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

Abstract

Introduction: Pulmonary fibrosis (PF) represents a debilitating disease of the lung that is often fatal without any known treatment. Although pirfenidone was approved for treatment of PF, patient response is limited and accompanied by severe adverse events. We evaluated the therapeutic potential of a novel, selective, and potent dual PI3Kd/g inhibitor, RP6503, in preclinical models of PF.Methods: PDGF or TGFb induced primary rat and human lung fibroblast proliferation was determined after 48 h incubation with RP6503 as a single agent or in combination with pirfenidone. Combination Index (CI) was calculated using CompuSyn version 1.0. In vivo efficacy was evaluated in a bleomycin induced pulmonary fibrosis model in Wistar rat.Results: RP6503 inhibited PDGF induced rat primary lung fibroblast proliferation with an EC₅₀ of 467 nM. A synergistic effect (CI <1) on inhibition of PDGF induced primary human fibroblast proliferation was noticed upon combining RP6503 with pirfenidone. Intranasal administration of 1 mg/kg RP6503 resulted in a 30% reduction in lung weight compared to the control. Body weight was not affected by treatment. Reduction in fibrosis and inflammation upon histopathological evaluation were 53% and 71% respectively. In addition, RP6503 reduced lung hydroxyproline content by 41%.Conclusions: Data demonstrate the therapeutic potential of RP6503 in pulmonary fibrosis. Efficacy studies using a combination of RP6503 and pirfenidone are currently in progress.

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K. Routhu, B. Govindrajulu, S. Veeraraghavan, S. Viswanadha, S. Vakkalanka (Hyderabad, India; La Chaux-de-Fonds, Switzerland). Pre-clinical evaluation of a novel and selective PI3K δ/gamma inhibitor in pulmonary fibrosis. Eur Respir J 2014; 44: Suppl. 58, 1507

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