ENSEM Therapeutics, Inc.

– First-in-human trial of ETX–636 to begin in Q2 2025 in patients with tumors harboring an activating PI3K α mutation, including breast cancer – ETX-636 preclinical data to be presented at the AACR annual meeting, showcasing superior potency and selectivity for all mutant forms of PI3K α while sparing wildtype PI3Kα WALTHAM, MA, USA I April 22, 2023 I 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 PI3Kα 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 PI3Kα mutations. Mutant PI3Kα 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 PI3Kα is central to glucose homeostasis, and ATP-binding-site inhibitors target both mutant and wildtype PI3Kα, resulting in hyperglycemia which limits the clinical utility of these therapeutics. “Targeting mutant PI3Kα within tumors while sparing wildtype PI3Kα 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 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. 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 PI3Kα 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 About ETX-636 ETX-636 was designed to optimally fit into a specific allosteric binding site in p110α, the catalytic subunit of PI3Kα. This allosteric binding site has been shown to selectively inhibit multiple activating mutant forms of PI3Kα, including hotspot kinase and helical domain PI3Kα mutants, while sparing wildtype PI3Kα. The selectivity of ETX-636 for mutant PI3Kα greatly reduces the risk for hyperglycemia and other wildtype PI3Kα-related adverse events compared to non-mutant selective PI3Kα inhibitors. In addition to its potent inhibitory effect on mutant PI3Kα catalytic activity, ETX-636 also leads to proteasome-dependent degradation of mutant PI3Kα, 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 PI3Kα-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 . SOURCE: Ensem Therapeutics

WALTHAM, Mass.--( BUSINESS WIRE )--Ensem Therapeutics, Inc. (ENSEM), a pioneering drug discovery and development company that leverages its unique Kinetic Ensemble ® platform to advance innovative small molecule precision medicines for oncology, today announced that Dr. Shengfang Jin, Chief Executive Officer of ENSEM, will present an overview of the company and its pipeline progress at the 43rd Annual J.P. Morgan Healthcare Conference on Thursday, January 16, 2025 at 7:30 a.m. PT/ 10:30 a.m. ET. About ETX-636 ETX-636 is a novel orally bioavailable allosteric pan-mutant-selective inhibitor and degrader of PI3Kα, which has demonstrated a dual mechanism of action, inhibition of mutant PI3Kα enzymatic activity, as well as proteosome-mediated selective degradation of mutant PI3Kα protein. The dual mechanism of action results in deep and durable pathway inhibition and induces concordant tumor regression in kinase and helical domain PI3Kα -mutant breast cancer xenografts. ETX-636 is in IND-enabling studies, with a first-in-human clinical trial anticipated to begin in the first half of 2025. About ETX-197/BG-68501 ETX-197/BG-68501 was designed through ENSEM’s Kinetic Ensemble platform to induce previously unexplored interactions within the CDK2 ATP binding pocket, leading to increased potency and selectivity compared to other CDK2 inhibitors. ETX-197/BG-68501 shows tight binding (slow off-rate) for CDK2 which results in potent and concordant pharmacodynamic modulation and anti-proliferative activity both in vitro and in vivo. BeiGene is currently conducting a first-in-human Phase 1a/1b clinical study ( NCT06257264 ) to assess the safety tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of ETX-197/BG-68501. 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 .

WALTHAM, Mass.--( BUSINESS WIRE )--Ensem Therapeutics, Inc. (ENSEM), a pioneering drug discovery and development company that leverages its unique Kinetic Ensemble® platform to advance innovative small molecule precision medicines for oncology, will report for the first time preclinical data on ETX-197/BG-68501, a potential best-in-class oral, selective CDK2 inhibitor at the 47 th Annual San Antonio Breast Cancer Symposium (“SABCS”) in San Antonio, Texas. ETX-197/BG-68501 has a differentiated preclinical profile and the potential to deliver clinical benefit to patients with tumors associated with CDK2 dependency. CDK2 is a well-established vulnerability of multiple cancers, including tumors with increased expression of Cyclin E (CCNE) or the mutation/loss of the Retinoblastoma 1 gene (RB1). There are currently no approved CDK2 specific drugs. ETX-197/BG-68501 was designed through ENSEM’s Kinetic Ensemble platform to induce previously unexplored interactions within the CDK2 ATP binding pocket, leading to increased potency and selectivity compared to other CDK2 inhibitors. ETX-197/BG-68501 shows tight binding (slow off-rate) for CDK2 which results in potent and concordant pharmacodynamic modulation and anti-proliferative activity both in vitro and in vivo. ETX-197/BG-68501 is 100-fold more selective for CDK2 over other kinases in the CDK family and this superior selectivity extends more broadly against 385 other kinases, indicating the potential for promising tolerability in the clinic. In mouse xenograft studies using a CCNE-amplified ovarian cancer cell line or patient-derived tumors, ETX-197/BG-68501 showed sustained target engagement, dose-dependent tumor growth inhibition with excellent tolerability. ETX-197/BG-68501 demonstrated single agent efficacy in a breast cancer xenograft model that had acquired resistance to a CDK4/CDK6 inhibitor. In addition, ETX-197/BG-68501 showed anti-tumor activity in other in vitro and in vivo tumor models including small cell lung and ovarian cancers, indicating its broad clinical potential beyond breast cancer. “Inhibiting CDK2 potently and selectively over other CDK family members represents a significant challenge,” said Shengfang Jin, CEO and Co-Founder of ENSEM. “The promising preclinical results with ETX-197/BG-68501 underscore the potential of our Kinetic Ensemble® platform to discover small molecules against high value and difficult to drug targets.” She noted that BeiGene is currently conducting a first-in-human Phase 1a/1b clinical study ( NCT06257264 ) to assess the safety tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of ETX-197/BG-68501, and is presenting a “Trial-in-Progress” poster for this ETX-197/BG-68501 clinical study at the Symposium. Poster Details Title: ETX-197/BG-68501, a potential best-in-class potent, selective oral small molecule CDK2 inhibitor, has anti-tumor activity in cancer models with Cyclin E amplification or deficiency in the Retinoblastoma 1 gene Poster ID: P4-12-29 Sessions: Poster Session Date/Time: Thursday, December 12, 2024, from 5:30 to 7 p.m. CT Location: Halls 2-3 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 .