Manufacturing‐dependent change in biological activity of the TLR4 agonist GSK1795091 and implications for lipid A analog development
Abstract 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 t...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-11-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13387 |
| _version_ | 1811230769744445440 |
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| author | Neeltje Steeghs Aaron R. Hansen Glenn J. Hanna Elena Garralda Haeseong Park James Strauss Michael Adam Gossett Campbell Jennifer Carver Rachael Easton Katherine Mays Peter Skrdla Herbert Struemper Michael L. Washburn Christopher Matheny Sarina A. Piha‐Paul |
| author_facet | Neeltje Steeghs Aaron R. Hansen Glenn J. Hanna Elena Garralda Haeseong Park James Strauss Michael Adam Gossett Campbell Jennifer Carver Rachael Easton Katherine Mays Peter Skrdla Herbert Struemper Michael L. Washburn Christopher Matheny Sarina A. Piha‐Paul |
| author_sort | Neeltje Steeghs |
| collection | DOAJ |
| description | Abstract 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. 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. |
| first_indexed | 2024-04-12T10:33:32Z |
| format | Article |
| id | doaj.art-49c13d90d7e24ea0911654cd99a602a9 |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-04-12T10:33:32Z |
| publishDate | 2022-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-49c13d90d7e24ea0911654cd99a602a92022-12-22T03:36:46ZengWileyClinical and Translational Science1752-80541752-80622022-11-0115112625263910.1111/cts.13387Manufacturing‐dependent change in biological activity of the TLR4 agonist GSK1795091 and implications for lipid A analog developmentNeeltje Steeghs0Aaron R. Hansen1Glenn J. Hanna2Elena Garralda3Haeseong Park4James Strauss5Michael Adam6Gossett Campbell7Jennifer Carver8Rachael Easton9Katherine Mays10Peter Skrdla11Herbert Struemper12Michael L. Washburn13Christopher Matheny14Sarina A. Piha‐Paul15Netherlands Cancer Institute Amsterdam The NetherlandsPrincess Margaret Cancer Centre Toronto Ontario CanadaNorthwest Medical Specialists Tacoma Washington State USAVall d'Hebron Institute of Oncology (VHIO) Hospital Universitari Vall d'Hebron Barcelona SpainWashington University St Louis Missouri USAMary Crowley Cancer Research Center Dallas Texas USAGlaxoSmithKline Collegeville Pennsylvania USAGlaxoSmithKline Collegeville Pennsylvania USAGlaxoSmithKline Collegeville Pennsylvania USAGlaxoSmithKline Collegeville Pennsylvania USAGlaxoSmithKline Collegeville Pennsylvania USAGlaxoSmithKline Collegeville Pennsylvania USAGlaxoSmithKline Durham North Carolina USAGlaxoSmithKline Collegeville Pennsylvania USAGlaxoSmithKline Collegeville Pennsylvania USAUniversity of Texas MD Anderson Cancer Center Houston Texas USAAbstract 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. 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.https://doi.org/10.1111/cts.13387 |
| spellingShingle | Neeltje Steeghs Aaron R. Hansen Glenn J. Hanna Elena Garralda Haeseong Park James Strauss Michael Adam Gossett Campbell Jennifer Carver Rachael Easton Katherine Mays Peter Skrdla Herbert Struemper Michael L. Washburn Christopher Matheny Sarina A. Piha‐Paul Manufacturing‐dependent change in biological activity of the TLR4 agonist GSK1795091 and implications for lipid A analog development Clinical and Translational Science |
| title | Manufacturing‐dependent change in biological activity of the TLR4 agonist GSK1795091 and implications for lipid A analog development |
| title_full | Manufacturing‐dependent change in biological activity of the TLR4 agonist GSK1795091 and implications for lipid A analog development |
| title_fullStr | Manufacturing‐dependent change in biological activity of the TLR4 agonist GSK1795091 and implications for lipid A analog development |
| title_full_unstemmed | Manufacturing‐dependent change in biological activity of the TLR4 agonist GSK1795091 and implications for lipid A analog development |
| title_short | Manufacturing‐dependent change in biological activity of the TLR4 agonist GSK1795091 and implications for lipid A analog development |
| title_sort | manufacturing dependent change in biological activity of the tlr4 agonist gsk1795091 and implications for lipid a analog development |
| url | https://doi.org/10.1111/cts.13387 |
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