Summary Basis of Decision for Onbrez Breezhaler

3.3.1 Pharmacodynamics

Onbrez Breezhaler (indacaterol) is a long-acting beta₂-adrenergic agonist. Upon inhalation, it acts locally in the lung as a bronchodilator. Onbrez Breezhaler has a rapid onset of action (within 5 minutes) following inhalation, and 24 hour duration of action.

The pharmacological effects of beta₂-adrenoceptor agonists are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of ATP to cAMP. Increased cAMP 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.

Although beta₂-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. The clinical safety programme included a thorough QT study in healthy subjects and additional pharmacology studies in COPD patients. The results of these studies did not reveal significant effect of indacaterol on QT prolongation, heart-rate, breathlessness, and health status.

3.3.2 Pharmacokinetics

Absorption

Following oral inhalation, indacaterol was rapidly absorbed, from a combination of pulmonary and intestinal absorption, and achieved peak serum concentrations in approximately 15 minutes following either single or repeated dosing. Systemic exposure to indacaterol increased with increasing dose (150 mcg to 600 mcg) in a dose proportional manner, and was about dose-proportional in the dose range of 75 mcg to 150 mcg. The absolute bioavailability of indacaterol after an inhaled dose was on average 43-45%.

Distribution

Following intravenous infusion, the volume of distribution of indacaterol during the terminal elimination phase 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 multiple dosing, pharmacokinetic steady-state was achieved within 12-15 days of inhalation.

Metabolism

After oral administration of radiolabelled indacaterol, unchanged indacaterol was the main component in serum, accounting for about one-third of the total drug-related exposure over 24 hours. 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, an N-glucuronide of indacaterol, and C- and N-dealkylated products were further metabolites identified. In vitro investigations indicated that indacaterol has negligible potential to cause metabolic interactions with medications (by inhibition or induction of cytochrome P450 enzymes, or induction of UGT1A1) at the systemic exposure levels achieved in clinical practice.

Clinical drug interaction studies were carried out using potent and specific inhibitors of CYP3A4 and P-gp (i.e. ketoconazole, erythromycin, verapamil and ritonavir). The data suggest that systemic clearance of indacaterol is influenced by modulation of both CYP3A4 and P-pg activities and that there is an approximate 2-fold increase in indacaterol systemic exposure (Area under the Curve) caused by the strong dual inhibitor ketoconazole reflects the impact of maximal combined inhibition. The increase in exposure observed was not considered a safety concern given the safety experience of treatment with Onbrez Breezhaler in clinical studies was up to one year at higher doses (up to 600 mcg).

Excretion

Following oral administration, indacaterol was excreted primarily through the faeces as unchanged parent drug (54% of the dose) and, to a lesser extent as hydroxylated indacaterol metabolites (23% of the dose).  Following inhalation, the amount of indacaterol excreted unchanged via urine was generally lower than 2% of the dose.

3.3.3 Clinical Efficacy

This NDS submission 143984 is a re-file of the NDS 127743, which received a Notice of Non-compliance (NON) on Jan 13, 2010 because the review concluded that the lowest effective dose of indacaterol in the management of COPD had not been established.

The sponsor re-filed the submission by proposing two lower doses, 75 mcg and 150 mcg for approval. With this re-file, the Sponsor has provided a satisfactory response to the key points raised in the NON. In addition, new clinical studies that complemented the original data package were submitted.

The efficacy of Onbrez Breezhaler was studied in 21 Phase III controlled studies in over 13,500 patients, where indacaterol was used at doses of 75 mcg, 150 mcg, 300 mcg, and 600 mcg. In addition to the clinical studies, which consisted of dose ranging studies, as well as pivotal studies for efficacy and safety, the sponsor provided pooled data, as well as a modelling report of the bronchodilatory dose-response analysis of indacaterol in COPD.

A dose-ranging study (Study B2357), conducted in bronchoreactive (asthma) population, suggested that the doses of 75 and 150 mcg had similar bronchodilatory effects after 14 days of dosing and that lower doses were suboptimal. A dose-ranging study (Study B2356) conducted in patients with COPD, confirmed the efficacy of the two doses, but also suggested that there were no meaningful differences in lung function between the 75 mcg and 150 mcg doses of indacaterol in this patient population.

The recommended for approval dose of Onbrez Breezhaler 75 mcg once daily was studied in two pivotal 12-week, multicentre, randomized, double-blind, placebo-controlled, parallel-group studies Study B2355 and Study B2354. These two studies enrolled 641 patients with a clinical diagnosis of COPD, who were 40 years or older; had a history of smoking; had a post-bronchodilator forced expiratory volume in one second (FEV₁) less than 80% and at least 30% of the predicted normal value and a post-bronchodilator ratio of FEV₁ over forced expiratory vital capacity (FVC) of less than 70%. The primary efficacy endpoint for both studies was 24-hour post-dose trough FEV₁, (defined as the average of two FEV₁ measurements taken after 23 hours 10 minutes and 23 hours and 45 minutes after the previous dose) following 12 weeks of treatment. Secondary efficacy variables included other FEV₁ and FVC time points, rescue medication use, symptoms, transition dyspnoea index (TDI), and health-related quality of life measured using the St. George's Respiratory Questionnaire (SGRQ), a disease-specific patient reported instrument which measures symptoms, activities, and impact of disease on daily life.

Results from the two pivotal studies demonstrated that compared to placebo, Onbrez Breezhaler 75 mcg led to a significantly greater trough FEV₁ (tFEV₁) at 12 weeks by 0.14 L and 0.12 L in study B2355 and B2354, respectively. Consistent with the expected response to a bronchodilator drug, other spirometry based endpoints also demonstrated superiority of indacaterol 75 mcg over placebo including tFEV₁ on Days 2, 29, 57 and 84; FEV₁ AUC_5min-4hr; peak FEV₁ over 5 minutes to 4 hours on Days 1 and Week 12. At 5 minutes post first dose, the treatment difference was statistically significant, 0.10 L (B2355) and 0.09 L (B2354). On day 84, the treatment difference achieved at 5 minutes post dose was 0.18 L (B2355 and B2354). There was no difference in the rate of change in tFEV₁ for indacaterol 75 mcg from Day 29 to Week 12. The key secondary end-point TDI, did not achieve a clinically and statistically significant improvement compared with placebo-treated patients in the B2355 study. However, in the B2354 study both statistically and clinically significant improvements versus placebo were noted. The quality of life questionnaire, SGRQ total score, which was -3.6 in Study B2355 and -3.8 in Study B2354, reached statistical significance versus placebo in both studies; however, it did not meet the predefined clinically meaningful difference of -4. Rescue medication use was also statistically significantly reduced over 12 weeks of treatment with indacaterol 75 mcg compared with placebo.

Pooled efficacy analyses showed that both the 75 and 150 mcg doses of indacaterol were clinically and statistically significantly superior to placebo in terms of spirometry endpoints, as well as symptom-related parameters, such as TDI, SGRQ, and rescue medication use. However, based on the clinical data, as well as the analysis of the modeling report, it was concluded that at this time, there is no robust evidence for any meaningful clinical benefit of the higher dose of 150 mcg over the 75 mcg of Onbrez Breezhaler.

3.3.4 Clinical Safety

The safety of Onbrez Breezhaler has been studied at doses of 75 mcg, 150 mcg, 300 mcg, and 600 mcg administered once daily. The COPD safety population consisted of 449 patients who received 75 mcg; 2,611 patients who received 150 mcg; 1,157 patients who received 300 mcg; and 547 patients who received 600 mcg up to 12 months. The safety profile of Onbrez Breezhaler was similar to that of other long-acting beta agonists.

The most common adverse drug reactions of Onbrez Breezhaler observed at the 75 mcg dose were: cough; nasopharyngitis; headache; nausea and oropharyngeal pain; muscle spasms; and viral upper respiratory tract infection. The severity of these events was in the vast majority mild to moderate.

In the B2355 study, no deaths were reported. Two deaths (myocardial infarction and a ruptured aortic aneurysm) were reported in the B2354 study within the placebo group.

Across the two studies, a total of 10 patients (3 patients in the Onbrez Breezhaler 75 mcg treatment group and 7 patients in the placebo group) had Serious Adverse Events which lead to discontinuation from the study. There were no clinically meaningful differences reported between treatment groups in the haematology, chemistry laboratory (including serum potassium, blood glucose and transaminases) or urinalysis assessments, vitals or electrocardiogram.

In a 12-month study (B2334), treatment with Onbrez Breezhaler 300 mcg and 600 mcg in COPD patients resulted in an increased number of serious cardiovascular or cerebrovascular adverse events [for example (e.g.) atrial fibrillation, myocardial ischemia, cardiac failure congestive, angina pectoris, ventricular tachycardia] in comparison with either formoterol or placebo. In the 12-month study, the increased risk was noticeable in a sub-group of patients with cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, obesity, etcetera) and/or with pre-existing cardiovascular or cerebrovascular conditions. However, analysis of pooled Phase 3 safety data (by Standardised MedDRA Queries analysis and Antiplatelet Trialists' Collaboration event analysis) did not show an overall excess of cardio-cerebrovascular (CCV) events, either as a whole or with respect to specific events, for any dose of indacaterol compared with placebo or active comparators. This observation has been identified within the Product Monograph with inclusion of a Long-Acting Beta₂-adrenergic Agonist (LABA) class labelling cautionary statement for the use of Onbrez Breezhaler in patients with cardiovascular disorders (coronary artery disease, acute myocardial infarction, cardiac arrhythmias and hypertension), in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to beta₂-adrenergic agonists.

In Phase III clinical studies, during clinic visits on average 14-15% of patients experienced a sporadic cough that occurred usually within 15 seconds following inhalation of Onbrez Breezhaler and typically lasted for 5 seconds. There is no evidence that cough experienced post inhalation is associated with bronchospasm, exacerbations, and deteriorations of disease or loss of efficacy.

Onbrez Breezhaler is a LABA. Data from a large placebo-controlled study conducted in the United States in patients with asthma which compared the safety of a twice-daily administration of another LABA to that of a placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving the LABA. The increased risk of asthma-related death may represent a class effect of all LABAs, including Onbrez Breezhaler. The safety and efficacy of Onbrez Breezhaler in patients with asthma has not been established; therefore Onbrez Breezhaler is not indicated for the treatment of asthma. However, the LABA class labeling, a serious boxed warning statement regarding the possible increased risk of asthma related death in patients using LABA, has been included in the Product Monograph of Onbrez Breezhaler in line with other LABA products currently marketed in Canada.