GSK1795091 / GSK - LARVOL DELTA

The protective effect of karanjin against sepsis-induced acute lung injury in mice is involved in the suppression of the TLR4 pathway. (PubMed, Chem Biol Drug Des) - "However, treatment with GSK1795091, an agonist of TLR4, attenuated the effects of karanjin on LPS-induced ALI...Overexpression of TLR4 attenuated karanjin effects on LPS-stimulated inflammatory responses in MLE-12 cells. In conclusion, karanjin repressed sepsis-stimulated ALI in mice by suppressing the TLR4 pathway."

Journal • Preclinical • Acute Lung Injury • Infectious Disease • Inflammation • Respiratory Diseases • Septic Shock • MPO • MYD88

A phase I, open-label study of GSK1795091 administered in combination with immunotherapies in participants with advanced solid tumours (NCT03447314) (ESMO 2019) - P1; "The current study will evaluate GSK1795091 with immunotherapies that have highly complementary mechanisms of action and supporting preclinical data (e.g. GSK3174998 [an OX40 agonist], GSK3359609 [an ICOS agonist], or pembrolizumab [a PD-1 inhibitor]) with the aim of generating greater antitumor activity than with monotherapy. Legal entity responsible for the study: GlaxoSmithKline. Funding: GlaxoSmithKline."

Clinical • Combination therapy • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

Manufacturing-dependent change in biological activity of the TLR4 agonist GSK1795091 and implications for lipid A analog development. (PubMed, Clin Transl Sci) - P1 | "A phase I trial (NCT03447314; 204686) evaluated the safety and efficacy of GSK1795091, a Toll-like receptor 4 (TLR4) agonist, in combination with immunotherapy (GSK3174998 [anti-OX40 monoclonal antibody], GSK3359609 [anti-ICOS monoclonal antibody], or pembrolizumab) in patients with solid tumors. Structural characterization revealed GSK1795091 aggregate size in the modified formulation to be twice that in the original formulation, suggesting a negative correlation between GSK1795091 aggregate size and PD activity. This may have important clinical implications for future development of structurally similar compounds."

Journal • Fatigue • Oncology • Solid Tumor • IL10 • IL1R1 • TLR4

Development of diamino allose phosphates (DAPs): A novel series of toll-like receptor 4 agonists, promising vaccine adjuvants and immunotherapeutics | Poster Board #2863 (ACS-Fall 2022) - "This DAP series is more potent than the known TLR4 agonists' benchmarks MPLA and GLA and demonstrates equivalent or improved TLR4 activity to other known synthetic TLR4 agonists CRX-524 and CRX-601. The new compounds are finding promise as adjuvants and monotherapy with a lead DAP expected to enter phase 1 clinical trial in 2023 to treat allergic rhinitis."

Clinical • Allergic Rhinitis • Immunology • Inflammation • TLR4

Study of a Combination of GSK1795091 and Immunotherapies in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=54 | Completed | Sponsor: GlaxoSmithKline | Active, not recruiting ➔ Completed

Trial completion • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CRP

Co-encapsulation of synthetic lipidated TLR4 and TLR7/8 agonists in the liposomal bilayer results in a rapid, synergistic enhancement of vaccine-mediated humoral immunity. (PubMed, J Control Release) - "Here, we create liposomes that stably co-encapsulate CRX-601, a synthetic TLR4 agonist, and UM-3004, a lipidated TLR7/8 agonist, within the liposomal bilayer in order to achieve co-delivery, allow tunable physical properties, and induce in vitro and in vivo immune synergy...This work demonstrates that co-incorporation of TLR4 and lipidated TLR7/8 agonists within the liposomal bilayer leads to innate and adaptive immune synergy which biases a Th1 immune response. Thus, liposomal co-encapsulation may be a useful and flexible tool for vaccine adjuvant formulation containing multiple TLR agonists."

Journal • Infectious Disease

Study of a Combination of GSK1795091 and Immunotherapies in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=162; Suspended; Sponsor: GlaxoSmithKline; Trial primary completion date: Dec 2021 ➔ Aug 2020

Clinical • Combination therapy • Trial primary completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CRP

Study of a Combination of GSK1795091 and Immunotherapies in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=54; Active, not recruiting; Sponsor: GlaxoSmithKline; Suspended ➔ Active, not recruiting; N=162 ➔ 54

Clinical • Combination therapy • Enrollment change • Enrollment closed • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CRP

"#GSK culls a host of pipeline meds after failures, prioritization, #GSK091 for #Cancer was terminated $GSK https://t.co/yPDbB7eupy" (@1stOncology)

Oncology

Safety, Pharmacokinetics, and Pharmacodynamics of the TLR4 Agonist GSK1795091 in Healthy Individuals: Results from a Randomized, Double-blind, Placebo-controlled, Ascending Dose Study. (PubMed, Clin Ther) - P1 | "Intravenously administered GSK1795091 was acceptably tolerated in healthy volunteers, had favorable PK properties, and stimulated immune cell changes in a dose-dependent manner, providing evidence of target engagement and downstream pharmacology. These results supported the design and initiation of a repeat-dose study of intravenous GSK1795091 in combination with other immunotherapies in patients with advanced cancer. ClinicalTrials.gov identifier: NCT02798978."

Clinical • Journal • PK/PD data • Back Pain • Infectious Disease • Musculoskeletal Pain • Oncology • Pain • TLR4

Study of a Combination of GSK1795091 and Immunotherapies in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=162; Suspended; Sponsor: GlaxoSmithKline; Trial completion date: Jun 2021 ➔ Dec 2021; Trial primary completion date: Jun 2021 ➔ Dec 2021

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Study of a Combination of GSK1795091 and Immunotherapies in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=162; Suspended; Sponsor: GlaxoSmithKline; Recruiting ➔ Suspended

Clinical • Combination therapy • Trial suspension • CRP

Study of a Combination of GSK1795091 and Immunotherapies in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=162; Recruiting; Sponsor: GlaxoSmithKline; Trial completion date: Feb 2020 ➔ Jun 2021; Trial primary completion date: Feb 2020 ➔ Jun 2021

Clinical • Combination therapy • Trial completion date • Trial primary completion date