Lixivaptan

点击蓝字 关注“华津生物” 常染色体显性多囊肾病（ADPKD）是最常见的遗传性肾脏疾病，也是导致肾衰竭的主要单基因病因。长期以来，托伐普坦作为唯一的疾病修饰疗法，虽验证了cAMP抑制的治疗思路，但其使用受限于多尿副作用和肝毒性风险，且仅能延缓疾病进展，无法根治。 近期发表于Kidney360的综述《Emerging Therapies in Autosomal Dominant Polycystic Kidney Disease》系统梳理了ADPKD治疗领域正在快速兴起的多维度策略，标志着该病管理正从单一通路干预迈向多机制、分层式、个体化治疗的新时代。 核心病理机制与新靶点解析 ADPKD的根源在于多囊蛋白功能缺失，导致纤毛钙信号紊乱、cAMP水平升高、细胞代谢重编程（转向糖酵解），进而驱动囊泡增殖与扩张。最新综述将新兴治疗策略归纳为以下几个关键方向，并已有多项疗法进入临床试验阶段： 1. 恢复多囊蛋白表达：基因剂量疗法  抗miR-17寡核苷酸（Farabursen）：miR-17过表达会抑制*PKD1/PKD2*翻译，降低多囊蛋白水平。新型ASO药物通过抑制miR-17，恢复多囊蛋白表达，在临床前模型中显著减少囊肿负荷。 PC1折叠纠正剂（VX-407）：针对约30%的PKD1错义突变导致蛋白错误折叠、滞留于内质网的问题，小分子药物VX-407作为药理性分子伴侣，帮助突变蛋白正确折叠并运输至纤毛膜，已进入基因型选择的II期临床试验。 2. 阻断局部生长信号：靶向IGF-1通路  抗PAPP-A单克隆抗体（ABBV-CLS-628）：PAPP-A是一种金属蛋白酶，在囊肿微环境中切割IGFBP-4，释放活性IGF-1，促进囊肿上皮增殖。单抗药物通过抑制PAPP-A，局部降低IGF-1活性，显著减缓囊肿生长，目前已进入全球II期试验。 3. 代谢重编程治疗：调整能量与合成代谢  二甲双胍：作为AMPK激活剂，抑制mTORC1信号、降低cAMP-CFTR介导的氯离子分泌，其大规模III期试验（IMPEDE-PKD）正在进行中。 贝派度酸（Bempedoic acid）：ATP柠檬酸裂解酶抑制剂，抑制脂肪合成，临床前研究显示与托伐普坦联用具有协同效应。 GLP-1受体激动剂：除减重、改善胰岛素敏感性外，还具有抗炎、抗纤维化及线粒体支持作用，其ADPKD专用试验已启动。 饮食干预：热量限制、限时进食、生酮饮食等可抑制mTORC1、增加酮体、促进脂肪酸氧化，在早期试点研究中显示出减缓疾病进展的潜力。 4. 新型cAMP调控：PDE4激活剂 作为cAMP水解的关键酶，长型PDE4亚型在囊肿上皮中高表达。其变构激活剂可局部增强cAMP水解，降低PKA活性，抑制囊肿生长，且不引起多尿副作用，目前正迈向首次人体试验。 5. 基因疗法与编辑：迈向功能性治愈 最令人振奋的进展之一是动物模型显示，在囊肿形成后重新表达Pkd1或Pkd2，不仅可阻止疾病进展，甚至可使囊肿消退、肾小管结构恢复正常。这证明ADPKD在适当条件下是可逆的。当前研发重点包括： 递送载体优化：通过定向进化开发肾趋向性AAV载体，或使用脂质纳米颗粒等非病毒平台。 编辑策略多样化：包括CRISPRa上调基因表达、碱基编辑纠正点突变、反式剪接实现大片段基因插入等。 微型PC1构建体：全长PKD1编码区过大（~13 kb），目前正在开发保留功能的截短型转基因作为过渡策略。 表4. 系统梳理并比较了当前处于不同研发阶段的ADPKD基因治疗策略，包括cDNA转导、CRISPR激活（CRISPRa）、碱基编辑、先导编辑、反义寡核苷酸以及翻译通读/剪接调控等六大技术方向。该表从载体装载需求、基因编辑范围、肾脏递送可行性、作用持久性和当前临床开发状态五个维度进行了横向对比，为评估不同基因治疗路径的技术特点与转化潜力提供了框架性参考。 近期失败项目与经验总结 多项临床试验因疗效不足或安全性问题终止，包括：  Venglustat（葡萄糖神经酰胺合酶抑制剂）：II/III期试验因无效而停止。 GLPG2737（CFTR抑制剂）：II期试验未显示疗效。 Lixivaptan（选择性V2受体拮抗剂）：因一例显著转氨酶升高病例，开发暂停。 这些经验强调了临床前模型的预测价值、可靠生物标志物的必要性以及长期用药安全性筛查的重要性。 未来展望：分层组合与精准医学 综述指出，未来ADPKD治疗将呈现分层化、组合化趋势： 近期：托伐普坦联合代谢调节剂（如二甲双胍、GLP-1激动剂）及信号通路抑制剂（如抗PAPP-A单抗）。 中期：引入基因型特异性疗法（如PC1折叠纠正剂）和无多尿副作用的cAMP调节剂（如PDE4激活剂）。 远期：基因编辑或基因增强疗法，旨在持久提升多囊蛋白水平至高于致病阈值，实现功能性治愈。 总 结 ADPKD治疗领域正处于从症状管理向疾病修饰乃至潜在治愈转变的关键时期。多囊蛋白功能恢复、局部信号通路调控、代谢重编程及基因治疗等策略的并行发展，标志着该领域已进入多靶点、多机制的精准治疗新时代。随着基因编辑技术、人工智能药物发现平台及人类肾脏类器官模型的深度融合，未来有望实现基于个体遗传背景和疾病分子特征的完全个性化治疗，最终改善ADPKD患者的长期预后。 参考文献： Chen CY, Hadla M, Khambati I, Kashyap S, Westerfield V, Fedeles S, Besse W, Hopp K, Harris PC, Patel V, Chini E, Salih M, Barry MA, Chebib FT. Emerging Therapies in Autosomal Dominant Polycystic Kidney Disease. Kidney360. 2025 Dec 12 END 关于我们 深圳华津生物科技有限公司致力于提升肾脏疾病研究和肾药开发创新水平。公司与全球最顶尖的干细胞再生医学领域科学家合作，聚焦iPSC来源肾脏细胞、肾类器官、肾类器官芯片及高仿生模拟物平台的打造，为肾脏疾病科研和肾脏药物发现提供最前沿的技术服务和整体解决方案。 公司目前已经建立了Kidnioid®技术平台，其中包括iPSC细胞库、肾类器官及心脏类器官分化技术平台、肾脏类器官疾病模型库，肾类器官芯片平台、动物肾脏疾病模型、分子/蛋白平台、病理平台以及肾类器官培养、分化试剂盒产品等一整套为肾脏疾病研究和肾药开发的完善体系。目前已经为国内众多临床肾病科、大学、科研院所及药企提供产品和技术服务，赢得了客户的信任，已经成为国内肾脏类器官技术平台领头羊。 华津肾类器官平台解决方案 Our Solutions 高度模拟人体生理环境：能够高度贴近人体的真实生理反应，更准确的药物毒性预测。 显著降本增效：大幅削减了药物开发的实验成本与研发周期。 契合伦理趋势：顺应全球减少动物实验的大势。 （点击查看大图） 联系我们 Contact Us 欢迎与我们联系，了解更多肾类器官在药物研发与肾毒性测试中的应用！   地址   广东省深圳市龙华区观澜银星智界2期A座11楼   官方网址   www.nephromedicine.com   联系电话   商务支持 17276665437（李先生） 技术支持 18843183823（田先生） 入群/投稿 13686113433（谭女士） 商务客服1 商务客服2 技术客服 添加客服小助理，了解更多内容 扫码关注华津生物 的官方微信 求点赞 求分享 求喜欢

Investors Claim Significant Losses Following Product Failures ONTARIO, Nov. 10, 2022 /PRNewswire/ -- McCune Law Group, McCune Wright Arevalo Vercoski Kusel Weck Brandt APC (MLG) – a national law firm specializing in Securities Litigation , Commercial Litigation, and Class Actions – informs investors that a class action lawsuit has been filed in the United States District Court for the Central District of California (captioned Fernandes v. Centessa Pharmaceuticals plc, No. 22-cv-07030 (C.D. Cal.)) on behalf of investors who purchased and/or acquired (1) Centessa Pharmaceuticals (NASDAQ: CNTA) ("Centessa" or the "Company") American Depositary Shares ("ADSs") pursuant and/or traceable to the Offering Documents issued in connection with Centessa's initial public offering conducted on or about May 28, 2021 (the "IPO"); and/or (2) Centessa securities between May 28, 2021 and June 1, 2022, inclusive (the "Class Period"). Investors have until November 28, 2022, to seek appointment as lead plaintiff in the action. Centessa Pharmaceuticals develops multiple medical products such as lixivaptan, a vasopressin V2 receptor small molecule inhibitor in Phase 3 clinical development for the treatment of autosomal dominant polycystic kidney disease. Centessa also is developing a small molecule pharmacological chaperon folding corrector of the Z variant of the DNA encoding protein alpha-1-antitrypsin, ZF874, which is in Phase 1 clinical development for the treatment of A1AT deficiency. On May 28, 2021, Centessa conducted the Initial Public Offering, issuing 16.5 million of its securities to the public at the price of $20 per ADS. The claims under investigation are whether Centessa made false and/or misleading statements and/or concealed that : (1) the company's product, lixivaptan, was less safe than Centessa had represented; (2) Centessa overstated lixivaptan's clinical and commercial prospects; (3) another Centessa product, ZF874, was less safe than it had been represented; (4) Centessa overstated ZF874's clinical and commercial prospects while downplaying the drug's safety issues; and (5) as a result, documents issued in connection with Centessa's initial public offering and the company's public statements throughout the class period were materially false and/or misleading and failed to state information required. On November 1, 2021, Centessa announced results from a Phase 1 study evaluating ZF874's in treating AATD. Centessa announced, among other things, potential safety issues related to increases in liver enzymes alanine aminotransferase ("ALT") and aspartate aminotransferase ("AST") in one of the study subjects. On this news, Centessa's ADS price fell by more than 18%. Then, on June 2, 2022, Centessa announced "it has made the strategic decision to discontinue development of lixivaptan for [ADPKD]," citing "a recent observation of [ALT] and [AST] elevations in one subject" from a Phase 3 study of lixivaptan that was designed to assess liver and non-liver safety in certain subjects. On this news, Centessa's ADS price fell by nearly 28%. Last, on August 10, 2022, Centessa announced "its decision to discontinue development of ZF874 following a recent report of an adverse event (AE) involving elevated liver enzymes (AST/ALT) in a . . . subject dosed with 5 mg/kg BID of ZF874 in the Phase 1 study." Centessa stated that "[b]ased on the results observed to date, [Centessa] concluded that ZF874 was unlikely to achieve the desired target product profile." On this news, Centessa's ADSs price fell by an additional 5.19%, further harming investors. McCune Law Group hopes to leverage its Securities Litigation practice area to protect investors from dishonest or misleading business practices that take advantage of their investors. "Centessa talked up their products while understating or ignoring the problems they faced," says MLG Partner Elaine. S Kusel , "Without the proper understanding of the situation at Centessa, investors were blindsided by these poor performance results and safety concerns. They deserve better from the businesses they support." About the Lead Plaintiff Process : The Private Securities Litigation Reform Act of 1995 permits any investor who purchased or otherwise acquired Centessa ADSs pursuant and/or traceable to the Offering Documents issued in connection with the IPO and/or Centessa securities during the Class Period to seek appointment as lead plaintiff. The lead plaintiff is generally the movant with the greatest financial interest in the relief sought by the putative class who is also typical and adequate of the putative class. The lead plaintiff acts on behalf of all other class members in directing the Centessa class action lawsuit. The lead plaintiff can select a law firm of its choice to litigate the Centessa class action lawsuit. An investor's ability to share in any potential future recovery is not dependent upon serving as lead plaintiff of the Centessa class action lawsuit. About MLG's Securities Litigation Practice: The Securities Litigation attorneys of MLG provide representation for investors who have been wronged through fraud, scams, and schemes. Our team has many years of experience bringing claims on behalf of investors and pursues all avenues of compensation to maximize our clients' recovery as they navigate this tumultuous time. With hard-hitting tactics and dedicated legal professionals protecting our clients' interests, MLG's Securities Litigation Practice Group hopes to hold companies accountable for their unfair or illegal financial practices. About McCune Law Group, McCune Wright Arevalo Vercoski Kusel Weck Brandt APC: McCune Law Group has a deep history of success for its clients, including a $203 million verdict against Wells Fargo Bank, recovery of over $1 billion for its clients, and over 100 contingency cases with recovery of $1 million or more. MLG maintains California offices in Ontario, San Bernardino, Calimesa, Palm Desert, and Irvine and supports its national practice with offices in Illinois and New Jersey. For over 30 years, MLG has successfully represented Southern California residents and grown to be the largest Inland Empire consumer rights firm. Visit  mccunewright.com  for more information.  CONTACT: [email protected] SOURCE McCune Law Group, McCune Wright Arevalo Vercoski Kusel Weck Brandt, APC