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

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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.

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Acknowledgements

The authors were assisted in the preparation of the manuscript by Melanie Stephens and Molly Heitz, professional medical writers contracted to CircleScience (Tytherington, Cheshire, UK; part of KnowledgePoint360, an Ashfield Company). Writing support was funded by Novartis Pharma AG (Basel, Switzerland).

Conflict of interest information

S.R. has received honoraria for consultation and lecture fees, and his institution has received grants to support research from many industry sponsors, including support from Novartis for studies on indacaterol and for consultation on clinical studies. S.R. had or currently has a number of relationships with companies who provide products and/or services relevant to outpatient management of COPD. These relationships include serving as a consultant, advising regarding clinical trials, speaking at continuing medical education programmes and performing funded research both at basic and clinical levels. S.R. does not own any stock in any pharmaceutical companies. S.R. has had relationships since 2011 for board memberships/consultancy/lectures from the American Association for Respiratory Care, American Board of Internal Medicine, Able Associates, Align2 Acton, Almirall, APT, AstraZeneca, American Thoracic Society, Beilenson, Boehringer Ingelheim, Chiesi, CIPLA, Clarus Acuity, CME Incite, COPDFoundation, Cory Paeth, CSA, CSL Behring, CTS Carmel, Dailchi Sankyo, Decision Resources, Dunn Group, Easton Associates, Elevation Pharma, FirstWord, Forest, GLG Research, Gilead, Globe Life Sciences, GlaxoSmithKline, Guidepoint, Health Advance, HealthStar, HSC Medical Education, Johnson and Johnson, Leerink Swan, LEK, McKinsey, Medical Knowledge, Medimmune, Merck, Navigant, Novartis, Nycomed, Osterman, Pearl, PeerVoice, Penn Technology, Pennside, Pfizer, Prescott, Pro Ed Communications, PriMed, Pulmatrix, Quadrant, Regeneron, Saatchi and Saatchi, Sankyo, Schering, Schlesinger Associates, Shaw Science, Strategic North, Summer Street Research, Synapse, Takeda, Telecon SC and ThinkEquity.

Ja.D. has received consultation fees or honorarium from Novartis for lectures, advisory boards and participation in review activities.

M.M. is a consultant or has participated in advisory boards for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Pfizer and Stallergen.

R.D. is a consultant or has received honoraria from ALK, Boehringer Ingelheim, Cytos, Cipla, Novartis, Meda and Vectura; payment for lectures, including service on speakers bureaus from ALK, AstraZeneca, Boehringer Ingelheim, Chesi, GlaxoSmithKline, Meda, Novartis and Teva; received grant support from ALK, Boehringer Ingelheim, Novartis, Pfizer and Stallergen.

K-M.B. has received compensation for organising or participating in advisory boards for Almirall Hermal, AstraZeneca, Boehringer Ingelheim, Chiesi, Cytos, Mundipharma, Novartis and Revotar Biopharmaceuticals and participated as a speaker in scientific meetings or courses supported by various pharmaceutical companies (Almirall Hermal, AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer and Takeda) in the past 3 years. K-M.B. has received consulting fees from Ablynx, Apellis Pharmaceuticals, Chiesi and Cytos. The institution where K-M.B. is employed (insaf Respiratory Research Institute) has received compensation for the design, performance or participation in single or multicentre clinical trials in the past 3 years from several companies, including Almirall Hermal, Boehringer Ingelheim, Cytos, GlaxoSmithKline, Mundipharma, Novartis, Pfizer, Revotar Biopharmaceuticals, Sterna AG and TEVA.

Ju.D. is an employee of Novartis. H-J.F., L.M. and D.Y. are employees of Novartis and also own stock options in the company. M.H. was an employee of Novartis and previously owned Novartis stock options during the early phase of manuscript development.

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Authors and Affiliations

  1. Novartis Horsham Research Centre, Novartis Pharmaceuticals UK Limited, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, UK

    Lorraine Murphy, Mark Higgins & David Young

  2. Pulmonary and Critical Care, University of Nebraska Medical Center, Omaha, NE, USA

    Stephen Rennard

  3. Pulmonary and Critical Care Medicine, University of North Carolina, Chapel Hill, NC, USA

    James Donohue

  4. Clinical Pharmacology, University of Bordeaux, Bordeaux, France

    Mathieu Molimard

  5. Odense University Hospital, Odense, Denmark

    Ronald Dahl

  6. Respiratory Research Institute, Wiesbaden, Germany

    Kai-Michael Beeh

  7. Novartis Pharma AG, Basel, Switzerland

    Juergen Dederichs & Hans-Jürgen Fülle

Authors
  1. Lorraine Murphy
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  2. Stephen Rennard
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  3. James Donohue
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  5. Ronald Dahl
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  6. Kai-Michael Beeh
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  7. Juergen Dederichs
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  8. Hans-Jürgen Fülle
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  9. Mark Higgins
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  10. David Young
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Correspondence to Lorraine Murphy.

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Murphy, L., Rennard, S., Donohue, J. et al. Turning a Molecule into a Medicine: the Development of Indacaterol as a Novel Once-Daily Bronchodilator Treatment for Patients with COPD. Drugs 74, 1635–1657 (2014). https://doi.org/10.1007/s40265-014-0284-7

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  • DOI: https://doi.org/10.1007/s40265-014-0284-7

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