Indacaterol: A Once-Daily Ultra-Long Acting β2 Agonist for the Treatment of COPD

Randa Hilal-Dandan


AccessMedicine from McGraw-Hill 

In This Article

Clinical Pharmacology

COPD is a progressive and life-threatening lung disease. Patients with COPD suffer from airway obstruction, chronic cough and excessive mucus that make breathing difficult. The use of bronchodilators to relax constricted airway smooth muscle is the mainstay for treatment in COPD. Indacaterol is the first ultra-LABA to be approved for treatment of COPD. The impetus for the development of this class of “once-daily” bronchodilators is to simplify the management of COPD by minimizing dosing frequency with the expectation of improving patients’ compliance and adherence to therapy.[4,5,13]

The efficacy of this new agent as a once-daily bronchodilator for the long term maintenance treatment of COPD was assessed in multiple randomized, double blind, placebo-controlled clinical trials of 1-52 week duration that involved more than 15,000 patients.[2,3] Meta-analysis of these clinical studies indicates that once-daily orally inhaled indacaterol maleate (in 75 µg, 150 µg, 300 µg and 600 µg doses) is an effective bronchodilator in the treatment of COPD, and is well-tolerated with a good safety profile and wide therapeutic index.[2,3,5,6,7,8,9,10,11] The doses were selected based on the ability to improve trough forced expiratory volume of breath in one second (FEV1) after 24 hours of dosing by 0.12 liters over placebo.[2] Once-daily indacaterol (150 µg and 300 µg) was shown to be more effective than twice-daily salmetrol (50 µg) or formoterol (12 µg) and at least as effective as once-daily tiotropium (18 µg) in improving trough FEV1.[9,10] In the INTENSITY study, once-daily indacaterol (150 µg) was reported to be as effective as the muscarinc antagonist tiotropium (18 µg; SPIRIVA) in improving lung function at week 12 in patients with COPD, but superior to tiotropium in improving COPD health-related quality of life as assessed by St. George’s Respiratory Questionnaire.[2,9]

ONBREZ BREEZHALER (indacaterol maleate), 150 µg and 300 µg once-daily capsules for treatment of COPD, has been approved by the European Medicines Agency (EMA) since November 2009. The initial new drug application (NDA), submitted by Novartis in December of 2008 for indacaterol maleate 150 µg and 300 µg doses, was rejected by the FDA review panel, which concluded that the doses proposed for marketing were too high and not supported by safety and efficacy data.[2,3] Since a major safety concern associated with the use of all LABAs is an increased risk of asthma-exacerbation and asthma-related deaths, the FDA requested additional studies to assess dosing frequency and to establish the efficacy and safety at lower doses (dose range 18.5 µg-150 µg). In December 2010, Novartis submitted a response addressing the FDA concerns and sought the approval of ARCAPTA NEOHALER in once-daily doses of 75 µg and 150 µg. In March 2011, after assessing safety and efficacy data obtained from six confirmatory clinical studies on 5474 patients >40 years of age diagnosed with COPD, the Pulmonary-Allergy Drugs Advisory committee voted for the FDA approval of indacaterol maleate in the 75 µg dose only, stating a lack of meaningful data demonstrating superior bronchodilation efficacy or further improvement in the quality of health-life with the higher dose and the potential of additional safety concerns.[1,2,3]

Once daily, dual-action drugs that are both ß2 agonists and muscarinic antagonists or inhaled corticosteroids (ICS) are in clinical development to help promote compliance and convenience to patients with COPD. Novartis is running clinical studies for approval of two new COPD drugs that combine once-daily indacaterol with the long-acting muscarinic antagonists (LAMA) glycopyrronium bromide or tiotropium. Data from phase III clinical studies of INTRUST 1 and 2 indicate that in patients with COPD, the combination drug indacaterol (150 µg) plus tiotropium (18 µg) significantly improves lung function when compared to tiotropium alone with no increased incidence of reported adverse effects.[12]

Mechanism of Action

Indacaterol (Figure 1) is a potent ß2 adrenergic receptor agonist with high intrinsic efficacy.[13] Stimulation of ß2 adrenergic receptors of bronchial smooth muscle cells induces relaxation by activation of the Gs-adenylyl cyclase-cAMP-PKA pathway (see Figure 2). Once-daily indacaterol provides a fast onset of action (<5 minutes) and sustained bronchodilation for >24 hours.[13,14] Indacaterol has an onset of action that is similar to formoterol but significantly faster than salmeterol, with much longer duration of action than formoterol or salmeterol.[4,13,14] In contrast to salmeterol (a partial ß2 agonist), indacaterol does not antagonize the bronchorelaxant effect of short-acting ß2 adrenergic agonists, which may be important if a rescue short-acting ß2 adrenergic agonist is needed.[4,13]

Figure 1.

Chemical Structure of: Indacaterol:5-(2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl)-8-hydroxy-1H-quinolin-2-one

Figure 2.

Molecular actions of β2 agonists to induce relaxation of airway smooth muscle cells. Activation of β2 receptors (β2AR) results in activation of adenylyl cyclase (AC) via a stimulatory G protein (Gs), leading to an increase in intracellular cyclic AMP and activation of PKA. PKA phosphorylates a variety of target substrates, resulting in opening of Ca2+-activated K+ channels (KCa), thereby facilitating hyperpolarization, decreased phosphoinositide (PI) hydrolysis, increased Na+/Ca2+ exchange, increased Na+,Ca2+- ATPase activity, and decreased myosin light chain kinase (MLCK) activity. β2 Receptors may also couple to KCa via Gs. PDE, cyclic nucleotide


ARCAPTA NEOHALER is a formulation of indacaterol maleate dry inhalation powder and lactose packaged in gelatin capsules.[3] The R enantiomer is the active component, which is a selective ß2 adrenergic agonist. The FDA recommended dose for indacaterol maleate is 75 µg administered once a day. In the European Union and other countries, indacaterol maleate (ONBREZ BREEZHALER) is supplied as 150 µg and 300 µg dose capsules. Systemic absorption of indacaterol increases with dose. Peak serum concentrations of indacaterol occur within 15 minutes following inhalation with bioavailability of about 45%. The effective t1/2 is >49 hours. Steady-state is achieved in 12 days. About 33% of absorbed indacaterol remains unchanged in the serum. Indacaterol is metabolized by CYP3A4 and UGT1A1 and is a low affinity substrate for P-gp. Elimination is predominantly (~90%) through the fecal route. About 54% of the drug is eliminated unchanged, and ~23% is excreted as hydoxylated indacaterol metabolite.[2,3]

Adverse Effects

Side effects include: exacerbation of COPD, paradoxical bronchospasm, transient cough, runny nose, sore throat, sinusitis and upper respiratory tract infection, headache, nausea and hyperglycemia.[3,6] Rare adverse effects that are dose-related due to stimulation of systemic ß receptors include muscle tremor, tachycardia, restlessness, hypokalemia and hypoxemia. Indacaterol has a good cardiovascular safety profile and no significant effects on the QT interval;[3,11,15] however, it should be administered with caution in patients taking sympathomimetic drugs or drugs that prolong QT interval (because of its hypokalemic effects). The therapeutic effect of indacaterol is blocked with the concomitant use of ß blockers. Hypokalemic effects of indacaterol may be potentiated in patients using diuretics, steroids or xanthine derivatives.[3]

All LABAs are associated with an increased risk of asthma-related deaths. Indacaterol is indicated for patients with COPD and not for patients with asthma. Indacaterol should not be used for treatment of acute symptoms of COPD or administered more than once a day. Indacaterol should not be administered with other LABAs. Similar to other LABAs, ARCAPTA NEOHALER carries a box warning of increased risk of asthma-associated deaths.[3]

Use of indacaterol is not indicated in children and its use should be restricted in pregnant women (classified as pregnancy category C) and nursing mothers. No dosage adjustment is needed for the elderly or for patients with renal or hepatic impairment.[2,3]