A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Ralinepag to Evaluate Safety and Effects on Exercise Capacity Assessed by CPET in Subjects With WHO Group 1 Pulmonary Hypertension Who Recently Initiated Therapy

Study ROR-PH-302, ADVANCE CAPACITY, is designed to evaluate the effects of ralinepag therapy on exercise capacity as assessed by change in peak oxygen consumption (VO2) derived from cardiopulmonary exercise testing (CPET) after 28 weeks of treatment

开始日期2021-01-20

申办/合作机构

United Therapeutics Corp.

NCT04613999 / Completed临床1期

A Phase 1 Open-label, Non-randomized, Single Ascending Dose Escalation Study To Evaluate The Pharmacokinetics, Safety, And Tolerability Of A Ralinepag Extended Release (XR) Tablet Formulation In Healthy Chinese Subjects

开始日期2020-10-09

申办/合作机构

Everstar Medicines Shanghai Ltd.

CTR20200001 / Recruiting临床1期

一项评价Ralinepag缓释片在健康中国受试者中的药代动力学、安全性及耐受性的开放标签、非随机的单剂量递增1期研究

主要目的：评价健康的中国受试者单次口服50、100、150μg ralinepag缓释（XR）片（50 μg缓释片）后ralinepag的血浆药代动力学（PK）次要目的：评价健康的中国受试者单剂口服ralinepag后的安全性与耐受性

开始日期2020-10-09

申办/合作机构

Arena Pharmaceuticals, Inc.

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100 项与 Ralinepag 相关的临床结果

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100 项与 Ralinepag 相关的转化医学

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100 项与 Ralinepag 相关的专利（医药）

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项与 Ralinepag 相关的文献（医药）

2020-04-01·Pulmonary circulation4区 · 医学

Safety, tolerability, and pharmacokinetics of the selective prostacyclin receptor agonist ralinepag in single and multiple dosing studies of an immediate‐release oral formulation in healthy volunteers

4区 · 医学

ArticleOA

作者: Grundy, John S. ; Cabell, Christopher H. ; Adams, John W. ; King, Christopher D.

Ralinepag (APD811), an oral, potent, and selective prostacyclin receptor (IP) agonist is being developed for treatment of pulmonary arterial hypertension. Two, single‐center, randomized, double‐blind, placebo‐controlled, Phase 1 studies (single ascending dose and multiple ascending dose) evaluated an oral immediate‐release capsule formulation of ralinepag in healthy subjects. Blood samples assessed plasma pharmacokinetics and safety and tolerability data monitored adverse events, vital signs, laboratory findings, physical examination, and electrocardiograms. Eighty‐two healthy subjects (single ascending dose (n = 32) and multiple ascending dose (n = 50)) completed the studies. No clinically significant safety issues were observed, except one serious adverse event of atrial fibrillation considered moderate in intensity. In the single ascending dose study, ralinepag was tolerated up to 100 µg (single dose), but not 200 µg due to nausea and vomiting. Dose proportional mean ralinepag plasma exposure measures were observed. Maximum plasma concentrations were reached within 1.0–1.5 h post‐dose and mean terminal elimination half‐life values from 20.5–26.4 h. In the multiple ascending dose study, ralinepag tolerability decreased with increasing QD or BID dose. Dose proportional steady‐state plasma exposure measures were observed where evaluable, with mean steady‐state peak‐to‐trough ratios ranging from 3.34–4.49 (QD dosing) and 1.95–2.36 (BID dosing). Mean effective half‐life values ranged from 17.5–18.4 h, reflecting ∼1.7‐fold (QD dosing) and ∼2.6‐fold (BID dosing) accumulation in plasma exposure. Safety and tolerability of oral immediate‐release ralinepag was generally consistent with expectations for this drug class, but more individualized dose escalation appears warranted. Ralinepag exhibited favorable pharmacokinetic properties, with BID dosing producing desired minimal steady‐state peak‐to‐trough fluctuation. Overall, results supported further clinical investigation of ralinepag and guided development of an extended‐release formulation to facilitate QD dosing.

2019-10-01·The European respiratory journal1区 · 医学

Efficacy and safety of ralinepag, a novel oral IP agonist, in PAH patients on mono or dual background therapy: results from a phase 2 randomised, parallel group, placebo-controlled trial

1区 · 医学

Article

作者: Ristic, Arsen ; Torres, Fernando ; Grundy, John ; Hoffmann, Ines ; D'Souza, Gwyn ; McLaughlin, Vallerie ; Klassen, Preston ; Escribano Subías, Pilar ; Cabell, Christopher ; Adams, John ; Keogh, Anne ; Zhang, Jinkun ; Rubin, Lewis ; Farber, Harrison ; Sood, Namita ; Shanahan, William

Purpose:

This phase 2 study was designed to assess the efficacy, safety and tolerability of immediate-release orally administered ralinepag, a selective, non-prostanoid prostacyclin receptor agonist with a 24-h terminal half-life, compared to placebo in adult patients with symptomatic pulmonary arterial hypertension (PAH).

Methods:

61 PAH patients who were receiving standard care, including mono or dual PAH-targeted background therapy were randomised 2:1 to ralinepag (n=40) or placebo (n=21). The starting dose of ralinepag was 10 μg twice daily. Dosage was then up-titrated as tolerated over the course of the 9-week dose-titration period, to a maximum total daily dose of 600 μg (300 μg twice daily). The primary efficacy end-point was the absolute change in pulmonary vascular resistance (PVR) from baseline to week 22. Additional end-points included percentage change in PVR from baseline, other haemodynamic parameters, 6-min walk distance (6MWD) and safety and tolerability.

Results:

Ralinepag significantly decreased PVR by 163.9 dyn·s·cm−5 compared to an increase of 0.7 dyn·s·cm−5 with placebo (p=0.02); the least-squares mean change from baseline PVR was −29.8% compared with placebo (p=0.03). 6MWD increased from baseline by 36.2 m with ralinepag and 29.4 m with placebo (p=0.90). Serious adverse events occurred in 10% of ralinepag patients and 29% of placebo patients. Study discontinuations occurred in 13% of ralinepag patients and 10% of placebo patients.

Summary:

Ralinepag reduced PVR compared with placebo in PAH patients on mono (41%) or dual combination (59%) background therapy.

2017-02-09·Journal of medicinal chemistry1区 · 医学

Discovery of 2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyl)oxy)methyl)cyclohexyl)methoxy)acetate (Ralinepag): An Orally Active Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension

1区 · 医学

Article

作者: Gaidarov, Ibragim ; Leakakos, Tina ; Chang, Steve ; Chen, Weichao ; Sadeque, Abu ; Ramirez, Juan ; Shin, Young-Jun ; Shi, Yunqing ; Blackburn, Anthony ; Sage, Carleton R. ; Boatman, P. Douglas ; Tran, Thuy-Anh ; Morgan, Michael ; Shu, Hsin-Hui ; Kramer, Bryan ; Unett, David J. ; Pal, Biman ; Behan, Dominic P. ; Vallar, Pureza ; Semple, Graeme ; Shakya, Sagar R. ; Krishnan, Ashwin ; Shifrina, Anna ; Chen, Xiaohua ; Gharbaoui, Tawfik ; Tung, Shiu-Feng ; Adams, John W. ; Garrido Montalban, Antonio ; Zou, Ning

The design and synthesis of a new series of potent non-prostanoid IP receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) are described. Detailed profiling of a number of analogues resulted in the identification of 5c (ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the prostanoid receptor family and a more modest 30- to 50-fold selectivity over the EP3 receptor. In our hands, its potency and efficacy are comparable or superior to MRE269 (the active metabolite of the clinical compound NS-304) with respect to in vitro IP receptor dependent cAMP accumulation assays. 5c had an excellent PK profile across species. Enterohepatic recirculation most probably contributes to a concentration-time profile after oral administration in the cynomolgus monkey that showed a very low peak-to-trough ratio. Following the identification of an acceptable solid form, 5c was selected for further development for the treatment of PAH.

项与 Ralinepag 相关的新闻（医药）

2024-04-16

·BioSpace

United Therapeutics to Feature Clinical Data Across its Commercial and Development Portfolio at the American Thoracic Society 2024 International Conference

Initial, interim long-term data from the ongoing ralinepag phase 3 ADVANCE EXTENSION open label study to be presented at a poster discussion session An annual update of the preliminary baseline data from the TETON phase 3 studies of inhaled treprostinil in idiopathic pulmonary fibrosis will be presented at a poster session SILVER SPRING, Md. & RESEARCH TRIANGLE PARK, N.C.--(BUSINESS WIRE)--United Therapeutics Corporation (Nasdaq: UTHR), a public benefit corporation, today announced that recent research across its commercial and development portfolio will be presented at the American Thoracic Society (ATS) International Conference in San Diego on May 17-22, 2024. At ATS, United Therapeutics will host an educational industry theater on implementing treprostinil induction strategies in pulmonary hypertension, and the company is sponsoring the ATS 2024 Women’s Forum. “We look forward to presenting the latest data on several of our key products and development programs,” said Andrew Nelsen, PharmD, Vice President, Global Medical Affairs at United Therapeutics. “Notably, our academic and industry collaborators will present initial interim efficacy data from the ADVANCE EXTENSION open label extension evaluating extended-release ralinepag for pulmonary arterial hypertension and baseline data updates for the ongoing TETON studies in idiopathic pulmonary fibrosis. We are also pleased to unveil the exciting preliminary findings from our collaboration with Tempus, a leader in artificial intelligence and precision medicine, laying the foundation for earlier identification of patients with pulmonary hypertension.” Posters, mini-symposia, and discussion sessions include: Mini Symposium, Sunday, May 19, 10:03 to 10:15 a.m. PT: A14 – Metabolomic Signatures of Pulmonary Hypertension Associated with Interstitial Lung Disease: A Post-hoc Analysis of the INCREASE Study. Presented by Aaron B. Waxman, M.D., Ph.D., Brigham and Women’s Hospital. Thematic poster session, Sunday, May 19, 11:30 a.m. to 1:15 p.m. PT: A46/P829 – Pulmonary Hypertension Screening Strategies in Patients with Interstitial Lung Disease: A Survey of PHINDER Study Sites. Presented by Eric Shen, PharmD, United Therapeutics. Thematic poster session, Monday, May 20, 11:30 a.m. to 1:15 p.m. PT: B48/P1259 – TETON Phase 3 Clinical Trials of Inhaled Treprostinil in the Treatment of Idiopathic Pulmonary Fibrosis: Annual Update of Preliminary Baseline Data. Presented by Steven D. Nathan, M.D., Inova Fairfax Hospital. Thematic poster session, Monday, May 20, 11:30 a.m. to 1:15 p.m. PT: B48/P1260 – Study Design and Rationale for the TETON-PPF Clinical Trial of Inhaled Treprostinil for the Treatment of Progressive Pulmonary Fibrosis. Presented by Steven D. Nathan, M.D., Inova Fairfax Hospital. Thematic poster session, Tuesday, May 21, 11:30 a.m. to 1:15 p.m. PT: C62/P284 – Real-World Transition and Persistence to Oral Treprostinil Therapy from Parenteral Prostacyclins in Patients with Pulmonary Arterial Hypertension. Presented by Ali Ataya, M.D., University of Florida. Poster discussion session, Wednesday, May 22, 11:00 a.m. to 1:00 p.m. PT: D105/410 – Clinical Improvements with Parenteral Induction Therapy in Intermediate-High Risk Patients With PAH: A Sub-Group Analysis of the EXPEDITE Study. Presented by Chad Miller, M.D., Piedmont Healthcare. Poster discussion session, Wednesday, May 22, 11:00 a.m. to 1:00 p.m. PT: D105/420 – Initial Long-term Data from a Phase 3 Open-label Extension Study (ROR-PH-303) Evaluating Ralinepag for the Treatment of Pulmonary Arterial Hypertension (ADVANCE EXTENSION). Presented by Joan A. Barberà, M.D., Ph.D., Hospital Clinic de Barcelona. Poster discussion session, Wednesday, May 22, 11:00 a.m. to 1:00 p.m. PT: D102/502 – Structured EHR Data Underestimates Prevalence and Misses Large Proportions of Patients with Pulmonary Hypertension. Presented by RuiJun Chen, M.D., Tempus. Poster discussion session, Wednesday, May 22, 11:00 a.m. to 1:00 p.m. PT: D102/503 – A Novel Phenotyping Pipeline to Improve Identification of Patients with Pulmonary Hypertension in Electronic Health Records. Presented by David Vidmar, Ph.D., Tempus. Poster discussion session, Wednesday, May 22, 11:00 a.m. to 1:00 p.m. PT: D102/504 – ECG-based Machine Learning Model Identifies Patients at High Risk for Incident Pulmonary Hypertension. Presented by Greg Lee, Tempus. Sponsored events include: The ATS 2024 Women’s Forum, Monday, May 20, 11:45 a.m. to 1:15 p.m. PT featuring Zea Borok, M.D., ATSF, formerly of the University of Southern California; Stephanie Davis, M.D., ATSF, University of North Carolina at Chapel Hill; Sonia Buist, M.D, Oregon Health & Science University; and Obianuju Ozoh, M.D., University of Lagos. Industry Theater, Sunday, May 19, 12:30 to 1:00 p.m. PT – Implementing Treprostinil Induction Strategies in Pulmonary Hypertension. Presented by Chad Miller, M.D., Piedmont Healthcare. United Therapeutics: Enabling Inspiration At United Therapeutics, our vision and mission are one. We use our enthusiasm, creativity, and persistence to innovate for the unmet medical needs of our patients and to benefit our other stakeholders. We are bold and unconventional. We have fun, we do good. We are the first publicly-traded biotech or pharmaceutical company to take the form of a public benefit corporation (PBC). Our public benefit purpose is to provide a brighter future for patients through (a) the development of novel pharmaceutical therapies; and (b) technologies that expand the availability of transplantable organs. You can learn more about what it means to be a PBC here: unither.com/pbc. Forward-Looking Statements Statements included in this press release that are not historical in nature are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include, among others, our goals of innovating for the unmet medical needs of our patients and to benefit our other stakeholders, furthering our public benefit purpose of developing novel pharmaceutical therapies and technologies that expand the availability of transplantable organs. These forward-looking statements are subject to certain risks and uncertainties, such as those described in our periodic reports filed with the Securities and Exchange Commission, that could cause actual results to differ materially from anticipated results. Consequently, such forward-looking statements are qualified by the cautionary statements, cautionary language and risk factors set forth in our periodic reports and documents filed with the Securities and Exchange Commission, including our most recent Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, and Current Reports on Form 8-K. We claim the protection of the safe harbor contained in the Private Securities Litigation Reform Act of 1995 for forward-looking statements. We are providing this information as of April 16, 2024, and assume no obligation to update or revise the information contained in this press release whether as a result of new information, future events, or any other reason.

临床3期

2024-04-09

·CPHI制药在线

被MNC看好的PAH，能成就默沙东的第二增长曲线吗？

关注并星标CPHI制药在线作者：云朵3月26日，默沙东的首创药物Winrevair（sotatercept-csrk）获得FDA批准，用于治疗成人肺动脉高压（PAH, 世界卫生组织[WHO] 1组）患者，以增加运动能力、改善WHO功能等级（FC）和减少临床恶化事件的风险。在Winrevair获批前几天，FDA也批准了强生的Opsynvi上市，Opsynv是内皮素拮抗剂马昔腾坦和PDE-5抑制剂他达拉非的固定剂量组合，是首个获FDA批准的PAH单片剂组合疗法。1烧钱500亿美元，MNC看好PAH肺动脉高压（PAH）是环境、遗传等多种因素引起肺动脉阻力进行性增高、肺血管重塑、右室肥厚，并最终引起右心衰竭甚至死亡的一种恶性心血管疾病，被称作“心血管中的癌症”。传统治疗PAH的方法如抗凝、地高辛、吸氧、L-精氨酸、硝酸甘油、利尿剂等，对肺动脉高压的疗效有限。随着对PAH病理的深入了解，近年来针对各个不同路径的靶点新药不断涌现。现有靶向新药疗法主要有针对PAH中失调的三种途径、五类靶向药物，包括内皮素受体拮抗剂（ERA）、磷酸二酯酶5型（PDE5）抑制剂、可溶性鸟苷酸环化酶（sGC）激动剂、前列环素类似物和前列环素受体激动剂，共12款药物获批上市。已上市PAH新药图源：公开数据整理在全球肺动脉高压药物市场，强生起步最早，也跑得最快，早在2017年强生以300亿美元天价收购Actelion，获得了Opsumit、Uptravi、Tracleer，Veletri和 Ventavis等一系列肺动脉高压产品。近几年，强生已凭借 Uptravi（赛乐西帕）和 Opsumit（马昔替坦）在PAH赛道占据主导地位，其中Opsumit是目前治疗PAH最畅销的药物，另外Uptravi也在全球超过40个国家获批。根据强生财报，2022年强生PAH业务线营收34亿美元左右，占总制药业务的6.5%，2023年强生的PAH管线总营收38.15亿美元，同比增长11.6%。其中Opsumit营收19.73亿美元，同比增长10.6%；Uptravi销售额15.82亿美元，同比增长19.7%。相对于肿瘤等其他领域动辄数十亿美元的大单品来说，PAH药物的营收不算惊艳，但是PAH是一种罕见、进展迅速且致死率高的疾病，具有不错的市场增长空间，据贝哲斯咨询统计，2023年全球肺动脉高压药物市场规模达到了449.58亿元，预估到2029年市场规模达到698.31亿元，2023-2029年复合增速约7.33%。除强生，不少MNC也看好这个赛道，纷纷重金押注入局。本次获批上市的Winrevair也并非默沙东原研，而是其在2021年以115亿美元收购Acceleron时获得的重要产品，另外2021年辉瑞也花了超60亿美元收购Arena获得其核心PAH资产的Ralinepag。仅强生，默沙东和辉瑞这三大巨头在PAH药物上的BD总金额，已接近500亿美元。2默沙东正面挑战强生 PAH是一种进行性疾病，特征是肺血管重构，由不同发病机制导致肺血管结构或功能改变，引起肺血管阻力和肺动脉血压升高，继而发展成右心衰竭甚至死亡，五年死亡率为43%，且预后极差，早期的传统药物并没有从根源对症。现有的所有靶向药物也只能舒张肺动脉，打开阻塞或狭窄的血管，让更多的氧气流通，延缓血管进一步变窄或血管壁增厚的速度，改善患者症状，尽量提高患者的生存率，但无法逆转由炎症、增殖和纤维化引起的血管重塑，治标不治本。尽管已是PAH领域的一把手，强生意识到了现有药物的局限性：全球已获批的十余款PAH靶向药包括前列腺素I2（PGI2）类似物、PGI2受体激动剂、内皮素受体拮抗剂（ERA）、PDE5抑制剂和一氧化氮（NO）均为单方制剂，不能解决现存的未被满足的临床治疗需求。 2022年欧洲心脏病学会(ESC) /欧洲呼吸学会(ERS)临床指南推荐对特发性PAH、遗传性药物相关性PAH或无心肺合并症的结缔组织病PAH患者进行ERA和PDE5抑制剂的初始联合治疗。 Opsynvi正是强生对于PAH联合用药的初次探索，基于Opsynvi的关键III期A DUE研究积极结果，该复方的安全性与既往研究中马昔腾坦和他达拉非单一疗法的安全性一致，并且未发现新的安全性信号。Opsynvi的获批使得强生PAH产品组合覆盖所有指南推荐的PAH靶向路径，强化了自己在该领域的优势。不过让强生始料未及的是，Opsynvi才获批没几天，默沙东就追上来了，而且，这个对手的实力不容小觑。默沙东的Winrevair 是一款 first-in-class 的融合蛋白，其可将ActRⅡA经过改造的细胞外域与抗体的Fc端融合，阻断激活素与细胞膜上的受体结合，从而降低激活素介导的信号传导，减少内皮细胞和平滑肌细胞增生，促进凋亡，达到抑制肺血管重塑的效果。获批之前，Winrevair已获得FDA的突破性疗法认定和孤儿药认定，以及欧洲药品管理局的治疗PAH的优先药物认定和孤儿药认定，其是全球首款获得突破性疗法认定的PAH在研疗法。基于Winrevair的III期STELLAR试验，与单独使用背景PAH治疗相比，Winrevair通过阻止动脉壁细胞的增生，来减缓患病者的病情，将Winrevair添加到背景PAH治疗中显示出显著的临床益处，延长了患者的生存时间或疾病进展时间。同时，对比传统的靶向治疗药物，Winrevair可皮下注射，只需每三周进行一次注射，而现有的PAH靶向药物（包括强生的Uptravi和Opsumit）以及刚获批上市复方制剂Opsynvi，都需每日、长期服药，Winrevair大大提高了患者的用药依从性。Winrevair成为了第一个可以改变PAH疾病进程的治疗药。随着Winrevair上市，默沙东正式进军PAH药物市场，强生的PAH产品也迎来了“史上最强”的对手。375亿峰值，默沙东押对宝了吗？显然，Winrevair具有成为治疗PAH基石性疗法的潜力，默沙东对Winrevair一直寄予厚望，将它视为自己心血管领域的重磅新药。根据财报，2023年默沙东全年总收入601.15亿美元，稳居全球MNC营收Top10的榜三，其中k药大卖250.11亿美元，贡献了约42%的营收，是第二大业绩助推器HPV疫苗88.86亿美元销售额的3倍。纵观2023年默沙东主要产品的营收情况，不难发现，除k药和HPV疫苗，其他年销售额能超过30亿美元的寥寥无几。2023年默沙东主要产品销售额图源：医药魔方近几年，默沙东凭借K药一路高歌猛进，但是硬币的反面，这款世界上最畅销的癌症治疗药物，在美国的主要专利将于2028年到期，届时K药销售额遭受重创将不可避免，与K药销售额深度绑定的默沙东，也将迎来增长瓶颈期，距离2028年，只剩4年，留给默沙东的时间不多了。实际上，过去几年，默沙东多次出手并购，以丰富产品管线，寻找K药、HPV疫苗之外的业绩增长新引擎。从近几年的交易并购情况来看，自免、ADC、心血管是重点布局的领域，几笔超100亿美元的重大交易并购都涵盖了这三大领域。2021年，以115亿美元收购Accleron获得Winrevair，便是为了加强心血管管线；2022年花118亿美元买下科伦博泰的9条ADC管线；2023年又以108亿美元收购Prometheus Biosciences，开始向自免领域进军。Winrevair的上市，使得默沙东的心血管领域领先同样重金押注的自免和ADC领域，率先开始造血，根据公开数据，默沙东Winrevair制定的价格是14000美元/支，按照每三周使用一支的频率，Winrevairt的年治疗费用为24.2万美元/年。摩根大通分析师Chris Schott预测：“Winrevair上市后销售将表现强劲，并迅速成为符合条件的肺动脉高压患者护理标准的一部分。”Schott还预计，到2030年，Winrevair的年销售额将达到50亿美元。另外，有华尔街分析师乐观估计，Winrevair的年销售额或将高达75亿美元。对于默沙东而言，在其他买进的管线还未成熟之前，Winrevair确实是解K药即将到来的专利危机的种子选手，可帮助默沙东弥补K药失去专利保护后的业绩损失。参考资料：1、强生、默沙东财报2、《五年死亡率近一半的肺动脉高压，终于迎来了作用于疾病根源的新药，为改善预后、延长生存期带来新希望》梅斯罕见新前沿，2024.03.313、《默沙东2023年财报：K药250亿美元登顶“药王”宝座，HPV疫苗近90亿美元》医药魔方，2023.02.02声明：本稿件仅用于分享，不代表本公众号立场，如涉及版权等问题，请尽快联系我们。本文仅为作者观点，不构成任何投资建议，且非治疗方案推荐。【智药研习社近期课程预告】来源：贝壳社声明：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~

上市批准并购财报寡核苷酸临床研究

2024-03-29

·药渡

最被期待的重磅炸弹

2024年以来，MNC巨头默沙东股价已经录得21.65%涨幅，这对于数千亿美金市值“大块头”来说是难得的。默沙东有如此凶猛的股价表现，得益于一款重磅药物商业化的预期。3月26日，美国FDA批准了治疗肺动脉高压病（PAH）新药Winrevair（商品名）上市申请，隔日默沙东股价大涨4.96%。Winrevair每瓶定价1.4万美元（一般可使用三周），全年的费用约为24.2万美元。Winrevair的获批对默沙东显然是“及时雨”，公司超过40%的收入来自于K药（关键专利2028年到期），且公司超过30亿美元的单品屈指可数（HPV九价、西格列汀），Winrevair的商业化能够使其营收更加多元化，平滑大单品下滑的风险。同时，Winrevair也是全球医药行业投资者备受期待的重磅炸弹，2023年Evaluate评选出最有价值的在研新药TOP10榜单中，Winrevair位列第一。（图数据来源：Evaluate）而摩根大通分析师预计，可预见Winrevair将迅速成为肺动脉高压患者护理标准的一部分，2030年销售额有望达到50亿美元。01肺动脉高压：肺血管“癌症”肺动脉高压（PAH）是一种以肺动脉压力增高，伴有小肺动脉病变为特征的极度肺血管恶性疾病。PAH患者随着肺动脉压力升高，心脏负荷会持续加重，最终导致右心室肥大、心力衰竭，严重则导致死亡；在临床表现上，患者往往会出现气喘、脚肿、肚子胀、肝脏肿大、咯血等。PAH发病诱因较为复杂，先天性心脏病、瓣膜病、慢阻肺、风湿免疫等疾病都可能引发疾病，而特发性、遗传性肺动脉高压则属于罕见病。2019年国内数据显示，PAH患者如果不治疗，患者平均生存期仅为2.8年，又被称为“肺血管疾病中的癌症”。不过，随着靶向药物的发展，PAH患者生存期有着显著改善，1年生存期达到89%；5年生存期提升至53%。据柳叶刀杂志最新报道，2021年全球患肺动脉高压的人数占世界人口总量的1％，全球大约有4000万名肺动脉高压患者；而据国内最新数据显示，我国肺动脉高压患者约有500万至800万人。据贝哲斯咨询统计，2023年全球肺动脉高压药物市场规模到达到了449.58亿元，预估到2029年市场规模达到698.31亿元，2023-2029年复合增速约7.33%。在肺动脉高压药物市场，MNC巨头强生可谓是一马当先，早在2017年以300亿美元收购瑞士生物技术公司Actelion，获得了Opsumit、Uptravi等一系列肺动脉高压产品。2023年，强生的肺动脉高压治疗管线总营收38.15亿美元，同比增长11.6%。其中马西替坦（Opsumit）营收19.73亿美元，同比增长10.6%；赛乐西帕（UPTRAVI）销售额15.82亿美元，同比增长19.7%。尽管强生这笔押注肺动脉高压资产的交易投资回报率非常平庸，但依旧不缺乏MNC看好这个看起来“狭小”的药物赛道，除了2021年115亿美元收购Acceleron获得Winrevair外，2021年辉瑞也花了超60亿美元收购Arena，其资产组合包括用于肺动脉高压检测的Ralinepag。02Winrevair的突破性默沙东的Winrevair，为何能承载如此厚重的市场期望？目前，肺动脉高压主要通过扩张血管的药物进行治疗，如内皮素拮抗剂（ERA）、前列环素类似物及PDE5抑制剂来增加肺部血流量。其中前列腺素/前列环素类似物，以明确的临床证据获益（降低肺动脉压力和肺血管阻力、增加心排量&六分钟步行距离、延长生存时间等益处）占据肺动脉高压药物市场的主导地位，2022年占整个市场规模的45%，随后分别是内皮素拮抗剂、鸟苷酸环化酶激活剂、PDE5抑制剂等。但上述提到的治疗药物，绝大部分的治疗思路只是通过各种途径来促进肺血管扩张，目的是为了血流通过顺畅一些，只具备延缓疾病进程或改善患者症状的作用，并不能够逆转疾病进展。聚焦逆转肺血管重构的治疗策略，才能够打破原有肺血管扩张的治疗模式，破除现有“治标不治本”的窘境，Winrevair让市场看到了这种可能性。与其他药物不同的是，Winrevair是一种激活素信号抑制剂，是激活素受体IIA-Fc型（ActRIIA Fc）融合蛋白。Winrevair可选择性结合TGF-β家族配体，恢复BMPR-2信号通路的平衡（该通路失衡恰恰是肺动脉高压的驱动因素之一）。一方面从Winrevair机制的角度，其能够恢复肺动脉壁和右心室重构相关的促增殖和抗增殖信号通路之间的平衡，起到抑制细胞增殖、逆转血管重构和畅通血管的效果；另一方面，在临床前实验中它也证实了可逆转肺动脉壁和右心室的重塑。在默沙东2023年3月公布Winrevair三期临床STELLAR研究数据显示，在PAH患者中，Winrevair在治疗24周后将患者的6分钟行走距离（6MWD）与基线相比提高40.8米，达到试验主要终点。在9项次要重点分析中的8项显著和具有临床意义的改善，仅有AH-SYMPACT认知/情绪影响领域评分没有显著改善。与安慰剂相比，在中位随访时间为32.7周时，它将患者的疾病临床恶化或死亡风险降低84%，改善在持续使用该药物治疗的18至24个月期间维持。在安全性方面，接受Winrevair治疗的最常见副作用为轻微出血（鼻出血和牙龈出血）、毛细管扩张、头晕、血小板减少和血红蛋白水平升高以及升高血压，整体安全可耐受。Winrevair的上市，无疑在PAH治疗领域具备里程碑意义，不仅将该疾病治疗带入精准生物制剂时代，同时也突破了原有的治疗策略，进而明证Winrevair可能是当前最好的PAH治疗药物。03国内的机会尽管国内PAH患者群体占到全球数量10-20%，但相关创新药物的研发热度远不及肿瘤、自免等热门领域，同时目前国内获批PAH药物也普遍以国际上的老药为主。（图源：CPHI制药在线）更热闹的可能是PAH仿制药市场，以内皮素拮抗剂为例，如马昔腾坦、波生坦专利还未完全过期，已经分别有2家、8家药企正在争夺首仿。而部分前列腺素/前列环素类似物已经进入国产仿制药竞争时代，如曲前列尼尔，复星医药、兆科药业仿制药已经获批在市销售，销售增长惊人。从国内在研PAH创新药管线进展来看，几乎很少将肺动脉高压适应症作为主要的研发方向，这可能与国内市场的支付体系和相关药物研发难度有一定的关系。值得一提的是Biotech鸿运华宁，其开发了ETa特异性单抗GMA301，其汲取了ETa选择性拮抗剂的疗效优点，并对潜在可能的副作用进行结构改良；临床前研究表明，GMA301具有靶向特异性好、药效作用时间长、无肝毒性的特点。目前，GMA301正在进行全球多中心的Ib期临床。另外还值得注意的是港股上市Biotech云顶新耀（子公司云屹药业），早在2017年公司从Arena获得了Ralinepag的大中华区权益。已有的Ralinepag二期数据显示：接受其治疗后的患者不仅能够明显改善肺血管阻力（PVR），还可显著改善6分钟行走距离（6MWD）。目前云顶新耀正在国内推进Ralinepag的三期临床，其可能成为进度最接近商业化的PAH创新药物。（图源：CPHI制药在线）结语：从整体国内对肺动脉高压疾病领域的研发热情来看，我们很可能忽视了这类药物所蕴藏的巨大的机会。或许，需要Winrevair迸发出极大的商业化能量时，国内药企们才会如梦惊醒。免责声明“药渡”公众号所转载该篇文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请及时告知，我们会在24小时内删除相关信息。微信公众号的推送规则又双叒叕改啦，如果您不点个“在看”或者没设为"星标"，我们可能就消散在茫茫文海之中~点这里，千万不要错过药渡的最新消息哦！

专利到期并购申请上市

100 项与 Ralinepag 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10725	-	-	DB12462

研发状态

适应症	最高研发状态	国家/地区	公司
肺动脉高压	申请上市	-	United Therapeutics Corp. 更多
家族性肺动脉高压	临床3期	中国台湾更多	United Therapeutics Corp. 更多
结缔组织病	临床3期	以色列更多	United Therapeutics Corp. 更多
高血压	临床3期	土耳其更多	United Therapeutics Corp. 更多

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03683186 (ATS2024) 人工标引	临床3期	肺动脉高压	96	Ralinepag (Weeks 28)	糧淵積鬱構艱簾顧繭糧(齋遞簾蓋餘齋襯製襯鏇) = Adverse events in the OLE have been consistent with the known safety profile of prostacyclin therapies, with headache (69.8%), diarrhea (39.6%), and nausea (31.3%) reported most commonly. 廠鏇簾範鹹願醖鹹獵醖 (簾窪網壓遞艱艱製衊壓 )	积极	2024-05-22
				Ralinepag (Weeks 52)
NCT02279745 (CTgov)	临床2期	肺动脉高压	45	Ralinepag	繭觸鏇鏇廠鑰簾糧網網(網積範鹽構窪鏇醖襯獵) = 鏇觸膚鹹積鹽積觸衊顧獵網網範構餘選糧襯壓 (觸築鹹築淵鏇鹹獵簾鬱, 鑰鑰鹽觸獵鏇窪範窪夢 ~ 鹹齋選餘觸繭廠遞艱選) 更多	-	2021-12-22
NCT02279160 (CTgov)	临床2期	肺动脉高压	61	APD811 (APD811)	夢餘醖觸齋網選廠鹹壓(衊壓窪憲遞鬱夢簾窪蓋) = 鹹繭構獵網醖鏇積觸憲鑰觸廠鏇構鹽襯齋顧膚 (構夢簾簾憲簾鏇鹽繭繭, 鏇願遞繭夢襯觸遞顧繭 ~ 糧餘憲築範範淵願網夢) 更多	-	2020-07-14
				Placebo (Placebo)	夢餘醖觸齋網選廠鹹壓(衊壓窪憲遞鬱夢簾窪蓋) = 淵膚齋鏇糧範鹽齋襯蓋鑰觸廠鏇構鹽襯齋顧膚 (構夢簾簾憲簾鏇鹽繭繭, 醖膚餘夢醖範遞醖獵獵 ~ 遞獵醖膚醖廠鹽鹽鏇齋) 更多
NCT02279160 (Pubmed \| Clin Chest Med)	临床2期	肺动脉高压	61	Ralinepag	鹽鏇範衊遞淵齋顧憲憲(憲鬱襯選鏇鑰繭構顧獵) = 願衊鑰憲壓顧壓艱鏇獵夢顧簾鏇夢製憲鏇築憲 (範餘糧範襯醖艱襯鹹壓 ) 更多	积极	2019-10-01
				Placebo	鹽鏇範衊遞淵齋顧憲憲(襯糧構鹹獵膚範願襯窪) = 餘積製餘鑰齋簾製餘簾廠獵遞構憲鹽鑰淵壓獵 (簾窪製廠網夢獵膚糧夢 ) 更多
ERS2017	N/A	肺动脉狭窄	-	APD811 (ralinepag)	製齋襯網築繭鬱壓醖憲(製窪鹹壓鹹簾糧憲鏇鏇) = 糧餘遞壓網鏇餘窪選壓構鬱顧鏇窪糧鹹構淵鹹 (範鏇網餘築簾衊簾衊餘 ) 更多	-	2017-09-01
				Iloprost	製齋襯網築繭鬱壓醖憲(製窪鹹壓鹹簾糧憲鏇鏇) = 鏇積顧顧鏇衊夢糧積顧構鬱顧鏇窪糧鹹構淵鹹 (範鏇網餘築簾衊簾衊餘 ) 更多
ESC2017	N/A	-	-	Ralinepag	願衊鹽鬱鹹襯襯製選夢(齋繭壓網衊憲糧鏇壓繭) = 窪築築鹽顧壓蓋齋網築鏇範窪齋鏇獵齋鹹獵襯 (鏇襯蓋餘窪遞齋夢鹹獵 ) 更多	-	2017-08-29
				MRE-269	鹹衊顧憲窪簾廠築蓋選(築壓簾窪製衊蓋簾繭鹹) = 範願夢鏇膚糧製築窪憲襯簾醖壓鹽顧築鏇繭製 (襯簾網壓選淵繭鏇鬱構 )