On April 8, 2022 Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage oncology company developing potentially first-in-class therapeutics that combine both targeted and immune-mediated mechanisms, reported the presentation of two poster presentations at the 2022 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting reporting new preclinical data that support the company’s preclinical TREX1 and clinical TPST-1495 programs (Press release, Tempest Therapeutics, APR 8, 2022, View Source [SID1234611671]).
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The first presentation reports on new preclinical data that support TPST-1495, a novel agent designed to specifically block the cancer-promoting EP2 and EP4 prostaglandin E2 (PGE2) receptors, further differentiating TPST-1495 from other approaches targeting the PGE2 pathway. The second presentation reports on proprietary inhibitors of TREX1, a cytosolic DNA exonuclease that inhibits activation of cGAS/STING in tumor and immune cells.
"As part of our diversified pipeline of innovative therapeutics, we reported the first preclinical data from our TREX1 program demonstrating the significant anti-tumor activity of our selective inhibitors. We believe TREX1 is the most promising approach to selectively activate the STING pathway broadly in metastatic disease with systemically administered, small molecule drugs," said Tom Dubensky, Ph.D., president of Tempest. "In addition, we presented preclinical data demonstrating that selective dual antagonism of both EP2 and EP4 prostaglandin receptors with TPST-1495 is a significantly superior approach to provide therapeutic anti-tumor benefit and activate human immune cell populations in vitro, as compared to either single EP2 and EP4 antagonists or NSAIDs. These data support the enthusiasm for our ongoing Phase 1 monotherapy and combination dose escalation and optimization study."
#1333: "Dual Blockade of the EP2 and EP4 PGE2 Receptors with TPST-1495 is an Optimal Approach for Drugging the Prostaglandin Pathway"
In vivo data demonstrated that monotherapy TPST-1495 significantly reduced tumor growth in mice via both T cell-independent and T-cell dependent mechanisms. The anti-tumor effect correlated with direct anti-proliferative effects on tumors in addition to increased tumor infiltration by NK cells, CD8+ T cells, AH1-specific CD8+ T cells, and other anti-tumor myeloid and adaptive immune cell populations. Demonstrating its differentiated potency, therapy with TPST-1495 resulted in a significant survival advantage as compared to therapy with single EP2 or EP4 antagonists, or the NSAID celecoxib, in the APCmin/+ spontaneous colorectal cancer tumor mouse model. Additional data demonstrated that the administration of TPST-1495 resulted in near-complete restoration of immune function in human immune cell assays, reversing prostaglandin-mediated suppression of lipopolysaccharide stimulation-induced TNF-α production, even in the presence of elevated PGE2 concentrations in which single EP4 or EP2 inhibitors were not effective.
#2075: "Systemic Small Molecule TREX1 Inhibitors to Selectively Activate STING in the TME of Metastatic Disease"
The inaugural presentation for the TREX1 program summarized the approach to develop selective TREX1 inhibitor small molecules with picomolar potency. TREX1 inhibitors were profiled in various human and mouse cell-based assays, demonstrating that inhibition of TREX1 nuclease activity resulted in increased cGAS/STING pathway signaling and production of a reporter or interferon β. The anti-tumor activity of TREX1 inhibitors was evaluated in mice given sub-therapeutic doses of doxorubicin to effect double-stranded breaks in tumor cell DNA and induce the production of TREX1, resulting in significant anti-tumor efficacy and survival.
About TPST-1495
TPST-1495 is an orally available small molecule designed to block the cancer-promoting 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 to enhance tumor progression through the stimulation of tumor proliferation, enhanced angiogenesis and suppression of immune function in the tumor microenvironment. 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 monotherapy and combination therapy 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 TREX1
Genetic evidence from human disease and mouse genetic knock-out studies identify the Stimulator of Interferon Genes (STING) pathway as a critical innate immune sensor for the development of immunity. Tumor cells can evolve to avoid immune recognition through inactivating the STING pathway by diverse mechanisms, indicating that it is important to generating tumor-specific immunity. Selective activation of the STING pathway may be achieved through targeted inhibition of TREX1, a cytosolic DNA exonuclease that modulates cGAS/STING signaling, which is overexpressed in tumor cells. Tempest is developing TREX-1 inhibitors with oral pharmacokinetics. In vitro and in vivo studies have shown that the company’s compounds enhance the activation of the STING pathway in DNA-stimulated human and mouse cells. Furthermore, preclinical results in several tumor models have shown synergies of its TREX-1 compounds with low doses of doxorubicin, demonstrating significant therapeutic anti-tumor efficacy and survival.