Anoro Ellipta Mechanism of Action

Bronchodilation (Long-acting muscarinic receptor antagonist/Long-acting beta₂ adrenergic agonist combination).
Pharmacology: Pharmacodynamics: Mechanism of Action: Umeclidinium/vilanterol is a combination inhaled long-acting muscarinic receptor antagonist/long-acting beta₂-adrenergic agonist (LAMA/LABA). Following inhalation both compounds act locally on airways to produce bronchodilation by separate mechanisms.
Umeclidinium: Umeclidinium is a long acting muscarinic receptor antagonist (also referred to as an anticholinergic). It is a quinuclidine derivative that is a muscarinic receptor antagonist with activity across multiple muscarinic cholinergic receptor subtypes. Umeclidinium exerts its bronchodilatory activity by competitively inhibiting the binding of acetylcholine with muscarinic acetylcholine receptors on airway smooth muscle. It demonstrates slow reversibility at the human M3 muscarinic receptor subtype in vitro and a long duration of action in vivo when administered directly to the lungs in pre-clinical models.
Vilanterol: Vilanterol is a selective long-acting, beta₂-adrenergic receptor agonist (beta₂-agonist).
The pharmacologic effects of beta₂-agonists, including vilanterol, are at least in part attributable to stimulation of intracellular adenylate cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.
Pharmacodynamic effects: In one placebo controlled clinical efficacy study Vilanterol + Umeclidinium (Anoro Ellipta) increased FEV₁ after the first dose on Day 1 with an improvement compared with placebo of 0.11 L (p<0.001) at 15 minutes following administration. The change from baseline to peak FEV₁ during 0-6 hours post-dose at Day 1 and Week 24 was 0.27 L and 0.32 L respectively for Umeclidinium + Vilanterol (Anoro Ellipta), compared with 0.11 L (Day 1) and 0.10 L (Week 24) for placebo.
Cardiovascular effects: The effect of umeclidinium/vilanterol on the QT interval was evaluated in a placebo and moxifloxacin controlled QT study involving once daily administration of umeclidinium/vilanterol 125/25 micrograms or 500/100 micrograms for 10 days in 103 healthy volunteers. The maximum mean difference in prolongations of QT interval (corrected using the Fridericia method, QTcF) from placebo after baseline-correction was 4.3 (90% CI=2.2 to 6.4) milliseconds seen 10 minutes after administration with umeclidinium/vilanterol 125/25 micrograms and 8.2 (90% CI=6.2 to 10.2) milliseconds seen 30 minutes after administration with umeclidinium/vilanterol 500/100 micrograms. No clinically relevant effect on prolongation of QT interval (corrected using the Fridericia method) was observed.
In addition, no clinically significant effects of umeclidinium/vilanterol on cardiac rhythm were observed on 24-hour Holter monitoring in 281 patients who received umeclidinium/vilanterol 125/25 micrograms once daily for up to 12 months.
Clinical Studies: The safety and efficacy of Umeclidinium + Vilanterol (Anoro Ellipta) administered once daily were evaluated in eight Phase III clinical studies in adult patients with a clinical diagnosis of COPD; five were 6-month efficacy studies (DB2113361, DB2113373, DB2113360, DB2113374 and ZEP117115), two were 12-week exercise endurance studies (DB2114417 and DB2114418) and one study (DB2113359) evaluated the safety of Umeclidinium/Vilanterol administered over a 12-month treatment period. Studies included Umeclidinium + Vilanterol (Anoro Ellipta) 62.5/25 micrograms and/or Umeclidinium/Vilanterol 125/25 micrograms, all once daily. Efficacy results for Umeclidinium + Vilanterol (Anoro Ellipta) 62.5/25 micrograms are presented as follows.
Placebo Controlled Studies: In a 6-month study, DB2113373, Umeclidinium + Vilanterol (Anoro Ellipta) 62.5/25 micrograms demonstrated a statistically significant improvement in lung function (as defined by change from baseline trough FEV₁ at Week 24) compared with placebo (see Table 1). Bronchodilatory effects with Umeclidinium + Vilanterol (Anoro Ellipta) compared with placebo were evident after the first day of treatment and were maintained over the 24 week treatment period. (See Table 1).

Click on icon to see table/diagram/image

Umeclidinium + Vilanterol (Anoro Ellipta) demonstrated a statistically significant greater improvement from baseline in weighted mean FEV₁ over 0-6 hours post-dose at Week 24 compared with placebo (0.24 L; p<0.001).
A statistically significant improvement from placebo in the Transitional Dyspnoea Index (TDI) focal score at Week 24 was demonstrated for Umeclidinium+ Vilanterol (Anoro Ellipta) (1.2 units; p<0.001). The percentage of patients receiving Umeclidinium+ Vilanterol (Anoro Ellipta) that responded with a minimum clinically important difference (MCID) of ≥1 unit TDI focal score at Week 24 was 58% (226/389) compared with 41% (106/260) for placebo.
A statistically significant improvement from placebo in the change from baseline in total score at Week 24 for the St. George's Respiratory Questionnaire (SGRQ), a disease-specific health status measure, was also demonstrated for Umeclidinium+ Vilanterol (Anoro Ellipta) (-5.51 units; p≤0.001). The percentage of patients receiving Umeclidinium+ Vilanterol (Anoro Ellipta) that responded with a reduction from baseline of ≥4 units (MCID) in SGRQ total score was 49% (188/381) compared with 34% (86/254) for placebo.
In addition, patients treated with Umeclidinium+ Vilanterol (Anoro Ellipta) required less rescue salbutamol than those treated with placebo (on average a statistically significant reduction of 0.8 puffs per day; p=0.001). Throughout the 24-week study, patients treated with Umeclidinium+ Vilanterol (Anoro Ellipta) had more days when no rescue medication was needed (on average 36.1%) compared with placebo (on average 21.7%; no formal statistical analysis was performed on this endpoint).
Treatment with Umeclidinium+ Vilanterol (Anoro Ellipta) resulted in a statistically significant 50% reduction in risk of a moderate/severe COPD exacerbation (based on analysis of time to first exacerbation) compared with placebo (Hazard Ratio 0.5; 95% CI: 0.3, 0.8; p=0.004) where the majority of patients reported no COPD exacerbations requiring oral/systemic corticosteroids and/or antibiotics (72%) and no COPD exacerbations requiring hospitalisation (89%) in the 12 months prior to screening.
Tiotropium Comparator Studies: In studies ZEP117115 and DB2113360, treatment with Umeclidinium+ Vilanterol (Anoro Ellipta) 62.5/25 micrograms provided statistically significant and clinically meaningful improvements in change from baseline in trough FEV₁ compared with tiotropium at Week 24 (see Table 2). In Study DB2113374, Umeclidinium + Vilanterol (Anoro Ellipta) 62.5/25 micrograms showed a clinically meaningful improvement in change from baseline in trough FEV₁ compared with tiotropium at Week 24 (see Table 2).

Click on icon to see table/diagram/image

In Studies ZEP117115 and DB2113360 Umeclidinium + Vilanterol (Anoro Ellipta) showed statistically significant greater improvements of 0.11 L and 0.07 L respectively in change from baseline in weighted mean FEV₁ over 0-6 hours at Week 24 compared with tiotropium (both p≤0.005). In Study DB2113374 Umeclidinium + Vilanterol (Anoro Ellipta) showed a clinically meaningful improvement of 0.10 L in change from baseline in weighted mean FEV₁ over 0-6 hours at Week 24 compared with tiotropium.
In Studies DB2113360 and DB2113374, Umeclidinium + Vilanterol (Anoro Ellipta) and tiotropium both improved measures of dyspnoea (TDI focal score) and health-related quality of life (SGRQ) compared with baseline. In the third active-comparator study (ZEP117115), a statistically significant improvement compared with tiotropium in the change from baseline in SGRQ total score at Week 24 was demonstrated for Umeclidinium + Vilanterol (Anoro Ellipta) (-2.10 units; p=0.006). The percentage of patients receiving Umeclidinium + Vilanterol (Anoro Ellipta) that responded with a reduction from baseline of ≥4 units (MCID) in SGRQ total score from this study was 53% (237/445) compared with 46% (196/430) for tiotropium.
Statistically significant improvements in rescue salbutamol use over weeks 1-24 were observed for Umeclidinium + Vilanterol (Anoro Ellipta) over tiotropium in studies ZEP117115 (-0.5 puffs per day; p<0.001) and DB2113360 (-0.7 puffs per day; p=0.022).
Throughout studies ZEP117115, DB2113360 and DB2113374, patients treated with for Umeclidinium + Vilanterol (Anoro Ellipta) had, on average, a greater reduction from baseline in the proportion of days when no rescue medication was needed (21.5%, 18.6% and 17.6% respectively) compared with tiotropium (13.3%, 11.7% and 13.4% respectively; no formal statistical analysis was performed on this endpoint).
In Study ZEP117115, treatment with Umeclidinium + Vilanterol (Anoro Ellipta) resulted in a statistically significant 50% reduction in risk of a moderate/severe COPD exacerbation (based on analysis of time to first exacerbation) compared with tiotropium (Hazard Ratio 0.5; 95% CI: 0.3,1.0; p=0.044) where the majority of patients reported no COPD exacerbations requiring oral/systemic corticosteroids and/or antibiotics (83%) and no COPD exacerbations requiring hospitalisation (93%) in the 12 months prior to screening.
Supportive 3-month exercise endurance studies: Exercise endurance was evaluated with the endurance shuttle walk test (ESWT) in adult COPD patients with hyperinflation (functional residual capacity [FRC] >120%) in two replicate, 12-week clinical studies.
In one study (DB2114418), treatment with Umeclidinium + Vilanterol (Anoro Ellipta) 62.5/25 micrograms demonstrated a statistically significant improvement over placebo in exercise endurance time (EET) obtained 3 hours after dosing at Week 12 of 69.4 seconds (p=0.003). Improvement in EET compared with placebo was seen at Day 2 and was sustained at Week 6 and Week 12. In the second study (DB2114417), treatment with Umeclidinium + Vilanterol (Anoro Ellipta) 62.5/25 micrograms did not show a statistically significant improvement over placebo in EET (21.9 seconds; p>0.05).
In Study DB2114418, Umeclidinium + Vilanterol (Anoro Ellipta) showed a statistically significant improvement compared to placebo in change from baseline in trough FEV₁ at Week 12 of 0.24 L (p<0.001), and statistically significant improvements compared to placebo in change from baseline in lung volume measures at trough and at 3 hours post dose at Week 12 (inspiratory capacity: 0.24 L and 0.32 L respectively, residual volume: -0.47 L and -0.64 L respectively and functional residual capacity: -0.35 L and -0.52 L respectively; all p<0.001). In Study DB2114417, Umeclidinium + Vilanterol (Anoro Ellipta) showed a clinically meaningful improvement compared to placebo in change from baseline in trough FEV₁ at Week 12 of 0.21 L, and improvements compared to placebo in change from baseline in lung volume measures at trough and at 3 hours post dose at Week 12 (inspiratory capacity: 0.20 L and 0.24 L respectively, residual volume: -0.29 L and -0.35 L respectively and functional residual capacity: -0.24 L and -0.30 L respectively).
Supporting efficacy studies: In a randomised, double-blind, 52-week study (CTT116855, IMPACT), adult patients with COPD and a history of 1 or more moderate or severe exacerbations in the prior 12 months were randomised (1:2:2) to receive Umeclidinium + Vilanterol (Anoro Ellipta) 62.5/25 micrograms, fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI 100/62.5/25 micrograms), or fluticasone furoate/vilanterol (FF/VI 100/25 micrograms) administered once daily. The primary endpoint was annual rate of on-treatment moderate and severe exacerbations in subjects treated with FF/UMEC/VI compared with FF/VI and Umeclidinium + Vilanterol (Anoro Ellipta). The mean annual rate of exacerbations was 0.91, 1.07 and 1.21 for FF/UMEC/VI, FF/VI, and Umeclidinium+ Vilanterol (Anoro Ellipta) respectively.
Treatment with Umeclidinium + Vilanterol (Anoro Ellipta) resulted in a similar risk of a moderate/severe exacerbation when compared with FF/VI (based on analysis of time to first exacerbation) (risk increase of +1.4%; Hazard Ratio: 1.01; 95% CI: 0.94, 1.09; p=0.708).
Umeclidinium: In the IMPACT study, treatment with umeclidinium as a component of FF/UMEC/VI compared with FF/VI resulted in a statistically significant 15% reduction in the annual rate of on-treatment moderate/severe exacerbations (Rate Ratio: 0.85; 95% CI: 0.80, 0.90; p<0.001).
Treatment with umeclidinium as a component of FF/UMEC/VI compared with FF/VI resulted in a statistically significant 14.8% reduction in risk of a moderate/severe exacerbation (based on analysis of time to first exacerbation) (Hazard Ratio: 0.85; 95% CI: 0.80, 0.91; p<0.001).
Vilanterol: In a placebo controlled study (HZC113782, SUMMIT), where patients with COPD were treated for up to 4 years (mean 1.7 years), the majority of patients reported no COPD exacerbations requiring oral/systemic corticosteroids and/or antibiotics (68%) and no COPD exacerbations requiring hospitalisation (87%) in the 12 months prior to screening. Treatment with vilanterol 25 micrograms resulted in a statistically significant 10% reduction in the annual rate of on-treatment moderate/severe exacerbations compared with placebo (Rate Ratio: 0.90; 95% CI: 0.82, 0.98; p=0.017). Vilanterol as a component of fluticasone furoate/vilanterol (FF/VI 100/25 micrograms) compared with fluticasone furoate (FF 100 micrograms) resulted in a statistically significant 19% reduction in the annual rate of on-treatment moderate/severe exacerbations (Rate Ratio: 0.81; 95% CI: 0.74, 0.88; p<0.001).
These findings were supported by a statistically significant 8.9% reduction in risk of a moderate/severe exacerbation (based on analysis of time to first exacerbation) for vilanterol compared with placebo (Hazard Ratio: 0.91; 95% CI: 0.84, 0.99; p=0.023) and by a statistically significant 18.2% reduction in risk of a moderate/severe exacerbation (based on analysis of time to first exacerbation) for vilanterol as a component of FF/VI compared with FF (Hazard Ratio: 0.82; 95% CI: 0.75, 0.89; p<0.001).
Pharmacokinetics: When umeclidinium and vilanterol were administered in combination by the inhaled route, the pharmacokinetics of each component was similar to those observed when each active substance was administered separately (see Metabolism and Drug-drug interactions as follows). For pharmacokinetic purposes each component can therefore be considered separately.
Absorption: Umeclidinium: Following inhaled administration of umeclidinium in healthy volunteers, C_max occurred at 5 to 15 minutes. The absolute bioavailability of inhaled umeclidinium was on average 13% of the dose, with negligible contribution from oral absorption. Following repeat dosing of inhaled umeclidinium, steady state was achieved within 7 to 10 days with 1.5 to 2-fold accumulation.
Vilanterol: Following inhaled administration of vilanterol in healthy volunteers, C_max occurred at 5 to 15 minutes. The absolute bioavailability of inhaled vilanterol was 27%, with negligible contribution from oral absorption. Following repeat dosing of inhaled vilanterol, steady state was achieved within 6 days with up to 2.4-fold accumulation.
Distribution: Umeclidinium: Following intravenous administration to healthy subjects, the mean volume of distribution was 86 litres. In vitro plasma protein binding in human plasma was on average 89%.
Vilanterol: Following intravenous administration to healthy volunteers, the mean volume of distribution at steady state was 165 litres. In vitro plasma protein binding in human plasma was on average 94%.
Metabolism: Umeclidinium: In vitro studies showed that umeclidinium is metabolised principally via cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (Pgp) transporter.
The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (glucuronidation, etc), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low.
Vilanterol: In vitro studies showed that vilanterol is metabolised principally via cytochrome P450 3A4 (CYP3A4) and is a substrate for the Pgp transporter. The primary metabolic routes are O-dealkylation to a range of metabolites with significantly reduced beta₁- and beta₂-agonist activity. Plasma metabolic profiles following oral administration of vilanterol in a human radiolabel study were consistent with high first-pass metabolism. Systemic exposure to the metabolites is low.
Drug-drug interactions: Available pharmacokinetic data in healthy volunteers and patients with COPD show that the systemic exposure (C_max and AUC) and population pharmacokinetic predicted exposures to umeclidinium and vilanterol is unaffected by administration with the umeclidinium/vilanterol combination compared to the components administered separately. Co-administration with the strong CYP3A4 inhibitor ketoconazole (400 mg) increased mean vilanterol AUC_(0-t) and C_max, 65% and 22% respectively. The increase in vilanterol exposure was not associated with an increase in beta-agonist related systemic effects on heart rate, blood potassium or QT interval (corrected using the Fridericia method).
Both umeclidinium and vilanterol are substrates of P-glycoprotein (P-gp). The effect of the moderate P-gp transporter inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of umeclidinium and vilanterol was assessed in healthy volunteers. No effect of verapamil was observed on umeclidinium or vilanterol C_max. An approximately 1.4-fold increase in umeclidinium AUC was observed with no effect on vilanterol AUC.
Elimination: Umeclidinium: Plasma clearance following intravenous administration was 151 litres/hour. Following intravenous administration, approximately 58% of the administered radiolabelled dose (or 73% of the recovered radioactivity) was excreted in faeces by 192 hours post-dose. Urinary elimination accounted for 22% of the administered radiolabelled dose by 168 hours (27% of recovered radioactivity). The excretion of the drug-related material in the faeces following intravenous dosing indicated secretion into the bile. Following oral administration to healthy male subjects, total radioactivity was excreted primarily in faeces (92% of the administered radiolabelled dose or 99% of the recovered radioactivity) by 168 hours post-dose. Less than 1% of the orally administered dose (1% of recovered radioactivity) was excreted in urine, suggesting negligible absorption following oral administration. Umeclidinium plasma elimination half-life following inhaled dosing for 10 days averaged 19 hours, with 3% to 4% drug excreted unchanged in urine at steady-state.
Vilanterol: Plasma clearance of vilanterol following intravenous administration was 108 litres/hour. Following oral administration of radiolabelled vilanterol, mass balance showed 70% of the radiolabel in urine and 30% in faeces. Primary elimination of vilanterol was by metabolism followed by excretion of metabolites in urine and faeces. Vilanterol plasma elimination half-life following inhaled dosing for 10 days averaged 11 hours.
Special patient populations: Elderly: A population pharmacokinetic analysis showed that pharmacokinetics of umeclidinium and vilanterol were similar between COPD patients 65 years and older and those younger than 65 years of age.
Renal impairment: Subjects with severe renal impairment showed no evidence of an increase in systemic exposure to either umeclidinium or vilanterol (C_max and AUC), and no evidence of altered protein binding between subjects with severe renal impairment and healthy volunteers.
Hepatic impairment: Subjects with moderate hepatic impairment showed no evidence of an increase in systemic exposure to either umeclidinium or vilanterol (C_max and AUC), and no evidence of altered protein binding between subjects with moderate hepatic impairment and healthy volunteers. Umeclidinium/vilanterol has not been evaluated in subjects with severe hepatic impairment.
Other patient characteristics: A population pharmacokinetic analysis showed that no dose adjustment is required for umeclidinium or vilanterol based on the effect of age, race, gender, inhaled corticosteroid use, or weight. A study in CYP2D6 poor metabolisers showed no evidence of a clinically significant effect of CYP2D6 genetic polymorphism on systemic exposure to umeclidinium.
Toxicology: Non-Clinical information: In nonclinical studies with umeclidinium and vilanterol, findings were those typically associated with the primary pharmacology of either muscarinic receptor antagonists or beta₂-agonists respectively and/or local irritancy.
Administration of umeclidinium and vilanterol in combination did not result in any new toxicity. The following statements reflect studies conducted on the individual components.
Carcinogenesis/mutagenesis: Umeclidinium was not genotoxic in a standard battery of studies and was not carcinogenic in lifetime inhalation studies in mice or rats at exposures ≥ 26 or ≥ 22-fold, times the human clinical exposure of umeclidinium 62.5 micrograms, based on AUC, respectively.
Genetic toxicity studies indicate vilanterol does not represent a genotoxic hazard to humans. Consistent with findings for other beta₂-agonists, in lifetime inhalation studies vilanterol caused proliferative effects in the female rat and mouse reproductive tract and in the rat pituitary gland. There was no increase in tumour incidence in rats or mice at exposures 0.5- or 13-fold, times the human clinical exposure of vilanterol 25 micrograms based on AUC, respectively.
Reproductive Toxicology: Neither umeclidinium nor vilanterol had any adverse effects on male or female fertility in rats.
Umeclidinium was not teratogenic in rats or rabbits. In a pre- and post-natal study, subcutaneous administration of umeclidinium to rats resulted in lower maternal body weight gain and food consumption and slightly decreased pre-weaning pup body weights in dams given 180 micrograms/kg/day dose (approximately 80-times the human clinical exposure of 62.5 micrograms umeclidinium, based on AUC).
Vilanterol was not teratogenic in rats. In inhalation studies in rabbits, vilanterol caused effects similar to those seen with other beta₂-agonists (cleft palate, open eyelids, sternebral fusion and limb flexure/malrotation) at 6-times the human clinical exposure based on AUC. When given subcutaneously there were no effects at 36-times the human clinical exposure of 25 micrograms vilanterol based on AUC.