Onbrez Breezhaler, administered once daily at doses of 150 and 300 mcg consistently provided clinically significant improvements in lung function (as measured by the forced expiratory volume in 1 sec, FEV1) over 24 hrs across a number of clinical pharmacodynamic and efficacy studies. There was a rapid onset of action within 5 min after inhalation, with an increase in FEV1 relative to baseline of 110-160 mL, comparable to the effect of the fast-acting β2
-agonist salbutamol 200 mcg and statistically significantly faster compared to salmeterol/fluticasone 50/500 mcg. Mean peak improvements in FEV1 relative to baseline were 250-330 mL at steady state.
The bronchodilator effect did not depend on the time of dosing, morning or evening.
Onbrez Breezhaler was shown to reduce lung hyperinflation, resulting in increased inspiratory capacity during exercise and at rest, compared to placebo.
Effects on Cardiac Electrophysiology:
A double-blind, placebo-controlled and active (moxifloxacin)-controlled study for 2 weeks in 404 healthy volunteers demonstrated maximum mean (90% confidence intervals) prolongations of the QTCF interval (in millisec) of 2.66 (0.55, 4.77) 2.98 (1.02, 4.93) and 3.34 (0.86, 5.82) following multiple doses of 150, 300 and 600 mcg, respectively. Therefore, this shows no concern for a pro-arrhythmic potential related to QT-interval prolongations at recommended therapeutic doses or at twice the maximum recommended dose. There was no evidence of a concentration-delta QTC relationship in the range of doses evaluated.
As demonstrated in 605 patients with chronic obstructive pulmonary disease (COPD) in a 26-week, double-blind, placebo-controlled phase III study, there was no clinically relevant difference in the development of arrhythmic events monitored over 24 hrs, at baseline and up to 3 times during the 26-week treatment period, between patients receiving recommended doses of Onbrez Breezhaler treatment and those patients who received placebo or treatment with tiotropium.
Clinical Efficacy and Safety:
The clinical development programme included one 12-week, two 6-month (one of which was extended to 1 year to evaluate safety and tolerability) and one 1-year randomized, controlled studies in patients with a clinical diagnosis of COPD. These studies included measures of lung function and of health outcomes eg, dyspnoea, exacerbations and health-related quality of life.
Onbrez Breezhaler, administered once daily at doses of 150 and 300 mcg, showed clinically meaningful improvements in lung function. At the 12-week primary endpoint (24-hr trough FEV1), the 150 mcg dose resulted in a 130-180 mL increase compared to placebo (p<0.001) and a 60 mL increase compared to salmeterol 50 mcg twice daily (p<0.001). The 300 mcg dose resulted in a 170-180 mL increase compared to placebo (p<0.001) and a 100 mL increase compared to formoterol 12 mcg twice daily (p<0.001). Both doses resulted in an increase of 40-50 mL over open-label tiotropium 18 mcg once daily (150 mcg, p=0.004; 300 mcg, p=0.01). The 24-hr bronchodilator effect of Onbrez Breezhaler was maintained from the 1st dose throughout a 1-year treatment period with no evidence of loss in efficacy (tachyphylaxis).
Both doses demonstrated statistically significant improvements in symptom relief over placebo for dyspnoea and health status [as evaluated by Transitional Dyspnoea Index (TDI) and St. George's Respiratory Questionnaire (SGRQ), respectively]. The magnitude of response was generally greater than seen with active comparators (see table). In addition, patients treated with Onbrez Breezhaler required significantly less rescue medication, had more days when no rescue medication was needed compared to placebo and had a significantly improved percentage of days with no daytime symptoms.
Pooled efficacy analysis over 6 months treatment demonstrated that the rate of COPD exacerbations was statistically significantly lower than the placebo rate. Treatment comparison compared to placebo showed a ratio of rates of 0.68 [95% CI (0.47, 0.98); p-value 0.036] and 0.74 [95% CI (0.56, 0.96); p-value 0.026] for 150 and 300 mcg, respectively.
Limited treatment experience is available in individuals of African descent.
Click on icon to see table/diagram/image
The European Medicines Agency has waived the obligation to submit the results of studies with Onbrez Breezhaler in all subsets of the paediatric population in COPD (see Use in children under Precautions).
Mechanism of Action:
The pharmacological effects of β2
-adrenoceptor agonists are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyses 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, a long-acting β2
-adrenergic agonist, has >24-fold greater agonist activity at β2
-receptors compared to β1
-receptors and 20-fold greater agonist activity compared to β3
When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a partial 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.
-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.
Indacaterol is a chiral molecule with R-configuration.
Pharmacokinetic data were obtained from a number of clinical studies, from healthy volunteers and COPD patients.
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, 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 and 600 mcg.
After IV infusion the volume of distribution of indacaterol during the terminal elimination phase 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.
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 1
of total drug-related AUC over 24 hrs. 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-dealkylated and N-dealkylated products were further metabolites identified.
investigations indicated that UGT1A1 is the only UGT isoform that metabolised 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 <2% of the dose. Renal clearance of indacaterol was, on average, between 0.46 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 faecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human faeces primarily as unchanged parent substance (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.
A population pharmacokinetic analysis showed that there is no clinically relevant effect of age (adults up to 88 years), sex, weight (32-168 kg) or race on the pharmacokinetics of indacaterol. It did not suggest any difference between ethnic subgroups in this population.
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: Preclinical Safety Data:
Effects on the cardiovascular system attributable to the β2
-agonistic properties of indacaterol included tachycardia, arrhythmias and myocardial lesions in dogs. Mild irritancy of the nasal cavity and larynx were seen in rodents. All these findings occurred at exposures sufficiently in excess of those anticipated in humans.
Although indacaterol did not affect general reproductive performance in a rat fertility study, a decrease in the number of pregnant F1 offspring was observed in the peridevelopmental and post-developmental rat study at an exposure 14-fold higher than in humans treated with Onbrez Breezhaler. Indacaterol was not embryotoxic or teratogenic in rats or rabbits.
Genotoxicity studies did not reveal any mutagenic or clastogenic potential. Carcinogenicity was assessed in a 2-year rat study and a 6-month transgenic mouse study. Increased incidences of benign ovarian leiomyoma and focal hyperplasia of ovarian smooth muscle in rats were consistent with similar findings reported for other β2
-adrenergic agonists. No evidence of carcinogenicity was seen in mice. Systemic exposures (AUC) in rats and mice at the no-observed adverse effect levels in these studies were at least 7- and 49-fold higher, respectively, than in humans treated with Onbrez Breezhaler once daily at a dose of 300 mcg.