Entinostat is an oral, small molecule HDAC inhibitor that has direct effects on both cancer cells and immune regulatory cells, potentially enhancing the body’s immune response to cancer. Entinostat has demonstrated synergistic anti-tumor activity in combination with immune checkpoint inhibitors in preclinical studies. We have also demonstrated that the delivery of entinostat in combination with hormone therapy can result in improvements in overall survival in advanced HR+ breast cancer patients.
HDACs are enzymes that are subdivided into four classes and are known to play a role in controlling cell survival, proliferation, angiogenesis and immunity. While most HDAC inhibitors broadly inhibit multiple classes of HDACs, preclinical studies have shown that entinostat’s inhibitory activity is selective to Class 1 HDACs, which have been shown to impact the number and activity of the population of immuno-suppressive cells known as myeloid-derived suppressor cells, or MDSCs, and regulatory T cells, or Tregs. By decreasing the population of MDSCs and Tregs, which localize in the area surrounding the tumor and dampen T cell activity, we believe entinostat acts on a different tumor-evasion mechanism than is targeted by most other immunotherapies in development which instead focus on the interaction between the T cell and the tumor. It is also hypothesized that entinostat’s Class 1 specificity is likely to lead to a better tolerability and combinability profile.
We believe entinostat is the therapy most advanced in development that can directly reduce both the number and activity of MDSCs and Tregs while sparing the cytotoxic T cells. Through this important effect on MDSCs and Tregs, entinostat has the potential to be used synergistically with therapies working to stimulate the immune system. The long half-life of entinostat allows for continuous exposure to therapy potentially resulting in positive immuno-modulatory effects without corresponding cytotoxic effects. Another benefit of entinostat’s long half-life is the potential to minimize the frequency of dosing and reduce the severity and frequency of adverse events. We believe entinostat’s well-characterized safety profile, demonstrated in clinical trials in more than 900 cancer patients, and mechanism of action allows it to be readily combined with, and thereby enhance the activity of, conventional and novel cancer therapies, such as immune checkpoint inhibitors, hormone therapies and chemotherapies.