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 cholangiocarcinoma (CCA) 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.

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. TPST-1120 is progressing through a Phase I/Ib study in combination with nivolumab (NCT03829436) and is expected to begin a Phase Ib/II randomized study in 2021 in combination with atezolizumab (TECENTRIQ®) and bevacizumab (Avastin®) in frontline patients with advanced hepatocellular carcinoma (HCC) pursuant to a collaboration with F. Hoffmann-La Roche Ltd.