Repurposing calcilytics for inflammatory lung diseases

P. L. Yarova1, M. Schepelmann1, E. J. Kidd1, W. R. Ford1, K. J. Broadley1, J. P. Ward2, C. J. Corrigan2, P. J. Kemp1, D. Riccardi1. 1Cardiff University, Cardiff, UNITED KINGDOM, 2King's College London, London, UNITED KINGDOM.

Introduction: The prevalence of chronic pro-inflammatory lung disorders such as asthma and chronic pulmonary disease (COPD) is increasing worldwide. Current treatments do not work for all the patients, and have unwanted side effects, therefore new therapies are needed. We have previously shown that inhibition of the extracellular calcium-sensing receptor (CaSR) with the calcilytic NPS89636 can suppress airway hyperresponsiveness (AHR) and inflammation in asthma animal models [1]. Four different calcilytics have been developed by Pharma (for systemic use) as a novel anti-osteoporosis treatment, but have been discarded due to lack of efficacy in Phase 1 and 2 clinical trials. Our overall goal is to repurpose calcilytics, delivered topically, as a novel therapy for pro-inflammatory lung diseases in humans. The aim of the current study was to test the ability of four calcilytics available for repurposing to alleviate asthma symptoms, using in vitro and in vivo models.

Methods and Results:In HEK293 cells stably expressing the human CaSR, custom-synthetized calcilytics, the quinazolin-2-one, AXT914 (Novartis), and the amino alcohols, JTT-305 (JT/Merck), NPS795 (Shire) and Ronacaleret (GSK/Shire), as well as commercially available NPS2143 (Tocris) successfully suppressed responses to high extracellular calcium (5mM; EC80~20 nM for custom-sensitized calcilytics, and EC80~200nM for NPS2143). The effect of calcilytics, delivered via inhalation, on AHR were determined in vivo using plethysmography in naïve male Balb/C mice in which poly-L-arginine was utilized to evoke AHR. All calcilytics (tested at three concentrations: optimal (1x, 300nM), low (0.1x, 30nM), and high (10x, 3μM)), dose-dependently inhibited poly-L-arginine-induced AHR. In the ovalbumin-sensitized, ovalbumin-challenged murine model of asthma, all tested calcilytics suppressed both AHR and inflammatory cell infiltration in the lung (N=6, one-way or two-way Anova with Bonferroni post hoc test).

Conclusion: Together, our results indicate that both quinazoline and amino alcohol calcilytics display comparable potency in suppressing AHR and inflammation suggestive that this effect on the airways CaSR is not class-mediated. Thus, inhaled calcilytics could be a promising new treatment for asthma and potentially other inflammatory lung disorders.

References: Yarova, P.L., et al., Calcium-sensing receptor antagonists abrogateairway hyperresponsiveness and inflammation in allergic asthma. Sciencetranslational medicine, 2015. 7(284): p. 284ra60.