PPARα Antagonism
Peroxisome proliferator-activated receptor alpha (PPARα) is a transcription factor that regulates fatty acid oxidation (FAO) and inflammation and is expressed by many cancers, including hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) to a significant degree. PPARα is in a known, druggable pathway; fenobibrates, are PPARα agonists, and have been prescribed to treat dyslipidemia for decades. TPST-1120 is a PPARα antagonist that has a dual mechanism of action to kill tumors, cells, both by targeting cancer cells dependent upon the FAO metabolic pathway directly and harnessing a patient’s immune system.
Tempest and our research partners have demonstrated that blocking PPARα with TPST-1120 directly kills primary tumor cells and tumor cell lines in vitro. TPST-1120 induces tumor-specific immunity and promotes a more inflamed tumor microenvironment (TME) through inhibiting immunosuppressive cell populations including M2 macrophages, myeloid suppressor cells and regulatory T cells, which all utilize FAO. Mechanistically, TPST-1120 is a competitive antagonist of PPARα and can block both endogenous and synthetic agonist induced transactivation. Novel co-crystal structures have confirmed TPST-1120 interacts in the active site of PPARα and locks the activation helix (AF-2) in an inactive confirmation.
Durable Responses in Combination with α-PD-1
Source: Dipak Panigrahy, Havard
Tempest is advancing TPST-1120, a first-in-class antagonist targeting PPARα. PPARα is a transcription factor which is over-expressed in many cancers and regulates the expression of about 100 genes, including those that enable fatty acid oxidation (FAO) and inflammation. TPST-1120 therapy shifts the metabolic balance in the TME towards glycolysis and favors the metabolic requirements of effector immune cell populations, including M1 tumor associated macrophages (TAMs) and effector T Cells (Teff), stimulating the development of tumor-specific immunity. After presenting Phase 1 data in an oral presentation at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Tempest released positive data from a global randomized Phase 1b/2 study of TPST-1120 in combination with atezolizumab (TECENTRIQ®) and bevacizumab (Avastin®) in first-line patients with advanced hepatocellular carcinoma (HCC) pursuant to a collaboration with F. Hoffmann-La Roche Ltd. The positive data showed clinical superiority of TPST-1120 in multiple study endpoints when combined with atezolizumab and bevacizumab, the standard of care in first-line HCC, when compared to standard of care alone. Tempest plans to advance TPST-1120 into a pivotal study in first-line HCC patients, as well as explore development beyond HCC given the signals observed in the Phase 1 study.