On April 17, 2023 Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage oncology company developing first-in-class1 therapeutics that combine both targeted and immune-mediated mechanisms, reported that new data from its TPST-1120 and TREX1 programs were highlighted in two poster presentations at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting taking place April 14-19, 2023 in Orlando, FL (Press release, Tempest Therapeutics, APR 17, 2023, View Source [SID1234630177]).
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The presentation for TPST-1120, a clinical-stage oral selective PPAR⍺ antagonist, highlighted new translational biomarker findings from the completed monotherapy and nivolumab combination therapy dose escalation Phase 1 trial showing on-target changes in gene signatures in the peripheral blood that were dependent upon drug exposure levels. In addition, distinct on-target changes in both lipid profile and NF-κB pathway regulated immune response gene signatures were observed in patients who achieved a RECIST response, compared with non-responders, following treatment with TPST-1120 and nivolumab.
The presentation for Tempest’s preclinical TREX1 inhibitor program, designed for tumor-selective activation of the STING pathway, is the first public demonstration of human TREX1 enzyme—TREX1 inhibitor X-ray co-crystal structures, which has facilitated the development of potent and specific TREX1 inhibitors with drug-like properties. Lead series molecules resulting from this activity demonstrated therapeutic benefit in tumor-bearing preclinical models.
"We are very excited to report these significant advances in the TPST-1120 and TREX1 programs," said Tom Dubensky, Ph.D., president of Tempest. "We look forward to the further clinical development of TPST-1120, potentially in multiple oncology indications, and are working to develop a TREX1 inhibitor to begin human clinical trials with this differentiated approach designed to selectively activate the STING pathway broadly in advanced metastatic disease."
About TPST-1120
TPST-1120 is an oral, small molecule, selective PPAR⍺ antagonist. Tempest’s preclinical data suggest that TPST-1120 can kill tumor cells directly and target suppressive immune pathways in the tumor microenvironment. Both types of targeted cells can be dependent on fatty acid metabolism, which is regulated by the PPAR⍺ transcription factor. In extensive non-clinical studies, TPST-1120 as a monotherapy or in combination with other anti-cancer drugs resulted in significant reductions in tumor growth and stimulation of durable anti-tumor immunity. In a Phase 1 clinical trial in patients with heavily-pretreated advanced solid tumors, TPST-1120 as monotherapy and in combination with the PD-1 inhibitor, nivolumab, demonstrated tumor reduction (including according to RECIST criteria), as well as biomarker modulation. TPST-1120 was well-tolerated both as a monotherapy and in combination with nivolumab. In addition, enrollment has completed in a Phase 1b/2 clinical trail conducted with F. Hoffman La-Roche, evaluating TPST-1120 + atezolizumab + bevacizumab in a randomized head-to-head comparison to atezolizumab + bevacizumab in the first line treatment of patients with unresectable or metastatic HCC. Initial results from this randomized study are expected in the first half of 2023.
About TREX1
TREX1 is a cytoplasmic DNA exonuclease that is upregulated in tumor cells in response to tumor growth, genomic instability and therapeutic intervention. TREX1 is both a negative regulator of the cGAS/STING signaling pathway and a DNA repair enzyme. Orally available TREX1 inhibitors are expected to both selectively inhibit tumor growth and induce tumor-specific immunity broadly against advanced metastatic disease. Tempest has shown proof of concept in animal models with this approach and is currently advancing a small molecule series through lead optimization.