The Premise

Our premise is that epigenetic modification of the tumor phenotype unleashes suppressed signaling pathways that restore sensitivity to targeted therapies. We believe this phenotypic modification can be achieved without adding significant toxicity to existing treatments. This is an essential component of our vision. Without a balance of potency and tolerability, new regimens—particularly those given on an outpatient basis—are not accepted by patients and are not commercially viable.

Histone deacetylase (HDAC) inhibitors are excellent candidates to test the therapeutic potential of tumor phenotype modification. Based on a robust preclinical platform and clinical studies in over 250 patients, we believe that entinostat (SNDX-275) is a highly promising oral HDAC inhibitor.

entinostat (SNDX-275) is highly selective for class I HDACs 1, 2, and 3—key HDACs that play a role in cancer—and has synergistic anti-tumor activity when given with targeted therapies like epidermal growth factor receptor (EGFR) inhibitors, aromatase inhibitors, or antiestrogens. The isoform selectivity of entinostat (SNDX-275) towards HDACs 1, 2, and 3 may translate into differentiated safety and efficacy profiles compared with non-selective pan-HDAC inhibitors. In addition, entinostat (SNDX-275) has a long half-life (~100 hrs) and can be dosed on a highly convenient once weekly schedule.

The result is a potentially market-changing combination of features with broad application:

• Extended or restored sensitivity to targeted agents such as EGFR inhibitors, aromatase inhibitors, or antiestrogens
• Combination therapy that is highly convenient
• All-oral combinations
• Infrequent dosing of entinostat (SNDX-275)
• Outpatient therapy

This vision is only possible if the combination of entinostat (SNDX-275) and targeted therapies can be achieved without a substantial increase in toxicity. entinostat (SNDX-275) has already been evaluated in over 250 patients across a variety of tumor types alone and in combination with other agents. Substantial safety data on entinostat (SNDX-275) has been and will be collected, and we believe future clinical studies will demonstrate a highly favorable therapeutic index of entinostat (SNDX-275) in combination with targeted therapies.