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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 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 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 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 ANORO ELLIPTA 62.5/25 micrograms and/or umeclidinium/vilanterol 125/25 micrograms, all once daily. Efficacy results for ANORO ELLIPTA 62.5/25 micrograms are presented below.
Placebo controlled studies: In a 6-month study, DB2113373, 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 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/imageANORO 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 ANORO ELLIPTA (1.2 units; p<0.001). The percentage of patients receiving 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 ANORO ELLIPTA (-5.51 units; p≤0.001). The percentage of patients receiving 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 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 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 ANORO ELLIPTA 62.5/25 micrograms resulted in a lower risk of COPD exacerbation compared with placebo (analysis of time to first exacerbation: Hazard Ratio (HR) 0.5, 95% CI=0.3 to 0.8, risk reduction 50%, p=0.004).
Tiotropium comparator studies: In studies ZEP117115 and DB2113360 treatment with 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, 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/imageIn Studies ZEP117115 and DB2113360 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 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, 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 ANORO ELLIPTA (-2.10 units; p=0.006). The percentage of patients receiving 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 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 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 ANORO ELLIPTA 62.5/25 micrograms resulted in a lower risk of COPD exacerbation compared with tiotropium (analysis of time to first exacerbation: Hazard Ratio (HR) 0.5, 95% CI=0.3 to 1.0, risk reduction 50%, p=0.044).
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 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 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, 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, 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).
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: 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, Cmax 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, Cmax 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 (Cmax 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 Cmax, 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 Cmax. 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 (Cmax 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 (Cmax 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: Pre-clinical Safety Data: 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.
