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Safety of β2-Agonists in Asthma: Linking Mechanisms, Meta-Analyses and Regulatory Practice

  • Meeting Report
  • Theme: Current Scientific and Regulatory Approaches for Development of Orally Inhaled and Nasal Drug Products
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Abstract

An epidemic of asthma fatalities in the 1970s prompted a series of case-control studies which indicated that short acting β-agonists increased the risk of death. Subsequent mechanistic and pharmacodynamic studies have suggested that β-agonist monotherapy facilitates airway inflammation, although when co-administered with inhaled corticosteroids (ICSs), similar evidence is lacking. The Salmeterol Multicenter Asthma Research Trial, which revealed a fourfold increase in asthma-related deaths in salmeterol-treated patients, prompted a paradigm shift in the evidential assessment of β-agonist safety. The FDA’s meta-analysis of over 60,000 patients ultimately concluded that long-acting β-agonist (LABA) therapy increased the risk of serious asthma-related events. However, this meta-analysis itself raised questions given a large body of omitted data and a limited emphasis on the risk of ICS-LABA co-administration. Subsequently, the FDA mandated the conduct of five large studies to definitively ascertain whether ICS-LABAs increase asthma-related risk. Whether this ambitious programme will provide certainty remains to be seen given issues of multiplicity, the very low frequency of fatal and near-fatal asthma, and the administration of a free combination of ICS and LABA in one trial. The FDA’s de facto use of FEV1 as a safety parameter, based on findings from the Foradil NDA, is a further topical issue: subsequent clinical study data, considerations relating to regional pulmonary drug deposition and pharmacological differences between different β-agonists suggest that FEV1 may be a suboptimal safety metric. Models evaluating airway inflammation and bronchial reactivity may be more appropriate to assess the relative risk of asthma-related events.

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Authors and Affiliations

  1. Respiratory Medical Sciences, Mundipharma Research Limited, Cambridge Science Park, Milton Road, Cambridge, CB4 0G, UK

    Sanjeeva. B. Dissanayake

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  1. Sanjeeva. B. Dissanayake
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Correspondence to Sanjeeva. B. Dissanayake.

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Guest Editors: Lawrence Yu, Sau L. Lee, Guenther Hochhaus, Lana Lyapustina, Martin Oliver and Craig Davies-Cutting

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Dissanayake, S.B. Safety of β2-Agonists in Asthma: Linking Mechanisms, Meta-Analyses and Regulatory Practice. AAPS J 17, 754–757 (2015). https://doi.org/10.1208/s12248-015-9734-8

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  • DOI: https://doi.org/10.1208/s12248-015-9734-8

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