Turning a Molecule into a Medicine: the Development of Indacaterol as a Novel Once-Daily Bronchodilator Treatment for Patients with COPD

Abstract

Indacaterol is the first once-daily, long-acting β2-adrenergic agonist (LABA) approved for the treatment of chronic obstructive pulmonary disease (COPD). Indacaterol was developed using a combination of informed drug design and molecular chemistry to generate a β2-adrenergic agonist with a fast onset and long duration of action, enabling once-daily dosing with an acceptable safety profile. Early preclinical studies with indacaterol demonstrated these characteristics, and this promising molecule was taken into clinical development, originally for asthma treatment. Subsequent safety concerns over LABA monotherapy in patients with asthma redirected indacaterol's development to centre on COPD, where a good evidence base and guideline recommendations for bronchodilator monotherapy existed. Clinical development was initially complicated by different inhaler devices and differing doses of indacaterol. Using a phase III innovative adaptive-design clinical trial (INHANCE), indacaterol 150 and 300 μg once-daily doses were selected to be taken forward into the phase III INERGIZE programme. This programme delivered placebo-controlled and active-comparator data, including comparisons with formoterol, tiotropium and salmeterol/fluticasone, as well as the use of indacaterol in combination with tiotropium. Together, these studies provided a comprehensive assessment of the benefit-risk profile of indacaterol, allowing for regulatory submission. Indacaterol was first approved at once-daily doses of 150 and 300 μg in the European Union in 2009, followed by 150 µg in Japan (2011) and China (2012), and 75 μg in the United States (2011). To date, indacaterol is approved and marketed in more than 100 countries worldwide for once-daily maintenance treatment of COPD.

The use of fluorescence correlation spectroscopy to monitor cell surface β2‐adrenoceptors at low expression levels in human embryonic stem cell‐derived cardiomyocytes and fibroblasts

“…10,11 Furthermore, the differential sensitivity of different cell phenotypes to agonist-induced internalization of the β 2 -adrenoceptor may also have implications for drug therapy with inhaled longacting β 2 -agonists. 63,64 In summary, the present study has demonstrated the power of FCS in investigating cell surface β 2 -adrenoceptors at the very low expression levels often seen in endogenously expressing cells. FCS was able to detect SNAP-tagged β 2 -adrenoceptor expression in both ES-derived cardiomyocytes and CRISPR/Cas9 genome-edited HEK293T cells, where the expression level was too low to detect them using standard confocal microscopy.…”

Tiotropium Bromide in Chronic Obstructive Pulmonary Disease and Bronchial Asthma

“…It was designed to have a quick onset of action (5 min), and ultra-long-acting duration, so it could be prescribed once daily. Indacaterol was initially approved in the EU in 2009 at doses of 150 - 300 µg; followed by 150 µg in Japan (2011), China (2012), and 75 µg in the US (2011) [ 40 ]. To date, indacaterol has been approved in more than 100 countries.…”

<p>Ultra Long-Acting β-Agonists in Chronic Obstructive Pulmonary Disease</p>

“…Other pre-clinical and early clinical trials of indacaterol have been reviewed. 17 Indacaterol improved breathlessness in a meta-analysis of six trials. 18,19 A Cochrane systemic review analyzed 13 trials comparing indacaterol with either placebo or twice daily β-agonist in the treatment of COPD and demonstrated that indacaterol produced statistically and clinically meaningful increases in both lung function and quality of life compared with placebo.…”