Ensem Therapeutics announced today that the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application for ETX-636, a novel allosteric pan-mutant-selective PI3Kα inhibitor and degrader. The company plans to initiate first-in-human clinical trials in the second quarter of 2025, targeting patients with tumors harboring activating PI3Kα mutations, including breast cancer.
The IND clearance represents a significant milestone for Ensem as it advances its second compound into clinical development. The company 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, 2025.
A Novel Approach to Targeting PI3Kα Mutations
Mutant PI3Kα is a key oncogenic driver across multiple cancer types, particularly in hormone receptor-positive (HR+)/HER2-negative advanced breast cancers, where it appears in up to 40 percent of cases. However, current ATP-binding-site inhibitors target both mutant and wildtype PI3Kα, leading to hyperglycemia that significantly limits their clinical utility.
"Targeting mutant PI3Kα within tumors while sparing wildtype PI3Kα in normal tissues represents a significant clinical challenge, which ETX-636 overcomes," said Shengfang Jin, PhD, CEO and Co-Founder of Ensem Therapeutics. "The IND clearance is an important milestone for the company, and we are laser-focused on driving ETX-636 through clinical development."
ETX-636 was specifically designed to fit into an allosteric binding site in p110α, the catalytic subunit of PI3Kα. This approach enables selective inhibition of multiple activating mutant forms of PI3Kα, including hotspot kinase and helical domain PI3Kα mutants, while sparing wildtype PI3Kα.
Dual Mechanism of Action
What sets ETX-636 apart from other compounds in its class is its dual mechanism of action. Beyond inhibiting mutant PI3Kα catalytic activity, ETX-636 also triggers proteasome-dependent degradation of mutant PI3Kα while sparing wildtype protein—a feature not observed with other pan-mutant allosteric inhibitors.
Jeffery Kutok, MD, PhD, Ensem's Chief Scientific Officer, explained, "ETX-636 is a potent pan mutant-specific allosteric PI3Kα inhibitor and degrader, which differentiates it from other compounds in its class. We are excited to evaluate ETX-636's therapeutic potential in patients in our upcoming clinical trial."
Preclinical studies demonstrate that this dual mechanism results in deep and durable pathway inhibition, inducing tumor regression in kinase and helical domain PI3Kα-mutant breast cancer xenograft models, both as monotherapy and in combination with fulvestrant. Importantly, toxicology studies across multiple species indicate that ETX-636 did not disrupt glucose homeostasis at predicted human efficacious doses.
Upcoming Clinical Trial Design
The initial Phase 1/2 study will evaluate ETX-636's safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity in participants with advanced solid tumors harboring PI3Kα mutations. The trial will assess ETX-636 both as a monotherapy and in combination with fulvestrant, a selective estrogen receptor degrader approved for treating advanced HR+/HER2- breast cancer.
Dr. Jin noted that ETX-636 is the second novel compound from Ensem to enter clinical development. The company's first clinical candidate, ETX-197, an oral selective CDK2 inhibitor licensed to BeOne and being developed as BG-68501, is currently in Phase 1 clinical trials for advanced or metastatic solid tumors associated with CDK2 dependency.
Expanding Pipeline
Ensem Therapeutics is building a robust pipeline of precision oncology therapeutics, with additional IND applications anticipated in 2026. The company leverages its proprietary Kinetic Ensemble® platform, which integrates AI deep learning with advanced computational and experimental methodologies to identify non-obvious binding pockets and accelerate structure-based drug design.
The upcoming poster presentation at AACR (Poster ID: 1659) will provide further details on ETX-636's mechanism of action and preclinical efficacy data. The presentation is scheduled for Monday, April 28, 2025, from 9am-12pm CT at Poster session 18, Board 19, under the Experimental and Molecular Therapeutics – Degraders and Glues 2 session.
For oncologists and researchers focused on targeted therapies for PI3Kα-mutated cancers, ETX-636 represents a potentially significant advance that could overcome the limitations of existing treatments while providing meaningful clinical benefit to patients with limited therapeutic options.
