On January 10, 2023 Hepion Pharmaceuticals, Inc. (NASDAQ:HEPA), a clinical stage biopharmaceutical company focused on Artificial Intelligence ("AI")-driven therapeutic drug development for the treatment of non-alcoholic steatohepatitis ("NASH"), hepatocellular carcinoma ("HCC"), and other chronic liver diseases, reported that its research collaborator, Carlos Perez-Stable, PhD, from the University of Miami Miller School of Medicine and Miami Veterans Affairs/Research, today presented new findings from a preclinical study on the Company’s lead drug candidate, rencofilstat, a potent inhibitor of cyclophilins, in a presentation at the 2023 State of Florida Cancer Symposium in Tampa, Florida (Press release, Hepion Pharmaceuticals, JAN 10, 2023, View Source [SID1234626146]).

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The presentation, entitled "A New Strategy to Increase Proteotoxic Stress in Prostate Cancer," highlighted a preclinical study which investigated the killing of cultured prostate cancer cells by rencofilstat in combination with a proteasome inhibitor, ixazomib. Proteosome inhibitors are a class of anti-cancer agents that are used for the treatment of multiple myeloma and other blood cancers. They kill cancer cells by inducing a process called proteotoxic stress. There has been long-standing interest in expanding the use of proteosome inhibitors for solid tumors, but clinical trials to date have not shown durable anti-tumor efficacy. The present study showed that rencofilstat could synergistically increase the proteotoxic stress and in vitro cancer killing properties of ixazomib. These results suggest that the addition of rencofilstat could expand the use of proteosome inhibitors for existing applications, or possibly for other cancers, such as prostate cancer.

In this preclinical study, rencofilstat and ixazomib were applied at low concentrations to several types of prostate cancer cell lines, and also to non-cancerous prostate cells. Neither drug alone at low concentrations caused proteotoxic stress or killed the cells. However, in combination they induced sustained proteotoxic stress and killed 70% – 90% of the cancer cells (4 different cell lines) over two days. In contrast, the drug combination caused only mild, transient stress and no killing of the non-cancer cells.

"The selective killing of several cancer cell lines by this drug combination without killing the non-cancer cells occurred because cancer cells are especially susceptible to proteotoxic stress due to their aggressive growth and high demand for proteins," said Dr. Perez-Stable. "Certain isoforms of cyclophilins participate in the efficient synthesis and function of proteins and contribute significantly to cancer cell growth. Inhibiting those cyclophilins with rencofilstat and impairing protein turnover with ixazomib together stressed the cells beyond a threshold and triggered their death."

"Dr. Perez-Stable’s findings open up new opportunities, in addition to our Phase 2 trials in NASH, for investigation of potential cancer treatments and therapeutic use of rencofilstat," said Daren Ure, PhD, Hepion’s Chief Scientific Officer. "The findings are similar to those of a previous, independent study in which cyclophilin inhibition in combination with the proteosome inhibitor, carfilzomib, synergistically killed multiple myeloma cells.1 A synergistic anti-cancer effect also has been observed in a liver cancer study in mice with a combination of rencofilstat and a checkpoint inhibitor, anti-PD1 antibody. Thus, evidence is accumulating that rencofilstat could potentiate the anti-cancer activities of multiple agents, through multiple mechanisms, and across a variety of cancer types. This makes us very optimistic that rencofilstat will have tremendous versatility as an anti-cancer agent."

Reference

1Nature Medicine, 2021 27(3):491-503. doi: 10.1038/s41591-021-01232-w