An update on the use of indacaterol in patients with COPD

Introduction

The Global Initiative for Chronic Obstructive Lung Disease (GOLD Executive and Scientific Committees) [GOLD, 2009] has established on the basis of an evidence A level that: (i) bronchodilator medications are central to the symptomatic treatment of chronic obstructive pulmonary disease (COPD); (ii) the principal bronchodilator treatments are β₂-agonists, anticholinergics and methylxanthines used singly or in combination; and (iii) regular treatment with long-acting bronchodilators is more effective and convenient than treatment with short-acting bronchodilators. Bronchodilators are therefore the cornerstone treatment for all COPD severity stages.

Upon the advent of long-acting bronchodilators, namely the twice-daily β₂-agonists formoterol and salmeterol and the once-daily anticholinergic tiotropium, the regular use of these active principles was shown to be more effective and beneficial than treatment with short-acting bronchodilators for the management of COPD, in terms of providing greater bronchodilator efficacy and symptomatic relief, increased tolerance to exercise, and improved rate of exacerbations and quality of life test scores [Neder et al. 2007; Maltais et al. 2005; O’Donnell et al. 2004; Vincken et al. 2002; Dahl et al. 2001; Mahler et al. 1999]. Furthermore, dosing regimens requiring less-frequent dosing were shown to be associated with improved patient compliance with therapies [Claxton et al. 2001]. Therefore, an effective once-daily β₂-agonist bronchodilator would add a significant advance to the therapeutic toolbox for COPD.

As of 30 November 2009, indacaterol (formerly QAB149) was approved in the European Union for maintenance bronchodilator treatment of airflow obstruction in adult patients with COPD [EMEA, 2009a], to be administered as a 150 or 300 µg indacaterol maleate once-daily dose and delivered by means of a single-dose dry powder inhaler (SDDPI). Since indacaterol has now become commercially available for prescription, the main focus of this review is on compiling and summarizing the published body of evidence generated as of today from the randomized trials performed along the clinical development of the drug as a COPD therapy, so as to contribute an independent, clinical practice-oriented synopsis.

Pharmacological profile and preclinical data

Sequential modifications of the chemical structure of catecholamines [Aranson and Rau, 1999] allowed the synthesis of agonists with improved selectivity for the β₂-adrenoreceptor and led to the subsequent development of short-acting β₂-bronchodilators such as fenoterol, salbutamol (albuterol) and terbutaline, and the long-acting β₂-agonists salmeterol and formoterol. Figure 1 outlines the intracellular signalling pathways involved in the mechanism of action of β₂-adrenergic bronchodilators. OPEN IN VIEWER

In vitro studies during the preclinical development of indacaterol [Battram et al. 2006] characterized this new agent as a having a high agonist efficacy at the human β₂-adrenoreceptor, with a binding affinity similar to formoterol, an intrinsic activity higher than salmeterol, and a functional selectivity similar to formoterol over the β₁-adrenoreceptor, and similar to formoterol and salbutamol over the β₃-adrenoreceptor. In isolated superfused guinea pig trachea [Battram et al. 2006], small airways in human and rat slices [Trifilieff et al. 2006] and isolated human bronchi obtained from surgical lung specimens resected due to carcinoma [Naline et al. 2007], indacaterol showed a fast onset of action similar to salbutamol and formoterol but significantly faster than salmeterol, and a long duration of action. In vivo, indacaterol produced a prolonged bronchoprotective effect against pharmacologically induced bronchoconstriction, and showed an improved cardiovascular safety profile [Battram et al. 2006]. The preclinical data suggested therefore that indacaterol was suitable for clinical development aiming at once-daily dosing in humans.

Reports on pharmacokinetics [EMEA, 2009b; Rennard et al. 2008] showed that indacaterol is rapidly absorbed and distributed after inhalation, with a median time to reach peak serum concentrations of approximately 15 minutes after single or repeated inhaled doses, although systemic exposure results from a composite of pulmonary and intestinal absorption. The absolute bioavailability after an inhaled dose is on average 43%. The drug is detectable in serum in dose-dependent concentrations, and a slight accumulation occurs upon administration of multiple daily doses, which reaches a steady state within 12–14 days of treatment. The plasma protein binding fraction is 95.1–96.2% in humans. Unchanged indacaterol is the main component found in serum, and a hydroxylated derivative is its most prominent metabolite. The biliary excretion route is the major route of elimination of indacaterol and its metabolites, whereas renal excretion plays a minor role (about 2–5% of systemic clearance). Based on rat data, it is estimated that the maximum amount of indacaterol and/or its metabolites that a breast-fed infant could be exposed to by ingesting 1 L of milk daily is 0.18% of a 300 µg adult dose.

In the toxicological assessments [EMEA, 2009b], indacaterol was considered negative in the standard battery of in vitro and in vivo genotoxicity tests, and did not raise concerns regarding potential carcinogenicity. There was as well no evidence of teratogenicity in the embryo–foetal development studies. An analysis of the effect of age, gender and weight on systemic exposure after inhalation indicated that indacaterol can be used safely in all age and weight groups within the COPD population, and regardless of gender. No difference was suggested either between ethnic subgroups in the population analysed. Studies on the potential for drug–drug interaction, based of co-administration of indacaterol with pharmacological inhibitors of core enzymes involved in drug metabolism, raised no clinically relevant concerns for the authorized indacaterol doses.

Clinical development

A synopsis of the reported clinical trial outcomes on indacaterol for COPD is provided in Table 1. At the time of closing this review, data reported in the form of articles and abstracts presented at major conferences are available from phase II and III clinical trials comprising over 7800 randomized COPD patients in total. Various doses of indacaterol, administered for up to 52-week treatment periods, were tested. Most trials selected for inclusion patients with moderate and severe COPD, defined as having a postbronchodilator forced expiratory volume in one second (FEV₁) of ≥30% and <80% of its predicted value, and a postbronchodilator FEV₁/forced vital capacity (FVC) ratio of less than 70%. Spirometry based endpoints included: (i) trough FEV₁ at 24 hours postdose on different days of the treatment period, usually day 1, trial midpoint and end of trial; (ii) FEV₁ at serial time points from 5 minutes to 24 hours postdose, with a particular attention to the onset of bronchodilator action at closely assessed early time points; (iii) the FEV₁ standardized area under the curve (AUC), which was in some trials subjected to subanalysis of early postdose stages, such as 30 minute–4 hour or 1–4 hour periods, and late stages such as a 22–24 hour period; (iv) predose FEV₁ on specific days within the treatment period; and (v) FVC. The size of the FEV₁ increments was analysed in terms of clinical significance, based on a 120 ml cutoff predefined as minimal clinically important difference. This cutoff is the midpoint of a 100–140 ml range that a joint European Respiratory Society/American Thoracic Society statement proposed as a minimal clinically relevant difference [Cazzola et al. 2008]. For comparison purposes, a difference of 100 ml has been reported as the threshold at which a COPD patient can perceive an effect [Donohue, 2005]. Overall, the data reported provide solid evidence of the efficacy of indacaterol in terms of improving lung function. Indacaterol once daily led to trough FEV₁ increments versus placebo that were statistically and clinically significant from the first dose (110–140 ml after a 150 µg dose and 140–170 ml after a 300 µg dose), and remained significant for up to 52 weeks (160 and 150 ml increments, respectively). Recorded mean increments at intermediate time points reached up to 180 ml. Serial FEV₁ increments from 5 minutes to 24 hour postdose were all significant and greater than 120 ml from day 1 with the doses tested. The 5-minute postdose FEV₁ mean increment versus placebo was in the range of 100–130 ml after 150 µg doses and 120–150 ml after 300 µg doses. In a single-dose study that involved a comparison with typical fast-onset rescue medication (salbutamol 200 µg) [Balint et al. 2009], the 5-minute FEV₁ mean increment elicited by the latter was 90 ml. FEV₁ AUC versus placebo was significantly increased across studies, as well as FVC at all doses and time points from day 1. The data demonstrating that the 24-hour bronchodilator effect of indacaterol is maintained without a decay at a 52-week checkpoint support that the sustained use of indacaterol does not lead to a loss of efficacy. This is an important property of the drug since the possibility of developing tolerance through downregulation of the β₂-adrenoreceptor, as an effect of chronic dosing with long-acting β₂-agonists, has been described in COPD [Donohue et al. 2003].

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Table 1.

Published clinical trial outcomes in chronic obstructive pulmonary disease (COPD).

Reference	Subjects randomized	Synopsis
[Beier et al. 2007]	163	Design: parallel-group, 28 days. Indacaterol 400 or 800 µg SID (SDDPI); placebo. Main output: significant increment of FEV1 at all postbaseline time points and trough FEV1 on days 14 and 28, versus placebo.
[Rennard et al. 2008]	635	Design: 7-day parallel-group (placebo; indacaterol 50, 100, 200 or 400 µg via MDDPI; indacaterol 400 µg via SDDPI) plus 8-day extension with open-label tiotropium. Main output: all indacaterol doses significantly superior to placebo for FEV1 AUC on Days 1 and 7. Dose–response effect over the range tested. Improvements of >120 ml relative to placebo with indacaterol 200 and 400 mg (MDDPI and SDDPI) on Day 1 and with all doses on Day 7. Onset of action ≤5 min. Serial FEV1 from 5 min to 24 h postdose significantly greater than placebo for all indacaterol doses on Days 1 and 7. Predose FEV1 on Day 7 significantly increased over placebo with all indacaterol doses; mean increases ranged from 160 ml (indacaterol 50 µg) to 230 ml (indacaterol 400 µg MDDPI). Mean trough FEV1 indacaterol-versus-placebo difference of 140 (50 µg dose), 160 (100–200 µg doses) and 210 (400 µg MDDPI and SDDPI dosing) ml on Day 7. FVC significantly superior to placebo at all time points for all indacaterol doses on Days 1 and 7. FEV1 AUC on days 1 (0–4 h postdose) and 7 (0–4 and 22–24 h postdose) significantly greater for indacaterol 400 µg (SDDPI and MDDPI) compared with open-label tiotropium extension.
[Balint et al. 2009]	89	Design: crossover, single-dose. Indacaterol 150 and 300 µg SID; salbutamol 200 µg SID; salmeterol/fluticasone 50/500 µg SID; placebo. Main output: 5 min postdose FEV1 differences versus placebo were 100 ml for indacaterol 150 µg, 120 ml for indacaterol 300 µg, 90 ml for salbutamol and 50 ml for salmeterol/fluticasone, all significant. Both indacaterol doses significantly superior to salmeterol/fluticasone. Percentage of patients with ≥12% FEV1 increase for indacaterol 150 and 300 µg significantly higher than for salmeterol/fluticasone (28.2%, 46.0% and 13.6% respectively).
[Bauwens et al. 2009]	51	Design: 5-block crossover, 1-day treatment periods. Indacaterol 150, 300 or 600 µg SID (SDDPI); formoterol 12 µg BID; placebo. Main output: trough FEV1 significantly increased versus placebo with all indacaterol doses and formoterol. Trough FEV1 with indacaterol 300 and 600 µg significantly greater than with formoterol. FEV1 AUC(30  min-4  h) for indacaterol all doses, significantly greater than placebo and similar to formoterol. All indacaterol doses and formoterol significantly increased FEV1 and FVC versus placebo at all time points postdose.
[Beeh et al. 2009a, 2009b] [Khindri et al. 2009a]	27	Design: crossover, 2-week blocks. Indacaterol 300 µg; placebo. Main output: statistically and clinically (>200 ml increment) improvement versus placebo on day 14, of IC during constant-load cycle-ergometer exercise.
[Beier et al. 2009]	30	Design: indacaterol 300 µg BID (SDDPI) or placebo, single-dose crossover. Extension with open-label formoterol 12 µg BID. One-day treatment blocks. Main output: FEV1 and IC significantly greater at all assessment time points (5 min–24 h) for indacaterol or open-label formoterol, versus placebo. Indacaterol values significantly higher than with open-label formoterol for FEV1 at 8 h and 24 h., and for IC at 4–24 h. Indacaterol had a significantly greater effect than formoterol on peak IC (31% versus 23% from predose, respectively).
[Kato et al. 2009]	50	Design: Four-block crossover, single-dose periods. Indacaterol 150, 300 or 600 µg (SDDPI); placebo. Main output: FEV1 AUC(22–24  h) significantly higher for all indacaterol doses versus placebo (170, 160 and 130 ml increments, respectively). FEV1 significantly increased at 5 min and at all time points tested up to 24 h.
[Magnussen et al. 2009]	96	Design: crossover, 14-day blocks. Indacaterol 300 µg SID a.m. or p.m.; salmeterol 50 µg BID; placebo. Main output: indacaterol, a.m. or p.m. and salmeterol BID provided 24-h bronchodilation. Indacaterol a.m. or p.m., but not salmeterol BID, improved significantly over placebo the % of: nights with no awakenings; days with no daytime symptoms; and days able to perform usual activities.
[Rennard et al. 2009]	414	Design: parallel groups, 26 weeks. Stage 3 of 52-week adaptive trial. Indacaterol 150 or 300 µg SID; placebo. Main output: trough FEV1 significantly increased at week 52 with indacaterol 150 µg (170 ml increment) and 300 µg (180 ml increment), versus placebo.
[Barnes et al. 2010]	805	Design: parallel-group, 2-week dose-finding stage of a two-stage adaptive design. Indacaterol 75, 150, 300 or 600 µg SID (SDDPI); placebo; formoterol 12 µg BID; open label tiotropium 18 µg SID. Main output: trough FEV1 and FEV1 AUC(1–4  h) significant over placebo for indacaterol all doses, formoterol and open-label tiotropium. Indacaterol 150 µg, lowest effective dose exceeding criteria for trough FEV1 (reference value 140 ml versus placebo) and FEV1 AUC(1–4h) (reference value 220 ml versus placebo). Trough FEV1 difference versus placebo significantly greater for indacaterol 300 µg compared with formoterol and open-label tiotropium. Indacaterol 150 and 300 µg selected for continuation in a 26-week confirmatory stage (see Donohue et al. [2010]).
[Dahl et al. 2010]	1732	Design: parallel-group, 52-weeks. Indacaterol 300 or 600 µg SID (SDDPI); formoterol 12 µg BID; placebo. Main output: trough VEF1 significantly increased with both doses of indacaterol, versus both placebo and formoterol, after day 1, and at weeks 12 and 52. Trough FEV1 increment over placebo with both indacaterol doses was at least 100 ml greater than the increment with formoterol. Postdose FEV1 at week 12 significantly higher with indacaterol 300 µg at 2 h and from 6 h to 23 h 45 min, and with indacaterol 600 µg at all time points beyond 5 min, versus formoterol. All active treatments superior to placebo for SGRQ, days of poor control, days able to perform usual activities and time to first exacerbation; differences between indacaterol and formoterol for these endpoints not significant. Exacerbations occurred in 32.8% (indacaterol 300 µg), 29.3% (indacaterol 600 µg), 31.5% (formoterol) and 36.3% (placebo) of patients, with time to first COPD exacerbation significantly improved for all active treatments versus placebo. Mean TDI score and BODE index improved significantly versus placebo with all active treatments. TDI differences between indacaterol and placebo close to or exceeding minimum clinically important difference. TDI scores significantly higher with indacaterol than with formoterol at week 12 but not at week 52. Reduction from baseline in daily inhalations of rescue medication, and days with no use of rescue medication, significantly greater with indacaterol both doses versus formoterol. Increase from baseline in morning (predose) and evening PEF significant with all active treatments, and significantly greater with indacaterol both doses versus formoterol. Percentage of nights with no awakenings significantly higher with indacaterol 600 µg versus formoterol.
[Donohue et al. 2010]	2059 (Stage 1) 1,683 (Stage 2)	Design: parallel-group, 26 weeks, two-stage adaptive design. Stage 1 (≥2 weeks): Indacaterol 75, 150, 300 or 600 µg SID (SDDPI); formoterol 12 µg BID; placebo; open-label tiotropium 18 µg SID. Stage 2: continuation of selected indacaterol dose groups (150 and 300 µg); placebo; open-label tiotropium 18 µg SID. Main output: trough FEV1 significantly increased over placebo with all active treatments on day 2 and weeks 2, 12 and 26. Trough FEV1 increment with indacaterol 150 and 300 µg superior to tiotropium on week 12 (increments versus placebo of 180 ml for both indacaterol doses and 140 ml for tiotropium), but not on week 26. FEV1 increment at 5 min postdose on day 1 superior with indacaterol 150 and 300 µg (120 ml versus placebo) versus tiotropium (60 ml versus placebo). Increments relative to placebo of serial FEV1 at week 26 superior with indacaterol 300 µg versus tiotropium at 50 and 15 min predose, and 5 min, 2 h, 4 h, and 23 h 10 min postdose. Peak FEV1 increased 210, 240 and 180 ml over placebo (indacaterol 150 and 300 µg and tiotropium, respectively). TDI significantly increased versus placebo at all time points assessed, and versus tiotropium for indacaterol 300 µg at weeks 4, 8 and 12 but not 26. TDI differences between indacaterol 300 µg and placebo above level of clinical importance. SGRQ total scores significantly improved versus placebo with both indacaterol doses (not with tiotropium), with a significant proportion of patients achieving a clinically relevant improvement. Effects significantly greater with indacaterol both doses versus tiotropium for decrease in rescue medication dosing, % of days with no use of rescue medication, and increase in morning and evening PEF; % of nights with no awakenings and % of days with no daytime symptoms significantly improved with both indacaterol doses but not with tiotropium.
[Feldman et al. 2010]	416	Design: parallel-group, 12-week. Indacaterol 150 µg SID (SDDPI); placebo. Main output: trough FEV1 significantly superior to placebo after the first dose (80 ml mean difference), on day 29 (140 ml mean difference) and at week 12 (130 ml mean difference). FEV1 statistically superior at 5 min postdose on day 1 (130 ml mean difference) and at all postbaseline time points. Mean peak FEV1 of 190 (day 1) and 160 (week 12) ml over placebo. Significant FEV1 AUC. Significant increase in daily morning and evening PEF, days of poor control reduced by 22% and use of rescue medication reduced.
[Kornmann et al. 2010]	1002	Design: parallel -group, 26 weeks. Indacaterol 150 µg SID; salmeterol 50 µg BID; placebo. Main output: trough FEV1 increment versus placebo significantly greater than pre-specified 120 ml clinically significant difference with indacaterol (170 ml at week 12; 180 ml at week 26) but not with salmeterol (110 ml at both week 12 and week 26). FEV1 increment at 5 min postdose significantly greater with indacaterol (110 ml over placebo) versus salmeterol (60 ml over placebo) on day 1, and 60–100 ml higher with indacaterol over salmeterol through the study. Improvement of SGRQ total score significantly greater than four-point minimum clinically important difference with both indacaterol and salmeterol at weeks 8, 12 and 26, and greater with indacaterol versus salmeterol at weeks 12 and 26. Clinically relevant improvement of TDI at weeks 4, 8, 12 and 26 with both indacaterol and salmeterol, and significantly greater with indacaterol versus salmeterol. Increment in days with no use of rescue medication, morning and evening PEF, and % of days able to perform usual activities, significantly greater with indacaterol versus salmeterol.
[Laforce et al. 2010]	68	Design: 14-day block crossover. Indacaterol 300 µg SID (SDDPI); placebo; open-label salmeterol 50 µg BID (MDDPI). Main output: trough FEV1 on day 14 significantly higher with indacaterol versus placebo (200 ml increment) and versus salmeterol (90 ml difference). Significantly higher trough FEV1 after day 1 (indacaterol versus placebo, 150 ml difference). FEV1 significantly higher versus placebo across full 24-h assessment period on days 1 and 14; significantly higher versus salmeterol at most time points postdose on day 1; and numerically or significantly higher versus salmeterol on day 14. FEV1 increment significantly greater with indacaterol versus salmeterol in the mean of 11 h 10 min and 11 h 45 min postdose, on days 1 and 14. Serial IC numerically or significantly greater with indacaterol versus salmeterol at all postbaseline time points on days 1 and 14.
[Vogelmeier et al. 2010]	169	Design: 14-day incomplete-block (three of four treatments each patient) crossover. Indacaterol 150 or 300 µg SID (SDDPI); tiotropium 18 µg SID; placebo. Main output: trough FEV1 at day 14 significantly higher with indacaterol 150 µg (170 ml increment) and 300 µg (150 ml increment) versus placebo. Trough FEV1 increment with indacaterol 150 µg significantly greater (50 ml difference) versus tiotropium. FEV1 increment of 130 ml over baseline at 5 min postdose on day 1, versus 60 ml with tiotropium.

The inspiratory capacity (IC), both at rest and during constant-load exercise on cycle ergometer, was evaluated in some of the trials. Despite the established role of the FEV₁ and FEV₁/FVC ratio in assessing the diagnosis and severity of COPD, the changes in spirometric values do not correlate well with the level of exertional dyspnoea and exercise capacity, and have been shown to be limited as predictors of clinical improvement in response to bronchodilators [O’Donnell et al. 1999]. The IC at rest is an indirect indicator of functional residual capacity and therefore the degree of resting hyperinflation, and is a good predictor of the extent of dynamic hyperinflation during exercise [Boni et al. 2002; O’Donnell et al. 2001]. In fact, reduction of dyspnoea during exercise and improved exercise tolerance upon the administration of a bronchodilator are closely related to the bronchodilator-induced change in IC at rest [Boni et al. 2002]. Moreover, an increased IC as measured by serial determinations during exercise serves as an index of reduced dynamic hyperinflation that best reflects the improvements in exercise endurance and the relief of exertional dyspnoea following β₂-agonist or anticholinergic therapy [O’Donnell et al. 1998; Belman et al. 1996]. The IC has therefore been proposed to be used in conjunction with the FEV₁ to evaluate therapeutic responses in patients with COPD. A single 300 µg indacaterol dose improved IC at rest significantly at all time points from 5 minutes to 24 hours, providing a mean peak IC increment of 380 ml over placebo and 31% over predose baseline [Beier et al. 2009]. After a 2-week treatment with indacaterol 300 µg daily, mean peak- and iso-time IC during constant-load cycle-ergometer exercise were increased by 317 and 268 ml over placebo, respectively, which exceeded a predefined clinically relevant difference of 200 ml [Beeh et al. 2009a, 2009b; Khindri et al. 2009a].

Beyond lung function parameters, patient-oriented clinical endpoints reflecting quality of life, symptoms and exacerbation rates are also relevant in the long-term evaluation of therapies for COPD. Indacaterol led to improved scores in: questionnaires such as the St George's Respiratory Questionnaire (SGRQ), Transition Dyspnea Index (TDI) and modified Medical Research Council (mMRC) dyspnoea scale; risk assessment by means of the BODE (body-mass index, airflow obstruction, dyspnoea and exercise capacity) index [Celli et al. 2004]; home monitoring of morning and evening peak expiratory flow (PEF); recording of the use of rescue medication; follow up of COPD exacerbations (frequency, time to first exacerbation, mean number of exacerbations); and other quality-of-life-related variables such as the numbers of nights with no awakenings, days with no symptoms, days with no rescue medication and days able to perform usual activities.

In addition to the placebo-controlled assessments of the therapeutic efficacy of indacaterol, noninferiority and superiority hypotheses were tested to compare indacaterol with the long-acting β₂-agonists salmeterol and formoterol, and the long-acting anticholinergic tiotropium. Different approaches were employed for the comparative trials, including parallel-group and crossover designs, and the use of double-blind interventions and open-label treatments. Formoterol 12 µg and salmeterol 50 µg, twice daily, were comparators as both open-label and double-blind treatments in various trials. In double-blind trials, indacaterol 300 µg once daily was reported to produce a significantly greater trough FEV₁ compared with formoterol, on day 1 and weeks 12, 26 and 52 in different studies [Barnes et al. 2010; Dahl et al. 2010; Bauwens et al. 2009]. The AUC_{(30  min-4  h)} was reported as similar to formoterol in a single-dose study [Bauwens et al. 2009]. Also in a double-blind fashion, the trough FEV₁ at weeks 12 and 26 was significantly higher with indacaterol 150 µg daily versus salmeterol [Kornmann et al. 2010]. Comparisons with formoterol or salmeterol also resulted in a favourable view regarding indacaterol in other endpoints such as improvements beyond minimum clinically important difference in the mean TDI, time point at which differences versus placebo reached clinical relevance in the SGRQ, decrease of use of rescue medication, PEF increases, nights with no awakenings, days with no daytime symptoms, and days able to perform usual activities.

Tiotropium 18 µg once daily was employed as an open-label treatment in all comparative trials published at the time of writing, with one exception [Vogelmeier et al. 2010] where a double-blind procedure was applied. The first study that compared indacaterol with tiotropium [Rennard et al. 2008] applied an indirect approach with two treatment periods: (i) a double-blind, placebo-controlled, 7-day dose-ranging trial of indacaterol; and (ii) a subsequent 8-day extension with open-label tiotropium. The indacaterol doses assessed during the dose-ranging block of the study (50, 100, 200 or 400 µg once daily) provided a FEV₁ AUC comparable or superior to subsequent open-label tiotropium 18 µg, at 0–4 hours on day 1, and at 0–4 and 22–24 hours on days 7 and 8, respectively. The serial postdose FEV₁ mean values were consistent with the FEV₁ AUC trend and exceeded a 120 ml difference over tiotropium for indacaterol 400 µg, administered via a SDDPI device. Bearing the limitations of being a short trial where tiotropium was administered in an open-label fashion, as an extension treatment block for all subjects in the absence of a randomized crossover design, the results were interpreted as suggestive of a greater efficacy of indacaterol that warranted further trials specifically designed to address this comparison. Two subsequent trials included a tiotropium arm also in an open-label fashion, but with a parallel-group design and a duration of 26 weeks [Barnes et al. 2010; Donohue et al. 2010]. In the study reported by Donohue and colleagues the increment over placebo of trough FEV₁ attained with indacaterol 300 and 600 µg was significantly greater than that of open-label tiotropium at week 12, but not at week 26. Total SGRQ scores improved significantly over placebo with indacaterol, but not with open-label tiotropium, at four assessment time points; the percentage of nights with no awakenings, days with no symptoms and days with no rescue medication was significantly greater with indacaterol versus open-label tiotropium. The study by Barnes and colleagues employed an open-label tiotropium arm as a reference of bronchodilator efficacy for an indacaterol dose-finding trial stage, and the data analysis strategy did not aim at drawing conclusions on an indacaterol versus tiotropium comparison. The data on day 15 (end of the dose-finding stage) reflect, however, on the basis of 95% confidence intervals, a higher mean trough FEV₁ difference versus placebo for indacaterol 300 and 600 µg, and a higher FEV₁ AUC_{(1–4  h)} for indacaterol 300 µg, in comparison with tiotropium. In the trial reported by Vogelmeier and colleagues a double-blind comparison was conducted by means of a three 14-day period (incomplete block) crossover design, where the patients were randomized into one of four treatment sequences combining indacaterol 150 or 300 µg, tiotropium 12 µg and placebo. After 14 days of treatment, the trough FEV₁ was numerically greater versus tiotropium for both indacaterol doses and significantly higher for the 150 µg dose. Serial FEV₁ measurements from –50 minutes predose to 14 hours postdose were numerically greater for both indacaterol doses versus tiotropium at all time points assessed, and significantly higher for the 150 µg dose at –50 to 30 minutes, 12 hours, and 23 hours and 10 minutes. As per the onset of bronchodilator effect on day 1, the increases from baseline at 5 minutes postdose were 60 ml with tiotropium, 130 ml with indacaterol 150 µg, and 140 ml with indacaterol 300 µg, significant versus tiotropium for both indacaterol doses. The difference in the increments remained significant for both indacaterol doses versus tiotropium at 15 minutes postdose, and for the 300 µg indacaterol dose at 30 and 60 minutes. Overall, the data from this double-blind trial were consistent with prior results using tiotropium as open label, and were reported as confirmatory of a clinically relevant 24-h bronchodilator effect of indacaterol at least as effective as tiotropium, with a faster onset of action.

Safety profile and side effects

Systemic bioavailability of β₂-agonist bronchodilators can elicit known β₂-adrenoceptor-mediated cardiovascular effects [Sears, 2002; Maconochie and Foster, 1992; Wong et al. 1990; Crane et al. 1989; Scheinin et al. 1987], such as palpitations, tachycardia, changes in blood pressure and electrocardiographic abnormalities such as a prolonged QT interval, as well as hypokalemia, hyperglycaemia, headache, and skeletal muscle tremor. The available data for indacaterol support overall an excellent safety profile, with no relevance of its long duration of action in terms of side effects.

In asthma (an indication under development), two studies where the indacaterol daily doses were scaled up to 800 µg [Yang et al. 2007] and 1000 µg [Brookman et al. 2007], respectively, yielded results consistent with the good safety profile shown for therapeutic doses in other studies. In the study by Yang and colleagues with 144 patients randomized, two patients had a serious adverse event reported thought to be related to the study drug, which was described as bronchospasm associated with dyspnoea and wheezing. The episodes occurred shortly after dosing with no obvious link with decreased FEV₁. No serious adverse events occurred in the study by Brookman and colleagues where 1000 µg doses were tested.

In COPD patients, a large data set was generated from various studies primarily aimed at dose ranging and safety analysis [Feldman et al. 2010; Chung et al. 2009a, 2009b; Khindri et al. 2009b, 2009c; Worth et al. 2009; Beier et al. 2008, 2007; Rennard et al. 2008; Pascoe et al. 2007]. Safety variables were also secondary endpoints in all studies primarily aimed at efficacy endpoints. Overall, the rate of adverse events was low and similar across treatment groups in the different trials. There was no evidence of drug- or dose-related changes in haematological parameters, and no clinically relevant differences were observed between treatment groups in any of the biochemical variables measured. Statistically significant differences versus placebo in postdose blood glucose and potassium levels occurred occasionally at particular doses and isolated time points and were considered not clinically relevant [Rennard et al. 2008]. The incidence of other β₂-agonist-related effects, including muscle spasm, headache and tremor, was comparable between indacaterol and placebo groups. Data generated across a wide dose range support a good cardiovascular safety, with no clinically significant differences in mean pulse rate, no drug-related trends in systolic or diastolic blood pressure, no statistically significant differences in mean QTc interval, and no differences in the numbers of subjects with notable QTc interval increases. Serious adverse events in subjects receiving indacaterol occurred with frequencies similar or inferior to placebo groups, and none were classed as suspected to be related to the study drug in COPD patients, in the trials reported. In a study that assessed the safety and tolerability of supra-therapeutic doses of indacaterol up to 3000 µg [Pascoe et al. 2007], most adverse events were mild or moderate, with none considered serious or leading to withdrawal. Minimal effects reported on potassium, glucose, heart rate and QTc interval, were considered within safe limits.

In various trials, cough upon treatment dosing was reported with a mean frequency ranging from 2.9% to 17.8% in indacaterol groups and 0.9% to 7.3% in placebo groups. The cough was described [Feldman et al. 2010] as occurring within 15 seconds following drug inhalation, with a median duration of 6 seconds, and with no association with bronchospasm or increased study discontinuation rates. In a dose-ranging trial where 635 patients were randomized to receive indacaterol 50, 100, 200 or 400 µg or placebo via a MDDPI, or indacaterol 400 µg via SDDPI, once daily for 7 days [Rennard et al. 2008], the occurrence of cough did not persist with continued treatment, and by day 7 the incidence of cough with indacaterol matched that of placebo. In this study, headache was reported with a frequency comparable across treatment groups (3.6–6.7%), except for a higher incidence (11.4%) in the 200 µg group.

Regarding former concerns on the safety of long-acting β₂-agonists in asthma in terms of an association with an increase in asthma-related deaths and life-threatening episodes [Martinez, 2006, 2005], no issues of this nature have been raised in COPD. In asthma, current disease management guidelines [GINA, 2009] establish that long-acting β₂-agonists should never be used as monotherapy, whereas they provide therapeutic benefit when combined with inhaled glucocorticosteroids, and this combination therapy is the preferred treatment when a medium dose of inhaled glucocorticosteroid alone fails to achieve control of asthma. In COPD, the GOLD guidelines [GOLD, 2009] establish long-acting bronchodilators as first-line therapy (added to a short-acting rescue bronchodilator when needed) for subjects with moderate or upper severity disease stages.

Conclusions

Indacaterol, a novel once-daily ultra-long-acting β₂-agonist bronchodilator now approved in the European Union for COPD, provides effective 24-h bronchodilation and a fast onset of action with an efficacy at least comparable or superior to current bronchodilator therapy standards. The data from clinical development support a favourable safety and tolerability profile within the β₂-agonist drug class, with no relevant issues identified. The recommended dose is 150 µg once daily, delivered with a SDDPI device. A 300 µg per capsule presentation for once-daily dosing is also approved and may provide additional clinical benefit for patients with severe COPD. The maximum dose is 300 µg once daily. Current evidence supports that indacaterol is suitable for use as first-line monotherapy in those COPD patients with moderate disease (GOLD Stage II) and beyond that do not require inhaled corticosteroids as per GOLD guidelines, or in combination with an inhaled corticosteroid in severe or very severe patients with repeated exacerbations. As with long-acting bronchodilators, a short-acting bronchodilator such as salbutamol/albuterol can be employed as on-demand rescue medication if needed. Further research should provide evidence on the benefits and safety profile of combining indacaterol with a long-acting anticholinergic bronchodilator.