Calcilytics: a non-steroidal replacement for inhaled steroid and SABA/LABA therapy of human asthma?

Asthma afflicts more than 300 million people. Contemporary mainstay therapies (inhaled corticosteroids and bronchodilators), prescribed empirically, control symptoms resulting from airways obstruction tolerably well in many patients but it is less clear that they alter the natural history of progressive airways inflammation and remodeling resulting in severe, therapy-resistant obstruction in a significant minority (5-10%), causing lifelong symptoms and elevated risk of recurrent hospital admission and death. Furthermore, no current anti-asthma drug targets bronchial smooth muscle hyperresponsiveness, a critical contributor to airways obstruction and the fundamental physiological abnormality characterizing asthma. Recent monoclonal antibody (biological) therapies reduce obstruction and exacerbations in some, but not all treated patients to an unpredictable extent, but are further limited by administration logistics and cost.

An overview of the cellular and molecular immunopathology of asthma, highlighting the need and logic for the development of a novel, non-steroidal, small molecule drug for topical delivery targeting bronchial smooth muscle hyperresponsiveness and airways inflammation, particularly corticosteroid-refractory inflammation.

This article elaborates evidence supporting the hypothesis that topically delivered, inhaled antagonists of the calcium-sensing receptor (CaSR) have the potential to meet these requirements, and the practicality of repurposing existing, small molecule CaSR antagonists (calcilytics) for this purpose.