FDA Grants Breakthrough Therapy Status to Entinostat for Advanced Breast Cancer

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Syndax Pharmaceuticals Inc announced that the U.S. Food and Drug Administration (FDA) has designated entinostat as a Breakthrough Therapy for the treatment of locally recurrent or metastatic estrogen receptor (ER)-positive breast cancer when added to exemestane in postmenopausal women whose disease has progressed following nonsteroidal aromatase inhibitor therapy. Entinostat is an investigational histone deacetylase (HDAC) inhibitor set to begin phase III testing in combination with exemestane in postmenopausal women with metastatic ER-positive breast cancer whose disease has progressed on hormonal therapy.

Clinical Trials

The Breakthrough Therapy designation for entinostat is based on data from the completed phase II ENCORE 301 study, in which entinostat was shown to extend both progression-free survival and overall survival when added to exemestane in postmenopausal women with ER-positive metastatic breast cancer whose cancer had progressed after treatment with a nonsteroidal aromatase inhibitor and with a very acceptable tolerability profile. A phase III trial, planned to begin enrolling patients in the first quarter of 2014, is currently being developed by the ECOG-ACRIN Cancer Research Group, which would conduct the study under the sponsorship of the National Cancer Institute’s Division of Cancer Treatment and Diagnosis.

“The FDA’s decision to designate entinostat a Breakthrough Therapy is important validation of the drug’s therapeutic potential in women with advanced breast cancer,” said Arlene M. Morris, Syndax’s Chief Executive Officer. “Currently, women with ER-positive breast cancer [that has] progressed on hormonal therapy have limited therapeutic options. Entinostat’s epigenetic mechanism may reverse resistance to hormonal therapy, delaying the need for toxic chemotherapeutic agents and improving survival when given in combination with aromatase inhibitors. This breakthrough designation will allow us to more rapidly bring this new treatment option to patients who may benefit from its availability.”

The FDA Safety and Innovation Act, signed in July 2012, created the Breakthrough Therapy Designation. According to the FDA, the designation allows the expedited development and review of a drug to treat a serious or life threatening disease or condition intended alone or in combination with one or more other drugs for which preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

About Entinostat

Entinostat has been studied in more than 800 cancer patients where objective tumor responses have been observed in both solid and hematologic malignancies. The drug’s established safety and efficacy profile as both a single agent and in combination with a number of commercially available targeted therapies differentiates it from other HDAC inhibitors.

Having demonstrated promising clinical results in breast and lung cancer, entinostat is moving toward pivotal clinical testing. It is an oral, novel inhibitor of class I histone deacetylases, key enzymes that alter the structure of chromatin to control gene expression.

Designed to selectively target the HDAC isoforms most relevant to the biology of tumors, entinostat can normalize dysregulated gene expression in cancer cells, thereby restoring sensitivity to targeted therapy. Entinostat is the first HDAC inhibitor with positive results in a randomized phase II study in breast cancer and is the only HDAC inhibitor in late-stage development for this indication. ■