TY - JOUR T1 - Single and repeat dose safety and pharmacodynamics studies with the selective intranasal TLR7 agonist GSK2245035 JF - European Respiratory Journal JO - Eur Respir J VL - 44 IS - Suppl 58 SP - P1047 AU - Diana Quint AU - Jo Hessey AU - Amanda Baines AU - Claire Ambery AU - Will Powley AU - Bob Gibbon AU - Keith Biggadike AU - Daphne Tsitoura Y1 - 2014/09/01 UR - http://erj.ersjournals.com/content/44/Suppl_58/P1047.abstract N2 - Introduction GSK2245035 is a novel selective TLR7 agonist small molecule capable of inducing strong type 1 IFN-mediated immune responses. It is hypothesized that intranasal (IN) administration of GSK2245035 may lead to down-regulation of Th2 adaptive responses to aeroallergens and offer a new form of treatment for allergic rhinitis (AR) and asthma.Methods Double-blind, placebo-controlled, randomized studies were conducted to assess safety, tolerability and pharmacodynamic (PD) GSK2245035 responses of single, escalating IN doses in healthy volunteers (HVT) and AR patients (NCT01480271) and of four repeat weekly IN doses in patients with AR and mild asthma (NCT01607372).Results Single IN dosing, from 2-100ng, was found overall tolerated. In HVT transient, mild to moderate adverse events (AE) related to TLR7-mediated cytokine release (CRS), such as fever, headache, myalgia and nausea, were observed at doses ≥ 40ng in a dose-dependent manner. In AR patients mild CRS-related AE were reported up to 40ng the maximum dose tested. Activation of the TLR7 pathway was confirmed in both HVT and AR patients at doses ≥20ng, as dose-dependent increase of IP-10 levels in the serum and nasal lavage and of IFNα-stimulated genes in nasal scrapes were detected.Following repeat IN weekly dosing, mild, potentially CRS-related Aes were noted with placebo (20%), 40ng (67%) and 80ng (14%). PD biomarkers, such as serum and nasal IP-10, demonstrated consistent increase after each dosing with no evidence for amplification or tolerization.Conclusions Single and repeat GSK2245035 IN administration has an acceptable safety profile at doses that induce local TLR7-mediated immune responses. ER -