Hoffmann-La Roche Ltd.

SAN DIEGO, April 29, 2025 /PRNewswire/ -- Blacksmith Medicines, Inc. (Blacksmith), a leading biopharma dedicated to discovering and developing therapeutics targeting metalloenzymes, today announced the company will present data on its oncology program targeting flap endonuclease 1 (FEN1), a structure-specific metallonuclease that cleaves 5' DNA flaps during replication and repair, at the American Association for Cancer Research (AACR) Annual Meeting 2025, taking place April 25-30 at the McCormick Place Convention Center, Chicago, IL. Details of the poster presentation are as follows: Abstract Number: 5720 Title: "Novel FEN1 nuclease inhibitor shows synergy with PARP-targeting drugs" Session Category: Experimental and Molecular Therapeutics Session Title: PARP Inhibitors Session Date and Time: Tuesday April 29, 2025 2:00 PM - 5:00 PM Location: Poster Section 24 Poster Board Number: 7 The abstract is now available on the conference website at AACR Annual Meeting 2025. About FEN1 Flap endonuclease 1 (FEN1) is a structure-specific di-magnesium metallonuclease that cleaves 5' DNA flaps during replication and repair. FEN1 is an attractive target for development of anticancer therapeutics because it is overexpressed in many tumor types and has a large number of synthetic lethality partners including genes in Homologous Recombination (HR) pathway. About metalloenzymes and the Blacksmith platform Metalloenzymes utilize a metal ion cofactor in the enzyme active site to perform essential biological functions. This diverse class of targets has historically been difficult to drug due to small molecule chemistry limitations that have plagued the industry. The Blacksmith metalloenzyme platform has solved this problem by leveraging the following: A large proprietary fragment library of metal-binding pharmacophores (MBPs); A comprehensive database containing a full characterization of the metalloenzyme genome including functions, metal cofactors, and associations to disease; A first-of-its-kind metallo-CRISPR library of custom single guide RNAs; An industry-leading metalloenzyme computational toolkit for docking, modeling and structure-based drug design; and A robust and blocking intellectual property estate covering bioinorganic, medicinal, and computational chemistry approaches for metalloenzyme-targeted medicines. About Blacksmith Medicines At Blacksmith Medicines, we are developing medicines targeting metal-dependent enzymes. Over 30% of known enzymes are metalloenzymes, covering all major enzyme classes: oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases. Metal ions, including magnesium, zinc, iron, manganese and copper, are the essential ingredient in these metalloenzymes. We recognized a large unmet need for new chemical matter and innovative approaches to drug this important class of enzymes. Our purpose-built platform for metalloenzyme-targeted medicines combines, for the first time in industry, a focused library of metal-binding pharmacophores with proprietary computational modeling approaches to rapidly and rationally design small molecule inhibitors that interact with key metal ions in the enzyme's active site. Our comprehensive knowledge of the metal environment and key active site interactions enables Blacksmith to rapidly build potent and selective inhibitors in a stepwise and predictable manner. Blacksmith has executed strategic drug discovery collaborations with Basilea Pharmaceutica International Ltd., Cyteir Therapeutics Inc., Eli Lilly and Company (Lilly), Hoffmann-La Roche Ltd., and Zoetis LLC., and has been awarded non-dilutive Federal funding agreements with CARB-X and NIH/NIAID. Blacksmith investors include Lilly, Evotec A.G., MP Healthcare Partners, MagnaSci Ventures, and Alexandria Venture Investments. For further information, please visit the company's website and LinkedIn Media Contact: Amy Conrad Juniper Point [email protected] 858-366-3243 SOURCE Blacksmith Medicines WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

▎药明康德内容团队编辑本期看点1. Arvinas公司宣布，其靶向富含亮氨酸重复激酶2（LRRK2）的在研靶向蛋白降解剂ARV-102在首个人体临床试验中表现出良好的安全性和耐受性，并显著降低中枢神经系统和外周LRRK2水平，支持其在神经退行性疾病中的继续评估。2. 罗氏（Roche）新一代阿尔茨海默病疗法在1b/2a期临床试验中快速清除受试者大脑中的β淀粉样蛋白（Aβ），计划今年启动3期临床试验。药明康德内容团队整理Arvinas帕金森病蛋白降解疗法临床结果积极Arvinas公司公布了其在研靶向蛋白降解嵌合体（PROTAC）候选药物ARV-102的首次人体临床试验数据。ARV-102是一种针对富含亮氨酸重复激酶2（LRRK2）的蛋白降解剂。LRRK2是一种大型多结构域支架激酶。LRRK2活性和表达升高被认为与多种神经系统疾病的发病机制相关，包括LRRK2基因型和散发型帕金森病以及进行性核上性麻痹。试验的主要发现包括：ARV-102在单次或多次给药后总体安全性良好，未报告严重不良事件ARV-102在脑脊液（CSF）中的暴露呈剂量依赖性增加，表明其具有良好的穿越血脑屏障的能力单次口服剂量≥60 mg，或每日重复口服剂量≥20 mg时，CSF中LRRK2降解率超过50%，外周单核细胞中LRRK2降解率超过90%，表明ARV-102可实现中枢神经系统及外周LRRK2蛋白的显著降解单次给药后观察到外周单核细胞中磷酸化Rab10的显著减少，这是LRRK2下游活性的生物标志物除了在健康志愿者中进行的这项1期临床试验，Arvinas也已在帕金森病患者中启动了ARV-102的1期单剂量递增（SAD）临床试验给药。公司预计将在2025年完成该SAD队列的入组并公布初步数据，并将在帕金森病患者中启动多剂量递增队列的临床研究。该公司首席医学官Noah Berkowitz博士在新闻稿中表示，ARV-102能够穿越血脑屏障并降解LRRK2蛋白的能力，为治疗严重神经退行性疾病提供了潜在的颠覆性治疗策略。罗氏新一代阿尔茨海默病疗法快速清除β淀粉样蛋白罗氏日前公布了其新一代抗Aβ抗体trontinemab在1b/2a期临床试验Brainshuttle AD中的最新结果。初步数据显示，114名参与者接受trontinemab治疗后，经淀粉样蛋白正电子发射断层扫描（PET）测量，其脑内淀粉样蛋白斑块迅速且明显地呈剂量依赖性减少。28周后，在3.6 mg/kg剂量组中，81%的参与者（n=21/26）的淀粉样蛋白斑块几乎全部清除。根据该领域数据，降低淀粉样蛋白斑块的速度以及早期将其降至阳性阈值以下的能力，对于在早期阿尔茨海默病患者中实现具有临床意义的益处至关重要。Trontinemab是一款运用罗氏大脑穿梭（brain shuttle）技术的新一代抗淀粉样蛋白单克隆抗体。它将靶向淀粉样蛋白的单克隆抗体与可以和转铁蛋白受体相结合的蛋白域融合，可以有效协助抗体穿越血脑屏障，在用药3-6个月后可以快速有效地清除大脑中的淀粉样蛋白沉积。罗氏计划在今年晚些时候，启动trontinemab的3期临床试验。KER-065：公布1期临床试验初步顶线结果Keros Therapeutics日前公布了KER-065在健康志愿者中进行的1期临床试验的初步顶线结果。KER-065是一种激活素受体IIA（ActRIIA）和激活素受体IIB（ActRIIB）配体陷阱（ligand trap），被设计用于结合并抑制肌生长抑制蛋白和激活素A，从而促进骨骼肌再生、增加肌肉体积和力量、降低体脂、减少骨骼肌纤维化并增强骨骼强度。Keros Therapeutics正在开发KER-065用于治疗神经肌肉疾病，初步聚焦于杜氏肌营养不良症（DMD）。试验的主要发现包括：KER-065总体耐受性良好，未报告严重不良事件或剂量限制性毒性在各相关组织中均显示出对激活素抑制作用的证据，受试者身体成分发生改变，表现为骨密度和肌肉量增加、脂肪量减少，这些变化总体上与激活素信号通路被抑制一致CER-1236：IND申请获FDA许可CERo Therapeutics公司宣布，该公司为在研细胞疗法CER-1236递交的IND申请已获得美国FDA的许可，用于针对晚期实体瘤的1期临床试验，具体包括非小细胞肺癌和卵巢癌。新闻稿指出，CER-1236是首个以Tim-4L为靶点的CAR-T细胞疗法，也是首个通过改造T细胞，赋予其吞噬活性的疗法。临床前数据表明，这种双重机制可能有助于克服一直困扰实体瘤CAR-T细胞疗法的耐药障碍。RB-164：IND申请获FDA许可Radiance Biopharma日前宣布，该公司为在研抗体偶联药物（ADC）RB-164递交的IND申请已经获得美国FDA的许可。它是一种以ROR-1为靶点的ADC。该IND支持在美国启动RB-164的1期剂量递增及扩展临床试验，试验对象为ROR-1阳性的血液癌症及实体瘤患者。RB-164是一种新一代ADC，采用Fc静默单克隆抗体靶向ROR-1，并通过位点特异性偶联实现药物/抗体比例分布均一，从而改善药代动力学及毒理学特性，其药物载荷为MMAE。EPI-321：IND申请获FDA许可Epicrispr Biotechnologies宣布，在研疗法EPI-321的IND申请已获FDA的许可。EPI-321是一种潜在“first-in-class”的表观遗传学疗法，用于治疗面肩肱肌营养不良症（FSHD），这是一种遗传性神经肌肉疾病。该公司计划于2025年启动全球性1/2期临床试验。EPI-321是一种在研一次性基因调节疗法，旨在抑制DUX4的异常表达，DUX4是一种在FSHD中被错误激活并导致渐进性肌肉变性的基因。EPI-321通过临床验证的腺相关病毒（AAV）载体进行全身给药，在临床前模型中已证明它能有效抑制DUX4的表达并保护肌肉组织。EPI-321已获得FDA快速通道资格、罕见儿科疾病认定和孤儿药资格。DM-101PX：1期临床试验结果积极Desentum Oy公司日前宣布了在研桦树花粉过敏疫苗DM-101PX的积极1期临床数据。数据显示，DM-101PX的短程治疗在桦树花粉过敏患者中表现出良好的安全性和耐受性，并能诱导出非常强烈且持久的过敏原特异性IgG4应答。研究发现，DM-101PX诱导产生的免疫球蛋白能够有效阻断IgE介导的嗜碱性粒细胞激活，从而支持该产品有望诱导出保护性免疫应答。DM-101PX是一款用于免疫治疗桦树花粉过敏的在研疗法，其活性成分是主要桦树花粉过敏原Bet v 1的重组变体，通过基因工程改造降低了其致敏性，同时保留了所需的免疫学特性。▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料（可上下滑动查看）[1] CERo Therapeutics Holdings, Inc. Receives FDA Clearance of Second Investigational New Drug Application to Initiate Phase 1 Clinical Trial of Lead Compound CER-1236 in Solid Tumors. Retrieved March 31, 2025, from https://www.globenewswire.com/news-release/2025/03/31/3052257/0/en/CERo-Therapeutics-Holdings-Inc-Receives-FDA-Clearance-of-Second-Investigational-New-Drug-Application-to-Initiate-Phase-1-Clinical-Trial-of-Lead-Compound-CER-1236-in-Solid-Tumors.html[2] Keros Therapeutics Announces Initial Topline Results from the Phase 1 Clinical Trial of KER-065 in Healthy Volunteers. Retrieved March 31, 2025, from https://www.globenewswire.com/news-release/2025/03/31/3052085/0/en/Keros-Therapeutics-Announces-Initial-Topline-Results-from-the-Phase-1-Clinical-Trial-of-KER-065-in-Healthy-Volunteers.html[3] Radiance Announces FDA Clearance of IND Application for a Phase 1 Clinical Trial of RB-164™, an ROR-1 Targeted ADC, for Hematologic and Solid Malignancies. Retrieved March 31, 2025, from https://www.globenewswire.com/news-release/2025/03/31/3052547/0/en/Radiance-Announces-FDA-Clearance-of-IND-Application-for-a-Phase-1-Clinical-Trial-of-RB-164-an-ROR-1-Targeted-ADC-for-Hematologic-and-Solid-Malignancies.html[4] Epicrispr Biotechnologies Announces FDA Clearance of IND Application for EPI-321, A First-in-Class Epigenetic Therapy for FSHD. Retrieved April 5, 2025, from  https://epicrispr.com/epicrispr-biotechnologies-announces-fda-clearance-of-ind-application-for-epi-321-a-first-in-class-epigenetic-therapy-for-fshd/[5] Desentum reports strong safety and immunological data from Phase 1 clinical study with investigational birch pollen allergy vaccine DM-101PX. Retrieved April 5, 2025, from https://desentum.fi/news/desentum-reports-strong-safety-and-immunological-data-from-phase-1-clinical-study-with-investigational-birch-pollen-allergy-vaccine-dm-101px/[6] Vividion Therapeutics Doses First Patient in Phase I Study of RAS-PI3Kα Inhibitor for Treatment of Advanced Solid Tumors. Retrieved April 5, 2025, from https://www.businesswire.com/news/home/20250403585991/en/Vividion-Therapeutics-Doses-First-Patient-in-Phase-I-Study-of-RAS-PI3K-Inhibitor-for-Treatment-of-Advanced-Solid-Tumors[7] Pretzel Therapeutics Initiates Phase 1 Clinical Study Evaluating PX578, Lead Therapeutic in its Bioenergetics Restoration Franchise. Retrieved April 5, 2025, from https://www.businesswire.com/news/home/20250403945637/en/Pretzel-Therapeutics-Initiates-Phase-1-Clinical-Study-Evaluating-PX578-Lead-Therapeutic-in-its-Bioenergetics-Restoration-Franchise[8] Arvinas Presents First-in-Human Data for Investigational Oral PROTAC ARV-102 Demonstrating Blood-Brain Barrier Penetration, and Central and Peripheral LRRK2 Degradation. Retrieved April 5, 2025, from https://ir.arvinas.com/news-releases/news-release-details/arvinas-presents-first-human-data-investigational-oral-protac[9] Roche presents novel therapeutic and diagnostic advancements in Alzheimer’s at AD/PD 2025. Retrieved April 5, 2025, from https://www.roche.com/media/releases/med-cor-2025-04-03[10] Jabez Biosciences, Inc. Announces First Patient Dosed in Phase 1 Oncology Clinical Study of JBZ-001. Retrieved April 5, 2025, from https://www.jabezbio.com/2025/04/03/jabez-biosciences-inc-announces-first-patient-dosed-in-phase-1-oncology-clinical-study-of-jbz-001/免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

FG-2101 is Blacksmith's non-hydroxamate small molecule inhibitor of LpxC for treating Gram-negative bacteria infections including drug-resistant strains Presentation highlights Blacksmith's novel chemistry platform for targeting metalloenzymes SAN DIEGO, March 26, 2025 /PRNewswire/ -- Blacksmith Medicines, Inc. (Blacksmith), a leading biopharma dedicated to discovering and developing therapeutics targeting metalloenzymes, today disclosed the discovery and structure of FG-2101 at the American Chemical Society Spring 2025 meeting in San Diego, CA. FG-2101 is a non-hydroxamate small molecule antibiotic candidate discovered at Blacksmith that is designed to selectively inhibit LpxC, a zinc-dependent metalloenzyme found only in Gram-negative bacteria. FG-2101 is being developed for intravenous and oral routes of administration to treat Gram-negative bacteria infections, including drug-resistant strains. FG-2101 has advanced through IND enabling studies and is poised to enter human trials later this year. "Today's presentation at the ACS meeting showcases Blacksmith's innovative small molecule chemistry platform that combines fragment-based drug design (FBDD) and structure-based drug design (SBDD) with proprietary computational approaches for metalloenzymes," said Zachary Zimmerman, Ph.D., CEO and co-founder of Blacksmith. "In addition to representing an important milestone for FG-2101 as a potential treatment for serious bacterial infections, today's presentation further validates the Blacksmith chemistry platform as a solution for novel small molecule inhibitors of disease-causing metalloenzymes that have been problematic to drug development." TITLE: First disclosure of FG-2101: A novel non-hydroxamate inhibitor of LpxC for treating Gram-negative bacteria infections including drug-resistant strains SESSION: First Time Disclosures DAY & TIME OF PRESENTATION: Wednesday, March 26, 2025, from 9:05 AM - 9:35 AM ROOM & LOCATION: Room 28A/B - San Diego Convention Center PRESENTER: Seth Cohen, Ph.D., co-founder of Blacksmith Medicines and Distinguished Professor of Chemistry and Biochemistry, U.C. San Diego "For the past 23 years, my lab at U.C. San Diego has been working on developing a novel fragment-based drug discovery approach for inhibitors of medically relevant metalloenzymes. This unique platform has been leveraged by Blacksmith to create first-in-class and best-in-class medicines," said Seth Cohen, Ph.D., co-founder of Blacksmith Medicines and Distinguished Professor of Chemistry and Biochemistry, U.C. San Diego. "As a scientific co-founder of Blacksmith, a chemistry-based platform company based in San Diego with technology from U.C. San Diego, I am proud to present Blacksmith's lead program FG-2101 at ACS First Time Disclosures session being held in our hometown of San Diego." The FG-2101 program is currently supported under a contract with NIAID (75N93022C00060). About LpxC LpxC, a zinc-dependent hydrolase, is an attractive and highly sought-after antibiotic target – it is conserved across Gram-negative bacteria and not found in Gram-positive bacteria or human cells. Inhibiting LpxC results in potent killing of Gram-negative bacteria with the expected benefit of sparing protective Gram-positive bacteria, such as those residing in the microbiome of the gut which help to deter opportunistic C. difficile infections. Other LpxC inhibitors have been evaluated by biopharma in the past, but chemistry limitations (e.g., use of hydroxamic acid-based warheads) have yielded ineffective compounds that suffer from poor drug-like properties. Thus, there are no approved therapeutics targeting LpxC. Blacksmith, using its proprietary chemistry platform, has developed novel non-hydroxamate inhibitors of LpxC that are safe and effective in animal models of Gram-negative infection and are able to kill Gram-negative 'superbugs' where other antibiotics are ineffective. About metalloenzymes and the Blacksmith platform Metalloenzymes utilize a metal ion cofactor in the enzyme active site to perform essential biological functions. This diverse class of targets has historically been difficult to drug due to small molecule chemistry limitations that have plagued the industry. The Blacksmith metalloenzyme platform has solved this problem by leveraging the following: A large proprietary fragment library of metal-binding pharmacophores (MBPs); A comprehensive database containing a full characterization of the metalloenzyme genome including functions, metal cofactors, and associations to disease; A first-of-its-kind metallo-CRISPR library of custom single guide RNAs; An industry-leading metalloenzyme computational toolkit for docking, modeling and structure-based drug design; and A robust and blocking intellectual property estate covering bioinorganic, medicinal, and computational chemistry approaches for metalloenzyme-targeted medicines. About Blacksmith Medicines At Blacksmith Medicines, we are developing medicines targeting metal-dependent enzymes. Over 30% of known enzymes are metalloenzymes, covering all major enzyme classes: oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases. Metal ions, including magnesium, zinc, iron, manganese and copper, are the essential ingredient in these metalloenzymes. We recognized a large unmet need for new chemical matter and innovative approaches to drug this important class of enzymes. Our purpose-built platform for metalloenzyme-targeted medicines combines, for the first time in industry, a focused library of metal-binding pharmacophores with proprietary computational modeling approaches to rapidly and rationally design small molecule inhibitors that interact with key metal ions in the enzyme's active site. Our comprehensive knowledge of the metal environment and key active site interactions enables Blacksmith to rapidly build potent and selective inhibitors in a stepwise and predictable manner. Blacksmith has executed strategic drug discovery collaborations with Basilea Pharmaceutica International Ltd., Cyteir Therapeutics Inc., Eli Lilly and Company (Lilly), Hoffmann-La Roche Ltd., and Zoetis LLC., and has been awarded non-dilutive Federal funding agreements with CARB-X and NIH/NIAID. Blacksmith investors include Lilly, Evotec A.G., MP Healthcare Partners, MagnaSci Ventures, and Alexandria Venture Investments. For further information, please visit the company's website and LinkedIn Media Contact: Amy Conrad Juniper Point [email protected] 858-366-3243 SOURCE Blacksmith Medicines WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED