CHD1L

MARTINSRIED, Germany I September 16, 2024 I Eisbach Bio GmbH (“Eisbach” or the “Company”), a privately-held clinical-stage biotechnology company pioneering cancer medicines leveraging synthetic lethality, today announced that the first patient has been dosed in Module 1 of the ongoing Phase 1/2 MATCH clinical trial (NCT06525298) investigating the small molecule ALC1 inhibitor EIS-12656 in solid tumors. In this trial, Eisbach seeks to assess the safety, pharmacokinetics, pharmacodynamics and preliminary clinical activity of the allosteric ALC1 inhibitor in the monotherapy setting. The trial, which is being conducted at The University of Texas MD Anderson Cancer Center (MD Anderson), is co-funded with an investment from the Cancer Focus Fund, a unique investment fund established in collaboration with MD Anderson to provide funding and clinical expertise to advance promising cancer therapies. EIS-12656 is a first-in-class, selective, potent, oral and brain-penetrant small molecule inhibitor of the chromatin helicase ALC1 (CHD1L), a key molecular machine involved in DNA damage and genome repair mechanisms. EIS-12656 targets ALC1 through allosteric mechanisms, suppressing the cancer-relevant genome reorganization induced by DNA damage. Eisbach’s preclinical in vivo data with EIS-12656 showed rapid tumor growth inhibition, high bioavailability and excellent tolerability. “This milestone marks Eisbach’s entry into the cancer clinic with a transformative target and unique allosteric approach. ALC1 is a superior, orthogonal target in tumors with impaired DNA damage and repair. Its inhibitor EIS-12656 is the result of our ability to disrupt the function of the powerful machines that reorganize our genome in a very targeted manner,” said Adrian Schomburg, Ph.D., Founder and CEO of Eisbach. “This clinical study will assess the impact of EIS-12656’s ability to hit both genetic and molecular vulnerabilities in our cancer indications, potentially enabling its advancement as a drug that is both efficacious and well-tolerated.” About the Phase 1/2 Clinical Trial The open label study of EIS-12656 will evaluate its safety, tolerability and efficacy in patients with genetically-defined advanced solid tumors. Led by Principal Investigator Timothy A. Yap, M.B.B.S., Ph.D., Vice President, Head of Clinical Development in the Therapeutics Discovery Division and Professor of Investigational Cancer Therapeutics at MD Anderson, the trial includes dose escalation of EIS-12656 monotherapy, followed by dose expansion modules and evaluation in gynecological, pancreatic and prostate cancer patients progressing under PARP inhibitor treatment. Eisbach selected CTI Clinical Trial & Consulting, a global full-service Contract Research Organization, as a strong partner providing regulatory and clinical trial management service for this trial. About Eisbach Eisbach is at the forefront of precision oncology, developing allosteric drugs that selectively disrupt molecular machines vital for tumor genome reorganization. Combining genetic vulnerabilities with its proprietary ALLOS platform, which hits the molecular vulnerability of its cancer targets, Eisbach pioneers first-in-class therapies with fewer side effects. For more information, visit http://www.eisbach.bio and follow us on LinkedIn . SOURCE: Eisbach Bio

5月6日，致力于利用合成致死性开发新型抗癌药物的Eisbach Bio GmbH宣布，美国食品和药品监督管理局 (FDA) 已批准其染色质解旋酶 ALC1 (CHD1L) 的小分子抑制剂 EIS-12656 的研究性新药 (IND)申请。ALC1（也称为 CHD1L）是一种染色质重塑酶，可调节 DNA 损伤和修复。它的表达在以同源重组缺陷（HRD 阳性）为标志的乳腺癌和卵巢癌中增加。它的缺失大大增强了 PARP 抑制剂和各种标准护理化疗的疗效。ALC1 抑制剂有望在 HR 缺陷的肿瘤中诱导合成致死作用，在出现 PARPi 耐药性的患者中增强 PARP 抑制剂的作用，并实现有效的联合治疗。经某数据库检索，时至当日，并未收录ALC1 (CHD1L)靶点，专利检索也只有Eisbach Bio 自家的WO2022117782专利，或许可以说， EIS-12656 是全球首款和唯一一款靶向新型合成致死靶点ALC1 (CHD1L) 的小分子临床抑制剂抑制剂。当然，国内这些年跟踪这类前沿靶点，最后说不定真就自己跑成了First，甚至Only。比如，那个RAD51，幸运之神（“前车之鉴”）啊！推荐阅读：RAD51抑制剂带头大哥折戟，公司解散！RAD51抑制剂单药受挫Pol θ：百济与再明专利的“瑜亮”之战！癌症治疗中合成致死性的一个主要例子涉及 PARP 抑制剂，它会影响我们靶向的相关 DNA 修复途径。虽然这种方法强大且有效，但可能会受到剂量限制性毒性和 PARP 抑制剂耐药性的挑战。新一代PARP1选择性小分子抑制剂被誉为可以具备更优的安全性，但是否对PARP耐药后的肿瘤患者依然有效，恐怕还须时日。EIS-12656 通过变构机制靶向 ALC1，抑制 DNA 损伤引起的与癌症相关的基因组重组。这会导致 ALC1 染色质捕获并杀死癌细胞。EIS-12656 影响 DNA 修复途径缺陷的肿瘤。它在临床前模型中表现出显着的肿瘤生长抑制作用，包括与标准护理疗法相结合。与相关合成致死靶标相比，其变构作用机制应具有选择性，有助于在所有相关临床前模型中观察到的卓越安全性。EIS-12656可不可以me-too?有专利、有蛋白晶体，剩下的看能力财力。▎药端洞察近日，又收集了一些药物结构，包括ORIC-114、azd5055、Alogabat、海思科EGFR降解剂、TYK2抑制剂ESK-001，但在ADC风浪下，是否依旧有人激情澎湃？比如，礼来买了那个组装式NECTIN-4 ADC药物LY4101174 (ETx-22)，在临床研究推进的同时，自己又开发了一款，还有了自己TOP1i毒素LSN3889710。当时写这个文章时（厉害了！这家公司的License in玩出了新境界），提出了这样的假设：近日，Macrogenics公布B7H3 ADC新药Vobramitamab Duocarmazine(MGC018)治疗前列腺癌二期临床TAMARACK的最新数据。详细数据将在ASCO发布，但安全性上，出现5例死亡事件，2.0mg/kg剂量组1例，2.7mg/kg剂量组4例，尽管公司认为与药物无关，Macrogenics股价还是下跌了77%。MGC018和已经消失的HER2 ADC药物SYD985、5T4 ADC药物syd1875一样的毒素设计。这种设计可与纯粹的前药设计不同，SYD985的机制就说明了，这样“九转回肠”呀！LP-184、LP-284就不会出现这样的“意外”吗？所以才有了上述假设，扯远了，文章结束！声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号   粉丝群/投稿/授权/广告等请联系公众号助手 觉得本文好看，请点这里↓

The FDA has cleared the investigational new drug (IND) application for EIS-12656, a first-in-class orally bioavailable and blood brain barrier-penetrant allosteric inhibitor of ALC1 (CHD1L), a key molecular machine in DNA repair. EIS-12656 targets homologous recombination repair deficient cancers. Its expected superior safety should facilitate novel combination therapies with and beyond PARP inhibitors in hard to treat cancers. Eisbach Bio expects to start enrolling patients in the second quarter of 2024. MARTINSRIED, Germany, May 6, 2024 /PRNewswire/ -- Eisbach Bio GmbH ("Eisbach" or the "Company"), a privately-held clinical-stage biotechnology company pioneering cancer medicines leveraging synthetic lethality, has announced United States Food and Drug Administration (FDA) clearance of its investigational new drug (IND) application for EIS-12656, a small molecule inhibiting the chromatin helicase ALC1 (CHD1L). EIS-12656 targets ALC1 through allosteric mechanisms, suppressing the cancer-relevant genome reorganization induced by DNA damage. This leads to ALC1 chromatin trapping and cancer cell killing. EIS-12656 impacts tumors deficient in DNA repair pathways. It demonstrated substantial tumor growth inhibition in preclinical models, including in combination with standard-of-care therapies. Its allosteric mechanism of action should afford selectivity compared to related synthetic lethal targets, contributing to the exceptional safety observed in all relevant preclinical models. "EIS-12656 selectively targets tumors with no apparent effects on normal tissues." said Adrian Schomburg, Ph.D., Founder and CEO of Eisbach. "Our clinical study will also explore combination therapies that were hindered by combinatorial toxicity in the past." The discovery of EIS-12656 builds on the pioneering research of Eisbach founder Prof. Andreas Ladurner, whose team discovered that PARP effects in cancer cells are reliant on chromatin remodeling by ALC1. Eisbach built upon this knowledge and designed a first-in-class, once-daily small molecule therapy, directly targeting cancer genome reorganization induced by DNA damage at its source – the PARP-activated helicase ALC1. About the Phase 1/2 Clinical Trial The open label study of EIS-12656 will evaluate its safety, tolerability and efficacy in patients with genetically-defined advanced solid tumors. Led by Principal Investigator Timothy A. Yap, M.B.B.S., Ph.D., Professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, the trial includes dose escalation of EIS-12656 monotherapy, followed by dose expansion modules and evaluation in patients progressing under PARP inhibitor treatment. About Eisbach Eisbach is at the forefront of precision oncology, developing allosteric drugs that selectively disrupt molecular machines vital for tumor genome reorganization. Combining genetic vulnerabilities with its proprietary ALLOS platform, which hits the molecular vulnerability of its cancer targets, Eisbach pioneers first-in-class therapies with fewer side effects. For more information, visit and follow us on LinkedIn. Contacts: Eisbach Bio GmbH Adrian Schomburg, CEO +49 89 2153 7900 Jonathan Iorio +49 89 2153 79013 Logo - SOURCE Eisbach Bio