WRN

IDE275 (GSK959) development is progressing into First-in-Human Phase 1 clinical trial(s) for the treatment of MSI-High solid tumors, representing IDEAYA's 5th potential first-in-class clinical program MSI-High prevalence in endometrial, colorectal, and gastric cancers is ~31%, 20%, and 19%, respectively, highlighting the market potential of IDE275 (GSK959) IDEAYA to receive a $7 million payment for IND acceptance, and potential future aggregate milestones of up to $950 million. IDEAYA has a 50/50 US Profit Share and an 80/20 (GSK/IDEAYA) global research and development cost share SOUTH SAN FRANCISCO, Calif., Oct. 28, 2024 /PRNewswire/ -- IDEAYA Biosciences, Inc. (Nasdaq:IDYA), a precision medicine oncology company committed to the discovery and development of targeted therapeutics, announced the clearance of an investigational new drug (IND) application with the U.S. Food and Drug Administration (FDA) for the initiation of a Phase 1 clinical trial to evaluate IDE275 (GSK959), a potential first-in-class and best-in-class Werner Helicase (WRN) inhibitor. IDE275 (GSK959) has demonstrated robust and selective synthetic lethality preclinically in the high microsatellite instability (MSI-High) biomarker setting, and the Phase 1 clinical trial will enroll patients having tumors characterized by MSI-High. "IDE275 represents IDEAYA's fifth potential first-in-class clinical program in our precision medicine oncology pipeline and has a potentially differentiated best-in-class profile that we are targeting to present at a future medical conference with GSK. The robust preclinical efficacy observed by IDE275 selectively in the MSH-High biomarker setting, including monotherapy regressions, provides a double-digit % prevalence target patient population across several major solid tumor types, including endometrial, colorectal and gastric cancer," added Yujiro S. Hata, President and Chief Executive Officer, IDEAYA Biosciences. IDE275 (GSK959) is a potential first-in-class small molecule inhibitor of Werner Helicase that was discovered by IDEAYA in collaboration with GSK. In preclinical studies, IDE275 has demonstrated robust and selective synthetic lethality in the MSI-High biomarker setting, including single-agent tumor regressions in-vivo in MSI-High CDX and PDX models derived from colorectal, endometrial and gastric cancers. Initiation of the Phase 1 trial for IDE275 is projected in the fourth quarter of 2024. GSK is the sponsor of the IND application and plans to develop IDE275 (GSK959) as both a monotherapy agent and in combination with a PD-1 inhibitor in a Phase 1 clinical trial for patients having MSI-High tumors. The percent prevalence of MSI-High in solid tumors, including endometrial, colorectal, and gastric cancers, has been reported at approximately 31%, 20%, and 19%, respectively (JCO Precision Oncology, September 2017). GSK is responsible for 80% of global research and development costs for IDE275 (GSK959) and IDEAYA is responsible for 20% of such costs. IDEAYA is eligible to receive a $7 million milestone payment upon acceptance of the IND by the U.S. Food and Drug Administration (FDA), and a potential additional $10 million milestone payment upon initiation of Phase 1 clinical dose expansion. IDEAYA may potentially also receive up to $465 million in further later-stage development and regulatory milestones. Upon potential commercialization, IDEAYA will be eligible to receive up to $475 million of commercial milestones 50% of U.S. net profits and tiered royalties on global non-U.S. net sales of IDE275 (GSK959) – ranging from high single-digit to sub-teen double-digit percentages, subject to certain customary reductions. About IDEAYA Biosciences IDEAYA is a precision medicine oncology company committed to the discovery and development of targeted therapeutics for patient populations selected using molecular diagnostics. IDEAYA's approach integrates capabilities in identifying and validating translational biomarkers with drug discovery to select patient populations most likely to benefit from its targeted therapies. IDEAYA is applying its research and drug discovery capabilities to synthetic lethality – which represents an emerging class of precision medicine targets. IDEAYA's updated corporate presentation is available on its website, at its Investor Relations page: . Forward-Looking Statements This press release contains forward-looking statements, including, but not limited to, statements related to (i) expectations regarding the clinical activity profile and potential advantages of IDEAYA's clinical programs, (ii) the initiation of a Phase 1 clinical trial to evaluate IDE275 (GSK959) and (iii) the receipt of development and regulatory milestones . Such forward-looking statements involve substantial risks and uncertainties that could cause IDEAYA's preclinical and clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainties inherent in the drug development process, including IDEAYA's programs' early stage of development, the process of designing and conducting preclinical and clinical trials, the regulatory approval processes, the timing of regulatory filings, the challenges associated with manufacturing drug products, IDEAYA's ability to successfully establish, protect and defend its intellectual property, and other matters that could affect the sufficiency of existing cash to fund operations. IDEAYA undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of IDEAYA in general, see IDEAYA's Annual Report on Form 10-K dated February 20, 2024 and any current and periodic reports filed with the U.S. Securities and Exchange Commission. Investor and Media Contact IDEAYA Biosciences Andres Ruiz Briseno SVP, Head of Finance and Investor Relations [email protected] SOURCE IDEAYA Biosciences, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

-- New development candidate, NTX-452, a non-covalent WRN inhibitor, demonstrated significant tumor regression and complete responses at low oral doses in MSI-H tumor models refractory to immunotherapy and chemotherapy -- -- Company plans to initiate clinical trial of NTX-452 in first half of 2025 -- BOSTON--(BUSINESS WIRE)-- Nimbus Therapeutics , LLC (“Nimbus Therapeutics” or “Nimbus”), a biotechnology company that designs and develops breakthrough medicines for patients through its powerful computational drug discovery engine, announced that it is presenting preclinical data on its new development candidate, NTX-452, a novel Werner syndrome helicase (WRN) inhibitor, at the 36 th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, taking place October 23-25, 2024 in Barcelona, Spain. WRN is a helicase required for DNA replication and DNA repair and is a validated target for tumors with microsatellite instability (MSI). MSI is a phenotypic consequence of defective mismatch repair (dMMR) and occurs in various tumor types, including colorectal, gastric and endometrial cancers. Inhibition of WRN activity has the potential to induce synthetic lethality in MSI-high (MSI-H) tumors. Using a structure-based drug design approach, Nimbus developed highly potent and selective covalent and non-covalent inhibitors of WRN, and has selected a novel non-covalent inhibitor, NTX-452, as the clinical candidate. In a poster (abstract #356) titled “Preclinical Characterization of NTX-452, a Potent, Selective and Highly Efficacious WRN Inhibitor for the Treatment of MSI-H Tumors,” Nimbus is presenting new data from preclinical assays and several tumor models that support the potential of the company’s non-covalent WRN inhibitor as a treatment for MSI-H tumors. Key findings from the preclinical studies include: NTX-452 demonstrated potent and selective inhibition of WRN activity with favorable drug-like properties. The compound showed synthetic lethality in MSI-H tumor cells, triggering a DNA damage response that suppressed cell viability and promoted cell death. Treatment with NTX-452 at low doses in vivo exhibited a robust pharmacodynamic response, resulting in tumor regression across multiple MSI-H cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) tumor models, including established models for colorectal, gastric and endometrial cancers. Significant tumor regression and complete responses were observed at low oral doses in MSI-H models refractory to immunotherapy and chemotherapy. “These compelling preclinical results for NTX-452 further highlight the significant potential of our WRN inhibitor as a promising therapeutic approach for patients with MSI-H tumors, many of whom fail to respond to or eventually relapse with current standard of care therapies including immune checkpoint inhibitors,” said Peter Tummino, Ph.D., Chief Scientific Officer of Nimbus. “Our novel non-covalent approach to WRN inhibition, coupled with the robust efficacy demonstrated across diverse tumor types and treatment settings, positions our program for potential best-in-class status. We are particularly encouraged by the low doses required to achieve robust anti-tumor activity in preclinical models, which may translate to an improved benefit-risk pro the clinic.” The preclinical pro NTX-452 suggests several potential advantages in the treatment of MSI-H tumors, including: The non-covalent mechanism may offer more durable on-target activity, and a greater safety window compared to covalent inhibitors. High potency and favorable pharmacokinetic properties indicate the potential for target levels of efficacy at lower doses. Broad efficacy across treatment-naïve, chemotherapy-pretreated, and immunotherapy-pretreated models suggests potential utility in both early-stage and advanced disease settings. Activity in multiple MSI-H tumor types, including those with diverse genetic alterations, indicates potential broad applicability across dMMR/MSI-H cancers. Nimbus is advancing NTX-452 with plans to enter the clinic in the first half of 2025. About Nimbus Therapeutics Nimbus Therapeutics is a clinical-stage, structure-based drug discovery company developing novel small molecule medicines designed to act against well-validated but difficult-to-drug targets implicated in multiple human diseases. The company advances promising research based on a unique strategy that combines leading-edge computational technologies with a tailored array of machine learning-based predictive modeling approaches. Nimbus’ pipeline includes a clinical-stage HPK1 inhibitor for the treatment of cancer (NCT05128487), as well as a diverse portfolio of preclinical programs focused on cancer, including the WRN program, autoimmune conditions, and metabolic diseases. The company is headquartered in Boston, Mass. To learn more about Nimbus, please visit . Contacts Media Cindy Fung, PhD Nimbus Therapeutics cindy.fung@nimbustx.com

9月11日，BioBAY园内企业英矽智能宣布提名临床前候选药物ISM2196，这是一款由AI驱动发现的、潜在“同类最佳”（best-in-class）WRN抑制剂，旨在通过合成致死策略治疗晚期转移性微卫星不稳定性（MSI）癌症。 DNA解旋酶Werner (WRN）是RecQ解旋酶家族成员，在维持基因组完整性和促进DNA损伤修复中起关键作用。最近的研究发现，WRN缺陷会选择性杀伤MSI-H癌细胞，同时不影响微卫星稳定（MSS）细胞生存，这使WRN成为MSI-H肿瘤的合成致死靶点。以结直肠癌、子宫内膜癌、胃癌为代表，超过20种不同类型的癌症中均观察到MSI-H状态，全球范围内每年MSI-H癌症的确诊病例数达到数十万。 ISM2196是一款创新强效WRN抑制剂，其设计与优化过程由Chemistry42下属模块Alchemistry赋能。Alchemistry利用非平衡切换，准确且快速地估算蛋白质-配体复合物的结合自由能，为药物发现与研发过程提供助力。在WRN项目的开发中，多数AI预测的化合物表现出优于参考化合物的活性。此后，英矽智能研发团队进一步整合并分析了来自Alchemistry的排序结果、ADMT活性及候选化合物的PK/PD属性，进而快速筛选出有前景的候选分子用于后续合成和测试。 ISM2196在临床前实验中显示了具有前景的研究结果，在多种癌症模型中，包括结直肠癌、子宫内膜癌和胃癌等，均表现出强大的体内抗肿瘤疗效。此外，它还展示了理想的类药性，包括出色的体外ADMET特性、良好的体内暴露、低血浆清除率和在多种物种模型中较好的口服生物利用度。这些发现突显了ISM2196作为潜在同类最佳WRN抑制剂治疗MSI-H肿瘤的潜力。英矽智能已在2024年的AACR年会上披露了关于这个项目的部分临床前关键数据。 英矽智能联合首席执行官兼首席科学官任峰博士表示，“尽管免疫检查点抑制剂已被批准用于治疗MSI-H肿瘤，但仍有相当一部分患者对现有疗法无应答，也有一部分患者饱受现有药物毒性的困扰。WRN抑制剂有望为他们带来新的希望，我们正在加紧推进ISM2196的IND-enabling研究，期待与经验丰富的合作伙伴一起，推进该候选药物的临床验证，为患者提供创新的治疗选择。” 英矽智能创始人兼首席执行官Alex Zhavoronkov博士表示，“我们从未停止过对Pharma.AI平台的开发和研究工作，集成了前沿技术的新AI模块正在展现出巨大的潜力。在WRN项目中，这些模块优化苗头化合物系列的经验，经验再次彰显了AI技术推动药物发现的可能性，我们期待尽快为那些具有未被满足医疗需求的患者带来下一代的创新疗法。” ▌文章来源：英矽智能 责编：何文正 审核：任旭 推荐阅读 研发动态丨睿健医药：全球首例！化学诱导细胞来源外囊泡临床启动，针对2种疾病 研发动态丨多玛医药双抗ADC IND获FDA批准，即将开启1期临床 研发动态丨炫景生物：首款siRNA药物在澳大利亚获批临床试验