Pharmacology: 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 hrs in a number of clinical pharmacodynamic and efficacy trials. There was a rapid onset of action within 5 min after inhalation of Onbrez Breezhaler, comparable to the effect of the fast-acting β2-agonist salbutamol and a peak effect occurring between 2-4 hrs 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).
Onbrez Breezhaler reduced both dynamic and resting hyperinflation in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Inspiratory capacity during constant, submaximal exercise increased by 317 mL compared to placebo after administration of 300 mcg 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 β2-adrenergic agonists occur as a result of activation of systemic β-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, 300 or 600 mcg once-daily for 2 weeks in 404 healthy volunteers. Fridericia's method for heart rate correction was employed to derive the corrected QT-interval (QTcF). Maximum mean prolongation of QTcF intervals were <5 millisec, 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 Chronic Obstructive Pulmonary Disease (COPD): The effect of Onbrez Breezhaler on heart rate and rhythm was assessed using continuous 24-hr electrocardiogram (ECG) recording (Holter monitoring) in a subset of 605 patients with COPD from a 26-week, double-blind, placebo-controlled Phase III study (see text on 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 hrs showed no increase from baseline for both doses evaluated, 150 and 300 mcg once daily. The hourly heart rate analysis was similar for both doses compared to placebo and tiotropium. The pattern of diurnal variation over 24 hrs 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 were 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 text on Clinical Studies as follows). At 1 hr post-dose at week 12, mean changes compared to placebo in serum potassium ranging from 0.03-0.05 mmol/L and in mean plasma glucose ranging from 0.25-0.31 mmol/L were observed.
Mechanism of Action: Indacaterol is an 'ultra' long-acting β2-adrenergic agonist for once-daily administration. The pharmacological effects of β2-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 AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol has >24-fold greater agonist activity at β2-receptors compared to β1-receptors and 20-fold greater agonist activity compared to β3-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 β2-adrenergic receptor with nanomolar potency. In isolated human bronchus, indacaterol has a rapid onset of action and a long duration of action.
Although β2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and β1-receptors are the predominant receptors in the human heart, there are also β2-adrenergic receptors in the human heart comprising 10-50% of the total adrenergic receptors. The precise function of β2-adrenergic receptors in the heart is not known, but their presence raises the possibility that even highly selective β2-adrenergic agonists may have cardiac effects.
Pharmacokinetics: Absorption: 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 (150-600 mcg) in a dose proportional manner. Absolute bioavailability of indacaterol after an inhaled dose was on average 43%. 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 12-14 days. The mean accumulation ratio of indacaterol ie, area under the plasma concentration-time curve (AUC) over the 24-hr dosing interval on Day 14 compared to Day 1, was in the range of 2.9-3.5 for once-daily inhaled doses between 150 mcg and 600 mcg.
Distribution: After IV infusion the volume of distribution (Vz) of indacaterol was 2557 L indicating an extensive distribution. The in vitro human serum and plasma protein binding was 94.1-95.3% and 95.1-96.2%, respectively.
Biotransformation/Metabolism: After oral administration of radiolabelled indacaterol in a human absorption, distribution, metabolism, excretion (ADME) study, unchanged indacaterol was the main component in serum, accounting for about ⅓ of total drug-related AUC over 24 hr. A hydroxylated derivative was the most prominent metabolite in serum. A phenolic O-glucuronide 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.
In vitro 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-glycoprotein (P-gp).
Elimination: In clinical studies which included urine collection, the amount of indacaterol excreted unchanged via urine was generally <2% of the dose. Renal clearance of indacaterol was, on average, between 0.46 L/hr and 1.20 L/hr. When compared with the serum clearance of indacaterol of 23.3 L/hr, it is evident that renal clearance plays a minor role (about 2-5% of systemic clearance) in the elimination of systemically available indacaterol.
In a human ADME study where indacaterol was given orally, the fecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human feces 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 45.5-126 hrs. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing, ranged from 40-52 hrs which is consistent with the observed time-to-steady state of approximately 12-14 days.
Special Populations: 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 2 different UGT1A1 genotypes, the fully functional [(TA)6, (TA)6] genotype and the low activity [(TA)7, (TA)7] genotype (Gilbert's syndrome genotype). The study demonstrated that steady-state AUC and maximum plasma concentration (Cmax) of indacaterol were 1.2-fold higher in the [(TA)7, (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.
Clinical Studies: The Onbrez Breezhaler Phase III clinical development program consisted of 8 key studies and enrolled 5430 patients with a clinical diagnosis of COPD, who were 40 years 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 <70%.
In these studies, indacaterol, administered once-daily at doses of 150 mcg and 300 mcg, showed clinically meaningful improvements in lung function (as measured by the FEV1) over 24 hrs. At the 12-week primary endpoint (24-hr trough FEV1), the 150 mcg 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 mcg twice daily (p<0.001). The 300 mcg 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 mcg twice daily (p<0.001). Both doses resulted in an increase of 0.04-0.05 L over open-label tiotropium 18 mcg once daily (150 mcg, p=0.004; 300 mcg, 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 min which is similar to that of salbutamol 200 mcg and statistically significantly faster compared to salmeterol/fluticasone 50/500 mcg, and mean peak improvements in FEV1 relative to baseline of 0.25-0.33 L at steady state occurring between 2-4 hrs following the dose. The 24-hr bronchodilator effect of Onbrez Breezhaler was maintained from the 1st dose throughout a 1-year period with no evidence of loss of efficacy (tachyphylaxis).
In a 26-week, placebo- and active (open label tiotropium)-controlled study in 2059 patients, the mean improvement relative to baseline in FEV1 at 5 min was 0.12 and 0.13 L for Onbrez Breezhaler 150 and 300 mcg once daily, respectively, and the mean peak improvement, relative to baseline, after the 1st 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 endpoint (Week 12), both Onbrez Breezhaler 150 and 300 mcg 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-hr serial spirometric measurements were performed in a subset of patients throughout daytime hours (12 hrs). Serial FEV1 values over 12 hrs 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 hrs after the 1st dose and consistently maintained over the 26-week treatment period with no evidence of tolerance (see Figures 1 and 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 mcg and 300 mcg 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 mcg 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 endpoint (Week 12), treatment with Onbrez Breezhaler 150 mcg 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 1002 patients which evaluated the Onbrez Breezhaler 150 mcg once-daily dose, the mean improvement in FEV1, relative to baseline, at 5 min was 0.11 L with a peak improvement of 0.25 L relative to baseline after the 1st dose (Day 1). At the primary end point (Week 12), treatment with Onbrez Breezhaler 150 mcg 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 1732 patients which evaluated the Onbrez Breezhaler 300 mcg once-daily dose and a higher dose, the mean improvement in FEV1, relative to baseline, at 5 min was 0.14 L with a peak improvement of 0.20 L relative to baseline after the 1st dose (Day 1). At the primary end point (Week 12), treatment with Onbrez Breezhaler 300 mcg 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-hr spirometry was assessed in 68 patients. Serial spirometry values over 24 hrs are displayed in Figure 3. After 14 days of once-daily treatment, improvement of lung function compared to placebo was maintained for 24 hrs, and in addition, the trough FEV1 value was statistically significantly higher compared to salmeterol (0.09 L, p=0.011). Similar results from 24-hr 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-hr 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 1st assessment (day 29), and this was maintained for the entire 26 weeks in the 150 mcg and 300 mcg once-daily treatments compared to placebo. Onbrez Breezhaler 300 mcg 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 (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 mcg once-daily and 300 mcg 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 mcg 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 (corresponding to a clinically important difference) was significantly greater in the indacaterol group at all 4 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 nighttime 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 nighttime 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 β2-adrenergic agonists with Onbrez Breezhaler 300 mcg 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 and 300 mcg 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 mcg once-daily.
Patients treated with Onbrez Breezhaler 150 and 300 mcg 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 mcg once-daily and in the 52-week study under treatment with 300 mcg once-daily (p=0.019 and p=0.03, respectively). Pooled analyses showed that patients treated with Onbrez Breezhaler 150 mcg and 300 mcg once-daily had statistically lower risks of COPD exacerbations compared to placebo in both the 6- 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 and 300 mcg doses once-daily (p=0.005 and p=0.006, respectively) and in the 12-month population under treatment with 300 mcg 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 0.7 (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 and 300 mcg, respectively, and the ratio of rates was of 0.78 (95% CI [0.62,0.98]; p-value 0.034) for treatment with 300 mcg once-daily over 12 months.
Onbrez Breezhaler also significantly improved health-related quality of life [as measured using the St. George's Respiratory Questionnaire (SGRQ) in long-term trials of 12-, 26- and 52-week treatment duration. Both doses of 150 and 300 mcg 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 weeks and 12 weeks in the 12-week study, and in the 52-week study, this was shown for treatment with 300 mcg once-daily at 8 weeks, 24 weeks, 44 weeks and 52 weeks. In the 26-week study, patients treated with 150 mcg 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 mcg versus placebo after 52 weeks of treatment. In the other 26-week study, treatment with both Onbrez Breezhaler 150 mcg 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 and 300 mcg 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).
Nonclinical Safety Data: Nonclinical 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 β2-agonistic properties of indacaterol. Other relevant effects noted in repeated-dose toxicity studies were mild irritation 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 >195-fold the maximum recommended daily inhalation dose of 300 mcg in humans (on a mg/m2 basis). The effects, namely an increased incidence of 1 skeletal variation, were observed in rabbits.
Indacaterol was not teratogenic in rats or rabbits following SC 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 mcg 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 mcg once-daily for humans (on a mg/m2 basis).