On July 1, 2025 Ensem Therapeutics, Inc. (ENSEM), a clinical stage, oncology-focused biopharmaceutical company, reported the first patient has been dosed in its phase 1/2 study of ETX-636, a potential best-in-class novel allosteric pan-mutant-selective PI3Kα inhibitor and degrader (Press release, ENSEM Therapeutics, JUL 1, 2025, View Source [SID1234654204]).
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"Dosing the initial patient in our first-in-human study of ETX-636 represents a critical milestone," said Ron Peck, M.D., Chief Medical Officer of ENSEM. "Mutant PI3Kα is a key and frequent oncogenic driver across a broad spectrum of cancers, including up to 40 percent of hormone receptor-positive (HR+) /HER2-negative advanced breast cancers. While the first generation PI3Kα inhibitors validate PI3Kα as a therapeutic target in patients, the toxicities associated with inhibiting non-mutant PI3Kα underscore the importance of developing better therapies. ETX-636 inhibits and degrades mutant PI3Kα within tumors through a novel allosteric approach and spares wildtype PI3Kα in normal tissues, affording a potentially superior tolerability profile while exerting a robust anti-tumor effect."
Shengfang Jin, Ph.D., Chief Executive Officer of ENSEM, added, "ENSEM is dedicated to bringing novel precision oncology therapies to patients. We are excited to demonstrate ETX-636’s clinical potential, building on its superior and differentiated preclinical profile compared to other compounds in its class. Dosing this first patient marks the second novel ENSEM oral inhibitor to enter the clinic. ENSEM also eagerly anticipates INDs for additional pipeline programs in 2026."
This first-in-human, Phase 1/2 study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of ETX-636 in participants with advanced solid tumors harboring a PI3Kα mutation (NCT06993844). The first patient was dosed at START San Antonio (Amita Patnaik, M.D.), under an IND cleared by the FDA in April 2025. ETX-636 will be administered alone and in combination with fulvestrant, a selective estrogen receptor degrader approved for the treatment of advanced hormone receptor HR+/HER2- breast cancer.
About ETX-636
ETX-636 was designed to optimally fit into a specific allosteric binding site in p110α, the catalytic subunit of PI3Kα. This allosteric binding site has been shown to selectively inhibit all activating mutant forms of PI3Kα, including hotspot kinase and helical domain PI3Kα mutants, while sparing wildtype PI3Kα. The high 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 to its potent inhibitory effect on mutant PI3Kα catalytic activity, 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). This dual mechanism of action results in deep and durable pathway inhibition and induces concordant tumor regression in kinase and helical domain PI3Kα-mutant breast cancer xenograft models as monotherapy and in combination with fulvestrant with or without a CDK4/6 inhibitor. In preclinical toxicology studies, ETX-636 did not disrupt glucose homeostasis at predicted human efficacious doses.