On November 10, 2022 Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage oncology company focused on developing first-in-class therapeutics that combine both targeted and immune-mediated mechanisms, reported the presentation of data on TPST-1120, an oral selective peroxisome-proliferator activated receptor-alpha (PPAR-α) antagonist, and TPST-1495, a dual antagonist of both EP2 and EP4 prostaglandin (PGE2) receptors, at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 37th Annual Meeting taking place November 10-12, 2022 in Boston, MA (Press release, Tempest Therapeutics, NOV 10, 2022, View Source [SID1234623683]).

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The biomarker results presented from the TPST-1120 Phase 1 clinical study demonstrate pharmacodynamic changes in circulating blood in patients who received clinical benefit from therapy that are consistent with blocking the activity of PPAR-α. In addition, data presented from TPST-1495 showed that its dual antagonism of EP2 and EP4 generated significantly greater immune activation in human immune cells and anticancer activity in mouse tumor models than single inhibitors of either receptor, or the COX-2 inhibitor, celecoxib.

"As we advance the Tempest pipeline, we continue to generate results that validate and differentiate the novel approaches of our product candidates," said Tom Dubensky, Ph.D., president of Tempest. "For patients who responded to treatment with TPST-1120 in our Phase 1 study, we have identified potential biomarkers in the peripheral blood of immune activation and alleviation of immune suppression. These discoveries may enable us to identify patient populations in future clinical studies that are most likely to benefit from treatment with TPST-1120."

TPST-1120: "Pharmacodynamic and Predictive Biomarkers Associated with Response in Cancer Patients Treated with TPST-1120: a First-in-class, Small Molecule Antagonist of Peroxisome-Proliferator Activated Receptor-Alpha"

In a late-breaking poster presentation, data from a Phase 1 trial with monotherapy and nivolumab combination arms were used to assess gene expression changes in post-treatment whole blood from 30 patients and to perform baseline mutational analysis on ctDNA to identify potential biomarkers. The data showed that seven genes were modulated by TPST-1120 exposure (p<0.05), including genes associated with enhanced immune responsiveness (CXCL16, TNFRSF1A), stimulation of monocytes or macrophages (ITGAX, FCGR2A) and PPAR-α blockade (NCF4). The results were consistent across monotherapy and combination arms. Patients in the combination arm who had a partial response (PR) to treatment had significant elevations (p<0.05) in multiple genes, including those associated with Th17 development (RORC), lipid transport (APOE) and down-regulation of CD155, a TIGIT ligand. Mutational analysis revealed that patients with a PR or stable disease were more likely to bear mutations in isocitrate dehydrogenase (IDH) and phosphatase and tensin homolog (PTEN) compared to patients with progressive disease.

TPST-1495: "Dual Blockade of the EP2 and EP4 PGE2 Receptors with TPST-1495 is an Optimal Approach for Drugging the Prostaglandin Pathway"

In a second presentation, the data demonstrated that TPST-1495 was more effective than EP2 and EP4 single antagonists, and the COX-2 antagonist, celecoxib, in mouse and human whole blood assays. TPST-1495 conferred a near complete restoration of immune function in cellular assays, even in the presence of high PGE2 concentrations. In lung carcinoma tumors and in a spontaneous tumor mouse model of CRC, TPST-1495 decreased tumor size and number of tumors. Immunohistochemistry analysis of the resected small intestine tumors revealed increased immune infiltrate and an enhanced adaptive immune transcriptional profile.