A Multicentric, Randomized, Double-blind, Parallel, Placebo-controlled Phase III Study to Assess the Safety and Efficacy of Sovateltide in Patients with Acute Cerebral Ischemic Stroke.

Extensive research is being conducted in search of neuroprotective agents for possible use in the acute phase of stroke and agents that can be used for neurorepair in later stages of stroke. Several trials have been conducted and are in progress using different pharmacological agents, but none of the studies involve the stimulation of ETB receptors to treat cerebral ischemic stroke. Sovateltide (IRL-1620, PMZ-1620) has been effective in animal models of cerebral ischemic stroke. Its safety and tolerability have been demonstrated in a human phase I study with 7 subjects. Clinical phase II and III results indicate that sovateltide is a novel, first-in-class, highly effective drug candidate for treating cerebral ischemic stroke. Safety and significant efficacy in improving the National Institutes of Health Stroke Scale (NIHSS), Modified Rankin scale (mRS), and Barthel index (BI) obtained in phase II and III studies in patients with cerebral ischemic stroke in India are convincing and encouraged us to investigate its safety and efficacy in cerebral ischemic stroke patients in the United States. Therefore, the plan is to conduct a phase III clinical study to evaluate the safety and efficacy of sovateltide therapy along with standard of care in patients of acute ischemic stroke.

开始日期2025-01-01

申办/合作机构

Pharmazz, Inc.

CTRI/2024/07/070459

/ Not yet recruiting临床4期

Safety and efficacy of sovateltide in acute cerebral ischemic stroke patients at a tertiary care centre-a double blinded block randomised placebo controlled study - NIL

开始日期2024-07-22

申办/合作机构

Pondicherry Institute of Medical Sciences

NCT05955326

/ Recruiting临床4期

A Prospective, Multicentric, Randomized, Double-blind, Parallel, Phase IV Study to Assess the Safety and Efficacy of Sovateltide in Patients With Acute Cerebral Ischemic Stroke

This is a prospective, multicenter, randomized, double-blind, parallel, phase IV study designed to evaluate the safety and efficacy of sovateltide (PMZ-1620, IRL-1620) as a potential treatment for cerebral ischemic stroke.

开始日期2024-01-08

申办/合作机构

Pharmazz, Inc.

100 项与 Sovateltide 相关的临床结果

登录后查看更多信息

100 项与 Sovateltide 相关的转化医学

登录后查看更多信息

100 项与 Sovateltide 相关的专利（医药）

登录后查看更多信息

337

项与 Sovateltide 相关的文献（医药）

2025-03-01·Experimental Neurology

Microglial cell proliferation is regulated, in part, by reactive astrocyte ETBR signaling after ischemic stroke

Article

作者: Reed, Leah F ; Del Rio-Guerra, Roxana ; Poynter, Matthew E ; McInnis, John J ; Spees, Jeffrey L ; LeComte, Matthew D ; Torsney, Emily E

Reciprocal communication between reactive astrocytes and microglial cells provides local, coordinated control over critical processes such as neuroinflammation, neuroprotection, and scar formation after CNS injury, but is poorly understood. The vasoactive peptide hormone endothelin (ET) is released and/or secreted by endothelial cells, microglial cells and astrocytes early after ischemic stroke and other forms of brain injury. To better understand glial cell communication after stroke, we sought to identify paracrine effectors produced and secreted downstream of astroglial endothelin receptor B (ETB_R) signaling. Using a genetic loss-of-function screen, we identified angiopoietin-2 (Ang-2) as a factor produced by reactive astrocytes in response to ET. In experiments with primary adult astrocytes stimulated by IRL1620, a specific ETB_R agonist, we found that ERK1/2 and NFkB mediated the effects of ET on Ang-2 production. To determine astroglial Ang-2 levels in vivo, reactive astrocytes expressing the high affinity glutamate transporter (GLAST, EAAT1) were isolated by magnetic-activated cell sorting 3 days after stroke. Astrocytes obtained from the ipsilateral hemisphere expressed significantly more Ang-2 compared with astrocytes isolated from the contralateral hemisphere, or from cortices of sham-operated (control) mice. Notably, analysis of microglia sorted from CX3CR1-eGFP mice demonstrated increased cell surface expression of Tie-2, the Ang-2 receptor, on cells obtained from ipsilateral versus contralateral tissue. Addition of recombinant Ang-2 to astrocyte-conditioned medium significantly increased the number of SIM-A9 murine microglial cells cultured under hypoxic conditions (1 % oxygen for 48 h). In transgenic GFAP-CreER™-EDNRB-^fl/fl mice with stroke, conditional knockout of astroglial ETB_R significantly decreased the number of proliferating cells in the peri-infarct area with a microglial phenotype (Ki67⁺/CD11b⁺). Our results indicate that Ang-2, and possibly other paracrine effectors functioning downstream of astroglial ETB_R signaling, are important mediators of microglial cell dynamics after stroke.

2024-12-01·Drugs

Efficacy and Safety of Sovateltide in Patients with Acute Cerebral Ischaemic Stroke: A Randomised, Double-Blind, Placebo-Controlled, Multicentre, Phase III Clinical Trial

Article

作者: Jain, Dinesh ; Sundarachary, Nagarjunakonda Venkata ; Aralikatte, Saroja ; Gulati, Anil ; Vijaya, Pamidimukkala ; Siddiqui, Mohd Shafat Imam ; Vibha, Deepti ; Karadan, Ummer ; Agrawal, Nilesh Radheshyam ; Sharma, Mridul ; Sardana, Vijay ; Pandian, Jeyaraj Durai ; Ramakrishnan, T C R ; Adwani, Sikandar Gokuldas ; Joshi, Deepika ; Sidhu, Gursaran Kaur ; Anand, Sidharth Shankar ; Rai, Hari Prakash ; Khurana, Dheeraj

BACKGROUND AND OBJECTIVESSovateltide (Tycamzzi™), an endothelin-B (ET-B) receptor agonist, increases cerebral blood flow, has anti-apoptotic activity, and promotes neural repair following cerebral ischaemic stroke. The objectives of this study were to evaluate the efficacy and safety of sovateltide in adult participants with acute cerebral ischaemic stroke.METHODSThis was a randomised, double-blind, placebo-controlled, multicentre, Phase III clinical trial of sovateltide in participants with cerebral ischaemic stroke receiving standard of care (SOC) in India. Patients aged 18-78 years presenting up to 24 h after the onset of symptoms with radiologic confirmation of ischaemic stroke and a National Institutes of Health Stroke Scale score (NIHSS) of ≥ 6 were enrolled. Patients with recurrent stroke, receiving endovascular therapy, or with intracranial haemorrhage were excluded. The study drug (saline or sovateltide [0.3 µg/kg] was administered intravenously in three doses at 3 ± 1 h intervals on Days 1, 3, and 6, and follow-up was 90 days). The Multivariate Imputation by Chained Equations (MICE) was used to impute the missing assessments on the endpoints. An unpaired t-test, two-way analysis of variance with Tukey's multiple comparison test, and the Chi-square test were used for the statistical analysis. The objective was to determine at Day 90 (1) the number of patients with a modified Rankin Scale score (mRS) 0-2, and (2) the number of patients with an NIHSS 0-5 at 90 days.RESULTSPatients were randomised with 80 patients in the sovateltide and 78 in the control group. Patients received the investigational drug at about 18 h of stroke onset in both control and sovateltide groups. The median NIHSS at randomisation was 10.00 (95% CI 9.99-11.65) in the control group and 9.00 (95% CI 9.11-10.46) in the sovateltide group. Seventy patients completed the 90-day follow-up in the control group and 67 in the sovateltide group. The proportion of intention-to-treat (ITT) patients with mRS 0-2 score at Day 90 post-randomisation was 22.67% higher (odds ratio [OR] 2.75, 95% CI 1.37-5.57); similarly, the proportion of patients with NIHSS score of 0-5 at Day 90 was 17.05% more (OR 2.67, 95% CI 1.27-5.90) in the sovateltide group than in the control group. An improvement of ≥ 2 points on the mRS was observed in 51.28% and 72.50% of patients in the control and sovateltide groups, respectively (OR 2.50, 95% CI 1.29-4.81). Seven of 78 patients (8.97%) in the control group and 7 of 80 (8.75%) in the sovateltide group developed intracranial haemorrhage (ICH). The adverse events were not related to sovateltide.CONCLUSIONSThe sovateltide group had a greater number of cerebral ischaemic stroke patients with lower mRS and NIHSS scores at 90 days post-treatment than the control group. This trial supported the regulatory approval of sovateltide in India, but a multinational RESPECT-ET_B trial will be conducted for US approval.TRIAL REGISTRATIONClinical Trials Registry, India (CTRI/2019/09/021373) and the United States National Library of Medicine, ClinicalTrials.gov (NCT04047563).

2024-10-01·Neurocritical Care

Sovateltide (ILR-1620) Improves Motor Function and Reduces Hyperalgesia in a Rat Model of Spinal Cord Injury

Article

作者: Galanos, Antonis ; Iacovidou, Nicoletta ; Xanthos, Theodoros ; Karampela, Eleftheria ; Mavridi, Artemis ; Gkiokas, George ; Mavridis, Theodoros

BACKGROUNDSpinal cord injury (SCI) presents a major global health challenge, with rising incidence rates and substantial disability. Although progress has been made in understanding SCI's pathophysiology and early management, there is still a lack of effective treatments to mitigate long-term consequences. This study investigates the potential of sovateltide, a selective endothelin B receptor agonist, in improving clinical outcomes in an acute SCI rat model.METHODSThirty male Sprague-Dawley rats underwent sham surgery (group A) or SCI and treated with vehicle (group B) or sovateltide (group C). Clinical tests, including Basso, Beattie, and Bresnahan scoring, inclined plane, and allodynia testing with von Frey hair, were performed at various time points. Statistical analyses assessed treatment effects.RESULTSSovateltide administration significantly improved motor function, reducing neurological deficits and enhancing locomotor recovery compared with vehicle-treated rats, starting from day 7 post injury. Additionally, the allodynic threshold improved, suggesting antinociceptive properties. Notably, the sovateltide group demonstrated sustained recovery, and even reached preinjury performance levels, whereas the vehicle group plateaued.CONCLUSIONSThis study suggests that sovateltide may offer neuroprotective effects, enhancing neurogenesis and angiogenesis. Furthermore, it may possess anti-inflammatory and antinociceptive properties. Future clinical trials are needed to validate these findings, but sovateltide shows promise as a potential therapeutic strategy to improve functional outcomes in SCI. Sovateltide, an endothelin B receptor agonist, exhibits neuroprotective properties, enhancing motor recovery and ameliorating hyperalgesia in a rat SCI model. These findings could pave the way for innovative pharmacological interventions for SCI in clinical settings.

项与 Sovateltide 相关的新闻（医药）

2024-08-26

·医药观澜

10家创新药公司完成新一轮融资，1家来自中国

▎药明康德内容团队报道根据即刻药数数据库，上周（8月19日~8月25日）全球生物制药领域至少10家致力于创新药研发的公司宣布完成新一轮融资，其中包括1家中国公司。这些获得融资的新锐主要致力于开发小分子药物、RNA疗法、线粒体疗法、癌症免疫疗法等，涉及肾病、肥胖和代谢，心血管以及癌症等治疗领域。 Borealis Biosciences 轮次：A轮金额：1.5亿美元 8月22日，Borealis Biosciences宣布走出隐匿模式并获得创始投资者Versant Ventures和诺华（Novartis）合计1.5亿美元的A轮融资。该公司也与诺华达成战略研究合作，共同开发用于治疗肾脏疾病的RNA疗法。 Borealis旨在通过开发RNA疗法促进科学和转化上的突破，以满足肾病患者的主要未满足需求。该公司的目标包括更好地了解患者分层、遗传学定义的治疗靶标，并致力将治疗有效载荷递送到特定肾细胞类型，以及推进RNA化学的进展。此次诺华参与了Borealis的A轮融资，并承诺提供高达1亿美元的前期和短期研究资金。作为协议的一部分，诺华将有权从Borealis收购两个未来的潜在开发项目，Borealis则有资格在达到临床和监管等里程碑后获得总额达7.5亿美元款项。 Ambrosia Biosciences 轮次：A轮金额：1600万美元 8月21日，Ambrosia Biosciences宣布成功完成A轮融资。本次融资总额为1600万美元，由BVF Partners和Boulder Ventures领投。Ambrosia将利用这笔融资扩大其药物发现项目和实验室运营。 Ambrosia Biosciences专注于发现和开发针对GLP-1受体及其他B类G蛋白偶联受体的全新口服小分子疗法。该公司的研发团队来自原Array BioPharma的药物化学团队。在Array BioPharma被辉瑞收购后，这一团队再度启程，在Ambrosia公司将利用在小分子药物发现方面的专长，开发治疗肥胖症和代谢疾病的药物。 Retension Pharmaceuticals 轮次：A轮金额：1040万美元 8月21日，Retension Pharmaceuticals宣布完成A轮1040万美元融资。Retension是一家临床阶段生物医药公司，专注于开发针对高血压和心血管疾病的创新疗法。该公司的主要候选药物RTN-001是在赛诺菲的全球独家许可下开发，为一款第二代PDE5抑制剂。与早期用于勃起功能障碍的PDE5抑制剂不同，该产品被设计优先分布于心血管组织，从而有望克服第一代PDE5抑制剂在高血压领域的局限性。在此前包括265多名受试者的多项临床试验中，该药耐受性良好，显示出对难治性高血压患者的疗效。根据新闻稿，本轮融资将用于启动RTN-001的一项2期临床研究，针对服用两种或两种以上抗高血压药物仍不受控制的高血压患者。 Pharmazz 轮次：战略投资金额：1500万美元 8月21日，Pharmazz公司宣布和Sun Pharma签署一项协议，Sun Pharma将向Pharmazz投资约1500万美元，支持其完成sovateltide治疗急性脑缺血患者的关键3期研究。同时双方将扩大此前签署的许可协议，Sun Pharma将拥有sovateltide在印度以及其他新兴国家的商业化权利。Sovateltide是一种高选择性内皮素B受体激动剂，可增加血流量，显示抗凋亡活性，保护神经线粒体，促进神经血管重塑。 Pharmazz公司专注于发现、收购、开发和商业化针对重症监护医学的治疗方法，产品类型包括肽和其他小分子药物。该公司正在开发三种针对多种重症监护适应症的新型药品，主要产品centhaquine用于治疗低血容量性休克，第二种化合物Sovateltide用于治疗脑缺血性中风、阿尔茨海默病和其他神经退行性疾病。第三种化合物正在开发中，用于治疗糖尿病酮症酸中毒和消除阿片类药物耐受。 Pathalys Pharma 轮次：B轮金额：1.05亿美元 8月20日，专注于肾病疗法研发的Pathalys Pharma宣布完成1.05亿美元的B轮融资，用于完成两项正在进行的临床试验，向美国FDA申报NDA以及加快批准前的商业化准备。该轮超额融资由TCGX牵头，其他投资者也加入其中，包括JP Morgan Life Sciences Private Capital、Samsara BioCapital、Marshall Wace、KB Investment、JPS Growth Investment Limited Partnership，以及得到了创始投资方Catalys Pacific和DaVita Venture Group的支持。 Pathalys专注的重点领域之一是改进继发性甲状旁腺功能亢进症（SHPT）的治疗。该公司在研疗法upacicalcet是一种新型拟钙剂（calcimimetic）。拟钙剂是一种通过激活钙敏感受体来模仿钙在组织上作用的药物，常用于治疗继发性SHPT。Upacicalcet可在透析结束时通过预填充注射器进行静脉注射。研究表明，它能有效降低甲状旁腺激素水平，并且可能为患者提供更好的耐受性。目前在接受透析的终末期肾病患者中进行的关键性3期临床试验项目已经完成首批患者入组。 GondolaBio 轮次：未知轮金额：3亿美元日前，BridgeBio Pharma公司披露，在投资者的支持下成立了一家名为GondolaBio的新公司，并将针对红细胞生成性原卟啉症、α-1抗胰蛋白酶缺乏症和结节性硬化症的早期临床和临床前项目转移到GondolaBio继续开发。此次GondolaBio的投资者包括Viking Global Investors LP、Patient Square Capital、红杉资本（Sequoia Capital）、Frazier Life Sciences、Cormorant Asset Management、Aisling Capital等机构。这些投资者承诺提供3亿美元的分期融资。同源康医药轮次：IPO 金额：5.06亿港元 8月20日，同源康医药正式在港交所上市，募资约5.06亿港元，约70%将用于核心产品的研究、开发及商业化，约20%将用于其他候选产品研发，约3%将用于潜在战略收购或合作机会。同源康医药致力于开发差异化癌症靶向疗法，以满足亟待满足的医疗需求，尤其是肺癌领域。该公司已建立由11款候选药物组成的管线，包括处于3期关键临床阶段的核心产品TY-9591（第三代EGFR-TKI）、其他6款临床阶段产品，以及4款临床前或早期开发阶段产品。 Vandria SA 轮次：A轮融资金额：3070万美元 8月21日，开发线粒体疗法的Vandria SA宣布完成A轮融资的第二次融资，使其总融资金额达到3070万美元（2830万瑞士法郎）。此次Hevolution Foundation和Dolby Family Ventures加入成为投资方，原创始风险投资公司为ND Capital。 Vandria正在开发一种新靶点小分子诱导剂，可诱导线粒体吞噬（选择性去除和替换受损线粒体）和抗炎作用，有望治疗与年龄相关的慢性疾病。其主要候选者VNA-318在临床前研究中被证明可显著改善记忆和学习。VNA-318在阿尔茨海默病和帕金森病模型中具有强疾病调节作用。而且毒性研究表明其具有广泛的安全窗口。除了VNA-318，Vandria还拥有其他促有丝分裂的小分子管线，以解决肌肉、肺和肝脏疾病中未满足的医疗需求。 PhotonPharma 轮次：种子轮金额：250万美元 8月21日，PhotonPharma宣布完成250万美元的种子轮融资。这笔资金将支持Innocell™的1期临床试验，这是一种治疗晚期癌症的新疗法。该公司成立于2018年，致力于开创新型药物输送系统和靶向治疗，旨在改善癌症治疗。2024年2月，PhotonPharma获得美国FDA的批准开始进行Innocell™的临床开发。临床1期试验预计将于2024年第四季度招募首位患者。 Talus Bioscience 轮次：种子+轮金额：1120万美元 8月20日，Talus Bioscience宣布获得1120万美元的种子+轮融资，由Two Bear Capital领投，WRF Capital、NFX、YC Continuity Fund、Funders Club VC和BoxOne Ventures参投。融资资金将用于推进其在研治疗项目，包括短距离驱动癌症和一种与前列腺有关的非药物转录因子等。 Talus Bio创立于2020年，专注于转录因子调节相关疾病的治疗研发。转录因子通过与DNA结合来协调基因开关进而调节蛋白表达。当它们出现问题时，通常会导致癌症和其他疾病过程。该公司专有发现平台MARMOT（转录因子正常调节的多重检测）集成了人工智能、下一代蛋白质组学、合成化学和计算生物学来设计和研究药物、蛋白质和基因组学。希望在投资市场的助力下，更多前沿技术和创新疗法可以早日造福病患。参考资料： [1]各公司官网和公开资料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。转载授权及其他合作需求，请联系wuxi_media@wuxiapptec.com。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。

并购临床2期免疫疗法信使RNA寡核苷酸

2024-08-21

·GlobeNewswire-Health Care

Pharmazz Inc. and Sun Pharma entered into an agreement under which Sun Pharma will invest up to $15 Million in Pharmazz, Inc.

Strategic equity investment of $15 M to support completion of Pharmazz's pivotal Phase 3 study for Sovateltide to treat patients with acute cerebral ischemic strokeExpansion of the exclusive license agreement with Sun Pharma for marketing and distribution of Sovateltide in India to certain additional Emerging Market countries WILLOWBROOK, Ill., Aug. 21, 2024 (GLOBE NEWSWIRE) -- Pharmazz, Inc. (“Pharmazz” or the “Company”), a biopharmaceutical company focused on developing and commercializing novel therapeutics to treat patients in critical care, announced that it has entered into an agreement with Sun Pharmaceutical Industries Limited (Reuters: SUN.BO, Bloomberg: SUNP IN, NSE: SUNPHARMA, BSE: 524715, "Sun Pharma" and includes its subsidiaries and/or affiliated companies) to support development of Sovateltide and extend the scope of its strong working relationship to commercialize a first-in-class innovative drug, Sovateltide (Tyvalzi™). Developed by Pharmazz for potential global use, Sovateltide is indicated for treating acute cerebral ischemic stroke in markets where it is launched. Pursuant to the agreement, Sun Pharma will make a strategic equity investment of $15 M in two tranches, subject to certain conditions, to support the development of Pharmazz's lead compound, Sovateltide, through a pivotal Phase 3 trial in the U.S. to treat patients with acute cerebral ischemic stroke. As the world's leading specialty generic pharmaceutical company, Sun Pharma’s equity investment further validates the promising developmental pathway for Sovateltide. Previously, Pharmazz entered into a license agreement with Sun Pharma to commercialize Sovateltide in India under Sun Pharma owned brand name Tyvalzi™. This collaboration is now being expanded to drive the asset’s commercialization efforts in certain additional Emerging Market countries. Sun Pharma’s investment and collaboration will bring valuable operational expertise and strategic inputs to the Pharmazz management team. About Sovateltide Sovateltide is a first-of-its-kind drug to treat acute cerebral ischemic stroke that can be administered up to 24 hours after the onset of symptoms. Pharmazz has received agreement from the U.S. Food and Drug Administration (FDA) under a Special Protocol Assessment (SPA) for the study design and statistical analysis plan of its Phase 3 clinical trial of Sovateltide for treating acute cerebral ischemic stroke patients. The protocol is titled, “A Multicentric, Randomized, Double-blind, Parallel, Placebo-controlled Phase III Study to Assess the Safety and Efficacy of Sovateltide in Patients With Acute Cerebral Ischemic Stroke.” ClinicalTrials.gov ID: NCT05691244. Sovateltide is a first-in-class drug to treat acute cerebral ischemic stroke, a condition in which the loss of blood supply to the brain prevents brain tissue from receiving oxygen and nutrients, resulting in potential brain damage, neurological deficits, or death. Sovateltide promotes neurovascular remodeling by forming new neurons (neurogenesis) and blood vessels (angiogenesis). Sovateltide also protects neural mitochondria and enhances their biogenesis. It can be given to patients along with thrombolytic, and about 30,000 acute cerebral ischemic patients have been treated in India. About Pharmazz, Inc. Pharmazz is a privately held company developing novel products in critical care medicine. Pharmazz obtained marketing authorization for two of its first-in-class drug molecules, Centhaquine and Sovateltide, for hypovolemic shock and acute cerebral ischemic stroke, respectively, in India. In addition, the U.S. Food and Drug Administration (FDA) has approved two phase III INDs for Centhaquine as an agent for hypovolemic shock and Sovateltide for acute cerebral ischemic stroke. Additional information may be found on the Company’s website, www.pharmazz.com, and follow us on LinkedIn & X (Formerly Twitter). About Sun Pharmaceutical Industries Limited (CIN - L24230GJ1993PLC019050): Sun Pharma is the world’s leading specialty generics company with a presence in specialty, generics and consumer healthcare products. It is the largest pharmaceutical company in India and is a leading generic company in the U.S. as well as global emerging markets. Sun Pharma’s high-growth global specialty portfolio spans innovative products in dermatology, ophthalmology, and onco-dermatology and accounts for over 18% of company sales. The company’s vertically integrated operations deliver high quality medicines, trusted by physicians and consumers in over 100 countries. Its manufacturing facilities are spread across six continents. Sun Pharma is proud of its multicultural workforce drawn from over 50 nations. For further information, please visit www.sunpharma.com and follow us on LinkedIn & X (Formerly Twitter). Disclaimer: Statements in this “Document” describing the Company’s objectives, projections, estimates, expectations, plans or predictions, or industry conditions or events may be “forward-looking statements” within the meaning of applicable securities laws and regulations. Actual results, performance, or achievements could differ materially from those expressed or implied. The Company undertakes no obligation to update or revise forward-looking statements to reflect developments or circumstances that arise or to reflect the occurrence of unanticipated developments/circumstances after the date hereof. Contacts: Pharmazz, Inc. Investors Media David Costello Shruti Gulati Tel+1 630 780 6087Tel+1 630 780 6087E maildavid.costello@pharmazz.comE mailshruti.gulati@pharmazz.com

临床3期引进/卖出上市批准

2024-05-27

·CPHI制药在线

浅谈内皮素受体靶向药进展，适应症愈发多样化

关注并星标CPHI制药在线内皮素（ET）是一类由21个氨基酸组成的内源性多肽激素，具有强烈而持久的缩血管效应。此外，ET还参与心血管细胞的凋亡、分化和表型转化等多种病理过程，是心血管活动的重要调节因子之一。 ET包括ET-1、 ET-2和ET-3三种亚型，其中ET-1主要由血管内皮细胞合成，ET-2由肠道和肾脏产生，ET-3由神经组织释放。ET-2和ET-3与ET-1在N末端的2个和5个残基上存在差异，这决定它们在受体结合和亲和力上的差异。 ET通过作用于内皮素受体（ETR）调节人体多种重要的生理和病理过程。ETR属于典型的A类G蛋白偶联受体，包括ETA和ETB两种类型，其中ETA受体与ET-1和ET-2的结合亲、和力高于与ET-3，ETB受体与这三种异肽的结合亲和力相当。在被ET-1激活后，ETA受体和ETB受体呈现相反的血管调节作用：ETA受体激活导致长时间的血管收缩效应，而ETB受体则介导血管扩张。内皮素系统在维持血管稳态中发挥着重要作用，与多种器官系统的血管疾病密切相关，是治疗心血管系统疾病的重要靶标之一。ETR作为内皮素系统的关键组成部分，因此成为药企积极布局的热门靶点。全球已获批的ETR靶向药据不完全统计，目前全球监管机构已批准7款ETR靶向药，这些药物主要针对ETA受体，被批准用于治疗肺动脉高压。辉瑞的ETA受体拮抗剂西他生坦（sitaxentan，Thelin）也曾获监管机构批准，但因可能引起不能预测的严重肝损伤撤市。值得一提的是，近几年获批的ETR靶向药适应症与此前获批的不同，除了心脑血管疾病，还涉及肾病。具体品种来看，克拉佐生坦是Idorsia公司开发的一种强效、选择性 ETA 受体拮抗剂，2022年1月在日本被批准用于预防脑血管痉挛、血管痉挛相关的脑梗死以及动脉瘤性蛛网膜下腔出血（aSAH）术后脑缺血症状。阿普昔腾坦是一款新型口服双重ETA/ETB拮抗剂，可有效抑制ET-1与ETA和ETB的结合，从而阻断ET-1的作用。该药是马昔腾坦的活性代谢产物，具有更长的半衰期（48 h vs. 14 h），可以1天1次使用，降低血压，是第一个用于高血压治疗的ET受体拮抗剂。2024年3月，该药被FDA批准用于治疗难治性高血压，成为30多年来高血压领域获批的全新机制药物。 Sparsentan是一种每日一次的口服小分子药物，选择性靶向ETA受体和血管紧张素II 1型受体（AT1R）。2023年2月，FDA加速批准Sparsentan用于降低有快速疾病进展风险的原发性IgAN成人的蛋白尿，通常尿蛋白/肌酐比(UPCR) ≥1.5g/g。这使Sparsentan成为首个获批治疗IgAN的非免疫抑制疗法。不过Sparsentan上市后遭遇多重质疑，首先是收到了FDA肝毒性和胚胎/胎儿毒性的黑框警告，其次在跟厄贝沙坦（血管舒张素Ⅱ受体阻滞剂）的"头对头"较量中错过了III期研究的次要终点。 Sovateltide是一种高选择性ETB受体激动剂，可增加血流量，显示抗凋亡活性，保护神经线粒体，促进神经血管重塑。2023年5月，该药在日本被批准用于治疗高血压急性脑缺血性中风。ETR靶向药研究进展此外，目前全球还有多款在研ETR靶向药，详见下表。在研ETR靶向药大多作用于ETA受体。在研ETB受体靶向药整体进展较ETA受体靶向药慢，且适应症涉及肿瘤。而且，在研ETR靶向药的药物类型也比较多样，除了小分子化药，还包括单抗、抗体偶联药物（ADC）。 Atrasentan进展较快，处于3期临床。该药是Chinook开发的ETA受体拮抗剂，可选择性阻断ETA受体，通过阻断肾小球系膜细胞活化，直接的抗炎和抗纤维化，降低球囊内压力和肾小球滤过屏障大分子通透性来减少免疫球蛋白A肾病(IgAN) 患者的尿蛋白。2023年6月，诺华通过收购Chinook将Atrasentan纳入囊中。2023年10月，atrasentan治疗高危进展型IgA肾病的关键3期临床试验ALIGN取得积极中期结果：研究达到主要疗效终点，IgAN患者中的蛋白尿具有统计学意义的显著减少。研究中Atrasentan的整体安全性及耐受性良好。我国药企在ETR靶点也有布局。智康弘义的SC0062是针对慢性肾脏病的ETA受体小分子拮抗剂，其针对慢性肾脏病进行了全新的分子设计，具有独特的ETA高选择性，目标在保证疗效的同时进一步提升药物安全性。目前，SC0062正在开展针对IgA肾病和糖尿病肾脏病的2期临床研究。临床前研究表明，SC0062具有良好的活性，能够有效改善急性肾损伤和慢性肾脏病模型的病理评分。在已完成的临床I期研究中，SC0062表现出良好的安全性和耐受性及药代动力学特征，同时未发现水钠潴留等副作用，有望成为潜在的Best-in-Class药物。信立泰的SAL0120是其自主研发的小分子ETA受体拮抗剂，通过选择性拮抗ETA受体，在现有用药基础上达到进一步降低血压的目的，拟开发适应症包括轻、中度原发性高血压。鸿运华宁开发了两款ETR靶向药。其中GMA131是其自主研发的一款ETA靶向单抗。临床前及临床研究显示：GMA131具有良好的安全性，且在高脂饲料联合STZ诱导的糖尿病肾病模型中表现出了优于小分子内皮素受体拮抗剂（ERA）的疗效。2022年11月，GMA131在美国获批临床，用于治疗糖尿病肾病。 ETB靶向药较少，其中DEDN6526A是一款ADC类候选药物，由人源化 IgG1 抗 ETB单克隆抗体MEDN6000A和一种强效抗有丝分裂剂(MMAE)通过蛋白酶抑制连接体马来酰亚胺基缬氨酸-瓜氨酸-对氨基苄氧羰基 (MC-VC-PAB) 连接而成。MEDN6000A 在与其配体结合位点不同的表位上对 ETB 具有选择性和高结合亲和力。总结整体来看，ETR是个多面手，其靶向药除被批准治疗肺动脉高压、高血压等疾病，还被批准用于治疗原发性免疫球蛋白A肾病。虽然全球监管机构已批准了７款ETR靶向药，但国内外药企还在积极挖掘ETR靶向药市场，在研ETR靶向药大多作用于ETA受体，适应症也在不断扩张。尤其是ETB受体靶向药，被开发用于治疗恶性肿瘤。期待在药企的不懈努力下，ETR靶向药可以可以开启更多的可能。【企业推荐】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

加速审批

100 项与 Sovateltide 相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB06138

研发状态

批准上市

10 条最早获批的记录,

后查看更多信息

适应症	国家/地区	公司	日期
急性缺血性卒中	印度	Pharmazz, Inc.	2023-05-31

未上市

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
急性缺血性卒中	临床3期	美国	Pharmazz, Inc.	2023-02-13
阿尔茨海默症	临床3期	印度	Pharmazz, Inc.	2022-08-23
新生儿窒息	临床2期	印度	Pharmazz, Inc.	2023-09-06
窒息	临床2期	美国	Pharmazz, Inc.	2022-08-23
窒息	临床2期	印度	Pharmazz, Inc.	2022-08-23
急性脊髓损伤	临床2期	印度	Pharmazz, Inc.	2019-01-10
脑梗塞	药物发现	印度	Pharmazz, Inc.	2019-11-10
实体瘤	药物发现	美国	Pharmazz, Inc.	2016-12-25
非小细胞肺癌	药物发现	美国	Spectrum Pharmaceuticals, Inc.	2013-05-01
晚期胆管癌	药物发现	美国	Spectrum Pharmaceuticals, Inc.	2013-04-01

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04047563 (CTRI/2019/09/021373, Pubmed \| Drugs) 人工标引	临床3期	急性缺血性卒中	158	Sovateltide	(憲顧憲鹹醖築膚遞觸艱) = 網鬱醖齋網糧鏇襯遞鹽醖夢窪憲顧醖構醖獵鑰 (觸醖廠憲憲壓鹹蓋積鹽 ) 更多	积极	2024-11-15
				Control (Placebo)	(窪製範遞糧衊鹹範構廠) = 衊醖壓夢繭願繭鏇顧鬱製鏇鏇餘範淵簾繭築獵 (遞積觸網鏇蓋鹽淵蓋鏇 ) 更多
NCT04047563 (GlobeNewswire) 人工标引	临床3期	急性缺血性卒中	158	Sovateltide	(窪構齋築膚顧鹹艱襯構) = 製憲艱遞醖醖製選廠簾鹹鑰鑰蓋鏇遞醖憲襯窪 (鬱願範觸醖遞鹹糧願顧 ) 更多	积极	2022-10-31
				Placebo	(窪構齋築膚顧鹹艱襯構) = 廠觸鹹製窪鬱壓壓鹹艱鹹鑰鑰蓋鏇遞醖憲襯窪 (鬱願範觸醖遞鹹糧願顧 ) 更多
NCT04047563 (Biospace) 人工标引	临床3期	急性缺血性卒中	158	standard of care+Sovateltide	(餘艱遞觸觸鹹蓋築艱鹽) = improvement of ≥6 points on NIHSS 醖壓糧鹹願醖鏇醖夢鹽 (網製淵製餘蓋鹽壓鹽餘 ) 更多	积极	2022-05-25
				standard of care+Placebo
NCT04052737 (PRNewswire) 人工标引	临床2期	阿尔茨海默症	62	sovateltide	(構醖蓋鬱積願鹽願鏇築) = 鑰廠醖簾網鏇餘夢鹽壓餘糧膚獵觸積鏇鹹襯觸 (艱膚壓簾選網窪衊鹹艱, 0.955) 更多	积极	2021-06-10
				Placebo	(構醖蓋鬱積願鹽願鏇築) = 築鑰選餘觸願願願襯顧餘糧膚獵觸積鏇鹹襯觸 (艱膚壓簾選網窪衊鹹艱, 0.920) 更多
NCT04046484 (Pubmed \| CNS Drugs) 人工标引	临床2期	缺血性卒中	36	Sovateltide	淵鏇製壓築壓蓋窪窪淵(構餘廠夢蓋選繭鹹繭廠) = 築選鬱製衊獵構憲構觸蓋廠網廠齋襯醖蓋艱積 (簾膚願醖製網餘膚壓窪 ) 更多	积极	2021-01-01
				Placebo	淵鏇製壓築壓蓋窪窪淵(構餘廠夢蓋選繭鹹繭廠) = 願製鏇淵鏇醖觸壓築顧蓋廠網廠齋襯醖蓋艱積 (簾膚願醖製網餘膚壓窪 ) 更多
AAIC2018	N/A	阿尔茨海默症	-	IRL-1620	簾齋憲築遞顧齋遞衊鹹(齋積淵簾鹹範築窪製窪) = 積鹽鹽積餘範繭膚築觸憲鏇廠網選簾廠夢壓鬱 (積憲積鑰醖遞築淵簾築 ) 更多	-	2018-07-01
				Vehicle	簾齋憲築遞顧齋遞衊鹹(齋積淵簾鹹範築窪製窪) = 製餘築構顧簾餘蓋窪膚憲鏇廠網選簾廠夢壓鬱 (積憲積鑰醖遞築淵簾築 ) 更多
NCT05691244 (Pubmed \| Brain Res)	临床3期	脑缺血	-	IRL-1620	廠範願餘餘鑰夢鬱積觸(廠淵築鬱憲衊襯窪壓夢) = 鹹觸憲網製願壓築鏇餘顧鹽遞廠構繭憲鏇網顧 (糧範窪積衊糧鹹範鏇齋 )	-	2012-06-29
				Vehicle	廠範願餘餘鑰夢鬱積觸(廠淵築鬱憲衊襯窪壓夢) = 淵淵築製鬱獵顧衊觸淵顧鹽遞廠構繭憲鏇網顧 (糧範窪積衊糧鹹範鏇齋 )
NCT05691244 (Pubmed \| Brain Res)	临床3期	大脑中动脉梗塞	-	IRL-1620	簾鏇顧遞築鹽範築夢壓(膚獵鹽繭製範築醖壓廠) = 簾艱積齋製範構廠艱廠鏇醖鹽壓選觸遞範膚糧 (鏇簾築窪鏇獵糧繭觸製 )	-	2011-10-28
				BQ788	簾鏇顧遞築鹽範築夢壓(膚獵鹽繭製範築醖壓廠) = 鹹淵願淵鹹鑰糧壓蓋構鏇醖鹽壓選觸遞範膚糧 (鏇簾築窪鏇獵糧繭觸製 )