Indacaterol

Indacaterol, a novel inhaled once daily ultra- long acting B2 agonist (uLABA) is now widely approved for the maintenance treatment of COPD, including chronic bronchitis and emphysema. In this issue of the journal, Beeh, et al evaluated the effects of two weeks treatment with indacaterol 300 mg on dynamic lung hyperinflation and breathlessness. On day 14, statistically significant improvements were observed with indacaterol over placebo in resting inspiratory capacity (IC), Peak IC and isotime IC as well as trough FEV1, dyspnea (BDI/TDI), BorgCR 10 scale and exercise endurance time (1). This confirms a previous 3 week study demonstrating indacaterol improving exercise endurance by 111seconds and increasing IC by 0.28L in COPD(2). Important questions remain. Is indacaterol effective for levels of severity of COPD? Patients with predominately moderate and severe COPD have been tested with indacaterol, but will it improve the very severely obstructed, the volume responder to bronchodilator? Also, how does it compare to tiotropium and other comparators? Lastly, is the lower dose of 75 mcg now approved in the United States effective on these important outcomes?

In dose ranging studies, indacaterol 18.75 to 600 mcg has been studied with most doses being effective and safe (3). The most rigorously tested doses are 150mcg and 300mcg which are now licensed worldwide (4). Additional studies on secondary outcomes like exercise endurance and hyperinflation are now being conducted with 150 mcg.

The MCID for inspiratory capacity is still in the process of being defined. Various numbers have been proposed including a change of 100mls, but previous studies have shown inspiratory capacity has a wide variability that could be as high as 9% or 220 ml. An increase of 0.3L or 10% of predicted in resting IC is indicative of a greater ability to expand tidal volume (5). Certainly the improvements noted with indacaterol at resting, peak and isotime IC are within this range.

What about the dose approved for use in the United States? The US Food and Drug Administration recently approved indacaterol 75 mcg (6). In the dose finding studies 4 doses were tested (75, 150, 300, and 600 mcgs) using an adaptive seamless design (7). After two weeks, an independent committee selected two optimal doses for long term study (150,300mcgs) based on three pre-specified criteria including a 120 ml increase in AM trough and 120 mls in the AUC one to four hours. (8) This level reflects the mid-range of the MCID for trough for 100–140 mls (8). Nonetheless, the FDA initially issued a complete response to the application, i.e. non approval of both doses since it appeared that lower doses such as 75 mcg could also effective. There were safety concerns about possible off label use of higher doses of LABAS in asthma that could lead to more adverse effects including hospitalizations and/or deaths. Once daily dosing of uLABAS might expose patients to higher drug concentrations especially at the peak.

Three month studies of 75 mg were therefore completed and this dose was approved based in part on the recommendation of an FDA advisory committee which noted 75mcg efficacy and safety profile, but the 150 mcg dose was not approved at this time (6). Although there were no head to head studies of 75 verses 150mcgs, similar improvements were noted in lung function in clinical trials. Although the 150 mcg dose appeared more effective from modeling studies (9) and based on larger changes in SGRQ and TDI, these outcomes are secondary and not pivotal for licensing. Clearly, head to head studies of 75 mcg indacaterol versus 150 mcg and perhaps chronic studies of lower doses are needed. Also, additional studies on outcomes such as static and dynamic hyperinflation, exercise endurance time across different severities, as well as exacerbation rates and symptoms are needed with the lower doses.

Indacaterol, the first approved 24 hour LABA, appears to be an important addition to COPD treatment given better patient compliance with other once daily inhaled bronchodilators (10). Indacaterol appears effective at 150 + 300 mcg doses on multiple outcomes including lung function, hyperinflation, exercise endurance, dyspnea and exacerbations (11) and appears to be as effective as, if not more effective than tiotropium (12). The overall safety profile from many studies so far is very good (13). The efficacy of the 75 mcg of indacaterol also appears to be robust and studies of secondary outcomes are awaited along with combination studies of this agent with ICS and LAMAS.