ATS 2021 will feature presentations of original research from accepted abstracts. Mini Symposia and Thematic Poster Sessions are abstract based sessions.
Please use the form below to browse scientific abstracts and case reports accepted for ATS 2021. Abstracts presented at the ATS 2021 will be published in the Online Abstract Issue of the American Journal of Respiratory and Critical Care Medicine, Volume 203, May 3, 2021.
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PI3Kγd Inhibitor, AZD8154, Demonstrates Improved Efficacious Profile Over PI3Kd Selective Inhibitor, GSK2269557, in a Rat Model of Asthma
Session Title
TP9 - TP009 MECHANISTIC AND TRANSLATIONAL ASTHMA STUDIES
Abstract
A1395 - PI3Kγd Inhibitor, AZD8154, Demonstrates Improved Efficacious Profile Over PI3Kd Selective Inhibitor, GSK2269557, in a Rat Model of Asthma
Author Block: J. W. Pinkerton1, J. J. Adcock2, D. Zervas1, T. Markou1, B. Dekkak1, E. Dubuis1, V. Cibert-Goton2, S. J. Bonvini2, W. Brailsford2, L. Yrlid2, E. Bergström2, M. G. Belvisi2, M. A. Birrell2; 1Imperial College London, South Kensington, United Kingdom, 2AstraZeneca, Mölndal, Sweden.
Rationale: Phosphoinositide 3-kinase (PI3K) has 4 isoforms, p110γ and p110δ are predominantly expressed in leukocytes and as such represent attractive therapeutic target for chronic inflammatory diseases such as asthma. Recently, an inhaled PI3Kδ selective inhibitor, GSK2269557 (GSK557) has been trialled in asthmatic patients but it failed to exhibit meaningful clinical improvement and was associated with increased coughing 1. AZD8154 is a highly potent and selective dual PI3Kγδ inhibitor with properties suitable for inhaled delivery, which is currently undergoing phase I clinical trials. The aim of this study was to compare the impact of AZD8154 compared to GSK557 in a preclinical rodent model of allergic asthma; and to explore any pro-tussive properties of the two molecules.Methods: Adult, male, Brown-Norway rats were sensitised to ovalbumin (OVA) and received either AZD8154, GSK557 or vehicle treatment intratracheally prior to inhaled OVA challenge. The late asthmatic response (LAR) was recorded from 1 to 6 hours after the end of antigen challenge and airway inflammation was assessed the next day 2. A parallel set of animals were used to explore the impact on pAkt levels, a downstream marker of PI3K activation, in the lung as an assessment of target engagement. Naïve rats were used to determine the ability of the compounds to trigger airway sensory (a precursor to coughing) 3. Results: The results showed that AZD8154, and not GSK557, reduced LAR (Fig. 1) to a similar extent as the clinical comparator (ICS). Both compounds reduced airway eosinophilia but the magnitude was greater with AZD8154 treatment and this compound, unlike GSK557, also reduced neutrophilia. Pharmacokinetic and pharmacodynamic assessment demonstrated appropriate compound levels present in the lungs and target engagement. Furthermore, preliminary data showed GSK557 to trigger extra-pulmonary airway sensory nerves from the Recurrent Laryngeal Nerve, whereas, at efficacious doses, AZD8154 did not (Fig. 1). Conclusion: These data suggest that a dual PI3Kγδ inhibitor has an improved therapeutic profile compared to the selective PI3Kδ inhibitor, GSK557. Furthermore, these data suggest that AZD8154 may not trigger the increase in coughing which was observed for GSK557. Together these data indicate that AZD8154 may be an effective treatment for people suffering from asthma. References:
1.Khindri et al. J Pharmacol Exp Ther. 2018
2.Hele et al. B J Pharmacol. 2001
3.Bonvini et al. J Allergy Clin Immunol. 2016
Author Block: J. W. Pinkerton1, J. J. Adcock2, D. Zervas1, T. Markou1, B. Dekkak1, E. Dubuis1, V. Cibert-Goton2, S. J. Bonvini2, W. Brailsford2, L. Yrlid2, E. Bergström2, M. G. Belvisi2, M. A. Birrell2; 1Imperial College London, South Kensington, United Kingdom, 2AstraZeneca, Mölndal, Sweden.
Rationale: Phosphoinositide 3-kinase (PI3K) has 4 isoforms, p110γ and p110δ are predominantly expressed in leukocytes and as such represent attractive therapeutic target for chronic inflammatory diseases such as asthma. Recently, an inhaled PI3Kδ selective inhibitor, GSK2269557 (GSK557) has been trialled in asthmatic patients but it failed to exhibit meaningful clinical improvement and was associated with increased coughing 1. AZD8154 is a highly potent and selective dual PI3Kγδ inhibitor with properties suitable for inhaled delivery, which is currently undergoing phase I clinical trials. The aim of this study was to compare the impact of AZD8154 compared to GSK557 in a preclinical rodent model of allergic asthma; and to explore any pro-tussive properties of the two molecules.Methods: Adult, male, Brown-Norway rats were sensitised to ovalbumin (OVA) and received either AZD8154, GSK557 or vehicle treatment intratracheally prior to inhaled OVA challenge. The late asthmatic response (LAR) was recorded from 1 to 6 hours after the end of antigen challenge and airway inflammation was assessed the next day 2. A parallel set of animals were used to explore the impact on pAkt levels, a downstream marker of PI3K activation, in the lung as an assessment of target engagement. Naïve rats were used to determine the ability of the compounds to trigger airway sensory (a precursor to coughing) 3. Results: The results showed that AZD8154, and not GSK557, reduced LAR (Fig. 1) to a similar extent as the clinical comparator (ICS). Both compounds reduced airway eosinophilia but the magnitude was greater with AZD8154 treatment and this compound, unlike GSK557, also reduced neutrophilia. Pharmacokinetic and pharmacodynamic assessment demonstrated appropriate compound levels present in the lungs and target engagement. Furthermore, preliminary data showed GSK557 to trigger extra-pulmonary airway sensory nerves from the Recurrent Laryngeal Nerve, whereas, at efficacious doses, AZD8154 did not (Fig. 1). Conclusion: These data suggest that a dual PI3Kγδ inhibitor has an improved therapeutic profile compared to the selective PI3Kδ inhibitor, GSK557. Furthermore, these data suggest that AZD8154 may not trigger the increase in coughing which was observed for GSK557. Together these data indicate that AZD8154 may be an effective treatment for people suffering from asthma. References:
1.Khindri et al. J Pharmacol Exp Ther. 2018
2.Hele et al. B J Pharmacol. 2001
3.Bonvini et al. J Allergy Clin Immunol. 2016
