title: 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.
authors.affiliation: Novartis Horsham Research Centre, Novartis Pharmaceuticals UK Limited, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, UK, lorraine.murphy@novartis.com.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Murphy
authors.forename: Stephen
authors.initials: S
authors.lastname: Rennard
authors.forename: James
authors.initials: J
authors.lastname: Donohue
authors.forename: Mathieu
authors.initials: M
authors.lastname: Molimard
authors.forename: Ronald
authors.initials: R
authors.lastname: Dahl
authors.forename: Kai-Michael
authors.initials: KM
authors.lastname: Beeh
authors.forename: Juergen
authors.initials: J
authors.lastname: Dederichs
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Fülle
authors.forename: Mark
authors.initials: M
authors.lastname: Higgins
authors.forename: David
authors.initials: D
authors.lastname: Young
mesh_terms: D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D007189:Indans / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use*; D015394:Molecular Structure; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D015363:Quinolones / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D001993:Bronchodilator Agents; D007189:Indans; D015363:Quinolones; C510790:indacaterol