Manufacturing‐dependent change in biological activity of the TLR4 agonist GSK1795091 and implications for lipid A analog development

A phase I trial ({"type":"clinical-trial","attrs":{"text":"NCT03447314","term_id":"NCT03447314"}}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. The primary endpoint was safety; other endpoints included efficacy, pharmacokinetics, and pharmacodynamics (PD). Manufacturing of GSK1795091 formulation was modified during the trial to streamline production and administration, resulting in reduced PD (cytokine) activity. Fifty‐four patients received GSK1795091 with a combination partner; 32 received only the modified GSK1795091 formulation, 15 received only the original formulation, and seven switched mid‐study from the original to the modified formulation. Despite the modified formulation demonstrating higher systemic GSK1795091 exposure compared with the original formulation, the transient, dose‐dependent elevations in cytokine and chemokine concentrations were no longer observed (e.g., IP‐10, IL10, IL1‐RA). Most patients (51/54; 94%) experienced ≥1 treatment‐emergent adverse event (TEAE) during the study. Safety profiles were similar between formulations, but a higher incidence of TEAEs associated with immune responses (chills, fatigue, pyrexia, nausea, and vomiting) were observed with the original formulation. No conclusions can be made regarding GSK1795091 anti‐tumor activity due to the limited data collected. Manufacturing changes were hypothesized to have caused the change in biological activity in this study. 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.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Toll‐like receptor 4 (TLR4) agonists, such as lipopolysaccharide (LPS) and lipid A analogs, have demonstrated anti‐cancer effects in patients. Previous studies offer conflicting evidence on the active form (monomeric vs. aggregates) of LPS/lipid A analogs and suggest that different forms can stimulate different immune pathways.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This phase I study investigated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of GSK1795091 with one of three immunotherapies in patients with solid tumors. In addition, the study addressed the effects of a manufacturing change on the biological activity of GSK1795091.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study enables a better understanding of the impact of the manufacturing process on drug aggregate morphology and activity. The formulation change led to the formation of particle aggregates with globular morphology, suggesting the initial dissolution of GSK1795091 in ethanol, instead of initial dissolution using sonication, was the likely contributor to the lowered biological activity of GSK1795091. This could have implications for the development of other lipid A analogs and TLR agonists.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Following manufacturing changes of LPS/other lipid A analogs and chemically manufactured active pharmaceutical ingredients that are prone to structural organization in solution, it is recommended to perform in vitro PD assessments to understand the impact on its biological activity prior to clinical assessment. PK and PD evaluations should be prioritized to ensure no clinically meaningful changes related to the manufacturing occur.