Pharmacology: Mechanism of Action:
Indacaterol is an 'ultra' long-acting beta2
-adrenergic agonist for once-daily administration. The pharmacological effects of beta2
-adrenoceptor agonists, including indacaterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro
studies have shown that indacaterol has more than 24-fold greater agonist activity at beta2
-receptors compared to beta1
-receptors and 20-fold greater agonist activity compared to beta3
-receptors. This selectivity profile is similar to formoterol.
When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a nearly full agonist at the human beta2
-adrenergic receptor with nanomolar potency. In isolated human bronchus, indacaterol has a rapid onset of action and a long duration of action.
-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1
-receptors are the predominant receptors in the human heart, there are also beta2
-adrenergic receptors in the human heart comprising 10% to 50% of the total adrenergic receptors. The precise function of beta2
-adrenergic receptors in the heart is not known, but their presence raises the possibility that even highly selective beta2
-adrenergic agonists may have cardiac effects.
Pharmacodynamics: Primary Pharmacodynamic Effects:
Onbrez Breezhaler provided consistently significant improvement in lung function (as measured by the forced expiratory volume in one second, FEV1
) over 24 hours in a number of clinical pharmacodynamic and efficacy trials. There was a rapid onset of action within 5 minutes after inhalation of Onbrez Breezhaler, comparable to the effect of the fast-acting beta2
-agonist salbutamol and a peak effect occurring between 2-4 hours following the dose. There was no evidence for tachyphylaxis to the bronchodilator effect after repeated dosing for up to 52 weeks. The bronchodilator effect did not depend on the time of dosing (morning or evening).
In a study in 27 patients, Onbrez Breezhaler reduced both dynamic and resting hyperinflation in patients with moderate to severe COPD. Inspiratory capacity during constant, sub-maximal exercise increased by 317 mL compared to placebo after administration of 300 microgram once-daily over 14 days. A statistically significant increase in resting inspiratory capacity, exercise endurance and FEV1
were also demonstrated as well as a significant improvement in measures of dyspnoea.
Secondary Pharmacodynamic Effects:
The characteristic adverse effects of inhaled beta2
-adrenergic agonists occur as a result of activation of systemic beta-adrenergic receptors. The most common adverse effects include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in serum potassium and increases in plasma glucose.
Effects on cardiac electrophysiology:
The effect of Onbrez Breezhaler on the QT interval was evaluated in a double-blind, placebo- and active (moxifloxacin)-controlled study following multiple doses of indacaterol 150 microgram, 300 microgram or 600 microgram once-daily for 2 weeks in 404 healthy volunteers. Fridericia's method for heart rate correction was employed to derive the corrected QT interval (QTc
F). Maximum mean prolongation of QTc
F intervals were <5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time-matched comparisons versus placebo. This shows that there is no concern for a pro-arrhythmic potential related to QT-interval prolongations at recommended therapeutic doses. There was no evidence of a concentration-delta QTc relationship in the range of doses evaluated.
Electrocardiographic monitoring in patients with COPD:
The effect of Onbrez Breezhaler on heart rate and rhythm was assessed using continuous 24- hour ECG recording (Holter monitoring) in a subset of 605 patients with COPD from a 26- week, double-blind, placebo-controlled Phase III study (see CLINICAL STUDIES as follows). Holter monitoring occurred once at baseline and up to 3 times during the 26-week treatment period (at weeks 2, 12 and 26).
A comparison of the mean heart rate over 24 hours showed no increase from baseline for both doses evaluated, 150 microgram once-daily and 300 microgram once-daily. The hourly heart rate analysis was similar for both doses compared to placebo and tiotropium. The pattern of diurnal variation over 24 hours was maintained and was similar to placebo.
No difference from placebo or tiotropium was seen in the rates of atrial fibrillation, time spent in atrial fibrillation and also the maximum ventricular rate of atrial fibrillation.
No clear patterns in the rates of single ectopic beats, couplets or runs were seen across visits.
Because the summary data on rates of ventricular ectopic beats can be difficult to interpret, specific pro-arrhythmic criteria were analyzed. In this analysis, baseline occurrence of ventricular ectopic beats was compared to change from baseline, setting certain parameters for the change to describe the pro-arrhythmic response. The number of patients with a documented pro-arrhythmic response was very similar across both indacaterol doses compared to placebo and tiotropium.
Overall, there was no clinically relevant difference in the development of arrhythmic events in patients receiving indacaterol treatment over those patients who received placebo or treatment with tiotropium.
Effects on serum potassium and plasma glucose:
Changes in serum potassium and plasma glucose were evaluated in a 26-week, double-blind, placebo-controlled Phase III study (see CLINICAL STUDIES as follows). At 1 hour post-dose at week 12, mean changes compared to placebo in serum potassium ranging from 0.03 to 0.05mmol/L and in mean plasma glucose ranging from 0.25 to 0.31mmol/L were observed.
The Onbrez Breezhaler Phase III clinical development program consisted of 16 key studies and enrolled over 9,000 patients with a clinical diagnosis of moderate to severe COPD, who were 40 years old or older, had a smoking history of at least 20 pack years, had a post-bronchodilator FEV1
<80% and ≥30% of the predicted normal value and a post-bronchodilator FEV1
/FVC ratio of less than 70%.
In these studies, indacaterol, administered once-daily at doses of 150 microgram and 300 microgram, showed clinically meaningful improvements in lung function (as measured by the forced expiratory volume in one second, FEV1
) over 24 hours. At the 12-week primary endpoint (24-hour trough FEV1
), the 150 microgram dose resulted in a 0.13-0.18 L increase compared to placebo (p<0.001) and a 0.06 L increase compared to salmeterol 50 microgram twice a day (p<0.001). The 300 microgram dose resulted in a 0.17-0.18 L increase compared to placebo (p<0.001) and a 0.1 L increase compared to formoterol 12 microgram twice a day (p<0.001). Both doses resulted in an increase of 0.04-0.05 L over open-label tiotropium 18- microgram once-daily (150 microgram, p=0.004; 300 microgram, p=0.01).
Indacaterol administered once-daily at the same time each day, either in the morning or evening, had a rapid onset of action within 5 minutes similar to that of salbutamol 200- microgram and statistically significantly faster compared to salmeterol/fluticasone 50/500 microgram, and mean peak improvements in FEV1
relative to baseline of 0.25-0.33 L at steady-state occurring between 2-4 hours following the dose. The 24-hour bronchodilator effect of Onbrez Breezhaler was maintained from the first dose throughout a one-year period with no evidence of loss of efficacy (tachyphylaxis).
In a 26-week, placebo- and active (open label tiotropium)-controlled study in 2,059 patients, the mean improvement relative to baseline in FEV1
at 5 minutes was 0.12 L and 0.13 L for Onbrez Breezhaler 150 microgram and 300 microgram once-daily, respectively, and the mean peak improvement, relative to baseline, after the first dose (Day 1) was 0.19 L and 0.24 L, respectively, and improved to 0.23 L and 0.26 L, respectively, when pharmacodynamic steady-state was reached (Day 14). At the primary end point (Week 12), both Onbrez Breezhaler 150 microgram and 300 microgram once-daily treatment groups showed a significantly higher trough FEV1
value compared to placebo (both 0.18 L, p<0.001) and to tiotropium (0.05 L, p=0.004, and 0.04 L, p=0.01, respectively).
In this study, 12-hour serial spirometric measurements were performed in a subset of patients throughout daytime hours (12 hours). Serial FEV1
values over 12 hours at Day 1 and trough FEV1
values at Day 2 are shown in Figure 1, and at Day 182/183 in Figure 2, respectively. Improvement of lung function was maintained for 24 hours after the first dose and consistently maintained over the 26-week treatment period with no evidence of tolerance. (See Figure 1 and Figure 2.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
In a 26-week, placebo-controlled safety extension to this study in 414 patients, efficacy was not a primary endpoint, however at the secondary end point (Week 52) of trough FEV1
, treatment with both Onbrez Breezhaler 150 microgram and 300 microgram once-daily resulted in a significantly higher trough FEV1 value compared to placebo (0.17 L, p<0.001 and 0.18L, p<0.001, respectively).
Results of a 12-week, placebo-controlled study in 416 patients which evaluated the 150 microgram once-daily dose, were similar to the results for this dose in the 26-week study. The mean peak improvement in FEV1
, relative to baseline, was 0.23 L after 1 day of once-daily treatment At the primary end point (Week 12), treatment with Onbrez Breezhaler 150 microgram once-daily resulted in a significantly higher trough FEV1 value compared to placebo (0.13 L, p<0.001).
In a 26-week, placebo- and active (blind salmeterol)-controlled study in 1,002 patients which evaluated the Onbrez Breezhaler 150 microgram once-daily dose, the mean improvement in FEV1
, relative to baseline, at 5 minutes was 0.11 L with a peak improvement of 0.25 L relative to baseline after the first dose (Day 1). At the primary end point (Week 12), treatment with Onbrez Breezhaler 150 microgram once-daily showed a significantly higher trough FEV1
value compared to both placebo (0.17 L, p<0.001) and to salmeterol (0.06 L, p<0.001).
In a 52-week, placebo- and active (formoterol)-controlled study in 1,732 patients which evaluated the Onbrez Breezhaler 300 microgram once-daily dose and a higher dose, the mean improvement in FEV1
, relative to baseline, at 5 minutes was 0.14 L with a peak improvement of 0.20 L relative to baseline after the first dose (Day 1). At the primary end point (Week 12), treatment with Onbrez Breezhaler 300 microgram once-daily resulted in a significantly higher trough FEV1
value compared to placebo (0.17 L, p<0.001) and to formoterol (0.1 L, p<0.001). This improvement of lung function was maintained over the 52-week treatment period with no evidence of loss of efficacy over this period. Onbrez Breezhaler was superior to formoterol with regard to trough FEV1
at all visits.
In a 2-week, placebo- and active (open label salmeterol)-controlled crossover study, 24-hour spirometry was assessed in 68 patients. Serial spirometry values over 24 hours are displayed in Figure 3. After 14 days of once-daily treatment, improvement of lung function compared to placebo was maintained for 24 hours, and in addition, the trough FEV1
value was statistically significantly higher compared to salmeterol (0.09 L, p=0.011). Similar results from 24-hour serial spirometry were observed after 26 weeks in a subset of patients (n=236) from the 26- week study. Both studies further support the improvement in FEV1
over placebo with Onbrez Breezhaler administered once-daily, and that bronchodilation was maintained throughout the 24-hour dosing interval, in comparison to placebo. (See Figure 3.)
Click on icon to see table/diagram/image
The following health outcome effects were demonstrated in the long-term studies of 12-, 26- and 52-week treatment duration: Onbrez Breezhaler significantly improved dyspnea compared to baseline in the 26-week study (as evaluated using the Transitional Dyspnea Index, TDI) by the first assessment (day 29), and this was maintained for the entire 26 weeks in the 150 microgram and 300 microgram once-daily treatments compared to placebo. Onbrez Breezhaler 300 microgram once-daily was also statistically superior to open label tiotropium at all timepoints (p≤0.01). The proportion of patients who achieved a score of ≥1.0 (corresponding to a clinically important difference) in TDI focal score was significantly greater in the indacaterol group at all 4 assessment points compared to the placebo group (p≤0.001). At 26 weeks, the proportions were 62.4% and 70.8% with Onbrez Breezhaler 150 microgram once-daily and 300 microgram once-daily, respectively, compared to 57.3% and 46.6% with tiotropium and with placebo, respectively. In the 26-week, placebo- and active (blind salmeterol)-controlled study Onbrez Breezhaler 150 microgram once-daily also significantly improved dyspnea over the entire 26-week treatment period. The proportion of patients who achieved a TDI focal score of ≥1.0 (corresponding to a clinically important difference) was significantly greater in the indacaterol group at all four assessment points (Day 29, Day 57, Day 84, and Day 182) than in the placebo group (p≤0.005).
In this study statistically significant differences between either active treatment and placebo were seen for the change from baseline in mean daily, daytime and night time number of puffs of rescue medication at every 4-weekly interval of the 26-week treatment period. Onbrez Breezhaler-treated patients required numerically fewer daily, daytime and night time puffs of rescue medication compared with salmeterol-treated patients at certain 4-week intervals, but none of the differences between active treatments were statistically significant. In the 52-week study there was a statistically significant reduction in the number of puffs of rescue short-acting beta2
-adrenergic agonists with Onbrez Breezhaler 300 microgram once-daily compared to formoterol and placebo (1.69, 1.35 and 0.02 fewer puffs, respectively). Similarly, in the 26-week study, reductions in rescue use in the Onbrez Breezhaler 150 microgram once-daily and 300 microgram once-daily groups were statistically significant compared to open label tiotropium and placebo (1.45 and 1.56 compared to 0.99 and 0.39 fewer puffs, respectively). In the 12-week study (which had no active comparator) a similar pattern was observed with Onbrez Breezhaler 150 microgram once-daily.
Patients treated with Onbrez Breezhaler 150 microgram and 300 microgram once-daily had numerically lower risks of COPD exacerbation compared to placebo in long-term trials of 12-, 26- and 52-week treatment duration. Time-to-first-COPD exacerbation as compared to placebo was significantly longer in the 26-week study under treatment with 150-microgram once-daily and in the 52-week study under treatment with 300 microgram once-daily (p=0.019 and p=0.03, respectively). Pooled analyses showed that patients treated with Onbrez Breezhaler 150 microgram and 300 microgram once-daily had statistically lower risks of COPD exacerbations compared to placebo in both the 6-month and 12-month pooled populations. Time-to-first-COPD exacerbation as compared to placebo was significantly longer in the 6-month population under treatment with 150 microgram and 300 microgram doses once-daily (p=0.005 and p=0.006, respectively) and in the 12-month population under treatment with 300 microgram once-daily (p=0.022). Pooled efficacy analysis over 6 and 12 months of treatment demonstrated that the rate of COPD exacerbations was statistically significantly lower than the placebo rate. Treatment comparisons to placebo over 6 months showed a ratio of rates of 0.70 (95% CI [0.53, 0.94]; p-value 0.014) and 0.74 (95% CI [0.57, 0.96]; p-value 0.024) for Onbrez Breezhaler 150 microgram and 300 microgram, respectively, and over 12 months the ratio of rates was of 0.78 (95% CI [0.62, 0.98]; p-value 0.034) for treatment with 300 microgram once-daily.
Onbrez Breezhaler also significantly improved health-related quality of life (as measured using the St. George's Respiratory Questionnaire) in long-term trials of 12-, 26- and 52-week treatment duration. Both doses of 150 microgram and 300 microgram once-daily demonstrated a significantly lower (improved) mean total score in the SGRQ, as well as each component score, in comparison to placebo: An improvement compared to placebo exceeding the minimal clinically important difference of 4 units was shown at 8 and 12 weeks in the 12- week study, and in the 52-week study this was shown for treatment with 300 microgram once-daily at 8, 24, 44 and 52 weeks. In the 26-week study, patients treated with 150-microgram once-daily showed a significantly lower mean total score in the SGRQ compared to tiotropium (p≤0.05), and at the end of the 26-week, placebo-controlled safety extension to this study the mean change in SGRQ total score was a decrease (improvement) of 3.2 units for Onbrez Breezhaler 150 microgram versus placebo after 52 weeks of treatment. In the other 26-week study, treatment with both Onbrez Breezhaler 150 microgram and salmeterol resulted in a significantly lower (improved) mean SGRQ total scores compared to placebo with mean differences of 6.3 units (p<0.001) and 4.2 units (p<0.001), respectively, that exceeded the minimal clinically important difference of 4 units after 12 weeks and thus were also clinically relevant. Onbrez Breezhaler also achieved statistical superiority over salmeterol by 2.1 units (p=0.033).
Onbrez Breezhaler 150 microgram and 300 microgram once-daily treatment over 26-weeks significantly improved the percentage of days with no daytime symptoms (p<0.02) and the percentage of days where patients were able to perform their normal daily activities as compared to placebo (p<0.001).
Inhalation: The median time to reach peak serum concentrations of indacaterol was approximately 15 min after single or repeated inhaled doses. Systemic exposure to indacaterol increased with increasing dose (150 microgram to 600 microgram) in a dose proportional manner. Absolute bioavailability of indacaterol after an inhaled dose was on average 43-45%. Systemic exposure results from a composite of pulmonary and intestinal absorption.
Indacaterol serum concentrations increased with repeated once-daily administration. Steady-state was achieved within 12 to 15 days. The mean accumulation ratio of indacaterol, i.e., AUC over the 24-h dosing interval on Day 14 or Day 15 compared to Day 1, was in the range of 2.9 to 3.8 for once-daily inhaled doses between 75 microgram and 600 microgram. Systemic exposure following inhalation results from a composite of oral and pulmonary absorption, with pulmonary absorption accounting for the principal amount.
Oral administration: The oral bioavailability of indacaterol when swallowed from a capsule is approximately 25% when the orogastrointestinal absorption rate of 30-50%. Cmax
is reached within 0.5-2 hours.
After intravenous infusion the volume of distribution (Vz
) of indacaterol was 2,361 L to 2,557 L indicating an extensive distribution. The in vitro
human serum and plasma protein binding was 94.1 to 95.3% and 95.1 to 96.2%, respectively.
After oral administration of radiolabelled indacaterol in a human ADME (absorption, distribution, metabolism, excretion) study, unchanged indacaterol was the main component in serum, accounting for about one third of total drug-related AUC over 24 h. A hydroxylated derivative was the most prominent metabolite in serum. Phenolic O-glucuronides of indacaterol and hydroxylated indacaterol were further prominent metabolites. A diastereomer of the hydroxylated derivative, a N-glucuronide of indacaterol, and C- and N-dealkylated products were further metabolites identified.
investigations indicated that UGT1A1 is the only UGT isoform that metabolized indacaterol to the phenolic O-glucuronide. The oxidative metabolites were found in incubations with recombinant CYP1A1, CYP2D6, and CYP3A4. CYP3A4 is concluded to be the predominant isoenzyme responsible for hydroxylation of indacaterol. In vitro
investigations further indicated that indacaterol is a low affinity substrate for the efflux pump P-gp.
In clinical studies which included urine collection, the amount of indacaterol excreted unchanged via urine was generally lower than 2% of the dose. Renal clearance of indacaterol was, on average, between 0.46 and 1.20 L/h. When compared with the serum clearance of indacaterol of 18.8 to 23.3 L/h, it is evident that renal clearance plays a minor role (about 2 to 6% of systemic clearance) in the elimination of systemically available indacaterol.
In a human ADME study where indacaterol was given orally, the faecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human faeces primarily as unchanged parent drug (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose). Mass balance was complete with ≥90% of the dose recovered in the excreta.
Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing ranged from 40 to 56 hours which is consistent with the observed time-to-steady state of approximately 12 to 15 days.
A population analysis of the effect of age, gender and weight on systemic exposure in COPD patients after inhalation indicated that Onbrez Breezhaler can be used safely in all age and weight groups and regardless of gender. It did not suggest any difference between ethnic subgroups in this population. Limited treatment experience is available for the black population.
The pharmacokinetics of indacaterol was investigated in two different UGT1A1 genotypes - the fully functional [(TA)6
] genotype and the low activity [(TA)7
] genotype (Gilbert's syndrome genotype). The study demonstrated that steady-state AUC and Cmax
of indacaterol were 1.2-fold higher in the [(TA)7
] genotype, indicating that systemic exposure to indacaterol is only insignificantly affected by this UGT1A1 genotypic variation.
Patients with mild and moderate hepatic impairment showed no relevant changes in Cmax
or AUC of indacaterol, nor did protein binding differ between mild and moderate hepatic impaired subjects and their healthy controls. Studies in subjects with severe hepatic impairment were not performed.
Due to the very low contribution of the urinary pathway to total body elimination, a study in renally impaired subjects was not performed.
Toxicology: Non-Clinical Safety Data:
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction. The effects of indacaterol seen in toxicity studies in dogs were mainly on the cardiovascular system and consisted of tachycardia, arrhythmias and myocardial lesions. These effects are known pharmacological effects and could be explained by the beta2
- agonistic properties of indacaterol. During a chronic toxicity study in dogs, elevated levels of creatinine were detected in the blood, but no evidence of altered renal function was seen in the results of either this or any other study. Other relevant effects noted in repeated-dose toxicity studies were mild irritancy of the upper respiratory tract in rats consisting of rhinitis and epithelial changes of the nasal cavity and larynx. All these findings were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Adverse effects with respect to fertility, pregnancy, embryonal/foetal development, pre- and postnatal development could only be demonstrated at doses more than 195-fold the maximum recommended daily inhalation dose of 300 microgram in humans (on a mg/m2
basis). The effects, namely an increased incidence of one skeletal variation, were observed in rabbits. Indacaterol was not teratogenic in rats or rabbits following subcutaneous administration. Studies on genotoxicity did not reveal any mutagenic or clastogenic potential. The carcinogenic potential of indacaterol has been evaluated in a 2-year inhalation study in rats and a 26-week oral transgenic mouse study. Lifetime treatment of rats resulted in increased incidences of benign ovarian leiomyoma and focal hyperplasia of ovarian smooth muscle in females at doses approximately 68-times the maximum recommended dose of 300 microgram once-daily for humans (on a mg/m2
basis). Increases in leiomyomas of the rat female genital tract have been similarly demonstrated with other β2
-adrenergic agonist drugs. A 26-week oral (gavage) study in CB6F1/TgrasH2 hemizygous mice with indacaterol did not show any evidence of tumorigenicity at doses approximately 9800-times the maximum recommended dose of 300 microgram once-daily for humans (on a mg/m2