'We're happy to present these data that build upon existing significant preclinical support for the hypothesis that selectively targeting the EP2 and EP4 receptors together, to the exclusion of EP1 and EP3, is the preferred approach to modulate the prostaglandin pathway for clinical benefit in cancer,' said
Presentation Highlights
TPST-1495 therapy promotes anti-tumor activity through both T cell-independent and T-cell dependent mechanisms, as evidenced by TME infiltration of effector immune cell populations and tumor antigen-specific CD8+ T cells
TPST-1495 therapy confers a significant survival advantage compared to therapy with single EP2 or EP4 antagonists, or the NSAID Celecoxib, in the APCmin/+ spontaneous tumor mouse model of CRC
TPST-1495 confers near complete restoration of immune function including activation of human antigen-specific CD8+ T cells in vitro, even in the presence of elevated PGE2 concentrations at which single EP4 or EP2 inhibitors are not effective
A summary of the near-term clinical development strategy that focuses on patients with histologies known to be prostaglandin-driven, as well as patients with the PIK3CA mutation, a potential biomarker.
Presentation Information
About the PGE2 Pathway and TPST-1495
Elevated expression of COX-2 and overproduction of PGE2 is correlated with progression of diverse malignancies by stimulating tumor cell proliferation via autocrine signaling through the EP2 and EP4 PGE2 receptors, which facilitates survival, evasion and metastasis. PGE2 also suppresses anti-tumor immunity by inhibiting the function of critical anti-tumor immune effector cell populations such as dendritic cells, macrophages, NK cells, and T cells. Recent studies have shown that increased expression of COX-2 and production of PGE2 may play a role in the effectiveness of immune checkpoint inhibitor ('ICI') therapy and in the development of adaptive immune resistance to ICI therapy.
TPST-1495 is an orally available small molecule designed to block the EP2 and EP4 receptors in the prostaglandin (PGE2) pathway, while sparing the homologous but differentially active EP1 and EP3 receptors. PGE2 signaling through EP2 and EP4 has been observed both to enhance tumor progression and promote immune suppression. Tempest has conducted head-to-head preclinical studies comparing TPST-1495 to single antagonists of EP2 and EP4 and observed significantly enhanced activity of TPST-1495 in both overcoming PGE2-mediated suppression of human immune cells in vitro, as well as significantly increased anti-tumor activity in mouse models of human colorectal cancer. Tempest is currently evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and possible anti-tumor activity of TPST-1495 in a multicenter Phase 1a/1b dose and schedule optimization study in subjects with advanced solid tumors, with the potential to expand in indications known to be prostaglandin-driven, including colorectal cancer, or CRC, and in a tumor indication-agnostic, biomarker-selected cohort.
About Tempest Therapeutics
Tempest Therapeutics is a clinical-stage oncology company advancing small molecules that combine both targeted and immune-mediated mechanisms with the potential to treat a wide range of tumors. The company's two novel clinical programs are TPST-1495 and TPST-1120, antagonists of EP2/EP4 and PPAR, respectively. Both TPST-1495 and TPST-1120 are advancing through Phase 1 studies designed to study both agents as monotherapies and in combination with other approved agents. In collaboration with
Forward-Looking Statements
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Aljanae Reynolds
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