On October 1, 2025 Ensem Therapeutics, Inc. (ENSEM) reported the U.S. Food and Drug Administration (FDA) granted Fast Track designation to its clinical stage pan mutant-specific allosteric PI3Kα inhibitor and degrader, ETX-636, for the treatment of adult patients with PIK3CA-mutant, hormone receptor positive (HR+)/human epidermal growth factor negative (HER2-) advanced breast cancer (Press release, ENSEM Therapeutics, OCT 1, 2025, View Source [SID1234656387]).
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ETX-636 was designed using ENSEM’s unique Kinetic Ensemble platform to optimally fit into a specific allosteric binding site in p110α, the catalytic subunit of PI3Kα and can selectively inhibit multiple activating mutant forms of PI3Kα, while sparing wildtype PI3Kα. The selectivity of ETX-636 for mutant PI3Kα greatly reduces the risk for hyperglycemia and other wildtype PI3Kα-related adverse events compared to non-mutant selective PI3Kα inhibitors. In addition, ETX-636 also leads to proteasome-dependent degradation of mutant PI3Kα, while sparing wildtype protein (a feature not seen with other pan-mutant allosteric inhibitors).
Activating mutations or alterations of the PI3Kα pathway are known to promote cancer cell growth and survival in a variety of tumor types, including breast cancer. In HR+/HER2- breast cancer (approximately 70% of all breast cancers), PIK3CA mutations are particularly prevalent, occurring in up to 40% of the cases.
"Patients with advanced HR+/HER2- breast cancer harboring PIK3CA mutations have poor prognosis, and there is an unmet need for therapies targeting this population that are safer and more efficacious than the current FDA approved non-mutant selective treatments," said Dr. Shengfang Jin, CEO and Co-Founder of ENSEM. "We are appreciative that the FDA has recognized ETX-636 as a potentially important treatment for this indication and we remain laser-focused on demonstrating its benefit to patients in our current clinical trials."
ETX-636 is currently being studied in an initial first-in-human, Phase 1/2 study which is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of ETX-636 in participants with advanced solid tumors harboring a PIK3CA mutation. ETX-636 will be administered alone or in combination with fulvestrant, a selective estrogen receptor degrader approved for the treatment of advanced hormone receptor HR+/HER2- breast cancer NCT06993844.
Fast Track designation is a program provided by the FDA to expedite the development and review of drugs and biologics that treat serious conditions with unmet medical needs. It provides the opportunity for frequent and early communication and collaboration with the FDA, as well as the potential for accelerated approval and priority review eligibility to allow faster access to promising treatment to patients.