Selexipag

点击蓝字关注我们肺动脉高压（PAH）是一种罕见、进展快速且最终危及生命的进展性心血管疾病，其特征是肺血管重构，导致肺动脉管腔进行性闭塞，肺血管阻力不断升高，进而导致心力衰竭甚至死亡。       关于肺动脉高压       根据柳叶刀杂志报道，全球患肺动脉高压的人数占世界人口总量的1％，常见于30至60岁的女性，约五分之一的患者有家族病史。PAH 的诊断常被延误，因为其症状如：呼吸短促、疲劳、脚和腿肿胀、头晕或昏厥、胸痛、心悸等与常见的心脏和肺部疾病的症状相似。从病理学机制上看，肺动脉高压是多个信号通路及环境因素、基因因素共同作用的结果。绿色箭头=通路激活剂，红色箭头=通路抑制剂，蓝色方框=通路，红色方框=通路抑制剂、绿色方框=通路激活物/调节剂。  肺动脉高压现有治疗药物  在缺乏靶向药物的传统治疗时代， PAH患者预后差，存活时间短，5年生存率仅有20%左右。自靶向药物广泛用于临床后，PAH患者生存率显著提高，5年生存率达到近60%。现阶段肺动脉高压的治疗方式仍以靶向药为主，目前PAH的靶向药物治疗主要针对三大致病途径调节血管收缩或舒张，包括内皮素通路、一氧化氮通路、前列环素通路。内皮素通路:内皮素受体拮抗剂(ERA)一氧化氮通路:磷酸二酯酶抑制剂(PDE5i)、可溶性鸟苷酸环化酶(sGC) 激动剂前列环素通路:前列环素及其类似物、前列环素IP受体激动剂目前国内已上市的PAH靶向药有波生坦、安立生坦、马昔腾坦；西地那非、他达拉非、利奥西呱；吸入伊洛前列素、皮下和静脉注射曲前列尼尔、司来帕格等。  临床治疗亟需更有效药物  既然现有的靶向药已经能够改善病症，为什么患者死亡率并没有显著改善？为什么新靶点药物仍受到研究人员高度关注？肺动脉高压的特征是肺血管重构，肺动脉管腔狭窄闭塞。血流通过肺血管时的阻力增大，导致缺氧和右心功能衰竭。现有的PAH靶向药如波生坦、西地那非、利奥西呱等，通过各种途径促进肺血管扩张，让血流通过顺畅一些，缓解患者症状，使患者能维持较好的生活质量，但未从源头上抑制疾病进展，即所谓“治标不治本”。肺动脉高压的治疗亟需打破过去单纯肺血管扩张模式，聚焦逆转肺血管重构的高效的全新一代治疗药物。2024年3月26日，美国食品药品管理局（FDA）批准由Acceleron Pharma和MERCK联合开发的sotatercept（商品名：Winrevair）用于治疗成年人的肺动脉高压，以增加运动能力，改善WHO功能分级并降低临床恶化事件的风险。该药物每瓶定价14000美元，全年的费用约为24.2万美元，约175万人民币。摩根大通股票分析师 Chris Schott预测到2030年，销售额可接近50亿美元。与传统药物不同，Sotatercept是一种激活素信号抑制剂，是First-in-class激活素受体IIA-Fc型（ActRIIA Fc）融合蛋白，可选择性结合TGF-β家族配体，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，机制上具有抑制平滑肌细胞增殖、逆转肺动脉壁和右心室重构潜力，但仍需更多直接的临床证据证实。广州喜鹊医药有限公司独家开发的创新1类化学药物MN-08，既能拮抗NMDA受体、改善患者症状，又能在体内释放一氧化氮，扩张血管增加血流。在临床前药效学实验中显示出良好的药效，在肺和脑组织中具有很高的药物浓度分布，可以扩张肺动脉和脑血管。在肺动脉高压的病理状态下，NMDA受体过度激活导致谷氨酸超载、肺血管收缩、增生和纤维化。MN-08可借助特殊的分子结构参与到这一过程中，从而抑制谷氨酸超载。同时，MN-08分子中的一氧化氮供体基团可释放一氧化氮，有助于舒张肺血管、降低肺动脉压，改善肺血流循环、抑制肺血管重构和纤维化。MN-08治疗肺动脉高压中国临床 1 期及 2 期第一阶段单次给药开放试验结果已显示明确的肺动脉压力下降及增加心输出量的效果，目前正在开展中国临床2期第二阶段研究。本文部分内容来源于：梅斯心血管新前沿。内容仅供参考，不构成任何投资及应用建议，亦不代表任何治疗指导及用药建议。如稿件涉及版权等问题，请与我司联系，我们将在第一时间协调给予处理或删除。

The company expects costs from tariffs that have so far been imposed to add up to about $200 million. With potential tariffs and other drug pricing policies on the horizon, the industry is navigating uncertain waters. Merck, while steadfast in its manufacturing push that aligns with the administration’s focus, is no different as it prepares for challenges ahead.While the company reaffirmed its full-year financial outlook of global sales between $64.1 billion and $65.6 billion in its first quarter earnings results, Merck noted that the number includes the hit of current tariffs that have been set in the U.S. That adds up to expected incremental costs of about $200 million, largely from those implemented between the U.S. and China, plus Canada and Mexico “to a lesser degree,” CEO Rob Davis explained on the company’s earnings call.President Donald Trump has not yet imposed tariffs specifically on pharmaceuticals, but with previous threats of pharma-targeted tariffs that could come in at 25% or more, it’s a concern that continues to cloud the industry. Merck, with more than $12 billion spent on U.S. manufacturing and R&D capabilities since 2018 and an additional $9 billion earmarked through 2028, has already been working on its supply chain strategy in a way that “aligns well with the new administration’s efforts to regrow the U.S. manufacturing base,” Davis noted. With its efforts so far, Merck has “done a good job of managing our inventory,” leaving the company “able to mitigate anything we could see in the short term,” the CEO said. For example, on-hand inventory for Keytruda in the U.S. will last through all of 2025, Davis said.Now, the focus is on gearing up for the medium and long-term. While the company made clear its business development strategy remains unchanged, the “uncertainty everyone is wrestling with” makes it “more complex to get things done,” Davis mused. An uncertain landscape One thing is for certain: uncertainty is the name of the game these days. With industry opposition to Europe’s low drug prices ramping up, especially as Trump reportedly considers an international drug pricing reference policy that would link U.S. drug prices to those of other countries, the higher prices and therefore greater incentive for innovation that the U.S. sees have been top of mind lately.“The price differential that exists between the United States and the rest of the world for our innovative medicines needs to be addressed,” Davis said, declaring Merck is “open and willing to work with the administration to do that.”As Merck and Davis see it, the focal areas in the drug pricing topic are pharmacy benefit manager (PBM) reform, “fair value” for innovation in other countries and protecting the “innovation engine” in the U.S.“We don't want to lose the leadership we have in this important field, and that's what we're trying to advocate for as we work with the administration,” he said.Elsewhere on the EU issue, Davis sided with “recent commentary” from his peers, some of whom, such as Novartis CEO Vas Narasimhan and Sanofi CEO Paul Hudson, have been outspoken about European drug pricing controls.“We have to continue to encourage foreign governments to understand that they need to give fair value for the innovation we bring,” at prices that “reward us for the risk in innovation that we have,” Davis said, adding that Merck is “spending time individually” and with its industry peers “promoting that point everywhere we can around the world.” Preparing for a post-Keytruda futureOutside of the industry-wide focus on tariffs and policy changes, the next few years will also be crucial for Merck as it prepares to lose exclusivity of its top-selling Keytruda. The megablockbuster oncology drug’s $7.2 billion in first quarter sales made up roughly half of the company’s total haul of $15.5 billion. As it stands, the plan is to use a pipeline of 20 potential growth drivers, “almost all of which have blockbuster potential,” to weather the storm and unlock over $50 billion by the mid-2030s, Davis said. New launches of pneumococcal disease vaccine Capvaxive and pulmonary arterial hypertension (PAH) drug Winrevair represent two of those 20 new products and have so far been delivering “meaningful contributions.”Winrevair specifically beat analysts' expectations at $280 million in first quarter sales, proving an “encouraging” launch so far, Citi Research analysts noted. More than 1,400 new patients received the drug over the quarter, while about 6,600 patients have been prescribed since its launch last April. The drug is going up against a hefty rival in Johnson & Johnson’s Uptravi, a prostacyclin receptor (IP) agonist that controlled half of the $7.3 billion market in 2023. But Merck is edging in on a group of patients whose background treatment does not include a prostacyclin with a “steady increase” in the percentage of prescriptions filled for that subset, the company pointed out.Meanwhile, a continuous headwind dragging down Merck’s sales is the sluggish demand for HPV vaccine Gardasil in China. With sales crashing 40% over the first quarter to $1.3 billion, the company doesn’t expect to ship further Gardasil products into China for the time being, Chief Financial Officer Caroline Litchfield noted. Excluding China, the vaccine’s sales swelled 14% over the quarter.