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A4643 - PI3kinase/mTOR Inhibition Alters Global Metabolism in IPF Patients: Exploratory Biomarker Analysis from a Phase I Proof of Mechanism Study
Author Block: C. B. Nanthakumar1, Y. Man1, A. Taylor1, P. F. Mercer2, R. C. Chambers2, R. Marshall1, P. T. Lukey1, W. A. Fahy1, T. M. Maher3; 1GlaxoSmithKline, Hertfordshire, United Kingdom, 2Centre for Inflammation and Tissue Repair, University College London, London, United Kingdom, 3Interstitial Lung Disease Unit, Royal Brompton Hospital, London, United Kingdom.
Idiopathic Pulmonary Fibrosis (IPF) is characterized by extracellular matrix (ECM) accumulation leading to structural distortion of lung architecture resulting in impaired gaseous exchange and death due to respiratory failure. Emerging evidence suggests cellular metabolic reprogramming may contribute to the pathogenesis of IPF including the observation of reproducibly increased 18fluorodeoxyglucose (FDG) pulmonary uptake in honeycombed lesions1 elevated lung lactic acid levels promoting activation of the central profibrotic mediator, transforming growth factor (TGF)-beta2 and metabolic changes associated with fibroblast-to-myofibroblast transdifferentiation3. Energetic adaption maybe modulated by the PI3kinase (PI3k)/mammalian target of rapamycin (mTOR) signalling pathway and recent advances in global metabolite profiling permit the application of high throughput metabolomics to clinical samples. Omipalasib (GSK2126458A), an ATP-competitive, class I PI3kinase/mTOR inhibitor was evaluated in a phase 1, randomized, double-blind, placebo-controlled, repeat-dose-escalation study in IPF patients. Pulmonary and systemic drug exposure and target engagement were confirmed and a pharmacokinetic (PK)/pharmacodynamic (PD) response established in lung and blood compartments. Further exploratory biomarker analysis was conducted to determine the effect of dual PI3K/mTOR inhibition on the global metabolite signature to address whether metabolic reprogramming contributes to disease activity and assess the utility of metabolites as PD biomarkers to assess pulmonary and systemic PI3k/mTOR activity in IPF. Patients were administered placebo or 0.25-2mg GSK2126458A over a 7-10day treatment period with bronchoalveolar lavage (BAL) conducted at baseline (before dosing) and mid-study (during dosing) and blood sampled on the first day of dosing (day 1) and final day of dosing (days 7-10). Global metabolite identification using liquid chromatography mass spectrometry (LC-MS, Metabolon HD4TM) was performed on BAL cell pellets and in the blood plasma fraction. 1197 metabolites were detected in plasma and 551 metabolites in BAL cells with changes in phospholipids, sphingolipid metabolism, catabolic energy pathways including glycolysis and protein degradation following treatment with GSK2126458A relative to placebo. Further pathway enrichment analysis was performed to assess biochemical changes in networks upon PI3K/mTOR modulation. Dysregulated metabolism is an emerging feature of IPF and patients with IPF receiving GSK2126458A revealed differences in metabolic signatures compared with placebo suggesting a critical role for PI3k/mTOR pathway activation. (1) Win et al., Eur J Nucl Med Mol Imaging (2012) 39: 521-528 (2) Kottmann et al., Am J Resp Crit Care Med (2012) 186: 740-751 (3) Bernard et al., J Biol Chem (2015) 290: 25427-25438