Entinostat

Entinostat is an investigational, targeted, epigenetic immunomodulator (EMOD), with demonstrated selective inhibitory activity against Class I histone deacetylases (HDACs). Entinostat has exhibited a wide range of anti-tumor activity alone and in combination with other therapies.

In cancer cells, HDAC activity is abnormally elevated, leading to silencing of certain genes important for normal cell growth and activation of other genes that drive cancer cell growth. Based on these effects, HDACs have become attractive targets for cancer therapy.

Recently, it has also been established that inhibition of HDAC2 (a member of the Class I HDAC family) can decrease the population of myeloid derived suppressor cells (MDSCs), a type of cell known to suppress the ability of the body to mount an immune response. In the presence of cancer cells, the population of MDSCs has been shown to expand, leading to suppression of the immune system. For this reason, MDSCs have also become attractive targets for cancer therapy, particularly in combination with immune checkpoint inhibitors.

Due to its ability to selectively target Class I HDACs, the downstream effects Class I HDACs have on MDSCs and immune regulation, as well as the preclinical and clinical activity observed to date, we believe entinostat holds great promise as a cornerstone combination therapy for a broad array of cancers. To date, entinostat has been studied in more than 900 patients with a favorable safety profile. Entinostat is orally bioavailable and has a unique, 140 hour half-life, allowing for continuous coverage with once-weekly dosing.

Entinostat is now entering clinical development to treat non-small cell lung cancer (NSCLC) and melanoma in combination with Merck’s KEYTRUDA® (pembrolizumab), a PD1 checkpoint inhibitor, in a Phase 1b/2 clinical trial (ENCORE 601).

A pivotal Phase 3 clinical study, conducted under a special protocol assessment (SPA), testing the combination of entinostat and exemestane for the treatment of hormone receptor-positive metastatic breast cancer is currently enrolling patients. Entinostat was granted Breakthrough Therapy designation by the U.S. Food and Drug Administration when used in combination with exemestane in HR+ advanced (locally advanced or metastatic) breast cancer based on the progression-free survival (PFS) and overall survival (OS) results observed in ENCORE 301 (a Phase 2 clinical trial in this same patient population). The Phase 3 study in HR+ advanced breast cancer is being conducted by ECOG-ACRIN under the sponsorship of the NCI and support from Syndax

A number of investigator- and NCI-sponsored combination trials studying the effects of adding entinostat to immunomodulators (such as IL2, PD1, CTLA4, HER2, TKIs) are also underway to validate the benefit of these combinations in treating additional types of solid tumors.

Syndax has entered into license agreements with Kyowa Hakko Kirin for the development and commercialization of entinostat in Japan and Korea and Eddingpharm for the development and commercialization of entinostat in China and certain other Asian countries and retains full rights to the drug candidate in all other major markets.