GSK2245035 / GSK - LARVOL DELTA

Activation of Most Toll-Like Receptors in Whole Human Blood Attenuates Platelet Deposition on Collagen under Flow. (PubMed, J Immunol Res) - "Following 90 sec of deposition under flow of untreated blood, the addition of various TLR-7 agonists (imiquimod, vesatolimod, and GSK2245035) all caused immediate blockade of further platelet deposition. Since TLR signaling can activate nuclear factor-kappaB (NF-κB), the IKK-inhibitor (IKK inhibitor VII) and NF-κB inhibitor (Bay 11-7082) were tested...Furthermore, addition of Pam3CSK4 (TLR1/2 ligand), MALP-2 (TLR2/6 ligand), and Imquimod (TLR7 ligand) reduced phosphotidylserine (PS) exposure. Activation of TLR1/2, TLR2/6, TLR3, TLR7, and TLR9 in whole blood reduced platelet deposition under flow on collagen; however, LPS (major Gram negative bacterial pathogenic component) activation of LTR4 was clearly prothrombotic."

Journal • Cardiovascular • Hematological Disorders • Infectious Disease • Thrombosis • CD61 • NF-κβ • TLR2 • TLR3 • TLR4 • TLR9

Effect of the GSK2245035 on the Allergen-induced Asthmatic Response (clinicaltrials.gov) - P2; N=36; Completed; Sponsor: GlaxoSmithKline; Phase classification: P1/2 ➔ P2

Phase classification • Asthma • Immunology • Respiratory Diseases

GSK2245035, a TLR7 agonist, Does Not Increase Pregnancy Loss in Cynomolgus Monkeys. (PubMed, J Reprod Immunol) - "Non-adverse effects included increased incidence of nasal discharge, increased maternal body temperature at 30 ng/kg/week and dose-dependent increases in maternal IP-10 and IFN-α and decreased infant anti-KLH IgM and IgG titers following KLH immunization at ≥3 ng/kg/week, relative to controls. Potentially, lower IFN-α and IP-10 levels as well as once-weekly intranasal dosing vs daily subcutaneous or intramuscular dosing with recombinant type I IFNs could explain the lack of pregnancy effects; however, there was an undesired impact on offspring immune function."

Journal • Immune Modulation • Inflammation • IL6

Intranasal GSK2245035, a Toll-like receptor 7 agonist, does not attenuate the allergen-induced asthmatic response in a randomized, double-blind, placebo-controlled experimental medicine study. (PubMed, PLoS One) - "Although target engagement was observed, weekly intranasal GSK2245035 20 ng for 8 weeks did not substantially attenuate the late asthmatic response in participants with mild allergic asthma. Overall, treatment was well tolerated."

Clinical • IO Biomarker • Journal • Asthma • Inflammation • Pain • Respiratory Diseases

Follow-up Study to Investigate the Effect of GSK2245035 on Nasal Allergic Reactivity in Subjects Completing Treatment in Study TL7116958 (clinicaltrials.gov) - P2; N=20; Not yet recruiting; Sponsor: GlaxoSmithKline

New P2 trial • Asthma • Biosimilar • Immunology • Inflammation

Optimisation of TLR7 agonists suitable for intranasal delivery (ACS-Sp 2020) - "The efforts resulted in compounds showing remarkable selectivity for induction of IFNα over the pro-inflammatory cytokine TNFβ and with suitable profiles for topical administration. The clinical candidate GSK2245035 was selected from the 8-oxo-adenine series and the pre-clinical and early clinical evaluation of this compound will be described."