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Ensem Therapeutics, Inc, a pioneering drug discovery and development company to leverage its unique kinetic ensemble platform to advance innovative small molecule precision medicines for oncology, announced 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 PI3Ka inhibitor and degrader.
“Dosing the initial patient in our first-in-human study of ETX-636 represents a critical milestone,” said Ron Peck, chief medical officer of Ensem Therapeutics. “Mutant PI3Ka is a key and frequent oncogenic driver across a broad spectrum of cancers, including up to 40 per cent of hormone receptor-positive (HR+)/HER2-negative advanced breast cancers. While the first generation PI3Ka inhibitors validate PI3Ka as a therapeutic target in patients, the toxicities associated with inhibiting non-mutant PI3Ka underscore the importance of developing better therapies. ETX-636 inhibits and degrades mutant PI3Ka within tumors through a novel allosteric approach and spares wildtype PI3Ka in normal tissues, affording a potentially superior tolerability profile while exerting a robust anti-tumor effect."
ETX–636 is being evaluated in patients with tumors harboring an activating PI3Ka mutation, including breast cancer. ETX-636 advanced to the clinic following preclinical observations showcasing superior potency and selectivity for all mutant forms of PI3Ka while sparing wildtype PI3Ka.
Shengfang Jin, CEO of Ensem, added, “Ensem Therapeutics 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 Therapeutics oral inhibitor to enter the clinic. Ensem also eagerly anticipates INDs for additional pipeline programmes 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 PI3Ka mutation. The first patient was dosed at START San Antonio (Amita Patnaik), under an IND cleared by the US 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.
ETX-636 was designed to optimally fit into a specific allosteric binding site in p110a, the catalytic subunit of PI3Ka. This allosteric binding site has been shown to selectively inhibit all activating mutant forms of PI3Ka, including hotspot kinase and helical domain PI3Ka mutants, while sparing wildtype PI3Ka. The high selectivity of ETX-636 for mutant PI3Ka greatly reduces the risk for hyperglycemia and other wildtype PI3Ka-related adverse events compared to non-mutant selective PI3Ka inhibitors. In addition to its potent inhibitory effect on mutant PI3Ka catalytic activity, ETX-636 also leads to proteasome-dependent degradation of mutant PI3Ka, 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 PI3Ka-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.
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