Source: International Congress 2014 – New treatments for cough, asthma, COPD and ILDs
Disease area: Airway diseases

Abstract

Introduction: Current treatment regimen for COPD is majorly restricted to inhaled corticosteroids although there is not much evidence of efficiency in this disease. Accentuating the anti-COPD effects by addition of dual PI3K d/g inhibitors represents a novel therapeutic strategy. The objective of this study was to explore the therapeutic potential of a combination of corticosteroid and RP6503, a novel, small molecule PI3Kd/g inhibitor, in COPD models.Methods: Specificity of RP6503, towards PI3Kd and g isoforms and subsequent downstream activity was determined in enzyme and several cell based assays. Pre-clinical efficacy of the combination RP6503 and corticosteroids was determined in in vitro and in vivo models relevant for COPD.Results: RP6503 demonstrated significant potency against PI3Kd (29.3 nM) and g (28.1 nM) enzymes with selectivity over a (>10000-fold) and b (>60-fold) isoforms. Addition of 1 mM or 100 nM RP6503 resulted in potentiation of dexamethasone activity with respect to reduction in IC₅₀ for IL-8 release in H₂O₂ treated human monocytic (U937) cells (>8-fold) as well as TGFb treated human lung alveolar basal epithelial (A549) cells (5-fold). While fluticasone (F) alone @ 55 mg/kg was ineffective in a cigarette smoke induced cellular infiltration model in Balb/c mice, combination with RP6503 resulted in a dose-dependent reduction in macrophage count upon intranasal administration (>80% inhibition for F + 300 mg RP6503) .Conclusions: Data demonstrate the therapeutic potential of the combination of corticosteroids and dual PI3Kd/g inhibitors in airway inflammation. Combination therapy might also be useful to overcome steroid resistance in COPD.

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K. Routhu, B. Govindrajulu, S. Veeraraghavan, S. Viswanadha, S. Vakkalanka (Hyderabad, India; La Chaux-de-Fonds, Switzerland). RP6503, a novel and selective PI3K δ/gamma inhibitor, potentiates the effect of steroids in pre-clinical models of COPD. Eur Respir J 2014; 44: Suppl. 58, 1504

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