaluated in a clinical development program that included 6 dose-ranging trials, 4 lung function trials of 6 months’ duration (2 placebo controlled and 2 active controlled), two 12-week crossover trials, and a 12-month long‑term safety trial. The efficacy of ANORO ELLIPTA is based primarily on the dose-ranging trials in 1,908 subjects with COPD or asthma [see Clinical Studies (14.1)] and the 2 placebo-controlled confirmatory trials, with additional support from the 2 active-controlled and 2 crossover trials in 5,388 subjects with COPD, including chronic bronchitis and/or emphysema [see Clinical Studies (14.2)]. Evidence of efficacy for ANORO ELLIPTA on COPD exacerbations was established by the efficacy of the umeclidinium component as part of a fixed-dose combination with an ICS/LABA, as assessed in a 12-month trial in 10,355 subjects [see Clinical Studies (14.2)].

14.1 Dose-Ranging Trials

Dose selection for ANORO ELLIPTA in COPD was based on dose-ranging trials for the individual components, vilanterol and umeclidinium. Based on the findings from these studies, once-daily doses of umeclidinium/vilanterol 62.5/25 mcg and umeclidinium/vilanterol 125/25 mcg were evaluated in the confirmatory COPD trials. ANORO ELLIPTA is not indicated for asthma.

Umeclidinium

Dose selection for umeclidinium in COPD was supported by a 7-day, randomized, double-blind, placebo-controlled, crossover trial evaluating 4 doses of umeclidinium (15.6 to 125 mcg) or placebo dosed once daily in the morning in 163 subjects with COPD. A dose ordering was observed, with the 62.5- and 125-mcg doses demonstrating larger improvements in FEV1 over 24 hours compared with the lower doses of 15.6 and 31.25 mcg (Figure 3).

The differences in trough FEV1 from baseline after 7 days for placebo and the 15.6-, 31.25-, 62.5-, and 125-mcg doses were -74 mL (95% CI: -118, -31), 38 mL (95% CI: -6, 83), 27 mL (95% CI: -18, 72), 49 mL (95% CI: 6, 93), and 109 mL (95% CI: 65, 152), respectively. Two additional dose-ranging trials in subjects with COPD demonstrated minimal additional benefit at doses above 125 mcg. The dose-ranging results supported the evaluation of 2 doses of umeclidinium, 62.5 and 125 mcg, in the confirmatory COPD trials to further assess dose response.

Evaluations of dosing interval by comparing once- and twice-daily dosing supported selection of a once-daily dosing interval for further evaluation in the confirmatory COPD trials.

Figure 3. Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (mL) on Days 1 and 7

Day 1

Figure 3. Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (mL) on Days 1 and 7, Day 1
(click image for full-size original)

Day 7

Figure 3. Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (mL) on Days 1 and 7, Day 7
(click image for full-size original)

Vilanterol

Dose selection for vilanterol in COPD was supported by a 28-day, randomized, double-blind, placebo-controlled, parallel-group trial evaluating 5 doses of vilanterol (3 to 50 mcg) or placebo dosed in the morning in 602 subjects with COPD. Results demonstrated dose-related increases from baseline in FEV1 at Day 1 and Day 28 (Figure 4).

Figure 4. Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (0-24 h) (mL) on Days 1 and 28

Day 1

Figure 4. Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (0-24 h) (mL) on Days 1 and 28, Day 1
(click image for full-size original)

Day 28

Figure 4. Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (0-24 h) (mL) on Days 1 and 28, Day 28
(click image for full-size original)

The differences in trough FEV1 after Day 28 from baseline for placebo and the 3-, 6.25-, 12.5-, 25-, and 50-mcg doses were 29 mL (95% CI: -8, 66), 120 mL (95% CI: 83, 158), 127 mL (95% CI: 90, 164), 138 mL (95% CI: 101, 176), 166 mL (95% CI: 129, 203), and 194 mL (95% CI: 156, 231), respectively. These results supported the evaluation of vilanterol 25 mcg in the confirmatory trials for COPD.

Dose-ranging trials in subjects with asthma evaluated doses from 3 to 50 mcg and 12.5 mcg once-daily versus 6.25 mcg twice-daily dosing frequency. The results supported the selection of the vilanterol 25 mcg once-daily dose for further evaluation in the confirmatory trials for COPD.

14.2 Confirmatory Trials

Lung Function

The clinical development program for ANORO ELLIPTA included two 6-month, randomized, double-blind, placebo-controlled, parallel-group trials; two 6-month active-controlled trials; and two 12-week crossover trials in subjects with COPD designed to evaluate the efficacy of ANORO ELLIPTA on lung function. The 6-month trials treated 4,733 subjects that had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking ≥10 pack-years, had a post-albuterol FEV1 ≤70% of predicted normal values, had a ratio of FEV1 /FVC of <0.7, and had a Modified Medical Research Council (mMRC) score ≥2. Of the 4,713 subjects included in the efficacy analysis, 68% were male and 84% were white. They had a mean age of 63 years and an average smoking history of 45 pack-years, with 50% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1 was 48% (range: 13% to 76%), the mean postbronchodilator FEV1 /FVC ratio was 0.47 (range: 0.13 to 0.78), and the mean percent reversibility was 14% (range: -36% to 109%).

Trial 1 (NCT01313650) evaluated ANORO ELLIPTA (umeclidinium/vilanterol 62.5/25 mcg), umeclidinium 62.5 mcg, vilanterol 25 mcg, and placebo. The primary endpoint was change from baseline in trough (predose) FEV1 at Day 169 (defined as the mean of the FEV1 values obtained at 23 and 24 hours after the previous dose on Day 168) compared with placebo, umeclidinium 62.5 mcg, and vilanterol 25 mcg. The comparison of ANORO ELLIPTA with umeclidinium 62.5 mcg and vilanterol 25 mcg was assessed to evaluate the contribution of the individual comparators to ANORO ELLIPTA. ANORO ELLIPTA demonstrated a larger increase in mean change from baseline in trough (predose) FEV1 relative to placebo, umeclidinium 62.5 mcg, and vilanterol 25 mcg (Table 2).

Table 2. Least Squares Mean Change from Baseline in Trough FEV1 (mL) at Day 169 in the Intent-to-Treat Population (Trial 1)
n = Number in intent-to-treat population.
a The umeclidinium and vilanterol comparators used the same inhaler and excipients as ANORO ELLIPTA.

Treatment

n

Trough FEV1 (mL) at Day 169

Difference from

Placebo

(95% CI)

n = 280

Umeclidinium

62.5 mcga

(95% CI)

n = 418

Vilanterol

25 mcga

(95% CI)

n = 421

ANORO ELLIPTA

413

167

(128, 207)

52

(17, 87)

95

(60, 130)

Trial 2 (NCT01313637) had a similar study design as Trial 1 but evaluated umeclidinium/vilanterol 125/25 mcg, umeclidinium 125 mcg, vilanterol 25 mcg, and placebo. Results for umeclidinium/vilanterol 125/25 mcg in Trial 2 were similar to those observed for ANORO ELLIPTA in Trial 1.

Results from the 2 active-controlled trials and the two 12-week trials provided additional support for the efficacy of ANORO ELLIPTA in terms of change from baseline in trough FEV1 compared with the single-ingredient comparators and placebo.

Serial spirometric evaluations throughout the 24-hour dosing interval were performed in a subset of subjects (n = 197) at Days 1, 84, and 168 in Trial 1. Results from Trial 1 at Day 1 and Day 168 are shown in Figure 5.

Figure 5. Least Squares (LS) Mean Change from Baseline in FEV1 (mL) over Time (0-24 h) on Days 1 and 168 (Trial 1 Subset Population)

Day 1

Figure 5. Least Squares (LS) Mean Change from Baseline in FEV1 (mL) over Time (0-24 h) on Days 1 and 168 (Trial 1 Subset Population), Day 1
(click image for full-size original)

Day 168

Figure 5. Least Squares (LS) Mean Change from Baseline in FEV1 (mL) over Time (0-24 h) on Days 1 and 168 (Trial 1 Subset Population), Day 168
(click image for full-size original)

The peak FEV1 was defined as the maximum FEV1 recorded within 6 hours after the dose of trial medicine on Days 1, 28, 84, and 168 (measurements recorded at 15 and 30 minutes and 1, 3, and 6 hours). The mean peak FEV1 improvement from baseline for ANORO ELLIPTA compared with placebo at Day 1 and at Day 168 was 167 and 224 mL, respectively. The median time to onset on Day 1, defined as a 100-mL increase from baseline in FEV1 , was 27 minutes in subjects receiving ANORO ELLIPTA.

Exacerbations

In Trial 6 (NCT02164513), 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 (1:2:2) to receive ANORO ELLIPTA (n = 2,070), fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 mcg (n = 4,151), or fluticasone furoate/vilanterol 100/25 mcg (n = 4,134) administered once daily in a 12-month trial. 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 trial 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% (standard deviation: 15%), the mean postbronchodilator FEV1 /FVC ratio was 0.47 (standard deviation: 0.12), and the mean percent reversibility was 10% (range: -59% to 125%).

The primary endpoint was annual rate of on-treatment moderate and severe exacerbations in subjects treated with fluticasone furoate/umeclidinium/vilanterol compared with the fixed-dose combinations of fluticasone furoate/vilanterol and ANORO ELLIPTA. 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 of moderate severity if treatment with systemic corticosteroids and/or antibiotics was required and were considered to be severe if resulted in hospitalization or death.

Contribution of Umeclidinium on COPD Exacerbations: Evidence of efficacy for ANORO ELLIPTA on COPD exacerbations was established by the efficacy of the umeclidinium component of fluticasone furoate/umeclidinium/vilanterol in Trial 6. Treatment with fluticasone furoate/umeclidinium/vilanterol statistically significantly reduced the on-treatment annual rate of moderate/severe exacerbations by 15% compared with fluticasone furoate/vilanterol (Table 3). A reduction in risk of on-treatment moderate/severe exacerbation (as measured by time to first) was also observed for the same comparison. The benefit of umeclidinium on exacerbations is not expected to diminish when combined with vilanterol in ANORO ELLIPTA.

ANORO ELLIPTA and COPD Exacerbations: In Trial 6, the primary efficacy analysis of the rate of moderate/severe exacerbations, treatment with fluticasone furoate/umeclidinium/vilanterol statistically significantly reduced the on-treatment annual rate of moderate/severe exacerbations by 25% compared with ANORO ELLIPTA (Table 3).

Table 3. Moderate and Severe Chronic Obstructive Pulmonary Disease Exacerbations (Trial 6)a
FF/UMEC/VI = Fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 mcg, FF/VI = Fluticasone furoate/vilanterol 100/25 mcg, ANORO ELLIPTA = 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/year)

FF/UMEC/VI Rate Ratio vs. Comparator

(95% CI)

% Reduction in Exacerbation Rate

(95% CI)

P Value

FF/UMEC/VI

4,145

0.91

FF/VI

4,133

1.07

0.85

(0.80, 0.90)

15

(10, 20)

P <0.001

ANORO ELLIPTA

2,069

1.21

0.75

(0.70, 0.81)

25

(19, 30)

P <0.001

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