Acetaminophen

一款新药从设计、研发、临床试验到走向市场，通常需耗费超过26亿美元的资金与10至15年的时间，而且越往后期成本越高。比如，不适当的药物如果进入临床试验，除了因为没有期望的治疗效果而浪费医护和病人的大量时间和精力，更可能因为其潜在的副作用而对病人的生命安全产生威胁。如何在研发早期快速、精准地判定药物的潜在治疗属性，成为当前药物设计与筛选中的关键问题。2025年4月7日，香港理工大学、四川大学、鹏城实验室的联合研究团队在Briefings in Bioinformatics期刊上发表了最新研究成果GraphATC。 该方法借助原子级图神经网络，仅需1.53毫秒，即可完成一种药物ATC药性进行预判（如：该药物是否可以治疗呼吸系统疾病、心脑血管疾病等），为药物筛选与开发提供了一种高效的技术路径，从而规避因盲目进入临床试验而带来的各种风险。数据集和代码都已开源！文章作者包括来自3所高校或研究机构的张翁渔，田奇，曹溢，范文琦，蒋冬梅，王耀威，李青，魏骁勇。魏骁勇教授为本文通讯作者。ATC药物分类系统简介ATC（Anatomical Therapeutic Chemical）分类系统是由世界卫生组织（WHO）制定的全球通用药物分类标准。该系统根据药物的作用器官或系统、治疗用途、药理机制及化学特性，将药物的活性成分划分为五个层级，其中从第一级到第五级分别表示解剖学，治疗学，药理学，化学，以及化合物上的分类。例如，在新冠期间，对乙酰氨基酚（泰诺、扑热息痛的主要成分）是一种常用的退热药，能够有效缓解新冠症状。对乙酰氨基酚的ATC代码是N02BE01，第一级N表示神经系统，第二级02表示止痛药，第三级B表示其他止痛退药及退热药，第四级E表示苯胺类，第五级01表示乙酰氨基酚。当前药物分类方法面临的挑战1.数据集陈旧与覆盖有限：主流药物分类数据集未能覆盖近年新上市的药物，且多数仅含ATC系统的第一级标签，难以满足精细化研发所需。2.深层分类样本稀缺：ATC系统中更细粒度的第二至五级，因数据稀缺难以训练有效模型，成为药物建模中的瓶颈。3.表示方法能力不足：传统方法依赖SMILES等线性字符串或预定义分子指纹，难以捕捉复杂结构间的拓扑与相互作用。图1：GraphATC框架图GraphATCGraphATC的核心创新在于将药物结构建模为图结构，利用图神经网络来捕捉原子与键之间的高阶关联关系。具体而言，该研究在两大关键方向进行了系统性改进：1.构建更全面的ATC分类数据集团队首先全面整合并扩充了现有的ATC药物数据集。为此，团队从多个国际权威数据库（如KEGG、PubChem、ChEMBL等）中收集了最新的药物信息，通过严格的清洗、校验和数据融合，构建出一个覆盖最广、数据最全的ATC-GRAPH数据集，如图1A所示。如图2所示，这一数据集不仅显著扩大了药物种类和数量，还首次覆盖了世界卫生组织ATC体系的五个层级，从广义的药物类别细化到具体化学成分，确保每种药物都有完整、准确的多级标签。这一全面的数据整合过程，不仅克服了现有数据集普遍存在的数据老旧、标签缺失、覆盖不足等问题，也极大提升了数据集的时效性和代表性，为后续的模型训练和高精度药物分类提供了坚实的基础。图2：ATC-GRAPH与现有数据集的数据对比2.构造更精确的药物表示形式为解决传统分子序列表示（SMILES）在结构表达上的局限性，GraphATC采用图神经网络进行建模（图1B），同时针对特定药物种类引入以下设计：加入虚拟原子与虚拟化学键：如图1C所示，对于聚合物，模型在结构连接点引入虚拟原子和虚拟化学键作为中介，使模型能够捕捉单体间的交互关系。实验显示该机制可使聚合物类药物分类准确率提升14.74%。引入基于RNN的子图融合机制：如图1D所示，对于多成分药物，GraphATC利用RNN对各组分进行加权聚合，根据组分分子量与结构复杂度自适应地调整各组分对整体分类的影响。相比平均融合策略，该方法在多成分分类中提升准确率14.46%。实验结果团队在三个数据集、ATC第一级、ATC第二级上对GraphATC进行了系统评估，GraphATC均取得了最优性能，如表1、表2所示。表1：与SOTA方法在ATC第一级上的性能比较。最佳结果以粗体显示表2：与SOTA方法在ATC第二级上的性能比较。最佳结果以粗体显示此外，模型在复杂药物上的结构关注机制表现显著：在聚合物药物中加入虚拟原子与虚拟化学键后，注意力由原先集中于单体中心，拓展至连接位点，如图3所示。在多成分药物中引入子图融合机制后，注意力由原先集中于较大子成分，扩散至多个子成分，如图4所示。图3：在聚合物药物中加入虚拟原子与虚拟化学键后的注意力图图4：在多成分药物中引入子图融合机制后的注意力图总结GraphATC提出了一种以图结构为基础进行药物多级分类的可行框架，显著提升了分类精度与推理效率。其主要贡献包括：构建了当前覆盖最广的ATC-GRAPH多级分类数据集；首次将ATC分类任务扩展至更细粒度的第二级；优化模型对复杂药物结构的精确表达能力；实现了分类性能和推理速度的双重优化。该方法为后续的药物发现、药效预测、以及分子生成等任务提供了重要参考框架，也为AI辅助药物研发建立了更为坚实的技术基础。或许未来某天，当一种新型疾病袭来，AI在短时间内就能从海量药物中锁定解药。GraphATC的数据集和代码均已开源，欢迎大家尝试！数据集和代码：https://github.com/lookwei/GraphATC参考资料：https://academic-oup-com.libproxy1.nus.edu.sg/bib/article-pdf/26/2/bbaf194/63012495/bbaf194.pdf本文转自【ScienceAI】公众号--------- End ---------感兴趣的读者，可以添加小邦微信加入读者实名讨论微信群。添加时请主动注明姓名-企业-职位/岗位或姓名-学校-职务/研究方向。

Reported positive initial data from the Heart-2 Phase 1b clinical trial of VERVE-102 demonstrating dose-dependent decreases in blood LDL-C and PCSK9 Mean reduction in LDL-C of 53%, with a maximum reduction of 69%, observed after a single infusion of VERVE-102 in the 0.6 mg/kg dose cohort in the Heart-2 clinical trial Pulse-1 Phase 1b clinical trial of VERVE-201 targeting ANGPTL3 continues to progress with a program update expected in the second half of 2025 Cash, cash equivalents, and marketable securities of approximately $500 million; cash runway into mid-2027 BOSTON , May 14, 2025 (GLOBE NEWSWIRE) -- Verve Therapeutics, a clinical-stage company developing a new class of genetic medicines for cardiovascular disease, today reported pipeline updates and financial results for the first quarter ended March 31, 2025. “2025 is off to a strong start with both clinical and regulatory progress. Last month, we reported exciting initial data from the Heart-2 clinical trial, which demonstrated that a single infusion of VERVE-102, a base editing medicine targeting PCSK9, was well-tolerated and led to compelling, dose-dependent reductions in LDL-C. These data, along with ongoing durability data of up to two years from our Heart-1 clinical trial, suggest a product profile that could fundamentally transform the journey for patients living with cardiovascular disease from decades of chronic care to a one dose future,” said Sekar Kathiresan, M.D., co-founder and chief executive officer of Verve Therapeutics. “As today’s LDL-C lowering options lead to transient reduction, frequent discontinuation, and thereby, inadequate efficacy, we believe VERVE-102 can become a highly competitive option compared to existing therapies for cardiovascular disease.” “With cash runway into mid-2027, we are well-positioned to achieve our goals. We expect to dose the first patient in the Phase 2 clinical trial of VERVE-102 in the second half of 2025,” Dr. Kathiresan continued. “In addition, we look forward to providing further updates in the second half of 2025, including final data from the dose escalation portion of the Heart-2 trial, delivery of the opt-in package, and a decision from Eli Lilly on the PCSK9 program, as well as a program update for VERVE-201 targeting ANGPTL3.” PCSK9 Program Positive Initial Data from Ongoing Heart-2 Phase 1b Clinical Trial of VERVE-102 VERVE-102 is a novel, in vivo, investigational base editing medicine designed to be a single course treatment that permanently turns off the PCSK9 gene in the liver and durably reduces disease-driving low-density lipoprotein cholesterol (LDL-C). VERVE-102 uses Verve’s proprietary GalNAc lipid nanoparticle (LNP) delivery technology, which has demonstrated a potentially best-in-class safety profile and is designed to allow the LNP to access liver cells using either the low-density lipoprotein receptor (LDLR) or the asialoglycoprotein receptor (ASGPR). VERVE-102 is being evaluated in the Heart-2 open-label Phase 1b clinical trial in two patient populations who require deep and durable reductions of LDL-C levels in the blood: adults living with heterozygous familial hypercholesterolemia (HeFH) and/or adults living with premature coronary artery disease (CAD). To date, the Heart-2 clinical trial has dosed patients in four weight-based dose cohorts, with each cohort expected to be comprised of three to nine participants. In April 2025, Verve presented initial data from the Heart-2 clinical trial with a data cutoff date of March 13, 2025 from 14 participants across the first three cohorts (weight-based cohorts of 0.3 mg/kg, 0.45 mg/kg, and 0.6 mg/kg) with at least 28 days of follow-up for each participant. A single infusion of VERVE-102 demonstrated: A favorable safety profile, with no treatment-related serious adverse events, no clinically significant laboratory abnormalities, and no cardiovascular events observed. Across all 14 participants, there was one infusion related reaction (Grade 2) which involved transient symptoms that resolved with acetaminophen. Dose-dependent decreases in blood LDL-C and PCSK9 protein levels, with mean reductions in blood LDL-C of 53% and PCSK9 protein of 60% in four participants in the 0.6 mg/kg dose cohort. The maximum reduction in blood LDL-C was 69% in a single participant in the 0.6 mg/kg dose cohort. Blood LDL-C and PCSK9 protein reductions are quantified as percent change from baseline using the time-average from day 28 through last available follow-up. Verve also evaluated the pharmacodynamic (PD) data across all 14 participants from the Heart-2 clinical trial of VERVE-102 by total RNA dose in milligrams, which is emerging as a key driver of PD for LNP-delivered in vivo gene editing medicines. Three of the 14 participants received a total RNA dose between 50 and 60 mg, with an average dose received of 55 mg. In this group, VERVE-102 demonstrated time-averaged mean reductions in blood LDL-C of 59% and PCSK9 protein of 65%. Each of the three participants who received a dose ≥ 50 mg achieved a > 50% time-averaged reduction of LDL-C from baseline. The Heart-2 clinical trial is enrolling participants in the fourth dose cohort of 0.7 mg/kg in the United Kingdom, Canada, Israel, Australia, and New Zealand. In March 2025, Verve announced the clearance by the U.S. Food and Drug Administration (FDA) of the investigational new drug (IND) application for VERVE-102. In April 2025, Verve announced the receipt of Fast Track designation for VERVE-102 for the treatment of patient groups with hyperlipidemia and high lifetime cardiovascular risk to reduce LDL-C from the FDA. Fast Track designation is designed to facilitate the development and expedite the review of drugs that are intended to treat serious or life-threatening conditions and demonstrate the potential to address an unmet medical need. Verve expects to announce the final data from the dose escalation portion of the Heart-2 clinical trial, deliver the opt-in package for the PCSK9 program to Eli Lilly and Company (Lilly), and receive a decision from Lilly in the second half of 2025. Subject to regulatory clearance, Verve plans to dose the first patient in the Phase 2 clinical trial of VERVE-102 in the second half of 2025. A favorable safety profile, with no treatment-related serious adverse events, no clinically significant laboratory abnormalities, and no cardiovascular events observed. Across all 14 participants, there was one infusion related reaction (Grade 2) which involved transient symptoms that resolved with acetaminophen. Dose-dependent decreases in blood LDL-C and PCSK9 protein levels, with mean reductions in blood LDL-C of 53% and PCSK9 protein of 60% in four participants in the 0.6 mg/kg dose cohort. The maximum reduction in blood LDL-C was 69% in a single participant in the 0.6 mg/kg dose cohort. Blood LDL-C and PCSK9 protein reductions are quantified as percent change from baseline using the time-average from day 28 through last available follow-up. Three of the 14 participants received a total RNA dose between 50 and 60 mg, with an average dose received of 55 mg. In this group, VERVE-102 demonstrated time-averaged mean reductions in blood LDL-C of 59% and PCSK9 protein of 65%. Each of the three participants who received a dose ≥ 50 mg achieved a > 50% time-averaged reduction of LDL-C from baseline. ANGPTL3 Program Pulse-1 Phase 1b Clinical Trial for VERVE-201 Continues to Progress VERVE-201 is a novel, in vivo, investigational base editing medicine designed to be a single course treatment that permanently turns off the ANGPTL3 gene in the liver to reduce disease-driving LDL-C as well as triglycerides and utilizes Verve’s proprietary GalNAc-LNP delivery technology. VERVE-201 is being developed in two patient populations: patients with refractory hypercholesterolemia (RH), defined as those who are unable to achieve adequate LDL-C reduction with maximally tolerated standard of care therapies, potentially including PCSK9 inhibitors, and patients living with homozygous familial hypercholesterolemia (HoFH), a rare and often fatal inherited cause of premature atherosclerotic cardiovascular disease (ASCVD) characterized by extremely high blood LDL-C. The aim of this medicine is to reduce the heavy treatment burden associated with available therapies, including the requirement for multiple oral, injectable, and intravenous infusions, often administered over decades. VERVE-201 is currently being evaluated in the ongoing Pulse-1 open-label Phase 1b clinical trial, which is designed to evaluate the safety and tolerability of VERVE-201 in adult patients with RH. Endpoints also include pharmacokinetics and changes in blood ANGPTL3 protein and LDL-C levels. Verve remains on track to provide a program update on VERVE-201 in the second half of 2025. LPA Program Development for VERVE-301 Ongoing VERVE-301 is a novel, in vivo, investigational gene editing medicine designed to be a single course treatment that permanently turns off the LPA gene in the liver to reduce blood lipoprotein (a) [Lp(a)] levels and utilizes Verve’s proprietary GalNAc-LNP delivery technology and a novel gene editor. Verve has an exclusive research collaboration with Lilly to advance this program to lower Lp(a) for the treatment of ASCVD. Lp(a) is a genetically validated, independent risk factor for ASCVD, ischemic stroke, thrombosis, and aortic stenosis. This increased risk is most pronounced in individuals with very high Lp(a) concentrations (e.g., ≥ 125 nmol/L). An estimated 1.4 billion people worldwide have an Lp(a) concentration above this threshold. Lp(a) concentrations are determined at birth. Unfortunately, lifestyle changes - such as diet and exercise - as well as currently approved lipid-lowering therapies have minimal to no impact on reducing Lp(a) levels. Verve received a milestone payment from Lilly in the first quarter of 2025 in conjunction with the nomination of VERVE-301 as the development candidate. Preclinical studies for VERVE-301 continue to advance. Upcoming Investor Events Verve plans to participate in a fireside chat during the following investor event: RBC Capital Markets Global Healthcare Conference, May 21 at 3:35 p.m. EDT, New York, NY Recent and Upcoming Medical Meeting Presentations European Atherosclerosis Society 93rd Congress Title: Nonclinical data demonstrate potent and precise inactivation of liver PCSK9 in vivo with the clinical stage GalNAc base editing medicine, VERVE-102 Session: Workshop – New targets for therapy Date: May 5 at 4:55 p.m. BST TIDES USA 2025: Oligonucleotide & Peptide Therapeutics Title: Single-course gene editing to durably lower harmful cholesterol Session: Genome editing technology and applications Date: May 22 at 4:30 p.m. PDT First Quarter 2025 Financial Results Cash Position: Cash, cash equivalents, and marketable securities were $497.1 million as of March 31, 2025, compared with $524.3 million as of December 31, 2024. Verve expects its capital position to be sufficient to fund its operations into mid-2027. Collaboration Revenue: Collaboration revenue was $33.0 million for the first quarter of 2025, compared to $5.7 million for the first quarter of 2024. The increase was primarily due to the recognition of the remaining deferred revenue related to the research collaboration with Vertex Pharmaceuticals upon the notification of termination from Vertex. Collaboration revenue also included an increase in recognition of amounts related to delivery of research services under the company’s collaboration with Lilly. Research & Development (R&D) Expenses: R&D expenses were $54.5 million for the first quarter of 2025, compared to $48.4 million for the first quarter of 2024. Stock-based compensation expense included in R&D expenses was $5.6 million for both the first quarter of 2025 and 2024. General & Administrative (G&A) Expenses: G&A expenses were $15.2 million for the first quarter of 2025, compared to $14.2 million for the first quarter of 2024. Stock-based compensation expense included in G&A expenses was $5.6 million and $4.7 million for the first quarter of 2025 and 2024, respectively. Net Loss: Net loss was $31.0 million, or $0.35 basic and diluted net loss per share, for the first quarter of 2025, compared to $48.7 million, or $0.59 basic and diluted net loss per share, for the first quarter of 2024. About Verve Therapeutics Verve Therapeutics, Inc. (Nasdaq: VERV) is a clinical-stage company developing a new class of genetic medicines for cardiovascular disease with the potential to transform treatment from chronic therapies to single-course gene editing medicines. The company’s lead programs – VERVE-102, VERVE-201, and VERVE-301 – target the three lipoprotein drivers of atherosclerosis: LDL-C, triglycerides, and Lp(a). VERVE-102 is designed to permanently turn off the PCSK9 gene in the liver and is being developed initially for heterozygous familial hypercholesterolemia (HeFH) and ultimately to treat patients with established atherosclerotic cardiovascular disease (ASCVD) who continue to be impacted by high LDL-C levels. VERVE- 201 is designed to permanently turn off the ANGPTL3 gene in the liver and is initially being developed for refractory hypercholesterolemia, where patients still have high LDL-C despite treatment with maximally tolerated standard of care therapies, and homozygous familial hypercholesterolemia (HoFH). VERVE-301 is designed to permanently turn off the LPA gene to reduce Lp(a) levels. Lp(a) is a genetically validated, independent risk factor for ASCVD, ischemic stroke, thrombosis, and aortic stenosis. For more information, please visit www.VerveTx.com. Cautionary Note Regarding Forward Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties, including statements regarding the company’s ongoing Heart-2 clinical trial and Pulse-1 clinical trial; the timing and availability of data for the Heart-2 trial and timing for initiation of the Phase 2 clinical trial for VERVE-102; the timing for delivery of the opt-in package and of Lilly’s decision for the PCSK9 program; the timing of an update for the ANGPTL3 program; the company’s research and development programs; the potential advantages and therapeutic potential of the company’s programs; and the period over which the company believes that its cash, cash equivalents and marketable securities will be sufficient to fund its operating expenses. All statements, other than statements of historical facts, contained in this press release, including statements regarding the company’s strategy, future operations, future financial position, prospects, plans and objectives of management, are forward-looking statements. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. These risks and uncertainties include, but are not limited to, risks associated with the company’s limited operating history; the company’s ability to timely submit and receive approvals of regulatory applications for its product candidates; advance its product candidates in clinical trials; initiate, enroll and complete its ongoing and future clinical trials on the timeline expected or at all; correctly estimate the potential patient population and/or market for the company’s product candidates; replicate in clinical trials positive results found in preclinical studies and/or earlier-stage clinical trials of VERVE-101, VERVE-102, and VERVE-201; advance the development of its product candidates under the timelines it anticipates in current and future clinical trials; obtain, maintain or protect intellectual property rights related to its product candidates; manage expenses; and raise the substantial additional capital needed to achieve its business objectives. For a discussion of other risks and uncertainties, and other important factors, any of which could cause the company’s actual results to differ from those contained in the forward-looking statements, see the “Risk Factors” section, as well as discussions of potential risks, uncertainties and other important factors, in the company’s most recent filings with the Securities and Exchange Commission and in other filings that the company makes with the Securities and Exchange Commission in the future. In addition, the forward-looking statements included in this press release represent the company’s views as of the date hereof and should not be relied upon as representing the company’s views as of any date subsequent to the date hereof. The company anticipates that subsequent events and developments will cause the company’s views to change. However, while the company may elect to update these forward-looking statements at some point in the future, the company specifically disclaims any obligation to do so. Investor Contact Jen Robinson Verve Therapeutics, Inc. jrobinson@vervetx.com Media Contact Ashlea Kosikowski 1AB ashlea@1abmedia.com