[April 22, 2025]

Ensem Therapeutics Announces U.S. FDA IND Clearance to Initiate Clinical Development of ETX-636

Ensem Therapeutics, Inc. (ENSEM) today announced the clearance of its Investigational New Drug (IND) application by the U.S. Food and Drug Administration (FDA) for ETX-636, a potential best-in-class novel allosteric pan-mutant-selective PI3Ka inhibitor and degrader, with its first-in-human study anticipated in the second quarter of 2025. In addition, ENSEM will present preclinical data on April 28^th at the American Association for Cancer Research ("AACR") Annual Meeting in Chicago, Illinois, supporting a differentiated profile of ETX-636 and its potential to deliver clinical benefit to patients with tumors harboring activating PI3Ka mutations.

Mutant PI3Ka 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. However, wildtype PI3Ka is central to glucose homeostasis, and ATP-binding-site inhibitors target both mutant and wildtype PI3Ka, resulting in hyperglycemia which limits the clinical utility of these therapeutics.

"Targeting mutant PI3Ka within tumors while sparing wildtype PI3Ka in normal tissues represents a significant clinical challenge, which ETX-636 overcomes. The IND clearance is an important milestone for the company, and we are laser-focused on driving ETX-636 through clinical development," said Shengfang Jin, PhD, CEO and Co-Founder of ENSEM.

Dr. Jin noted that ETX-636 is the second novel ENSEM compound entering clinical development. ETX-197, an oral selective CDK2 inhibitor licensed to BeOne and being developed as BG-68501, is currently undergoing Phase 1 clinical development in advanced or metastatic solid tumors associated with CDK2 dependency.

Jeffery Kutok, MD, PhD, ENSEM's Chief Scientific Officer, added, "ETX-636 is a potent pan mutant-specific allosteric PI3Ka inhibitor and degrader, which differentiates it from other compouns in its class. We are excited to evaluate ETX-636's therapeutic potential in patients in our upcoming clinical trial. ENSEM also eagerly anticipates INDs for additional pipeline programs in 2026."

The initial 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. 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.

Poster Details

• Title: ETX-636, a novel allosteric pan-mutant-selective PI3Ka dual inhibitor and degrader with best-in-class potential
• Poster ID: 1659
• Sessions: Experimental and Molecular Therapeutics - Degraders and Glues 2
• Date/Time: Monday, April 28, 2025, from 9am-12pm CT
• Location: Poster session 18, Board 19

About ETX-636
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 multiple activating mutant forms of PI3Ka, including hotspot kinase and helical domain PI3Ka mutants, while sparing wildtype PI3Ka. The 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. In preclinical toxicology studies, blood glucose levels after dosing in multiple species indicate that ETX-636 did not disrupt glucose homeostasis at predicted human efficacious doses.

About Ensem Therapeutics
ENSEM is a pioneering drug discovery and development company that leverages its unique Kinetic Ensemble^® platform to advance innovative small molecule precision medicines for oncology. ENSEM integrates AI deep learning and advanced computational and cutting-edge experimental methodologies to identify non-obvious binding pockets and accelerate structure-based drug design, with a focus on high-value and difficult-to-drug targets.

For more information, please visit www.ensemtx.com, or engage with us on LinkedIn.

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