Clazosentan sodium

Tokyo, Japan and Cambridge, UK, 7 August 202 6 – Nxera Pharma (“the Company” or “Nxera”; TSE: 4565) provides an update on operational activities and reports its consolidated results for the second quarter ended 30 June 2026. The full report can be found here . Chris Cargill, President and CEO of Nxera, commented: “During the second quarter of FY2026, we continued to make steady progress across the business, building on the momentum achieved in the first quarter. Revenues from PIVLAZ® and QUVIVIQ® in Japan continued to increase steadily. For vamorolone, our treatment for Duchenne Muscular Dystrophy, we obtained key regulatory designations in South Korea that support faster patient access. As we work towards submitting a Marketing Authorization Application in South Korea during 2026, we will continue to work closely with the regulatory authorities to bring this medicine to patients in Korea as quickly as possible. “We also made progress across our partnered programs, achieving multiple important revenue-generating milestones. These included the achievement of the second development milestone with Lilly and the third and fourth milestones under our drug discovery collaboration with AbbVie. In addition, we continued to advance the development of new candidates within our proprietary pipeline, as well as related partnering activities. “Further highlighting the value and potential of assets developed using Nxera technology, on 24 June, Lilly completed the acquisition of Centessa Pharmaceuticals. Centessa’s orexin receptor agonist programs for the treatment of sleep disorders were jointly created by Centessa and Nxera, and Nxera retains the right to receive future milestone and royalty payments from this pipeline. With Lilly’s substantial resources and expertise, we believe the development of this program will be further strengthened. Supported by this continuing momentum and our robust financial position, we remain focused on driving sustained growth and value creation for patients and shareholders in the second half of 2026.” ezstandalone.cmd.push(function () { ezstandalone.showAds(131); }); Operational Highlights for the first half of FY2026 Progress in Japan and APAC Business Licensing agreement signed with Santhera Pharmaceuticals for the development, manufacturing and commercialization of vamorolone (commercialized internationally as AGAMREE®) for the treatment of Duchenne Muscular Dystrophy (DMD) in Japan, South Korea, Australia and New Zealand The Ministry of Food and Drug Safety (MFDS) of South Korea granted Orphan Drug Designation (ODD) and Global Innovative Products on Fast Track (GIFT) designation to vamorolone for the treatment of DMD to support faster patient access Nxera is on track to submit a planned Marketing Authorization Application (MAA) for vamorolone in South Korea during 2026 Positive topline results announced from a randomized, double-blind, placebo-controlled Phase 3 trial in South Korea evaluating daridorexant, a dual orexin receptor antagonist, in adult and elderly patients diagnosed with insomnia disorder On 4 March 2026, an MAA was submitted to MFDS in South Korea for daridorexant for this patient population Marketing approval received by Nxera’s commercial licensing partner Holling Bio-Pharma Corp. ("Holling"), the largest pharmaceutical distribution and sales company in Taiwan, from the Taiwan Food and Drug Administration (TFDA) for QUVIVIQ® (daridorexant; Taiwan brand name: 科唯可®) 25 mg and 50 mg for the treatment of insomnia in adult patients Nxera will be responsible for the supply of drug product, while Holling will be responsible for distribution and sales Nxera is entitled to receive initial sales-related milestones, tiered royalties on net sales, and revenue from product supply QUVIVIQ® is expected to be launched in Taiwan during 2026 Progress with partnered programs Neurocrine Biosciences ("Neurocrine") initiated and dosed the first patients in a Phase 2 clinical study of NBI-1117570 (“NBI-’570”) – an oral dual muscarinic M1/M4 receptor agonist – in adults with schizophrenia. As a result, Nxera received milestone payments of US$22.5 million from Neurocrine, which were recognised as revenue in Q1 FY2026. The status of the other programs in the partnered muscarinic receptor agonist portfolio is as follows: Direclidine/NBI-1117568 (an oral, muscarinic M4-selective agonist): Phase 3 studies in schizophrenia ongoing, with readouts expected in 2027 and 2028; a Phase 2 study in bipolar mania also ongoing NBI-1117569 (a dual M1/M4 agonist): results from a Phase 1 study targeting Alzheimer's psychosis expected to be announced in 2027 Centessa Pharmaceuticals Limited (“Centessa”) entered a definitive agreement to be acquired by Eli Lilly and Company ("Lilly") on 31 March 2026 and the transaction was successfully completed on 24 June 2026 The acquisition centers on Centessa's novel orexin receptor 2 (OX2R) agonist series, cleminorexton/ORX750, ORX142 and ORX489, which was jointly created by Centessa and Nxera. Nxera remains entitled to receive certain success-based milestone payments and royalties for all these OX2R agonists, and the original contractual terms are unaffected by this transaction. Under the collaboration with Centessa, an early-stage development milestone was achieved for ORX142, the second novel orexin receptor 2 (OX2R) agonist, resulting in a payment of US$3.6 million. Two early-stage development milestones were also achieved for ORX489, an OX2R agonist being developed for neuropsychiatric disorders, resulting in further payments of US$4.8 million. Achievement of a second development milestone under the multi-target collaboration and license agreement with Lilly targeting diabetes and metabolic diseases As a result, Nxera has received an undisclosed milestone amount, which was recognized as revenue in Q1 2026 Achievement of a third and fourth important research milestone under the multi-target discovery collaboration with AbbVie focused on neurological diseases, resulting in US$20 million in milestone payments to Nxera. The majority of these payments will be recognized as revenue in 2026, with the remainder to be recognized in 2027 and beyond License agreement signed with a newly established company ("NewCo") co-founded by Nxera and leading healthcare and life sciences-focused investment firms regarding a GPCR-targeted program discovered and developed by Nxera Nxera acquired an equity stake in NewCo and is entitled to receive up to US$275 million in milestone payments based on development and commercialization progress, as well as tiered royalties on sales Nxera retains rights to develop and commercialize any assets generated by the program in Japan and certain Asia-Pacific territories Nxera also participated in NewCo’s Series A financing Financial Highlights for the Six -month Period ended 3 0 June 202 6 Revenue totalled JPY 18,910 million (US$119.6 million*), an increase of JPY 3,815 million (US$18.0 million) vs. the prior corresponding period. This increase was primarily due to the occurrence of eight R&D milestone events in the current quarter vs. five R&D milestone events in the prior corresponding period. R&D expenses totalled JPY 6,000 million (US$37.9 million), a decrease of JPY 1,474 million (US$12.4 million) vs. the prior corresponding period. This decrease was primarily due to the maturation of several clinical programs, together with the adoption of a more streamlined R&D focus. SG&A expenses totalled JPY 6,953 million (US$44.0 million), a decrease of JPY 612 million (US$7.0 million) vs. the prior corresponding period. This decrease was primarily due to targeted cost reduction initiatives. Operating profit totalled JPY 1,881 million (US$11.9 million) vs. an operating loss of JPY 2,756 million (US$18.5 million) in the prior corresponding period. Profit before income tax totalled JPY 1,399 million (US$8.8 million) vs. a loss before income tax of JPY 3,722 million (US$25.1 million) in the prior corresponding period. Net profit totalled JPY 1,591 million (US$10.1 million) vs. a net loss of JPY 3,137 million (US$21.1 million) in the prior corresponding period. Core operating profit** totalled JPY 6,494 million (US$41.1 million) vs. a core operating profit of JPY 364 million (US$2.5 million) in the prior corresponding period. Cash and cash equivalents as at 30 June 2026 amounted to JPY 17,748 million (US$109.6 million), having decreased by JPY 2,616 million (US$20.6 million) from the prior financial year end. *Convenience conversion to US$ at the following rates: FY 202 6 : 1US$ = 158.15 JPY; FY 20 25 : 1US$ = 148.56 JPY; 30 Jun 202 6 : 1US$ = 161.94 JPY; 31 Dec 202 5 : 1US$ = 156.47 JPY ** Core operating profit / loss is an alternative performance measure which adjusts for material non-cash costs and one-off costs in order to provide insights into the recurring cash generation capability of the core business. –END– About Nxera Pharma Nxera Pharma is a technology powered biopharma company in pursuit of new specialty medicines to improve the lives of patients with unmet needs in Japan and globally. The Company has built an agile, new-generation commercial business in Japan to develop and commercialize innovative medicines, including several launched products, to address this high-value, large and growing market and those in the broader APAC region. In addition, the Company is advancing an extensive pipeline internally and in partnership with leading pharma and biotech companies powered by its unique NxWave™ GPCR structure-based drug discovery platform. Nxera Pharma operates at key locations in Tokyo and Osaka (Japan), London and Cambridge (UK), Basel (Switzerland) and Seoul (South Korea) and is listed on the Tokyo Stock Exchange (ticker: 4565). For more information, please visit LinkedIn: @NxeraPharma | X: @NxeraPharma | YouTube: @NxeraPharma Enquiries: Nxera – Media and Investor Relations Shinya Tsuzuki, VP, Head of Investor Relations +81 (0)3 5210 3399 | +44 (0)1223 949390 |IR@Nxera.life MEDiSTRAVA (for International Media) Mark Swallow, Frazer Hall, Erica Hollingsworth +44 (0)203 928 6900 | Nxera@medistrava.com Forward-looking statements This press release contains forward-looking statements, including statements about the discovery, development, and commercialization of products. Various risks may cause Nxera Pharma Group’s actual results to differ materially from those expressed or implied by the forward looking statements, including: adverse results in clinical development programs; failure to obtain patent protection for inventions; commercial limitations imposed by patents owned or controlled by third parties; dependence upon strategic alliance partners to develop and commercialize products and services; difficulties or delays in obtaining regulatory approvals to market products and services resulting from development efforts; the requirement for substantial funding to conduct research and development and to expand commercialization activities; and product initiatives by competitors. As a result of these factors, prospective investors are cautioned not to rely on any forward-looking statements. We disclaim any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise. Attachment FY26Q2 Tanshin

内皮素-1（endothelin-1, ET-1）于1988年被发现，随后于1990年鉴定出ETA和ETB受体，推动了首批内皮素受体拮抗剂――波生坦（bosentan）、安立生坦（ambrisentan）和马昔腾坦（macitentan）――的快速研发，用于以ET-1升高为特征的疾病肺动脉高压（pulmonary arterial hypertension, PAH）。近十年后，治疗领域开启新一轮浪潮：2021年获批用于脑缺血性卒中的ETB激动剂sovateltide，证实了激活ETB通路的获益。此后拮抗剂研发转向ETA选择性药物以保留ETB功能：用于脑血管痉挛的ETA拮抗剂克拉生坦（clazosentan）及用于难治性高血压的ETA/ETB拮抗剂阿普昔腾坦（aprocitentan），将内皮素靶向治疗拓展至更常见疾病。肾脏疾病领域，AT1/ETA双重拮抗剂司帕生坦（sparsentan）与ETA拮抗剂阿曲生坦（atrasentan）均获批用于IgA肾病，其中阿曲生坦在早期多项临床试验失败后终获成功。药物重定位已成为G蛋白偶联受体（G protein-coupled receptor, GPCR）药物研发的重要策略。本综述以ETA拮抗剂齐博生坦（zibotentan）为例――其目前正与达格列净联合用药以减轻既往临床研究中限制应用的液体潴留――阐述了筛选适用于新适应症的经典内皮素化合物的路径。肾脏疾病仍是当前临床试验的核心焦点，在研药物包括新型ETA选择性小分子迪奥舒生坦（diosuxentan）、单克隆抗体getagozumab，以及ETB肽类拮抗剂vodudeutentan。综述总结了近期药理学与临床数据，并展望了下一代内皮素通路治疗的新兴策略。引言 内皮素-1（ET-1）是目前已知作用最强的血管收缩肽，主要由内皮细胞释放，调控心血管、肾脏、肺及炎症通路，在血管张力、血压调节及多种生理病理过程中发挥核心作用。ETA受体主要介导血管收缩与细胞增殖，ETB受体在内皮细胞上具有双重功能：介导血管舒张与ET-1清除。1990年两类受体的鉴定推动了首批小分子ETA/ETB受体拮抗剂的发现与临床获批：2001年起先后上市波生坦（ETA/ETB双重拮抗）、安立生坦（ETA选择性）与马昔腾坦（ETA/ETB双重拮抗），均用于单一罕见病PAH――该疾病以血浆ET-1水平升高为共同生物标志物。近十年后才有下一款药物获批：2021年肽类药物sovateltide（IRL-1620）在印度获批用于急性脑缺血性卒中，这是首个ETB激动剂，其全新机制验证了激活ETB通路的治疗价值。此后成功获批的拮抗剂中，3款均转向ETA亚型选择性设计以避免阻断ETB。值得注意的是，克拉生坦（用于动脉瘤性蛛网膜下腔出血后脑血管痉挛）与阿普昔腾坦（用于难治性高血压）将内皮素拮抗剂的应用拓展至常见临床疾病。司帕生坦（血管紧张素AT1/ETA双重拮抗剂）与阿曲生坦先后获批用于IgA肾病――这一最常见的原发性肾小球肾炎是慢性肾脏病的重要病因。阿曲生坦作为经典药物实现了最显著的复兴：自发现以来30年、历经40余项失败临床试验后终获FDA批准。药物重定位现已成为GPCR药物研发的核心驱动力：约165种已获批GPCR药物正在开展新适应症临床试验。本综述以齐博生坦为例，探讨筛选可重定位的经典内皮素化合物的策略――该ETA拮抗剂正与钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂达格列净联合用药，以减轻既往临床试验中限制其应用的液体潴留。 已获批拮抗剂 波生坦、马昔腾坦（ETA/ETB双重拮抗）与安立生坦（ETA选择性）获批用于肺动脉高压 作为首款口服活性内皮素拮抗剂，波生坦彻底改变了PAH的治疗格局――此前标准治疗仅为吸入一氧化氮或静脉前列环素。安立生坦属于丙酸类化合物，ETA选择性优于波生坦，肝毒性更低但更易引发水肿与鼻塞。马昔腾坦设计为波生坦的升级版本，是不可逆拮抗剂，亲和力更高、受体占据时间更长、解离更慢，在PAH治疗中疗效更优。这类拮抗剂常与磷酸二酯酶-5抑制剂、前列环素类似物、可溶性鸟苷酸环化酶刺激剂等药物联合使用，通过协同舒张血管发挥作用。 已获批拮抗剂拓展至其他疾病时的局限性 所有内皮素拮抗剂均被FDA标注最高级别致畸风险警告，妊娠禁用。此外，肝毒性限制了其应用拓展。波生坦因抑制胆盐外排泵升高肝酶，需常规监测肝功能；同属磺酰胺类的西他生坦因致死性肝损伤已被撤市。现有证据表明肝毒性并非类效应：波生坦与西他生坦的肝毒性风险显著更高，而阿曲生坦与齐博生坦的大规模临床研究未发现肝毒性失衡，仅观察到肝酶轻度改善。除肝毒性外，这类药物还存在外周水肿、液体潴留、贫血等共性不良反应，降低患者依从性。 司帕生坦：ETA与AT1双重拮抗剂获批用于IgA肾病 司帕生坦是首款口服活性AT1/ETA双重拮抗剂，2023年获FDA附条件批准、2024年完全获批用于IgA肾病。IgAN由肾小球内IgA抗体沉积触发炎症与肾损伤，标准治疗为ACEI或ARB。ET-1通过ETA受体介导的血管收缩、蛋白尿、细胞外基质积聚与纤维化等作用参与肾损伤进展。司帕生坦分子中整合了厄贝沙坦来源的AT1受体结合基团与联苯磺酰胺ETA结合基团，可同时调控两大血管稳态通路，避免两种单药联用的药代动力学不匹配问题，提升患者依从性。III期研究显示，最大耐受肾素-血管紧张素系统（RAS）抑制基础上，司帕生坦400 mg每日一次较厄贝沙坦300 mg每日一次，36周内尿白蛋白肌酐比（uACR）相对降低41%，疗效持续至114周，更好地保护了肾功能。其局限性在于仍需监测肝毒性，常见低血压与外周水肿。初步研究显示，司帕生坦联合SGLT2抑制剂可进一步显著降低uACR，相关III期研究正在进行中。 克拉生坦：ETA拮抗剂获批用于动脉瘤性蛛网膜下腔出血后脑血管痉挛 克拉生坦是ETA高选择性（约2000倍）竞争性拮抗剂，无口服活性，需静脉持续输注，2022年在日本与韩国获批用于预防动脉瘤性蛛网膜下腔出血（aSAH）后脑血管痉挛。aSAH是致死致残率极高的出血性卒中，破裂后引发的迟发性脑缺血（DCI）是幸存者主要致残原因，与大血管痉挛、微血管功能障碍、微血栓形成等多因素相关，其中ET-1升高、一氧化氮生物利用度下降是核心机制。IIb期CONSCIOUS-1研究显示克拉生坦呈剂量依赖性减少造影证实的中重度脑血管痉挛。两项III期研究CONSCIOUS-2（手术夹闭人群）与CONSCIOUS-3（介入栓塞人群）未显示复合临床终点显著获益，但15 mg/h剂量组在CONSCIOUS-3中降低了死亡与血管痉挛相关发病率的复合终点。日本III期研究在aSAH人群中证实了克拉生坦降低血管痉挛相关发病率的疗效，但不良事件（液体潴留、低钠血症、稀释性贫血、肺水肿等）发生率更高。最新的REACT III期研究在欧洲与北美人群中评估克拉生坦联合标准治疗（尼莫地平）的疗效，未显示额外临床获益。Meta分析证实克拉生坦可降低血管痉挛相关并发症，但高剂量（10-15 mg/h）伴随更高的贫血、低血压、胸腔积液等不良事件风险，且未显著降低死亡率或改善功能结局。现有证据提示，克拉生坦的获益可能局限于未常规使用尼莫地平等血管扩张剂的治疗体系。 阿普昔腾坦：ETA/ETB拮抗剂获批用于难治性高血压 阿普昔腾坦是小分子ETA/ETB双重拮抗剂，由马昔腾坦的代谢产物优化而来，效力低于母药，2024年获美国与欧盟批准用于难治性高血压――定义为联合三种及以上降压药物仍无法控制血压，约占高血压人群的15%。PRECISION III期研究显示，在最大耐受三联降压方案基础上，阿普昔腾坦12.5 mg或25 mg每日一次均可显著降低收缩压，24小时动态收缩压分别降低4.2 mmHg与5.9 mmHg，且降压效应可持续32周，停药后血压回升。液体潴留是其最主要不良反应，发生率呈剂量依赖性（12.5 mg组9%、25 mg组18%），FDA因此仅批准12.5 mg剂量在美国使用。事后分析显示，阿普昔腾坦可有效降低难治性高血压合并慢性肾脏病（CKD）患者的夜间动态血压与uACR。值得注意的是，阿普昔腾坦是唯一近期获批的双重拮抗剂：阻断ETB受体可导致循环ET-1水平升高，PRECISION试验中12.5 mg与25 mg剂量分别使血浆ET-1升高34%与53%，C末端前内皮素-1（CT-proET-1）升高38%与47%，提示ET-1合成代偿性增加。 Sovateltide：ETB肽类激动剂获批用于急性脑缺血性卒中 Sovateltide是首个选择性ETB肽类激动剂，2023年5月在印度获批用于急性脑缺血性卒中（ACIS），需在发病24小时内静脉给药3次（0.3 μg/kg），第3天与第6天重复给药。I期研究确定了0.6 μg/kg的最大耐受剂量，II期与III期研究证实了其安全性与有效性：治疗组90天改良Rankin量表（mRS）与美国国立卫生研究院卒中量表（NIHSS）评分显著低于对照组，神经功能恢复更快。目前美国III期RESPECT-ETB研究正在招募中，拟在美、加、英、欧多国评估其联合标准治疗的疗效。临床前研究证实，sovateltide通过激活神经元祖细胞上的ETB受体，减少凋亡与氧化应激，促进血管生成与神经发生，改善缺血后脑血流与功能修复。该药还在阿尔茨海默病、脊髓损伤、新生儿缺氧缺血性脑病等适应症中开展II期试验，临床前与早期临床数据均显示出神经保护潜力。 重定位的已获批拮抗剂 阿曲生坦：ETA拮抗剂获批用于IgA肾病 阿曲生坦是1996年发现的ETA高选择性拮抗剂，早期开发聚焦于转移性去势抵抗性前列腺癌，但未达到临床终点。后续研究证实其对肾脏疾病（糖尿病肾病、IgA肾病、CKD）有效，且无临床相关肝毒性。II期剂量探索研究显示，0.75 mg与1.25 mg剂量可使2型糖尿病肾病患者的uACR降低约40%，液体潴留轻微。III期SONAR研究纳入5000余例糖尿病肾病患者，经6周富集期筛选应答者后随机分组，中位治疗2.2年显示，阿曲生坦显著降低肾脏复合终点（血清肌酐倍增或终末期肾病）风险35%，但液体潴留与贫血发生率更高。亚组分析发现，联合SGLT2抑制剂可抵消阿曲生坦导致的液体潴留，并增强uACR降低效应。鉴于糖尿病肾病领域已获批SGLT2抑制剂与非甾体类盐皮质激素受体拮抗剂，阿曲生坦的开发转向IgA肾病――这类患者心力衰竭风险更低，更适合该药物治疗。III期ALIGN研究显示，最大耐受RAS抑制基础上加用0.75 mg每日一次阿曲生坦，36周内uACR较安慰剂降低36%，疗效最早6周显现并持续至研究结束，安全性良好，无心力衰竭报告。2025年4月，阿曲生坦（商品名VANRAFIA?）获FDA加速批准用于有快速进展风险的成人IgA肾病患者。 在研新化学实体 迪奥舒生坦（SC0062）：小分子ETA拮抗剂 SC0062是十余年来首个新专利的小分子ETA拮抗剂，属于嘧啶磺酰胺类，口服活性，对ETA具有高亲和力（IC50=2.3 nmol/L）与超过8000倍的选择性，临床浓度下无ETB活性。其体内活性代谢物M18同样保留高ETA亲和力。I期研究显示其安全性与药代动力学特征良好，单次给药10-100 mg后半衰期约7.25小时，多次给药20 mg每日一次耐受性佳，血浆ET-1水平呈剂量依赖性升高，未观察到水肿、体重增加或贫血。II期剂量探索研究纳入糖尿病肾病与IgA肾病患者，在RAS抑制（±SGLT2抑制剂）基础上加用SC00625、10或20 mg每日一次治疗24周，总体耐受性良好，仅高剂量组贫血发生率略高；与多数拮抗剂不同，其外周水肿发生率低于安慰剂组，且未观察到剂量依赖性液体潴留。研究达到主要终点，IgA肾病患者uACR呈剂量依赖性降低。目前III期SUCCESS研究正在设计中，拟评估其对高风险IgA肾病患者的肾脏保护作用。 Getagozumab：单抗类ETA拮抗剂用于肺动脉高压 Getagozumab是首款进入临床的人源化ETA特异性单抗拮抗剂，亲和力与已获批小分子相当，无ETB活性。食蟹猴PAH模型中，每两周5 mg/kg给药6周可减轻左心室肥厚与右心室收缩压，疗效不劣于每日1 mg/kg安立生坦。I期临床显示其半衰期长达约21天，远长于小分子拮抗剂。单抗类药物可靶向GPCR的细胞外表位，探索全新作用模式，突破了小分子仅能结合正构位点的局限。目前III期剂量递增研究正在进行中，拟验证长效高选择性ETA单抗是否可避免小分子常见的液体潴留等不良反应。 Vodudeutentan（ENB003）：ETB肽类拮抗剂联合免疫检查点抑制剂用于癌症 ENB003是ETB选择性肽类拮抗剂BQ788的氘代类似物，目前正联合PD-1单抗帕博利珠单抗开展I/II期临床研究，针对转移性黑色素瘤、铂耐药卵巢癌与胰腺癌。中期数据显示其安全性良好，8个月无进展生存率达60%，优于历史对照的单药免疫治疗。其作用机制为：肿瘤血管内皮细胞过表达ETB受体可抑制细胞间黏附分子-1（ICAM-1），阻碍T细胞浸润；ENB003阻断ETB受体可恢复ICAM-1表达，促进活化T细胞进入肿瘤组织，同时增强帕博利珠单抗的PD-1阻断效应，逆转肿瘤免疫抑制微环境。既往ETA/ETA+ETB拮抗剂在实体瘤临床试验中均未显示生存获益，选择性阻断ETB受体联合现有抗癌药物提供了全新策略，联合利尿剂或可进一步抵消液体潴留的类效应。 经典药物重定位策略 齐博生坦：ETA拮抗剂 齐博生坦是ETA选择性最高的拮抗剂之一，曾在肿瘤、微血管心绞痛、CKD、肝硬化等领域开展临床研究，目前正针对高蛋白尿CKD开展III期试验。其高选择性可在拮抗ETA的同时保留ETB介导的ET-1清除功能。早期开发聚焦于转移性前列腺癌，III期研究虽未显示生存获益，但证实了其血管活性作用，且未观察到肝毒性失衡，液体潴留为其主要不良反应。前列腺癌项目终止后，其开发转向其他适应症：II期ZEBRA研究（系统性硬化症）显示其可延缓肾小球滤过率（GFR）下降，但液体潴留导致治疗中断；II期PRIZE研究（微血管心绞痛）未改善运动耐量，但降低血压、肝酶与HbA1c，改善血脂谱，液体潴留与头痛发生率较高。后续研究转向更低剂量联合SGLT2抑制剂的策略，以分离疗效与液体潴留效应。 齐博生坦重定位的经验：2020年至今 系统性硬化症ZEBRA研究显示10 mg剂量可延缓GFR下降，但下肢水肿、液体潴留与体重增加常见，需干预甚至导致停药。微血管心绞痛PRIZE研究采用10 mg剂量，未改善运动时间，液体潴留与头痛发生率分别为12%与36%，提示剂量过高。肝硬化ZEAL研究评估2.5 mg齐博生坦联合10 mg达格列净的安全性，6周时肝静脉压力梯度（HVPG）较安慰剂无显著差异，但在基线HVPG≥12 mmHg患者中呈下降趋势，仅3例轻度外周水肿，无严重不良事件。慢性肾脏病ZENITH-CKD IIb期研究评估0.25 mg或1.5 mg齐博生坦联合10 mg达格列净的疗效，12周时uACR分别较单药达格列净降低27%与34%；液体潴留发生率随剂量升高而增加（1.5 mg组18%、0.25 mg组9%、单药达格列净组8%），5 mg剂量因液体潴留风险过高被终止。低基线eGFR是液体潴留的重要风险因素，联合达格列净可显著降低该风险。基于上述结果，III期ZENITH高蛋白尿研究采用基于肾功能的剂量策略：eGFR≥45 mL/min/1.73 m2者起始0.75 mg/10 mg，eGFR<45 mL/min/1.73 m2者起始0.25 mg/10 mg，预计2027年初获得结果。交叉研究ZODIAC进一步证实，齐博生坦联合达格列净可叠加降低uACR并减轻液体潴留，两者通过互补机制改善内皮功能，同时抵消内皮素拮抗的钠水潴留效应。 减少液体潴留的剂量策略 ZENITH-CKD研究设计了20倍的剂量范围，即使终止5 mg剂量后仍保留6倍剂量差异，可通过模型插值识别治疗窗。剂量-效应模型显示，0.25 mg与0.75 mg剂量可在最大化降低uACR的同时最小化液体潴留风险，据此制定了基于肾功能的III期剂量方案，平衡获益与风险。 结论 内皮素领域正从PAH等罕见病转向急性缺血性卒中、难治性高血压、脑血管痉挛、CKD等更常见且临床需求迫切的疾病。这一转变由新机制（如sovateltide诱导神经元祖细胞分化）、新化学类型（迪奥舒生坦、getagozumab单抗、ENB003等）驱动，同时疾病相关血浆ET-1升高为靶点拓展提供了依据。大规模蛋白质组学与遗传学研究发现更多与ET信号通路异常相关的疾病，未来结合生物标志物与患者分层的精准医疗，将进一步识别最可能从内皮素通路治疗中获益的人群，推动该领域的持续发展。