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 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 is a selective long-acting, beta2
-adrenergic receptor agonist (beta2
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.
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.
The effect of umeclidinium/vilanterol on the QT interval was evaluated in a placebo and active (moxifloxacin) controlled QT study involving once daily administration of umeclidinium/vilanterol 125/25 micrograms or 500/100 micrograms (with umeclidinium at eight times the recommended dose and vilanterol at four times the recommended dose) 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. Therefore, no clinically relevant pro-arrhythmic potential related to QT interval prolongations was observed with umeclidinium/vilanterol 125/25 micrograms.
A dose-dependent increase in heart rate was also observed. The maximum mean difference in heart rate from placebo after baseline-correction was 8.4 (90% CI=7.0 to 9.8) beats/minute and 20.3 (90% CI=18.9 to 21.7) beats/minute seen 10 minutes after administration of umeclidinium/vilanterol 125/25 micrograms and 500/100 micrograms respectively.
In addition, no clinically significant effects on cardiac rhythm were observed on 24-hour Holter monitoring in 53 patients with COPD who were treated with umeclidinium/vilanterol 62.5/25 micrograms once daily in one 6-month study, or in a further 55 patients who received umeclidinium/vilanterol 125/25 micrograms once daily in another 6-month study and 226 patients who received 125/25 micrograms once daily in the 12 month study.
The clinical efficacy of umeclidinium/vilanterol of ANORO ELLIPTA administered once daily were evaluated in eight Phase III clinical studies in 6,835 adult patients with a clinical diagnosis of COPD; 5,618 patients from five 6-month studies (two placebo-controlled and three active (tiotropium)-comparator controlled), 655 patients from two 3-month exercise endurance/lung function studies and 562 patients from a 12-month supportive study.
Effects on Lung Function:
ANORO ELLIPTA demonstrated improvements in lung function (as defined by change from baseline in trough FEV1
) in several studies. In one 6-month Phase III study, ANORO ELLIPTA demonstrated statistically significant improvements in trough FEV1
(primary endpoint) at Week 24 compared with placebo and each monotherapy component treatment arm. In addition, ANORO ELLIPTA demonstrated clinically meaningful and statistically significant improvements in trough FEV1
compared with tiotropium in two of the three 6-month active-comparator studies and numerically-greater improvements from tiotropium in the third active-comparator study (see Table 1). There was no attenuation of the bronchodilator effect over time.
Symptomatic Outcomes: Breathlessness:
ANORO ELLIPTA demonstrated a statistically significant and clinically meaningful reduction in breathlessness as evaluated by an increase in TDI focal score at Week 24 (key secondary end-point) compared with placebo (see Table 1). Improvements in TDI focal score compared with each monotherapy component and tiotropium were not statistically significant (see Table 1).
The proportion of patients who responded with at least the minimum clinically important difference (MCID) of 1 unit TDI focal score at Week 24 was greater for ANORO ELLIPTA (59%) compared with placebo (41%) and each monotherapy component (53% for umeclidinium and 51% for vilanterol).
Health-Related Quality of Life:
ANORO ELLIPTA has also shown an improvement in health-related quality of life measured using the St. George's Respiratory Questionnaire (SGRQ) as indicated by a reduction in SGRQ total score at Week 24 compared with placebo and each monotherapy component (see Table 1). ANORO ELLIPTA showed a statistically significant reduction in SGRQ total score compared with tiotropium in one of the three active-comparator studies (see Table 1).
The proportion of patients who responded with at least the MCID in SGRQ score (defined as a decrease of 4 units from baseline) at Week 24 was greater for ANORO ELLIPTA (49%) compared with placebo (34%) and each monotherapy component (44% for umeclidinium and 48% for vilanterol). In one active-comparator study, a higher percentage of patients receiving ANORO ELLIPTA responded with a clinically meaningful improvement in SGRQ score at Week 24 (53%) compared to tiotropium (46%). In the other two active-comparator studies, a similar proportion of patients achieved at least the MCID with ANORO and tiotropium; 49% and 54% for ANORO 62.5/25 micrograms and 52% and 55% for tiotropium.
Use of Rescue Medication:
ANORO ELLIPTA reduced the use of rescue medication with salbutamol compared with placebo and umeclidinium (see Table 1) and demonstrated a higher percentage of days when no rescue medication was needed (on average 36.1%) compared with placebo (on average 21.7%).
In the three 6-month active-comparator-controlled studies, ANORO ELLIPTA reduced the use rescue medication with salbutamol compared with tiotropium, with statistically significant reductions observed in two of the studies (see Table 1). ANORO ELLIPTA also demonstrated a higher percentage of days when no rescue medication was needed in all three studies (average within the range 17.6% to 21.5%) compared with tiotropium (average within the range 11.7% to 13.4%). (See Table 1.)
Click on icon to see table/diagram/image
A higher dose of umeclidinium/vilanterol (125/25 micrograms) was also studied in a 24-week placebo controlled clinical study and in two of the three 24-week active-controlled studies. The results were similar to those for the ANORO ELLIPTA dose and provided additional supportive evidence for the efficacy of ANORO ELLIPTA.
ANORO ELLIPTA reduced the risk of a COPD exacerbation by 50% compared with placebo (based analysis of time to first exacerbation: Hazard Ratio (HR) 0.5, p=0.004*); by 20% compared with umeclidinium (HR 0.8, p=0.391); and by 30% compared with vilanterol (HR 0.7, p=0.121). From the three active-comparator studies, the risk of a COPD exacerbation compared with tiotropium was reduced by 50% in one study, (HR 0.5, p-0.044) and was increased by 20% and 90% in two studies (HR 1.2, p=0.709 and HR 1.9, p=0.062 respectively). These studies were not specifically designed to evaluate the effect of treatments on COPD exacerbations and patients were withdrawn from the study if an exacerbation occurred.
Exercise Endurance and Lung Volumes:
ANORO ELLIPTA 62.5/25 micrograms improved exercise endurance time compared with placebo, as evaluated with the endurance shuttle walk test (ESWT), in one study but not the second and improved lung volume measures compared with placebo in both studies in adult (COPD) patients with hyperinflation [functional residual capacity (FRC)>120%]. In the first study ANORO ELLIPTA 62.5/25 micrograms demonstrated a statistically significant and clinically relevant improvement (based on a minimally clinically important difference (MCID) between 45 to 85 seconds) over placebo in exercise endurance time (EET) obtained 3 hours after dosing at Week 12 [69.5 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, the treatment difference in EET between ANORO ELLIPTA 62.5/25 micrograms and placebo was 21.9 seconds (p=0.234) at Week 12.
ANORO ELLIPTA 62.5/25 micrograms also showed statistically significant improvements compared with placebo in change from baseline in lung volume measures at trough and at 3 hours post dose at Week 12 in the first study (inspiratory capacity: 237 ml and 316 ml respectively, residual volume: -466 ml and -643 ml respectively and functional residual capacity: -351 ml and -522 ml respectively; all p<0.001). In the second study, ANORO ELLIPTA 62.5/25 micrograms showed improvements compared with placebo in change from baseline in lung volume measures at trough and at 3 hours post dose at Week 12 (inspiratory capacity: 198 ml and 238 ml respectively, residual volume: -295 ml and -351 ml respectively and functional residual capacity: -238 ml and-302 ml respectively); all p<0.001*).
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.
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.
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.
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%.
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.
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)
, 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.
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.
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.
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.
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: Preclinical 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.
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.
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.