WALTHAM, Mass. — Ensem Therapeutics announced it has received clearance from the U.S. Food and Drug Administration (FDA) to initiate clinical development of ETX-636, a novel allosteric pan-mutant-selective PI3Kα inhibitor and degrader. The company plans to launch its first-in-human trial in the second quarter of 2025, focusing on patients with advanced solid tumors carrying activating PI3Kα mutations, including breast cancer.
ETX-636 is designed to offer superior potency and selectivity across all mutant forms of PI3Kα while sparing the wildtype PI3Kα, a key feature that sets it apart from traditional ATP-binding-site inhibitors. This approach aims to mitigate common side effects such as hyperglycemia, which typically limit the utility of other PI3Kα-targeting therapies. Mutations in PI3Kα are a significant oncogenic driver across multiple cancers, present in up to 40 percent of hormone receptor-positive (HR+)/HER2-negative advanced breast cancers.
“Targeting mutant PI3Kα without impacting the wildtype form in normal tissues has been a major clinical hurdle,” said Shengfang Jin, PhD, CEO and co-founder of Ensem. “ETX-636 overcomes this challenge, and the FDA’s IND clearance marks a pivotal milestone for us. We remain focused on advancing ETX-636 through clinical development to bring this potential best-in-class therapy to patients.”
This will be Ensem’s second compound to enter clinical trials, following ETX-197, a selective CDK2 inhibitor now in Phase 1 development for advanced solid tumors through a licensing agreement with BeOne, where it is being developed as BG-68501.
Jeffery Kutok, MD, PhD, Chief Scientific Officer at Ensem, emphasized the differentiating aspects of ETX-636. “As a potent, pan-mutant-specific allosteric PI3Kα inhibitor and degrader, ETX-636 stands out from others in this therapeutic class. We look forward to assessing its therapeutic potential in patients through our upcoming clinical trial, and we expect to advance additional programs into clinical development in 2026.”
The upcoming Phase 1/2 clinical trial will evaluate ETX-636 as a monotherapy and in combination with fulvestrant, an approved estrogen receptor degrader commonly used in treating HR+/HER2- breast cancer. The trial will assess safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity in patients with advanced solid tumors harboring PI3Kα mutations.
Ensem will also present preclinical data supporting ETX-636’s differentiated profile at the American Association for Cancer Research (AACR) Annual Meeting in Chicago on April 28. The data showcase the compound’s superior potency and selectivity for mutant PI3Kα while sparing the wildtype form, reinforcing its clinical potential.
