Ensem Therapeutics, Inc., headquartered in Waltham, Massachusetts, has recently received approval from the U.S. Food and Drug Administration (FDA) to proceed with the Investigational New Drug (IND) application for
ETX-636. This compound is an innovative allosteric pan-mutant-selective
PI3Kα inhibitor and degrader, anticipated to enter its first human trial in the second quarter of 2025. Upcoming preclinical data will be shared on April 28 at the American Association for
Cancer Research Annual Meeting in Chicago, underscoring the unique attributes of ETX-636 and its potential benefits for patients with tumors characterized by activating PI3Kα mutations.
Mutations in PI3Kα are a significant driving factor in various cancers, notably affecting up to 40% of hormone receptor-positive (
HR+)/
HER2-negative
advanced breast cancers. Traditional therapies targeting both mutant and wildtype PI3Kα often lead to hyperglycemia, limiting their effectiveness. This condition arises because wildtype PI3Kα is crucial for maintaining glucose balance in the body. The development of ETX-636 specifically targets mutant forms of PI3Kα while sparing the wildtype protein, overcoming this clinical challenge and offering a promising therapeutic option.
Shengfang Jin, Ph.D., CEO and Co-Founder of Ensem Therapeutics, emphasized the importance of FDA clearance for ETX-636, marking a significant advancement for the company. ETX-636 is the company’s second major compound moving into clinical trials, following ETX-197 (developed as BG-68501), an oral selective CDK2 inhibitor currently in Phase 1 trials for solid tumors linked to CDK2 dependency.
Jeffery Kutok, MD, Ph.D., ENSEM's Chief Scientific Officer, highlighted the compound's potential, noting ETX-636's unique differentiation as a potent inhibitor and degrader of mutant PI3Kα. The company is eager to commence clinical trials to explore its therapeutic efficacy. Additionally, ENSEM plans to file INDs for further pipeline programs by 2026.
The first human trial, a Phase 1/2 study, aims to assess ETX-636's safety, tolerability, pharmacokinetics, pharmacodynamics, and initial antitumor activity in participants with advanced solid tumors exhibiting a PI3Kα mutation. The study will examine ETX-636 both as a standalone treatment and in conjunction with fulvestrant, a selective estrogen receptor degrader used in treating advanced HR+/HER2- breast cancer.
ETX-636’s design focuses on an allosteric binding site in the catalytic subunit of PI3Kα, p110α. This site’s targeting selectively inhibits various activating mutant forms, such as hotspot kinase and helical domain PI3Kα mutants, without affecting the wildtype form. This selectivity minimizes the risk of hyperglycemia and other side effects typically associated with non-mutant selective PI3Kα inhibitors. Besides its potent inhibitory action, ETX-636 promotes the degradation of mutant PI3Kα via the proteasome, sparing the wildtype protein. This dual action leads to sustained pathway inhibition and tumor regression, demonstrated in preclinical models of PI3Kα-mutant breast cancer when used alone or with fulvestrant. Toxicology studies in animals indicate that ETX-636 does not disrupt glucose homeostasis at expected therapeutic doses for humans.
Ensem Therapeutics stands at the forefront of drug discovery, employing its proprietary Kinetic Ensemble technology to develop precise small molecule medicines for cancer treatment. By integrating artificial intelligence and advanced computational methods, ENSEM identifies unique binding opportunities, accelerating the design of new drugs tailored to high-value targets.
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