Epoprostenol Sodium

关注并星标CPHI制药在线肺动脉高压（pulmonary Artery hypertension，PAH）是常见的肺血管疾病，是多种异源性疾病（病因）和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压力升高的临床和病理生理综合征，继而发展成右心衰竭甚至死亡。       根据不完全统计，2021年全球约4000万例PAH患者，5年死亡率约为43%，在美国成年人PAH的患病率估计为10.6/100万。如果未经治疗，PAH通常会发展为右室衰竭甚至死亡。过去十年中，PAH的治疗显著改善了预后，市场上现有的PAH疗法可通过促进肺血管扩张来缓解患者病情，但无法从根本上解决肺血管重塑的问题，换句话说，PAH领域依然充满诸多挑战，存在大量未满足的临床药物需求，而手握多款PAH重磅药物的强生以及迎来革命性药物的默沙东，正是肺动脉高压药物开发者里两颗闪亮的明星。       无独有偶，在一周时间内，FDA接连宣布批准了开发的Opsynvi以及默沙东开发的Sotatercept（商品名：Winrevair），分别用于世界卫生组织（WHO）功能分级（FC）为II-III级的肺动脉高压（PAH）成人患者的长期治疗以及治疗成人肺动脉高压，改善WHO功能分级( FC )，降低临床恶化事件的风险。       更巧的是，无论是强生的Opsynvi，还是默沙东的Sotatercept，也均是花重金收购其他公司管线得来--强生于2017年以300亿美金重金收购罕见病公司Actelion，将Opsumit，Uptravi，Tracleer，Veletri和 Ventavis等5款PAH药物收入囊中，而Opsumit（马昔腾坦）以及Uptravi（司来帕格）目前已经成为了强生的重要收入组成部分，也是名副其实的"重磅炸弹"，Tracleer在专利到期前也有过辉煌历史；而Sotatercept则是被默沙东以115亿美元收购的Acceleron公司旗下最重磅的产品，Sotatercept也被默沙东寄予厚望，在未来成为其业绩支柱之一。       强生和默沙东，彼时以重金收购上述两家公司之时，相信都承载了巨大压力和质疑，PAH这一疾病领域在一定程度而言甚至可以属于罕见疾病，从商业结果而言，强生得到了自己要的，之后所做的便是围绕这一领域继续添砖加瓦，而默沙东在为后药王（K药）时代做铺垫，从患者角度而言，巨头的加入加速了药物的商业化以及可及性，也极大程度上造福了患者。       01强生：需要守住优势这次FDA批准的Opsynvi其实并不算一款完全的创新药，其是一种由内皮素受体拮抗剂（ERA）马昔腾坦（macitentan）和磷酸二酯酶5（PDE5）抑制剂他达拉非（tadalafil）制成的单片复方制剂，马昔腾坦自不必说，上文也已经介绍过，目前是强生PAH药物矩阵里的王牌，他达拉非自然也不必多言，也是一款网红药物。       通过查阅本次FDA批准的数据可知，美国FDA对Opsynvi的批准主要基于关键的A DUE临床3期研究结果，其中Opsynvi证明与他达拉非或马昔腾坦单药治疗相比，患者在接受治疗16周后在肺血管阻力（PVR）上有了更大的降低。与马昔腾坦相比，Opsynvi的PVR变化显著更大（治疗效果：29%；95% CI：-18%、-39%，p<0.0001）。与他达拉非相比，Opsynvi的PVR变化也显著更大（治疗效果：28%；95% CI：-20%、-36%，p<0.0001）。Opsynvi的安全性与马昔腾坦和他达拉非单一疗法的已知安全性一致，没有发现新的安全性问题，此外Opsynvi只需要每天服用一次，大大加强了依从性，简言之，二者组合的单一制剂可以协同发挥疗效，固定比例混合可以避免患者在用药中出现剂量不匹配的情况，从而减少药物副作用和安全性风险，毫无疑问Opsynvi将会是老药新用的又一典范案例。图1：Opsynvi临床数据       打开强生的2023年年报可以看到，其肺动脉高压药物板块营收38亿美元，增长12%。在这其中其中马昔腾坦营收19.73亿美元，同比增长10.6%；司来帕格销售额15.82亿美元，同比增长19.7%，其它产品总销售额2.6亿美元，同比下降16.7%，考虑到强生毕竟花了300亿美金重金搭建了PAH药物矩阵，尽管目前在这一领域其稳稳坐上了全球首把交椅，但强生需要做的是守住优势，而本次Opsynvi的获批无疑又延长了旗下PAH药物的生命周期，强生目前已拥有肺动脉高压所有3种基础和指南推荐的治疗药：一氧化氮、内皮素和前列环素，在PAH领域，其余对手难以望其项背。       02默沙东：一场不能输的战役在过去的2023 年，作为默沙东支柱产品的 K 药实现销售额 250 亿美元，以悬殊的差距强势击败昔日药王修美乐（销售额 144 亿美元），终于得偿所愿问鼎全球药王宝座，但需要注意的是， K 药的关键专利也将于2028年后相继到期，面临专利悬崖是每个药企所不得不面对的残酷事实，默沙东自然也不例外。       默沙东在近些年来一直试图通过联合开发、增加适应症等方式，以推动K药的营收增长，并通过不断收购公司和管线，寻找除K药以外的第二增长曲线，无论是以同科伦博泰的重磅ADC合作，还是以108亿美元收购的Prometheus，都是默沙东做出的努力尝试，而Sotatercept的获批，为默沙东寻找第二增长曲线之路开了一个好头。       Sotatercept是一款first-in-class ACVR2A-Fc融合蛋白，由人Activin受体IIA的胞外结构域与IgG1的Fc结构域融合而成，可以结合和捕获TGF-β家族配体（TGF-β配体陷阱），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。       Sotatercept是迄今为止积累了最多证据作为未来治疗PAH的潜在重磅药物，其每21周皮下注射一次。它已经在II期(PULSAR, PULSAR-open label extension, SPECTRA)和III期临床试验(STELLAR)中进行了研究，并证明了有效性和良好的安全性，2023年3月6日，Sotatercept治疗肺动脉高压的三期临床数据在NEJM期刊上发表。图2：Sotatercept临床数据       在STELLAR试验中，在目前可用药物的背景治疗的基础上增加24周的Sotatercept治疗，可以改善肺动脉高压患者的运动能力，以6分钟步行距离评估。在肺血管阻力、WHO功能分级、NT-proBNP水平、通过简化的法国风险模型评估的死亡风险以及PAH-SYMPACT生活质量工具的身体影响和心肺症状领域得分方面也有改善。在试验结束前评估的死亡或非致命性临床恶化事件的风险，Sotatercept比安慰剂低84%。Sotatercept的安全性与2期PULSAR试验11,12包括其扩展研究中观察到的一致，最明显的副作用是毛细血管扩张和出血（主要是鼻衄和牙龈出血）。       在这项试验中，Sotatercept的治疗改善了由6分钟步行距离决定的运动能力，并在多个疗效终点中显示出临床获益。sotatercept具有良好的效益风险比，这些发现证实并扩展了以前的研究结果，Sotatercept的获批，也标志着PAH治疗也正式迈入了生物制剂时代。默沙东为Sotatercept制定的价格是14000美元/支，按照每三周使用一支的频率，Sotatercept的年治疗费用为24.2万美元/年，就目前释放的信号而言，默沙东对Sotatercept的前景尤为看好，并给出了接近三十亿美元销售峰值的预测，对于这一场不能输的战役，默沙东已经开了一个好头，此外默沙东的PAH产品组合中还有每日一次的吸入疗法MK-5475。概念试验的临床前证明显示其有针对性地降低血管阻力和压力，该药物已进入II/III期研究。       03搅局者：United Therapeutics？除了默沙东和强生这样的明星药企，以United Therapeutics为代表的专注于PAH药物开发的公司也将迎来大放异彩的机会。United Therapeutics是一家Biotech公司，总部位于美国马里兰，其成立于1996年，于1999年6月上市。United Therapeutics专门从事肺动脉高压的药物研发，致力于为慢性和危及生命的疾病患者开发产品并将其商业化，而其对于曲前列尼尔（treprostinil）的开发，成为了PAH甚至药物研发领域的典范。       曲前列尼尔（treprostinil）是一种人工合成的前列环素模拟物，主要通过直接舒张肺和全身动脉血管床并抑制血小板聚集发挥作用。United Therapeutics已针对曲前列尼尔推出了多种剂型，包括：Tyvaso（吸入性溶液）、Orenitram（缓释片）、Remodulin（注射剂），Tyvaso DPI（干粉吸入剂）。2022年5月，FDA批准Tyvaso DPI用于治疗PAH和PH-ILD，以提高运动能力。Tyvaso DPI代表了一种用于吸入曲前列尼尔的新配方和吸入装置，是FDA批准用于PAH和 PH-ILD的唯一干粉吸入装置，Tyvaso DPI的上市则直接延长了的生命周期并开启了第二春，Tyvaso的总收入在2023年增长了41 %，达到12.4亿美元，并有望达到近20亿美元的销售峰值。图3：United Therapeutics 2023年第四季度财报       尽管在过去的二十年中在PAH治疗方面取得了显著进展，也涌现出了一大批如United Therapeutics一般优秀的企业，但仍需要创新的治疗方法来改善这种进行性致命疾病的发病率和死亡率。除了目前已有的治疗方法外，BMP信号通路、酪氨酸激酶信号通路、Bromodomain蛋白、性激素以及其他更新颖的方法，如靶向肺血管重塑的基因治疗，正在不同阶段的开发中。通过持续的科学研究来探索新的信号通路和机制，阻止甚至逆转这种毁灭性疾病更近了一步，而最终受益的，将是数以千万计的患者。       参考文献：       1. JAMA | Review Diagnosis and Treatment of Pulmonary Arterial Hypertension: A Review；       2. Late-Breaking Phase 3 A DUE Data Show Investigational Single Tablet Combination Therapy of Macitentan and Tadalafil Significantly Improves Pulmonary Hemodynamics versus Monotherapy in Patients with Pulmonary Arterial Hypertension (PAH)；       3. MSD：FDA Approves Merck's WINREVAIR? (sotatercept-csrk), a First-in-Class Treatment for Adults with Pulmonary Arterial Hypertension (PAH, WHO* Group 1)；       4. 生物制药小编：谁能在肺动脉高压最 先应用生物制剂？       5. Jennifer L. Keen, Nadine Al-Naamani, Corey E. Ventetuolo; The Future of PAH Treatment. Advances in Pulmonary Hypertension 1 January 2023; 22 (1): 55-61. doi: https://doi.org/10.21693/1933-088X-22.1.55       6. Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension，NEJM【智药研习社近期课程预告】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~

WINREVAIR is a breakthrough biologic for this rare, progressive disease WINREVAIR on top of background therapy significantly improved exercise capacity and multiple important secondary outcome measures compared to background therapy alone RAHWAY, N.J.--(BUSINESS WIRE)-- Merck & Co. (NYSE: MRK), known as MSD outside of the United States and Canada, announced today that the U.S. Food and Drug Administration (FDA) has approved sotatercept-csrk (U.S. Brand Name: WINREVAIR™, for injection, 45mg, 60mg) for the treatment of adults with pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group 1) to increase exercise capacity, improve WHO functional class (FC), and reduce the risk of clinical worsening events. WINREVAIR was previously granted Breakthrough Therapy Designation by the FDA. WINREVAIR is the first FDA-approved activin signaling inhibitor therapy for PAH, representing a new class of therapy that works by improving the balance between pro- and anti-proliferative signaling to regulate vascular cell proliferation underlying PAH. This press release features multimedia. View the full release here: WINREVAIR logo (Graphic: Merck & Co., Inc.) “Pulmonary arterial hypertension is a rare, progressive and ultimately life-threatening disease in which blood vessels in the lungs thicken and narrow, causing significant strain on the heart,” said Dr. Marc Humbert, Professor of Medicine and Director of the Pulmonary Hypertension Reference Center at the Université Paris-Saclay and investigator on the Phase 3 STELLAR study. “Based on the Phase 3 STELLAR trial, adding WINREVAIR to background PAH therapy demonstrated significant clinical benefits compared to background PAH therapy alone. This approval is an important milestone, as it offers healthcare providers a novel therapeutic option that targets a new PAH treatment pathway.” The approval is based on the Phase 3 STELLAR trial, which compared WINREVAIR (n=163) to placebo (n=160), both in combination with background standard of care therapies in adult patients with PAH (WHO Group 1 FC II or III). Results showed adding WINREVAIR to background therapy increased six-minute walk distance from baseline by 41 meters (95% CI: 28, 54; p<0.001; placebo-adjusted) at Week 24 and significantly improved multiple important secondary outcome measures, including reducing the risk of death from any cause or PAH clinical worsening events by 84% versus background therapy alone (number of events: 9 vs 42, hazard ratio=0.16; 95% CI: 0.08, 0.35; p<0.001). Healthcare providers should monitor hemoglobin and platelets before each dose of WINREVAIR for the first 5 doses, or longer if values are unstable, and periodically thereafter to determine if dose adjustments are required. WINREVAIR may increase hemoglobin and may lead to erythrocytosis, which if severe may increase the risk of thromboembolic events or hyperviscosity syndrome. WINREVAIR also may decrease platelet count and lead to severe thrombocytopenia, which may increase the risk of bleeding; thrombocytopenia occurred more frequently in patients also receiving prostacyclin infusion. Treatment should not be initiated if platelet count is <50,000/mm3. See additional Selected Safety Information below. “The Pulmonary Hypertension Association welcomes the development of new therapies for those with PAH,” said Matt Granato, president and chief executive officer, Pulmonary Hypertension Association. “A diagnosis of PAH is a life-changing experience for patients and families due to its chronic, progressive nature. Patients with PAH experience limiting symptoms such as shortness of breath and fatigue. We are excited to see industry research leading to a better understanding of PAH and the development of a medicine in a novel treatment pathway that expands options for the patient community.” “New treatment options continue to be needed for patients with pulmonary arterial hypertension that support important clinical goals, including increasing exercise capacity and improving functional class,” said Dr. Aaron Waxman, Executive Director of the Center for Pulmonary Heart Diseases at Brigham and Women’s Hospital and investigator on the Phase 3 STELLAR study. “Sotatercept added to background therapy has the potential to become a new standard of care option for patients with pulmonary arterial hypertension.” WINREVAIR is given once every three weeks by subcutaneous injection and may be administered by appropriate patients or caregivers with guidance, training and follow-up from a healthcare provider. Healthcare providers and patients/caregivers should refer to the Instructions for Use for information on the proper preparation and administration of WINREVAIR. Merck estimates that WINREVAIR will be available for dispensing by select specialty pharmacies in the U.S. by the end of April. “PAH remains a debilitating disease with high morbidity and mortality,” said Dr. Eliav Barr, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “This approval of WINREVAIR is an important milestone and a testament to our science-led strategy and focus on the development of innovations that can help people affected by rare diseases like PAH. We are proud to bring this novel medicine to patients.” Merck offers support to patients who are prescribed WINREVAIR, including information about insurance coverage and help for eligible patients with out-of-pocket costs and co-pay assistance options, through the Merck Access Program. For additional information, healthcare providers and patients can call 1-888-637-2502 or visit in the coming days. STELLAR Study Results The primary efficacy endpoint in the STELLAR trial was the change from baseline at Week 24 in 6-Minute Walk Distance (6MWD). In the WINREVAIR treatment group, the placebo-adjusted median increase in 6MWD was 41 meters (95% CI: 28, 54; p<0.001, Hodges-Lehmann estimate). Additionally, patients who added WINREVAIR had statistically significantly greater improvements compared to placebo across multiple secondary endpoints: Treatment with WINREVAIR led to an improvement in FC from baseline at Week 24 in 29% of patients compared to 14% of patients treated with placebo (p<0.001). Treatment with WINREVAIR resulted in an 84% reduction in the occurrence of death or PAH clinical worsening events compared to placebo (median duration of exposure 33.6 weeks; number of events: 9/163 vs 42/160, hazard ratio=0.16; 95% CI: 0.08, 0.35; p<0.001). Treatment with WINREVAIR led to an improvement from baseline in pulmonary vascular resistance (PVR). The median treatment difference in PVR between WINREVAIR and placebo was -235 dynes*sec/cm5 (95% CI: -288, -181; p<0.001). Treatment with WINREVAIR led to an improvement from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. The median treatment difference in NT-proBNP between WINREVAIR and placebo was -442 pg/mL (95% CI: -574, -310; p<0.001). About STELLAR The STELLAR study (NCT04576988) was a global, double-blind, placebo-controlled, multicenter, parallel-group clinical trial in which 323 patients with PAH (WHO Group 1 FC II or III) were randomized 1:1 to WINREVAIR (target dose 0.7 mg/kg) (n=163) or placebo (n=160) plus stable background therapy administered subcutaneously once every 3 weeks. The most common PAH etiologies were idiopathic PAH (59%), heritable PAH (18%), and PAH associated with connective tissue diseases (CTD) (15%). Most participants were receiving either three (61%) or two (35%) background drugs for PAH, and 40% were receiving prostacyclin infusions. The mean time from PAH diagnosis was 8.8 years. Patients had a WHO FC II (49%) or III (51%) at baseline. About WINREVAIR™ (sotatercept-csrk) for injection, for subcutaneous use, 45 mg, 60 mg WINREVAIR is FDA-approved for the treatment of adults with pulmonary arterial hypertension (PAH, WHO Group 1) to increase exercise capacity, improve WHO functional class (FC) and reduce the risk of clinical worsening events. WINREVAIR is the first activin signaling inhibitor therapy approved to treat PAH. WINREVAIR improves the balance between pro-proliferative and anti-proliferative signaling to modulate vascular proliferation. In preclinical models, WINREVAIR induced cellular changes that were associated with thinner vessel walls, partial reversal of right ventricular remodeling, and improved hemodynamics. WINREVAIR is the subject of a licensing agreement with Bristol Myers Squibb. Selected Safety Information WINREVAIR may increase hemoglobin and may lead to erythrocytosis. Severe erythrocytosis may increase the risk of thromboembolic events or hyperviscosity syndrome. Monitor Hgb before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter, to determine if dose adjustments are required. WINREVAIR may decrease platelet count and lead to severe thrombocytopenia, which may increase the risk of bleeding; thrombocytopenia occurred more frequently in patients also receiving prostacyclin infusion. Do not initiate treatment if platelet count is <50,000/mm3. Monitor platelets before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter to determine if dose adjustments are required. In clinical studies, serious bleeding (e.g., gastrointestinal, intracranial hemorrhage) was reported in 4% of patients taking WINREVAIR and 1% of patients taking placebo. Serious bleeding was more likely in patients on prostacyclin background therapy and/or antithrombotic agents, or with low platelet counts. Advise patients about signs and symptoms of blood loss. Do not administer WINREVAIR if the patient is experiencing serious bleeding. WINREVAIR may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with WINREVAIR and for at least 4 months after the final dose. Pregnancy testing is recommended for females of reproductive potential before starting WINREVAIR treatment. Based on findings in animals, WINREVAIR may impair female and male fertility. Advise patients on the potential effects on fertility. The most common adverse reactions occurring in the Phase 3 clinical trial (≥10% for WINREVAIR and at least 5% more than placebo) were headache (24.5% vs 17.5%), epistaxis (22.1% vs 1.9%), rash (20.2% vs 8.1%), telangiectasia (16.6% vs 4.4%), diarrhea (15.3% vs 10.0%), dizziness (14.7% vs 6.2%), and erythema (13.5% vs 3.1%). Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with WINREVAIR, and for 4 months after the final dose. About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn. Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2023 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site ( ). Please see Prescribing Information for WINREVAIR (sotatercept-csrk) at , Patient Information for WINREVAIR at , and Instructions for Use for WINREVAIR (1-vial kit, 2-vial kit) at . *WHO = World Health Organization