Ataciguat

By Nancy Lapid Bengaluru: An experimental drug being developed by Sanofi significantly curbed progression of aortic valve stenosis, a common heart problem, in clinical trials, potentially preventing the need for surgery, researchers reported. Aortic valve stenosis, a narrowing due to calcium deposits that forces the heart to work harder to move blood to the body, currently can only be monitored until the condition becomes severe enough to warrant valve replacement surgery . The drug ataciguat has been tested in early and mid-stage trials of patients with moderate aortic valve stenosis. The most recent 23-patient trial showed a nearly 70 per cent reduction in aortic valve calcification progression at six months compared to placebo. Patients receiving ataciguat tended to maintain better heart muscle function as well, researchers reported in the journal Circulation. "This research represents a significant advancement in the treatment of aortic valve stenosis," study leader Jordan Miller of the Mayo Clinic in Rochester, Minnesota said in a statement. "Ataciguat has the potential to substantially delay or even prevent the need for valve replacement surgery, significantly improving the lives of millions." Patients who require valve replacement before age 55 are highly likely to need additional valve replacement surgeries over their lifetime due to recalcification of the implanted valve, Miller said. By slowing progression of the disease in the patient's native aortic valve, ataciguat offers the potential for a once-in-a-lifetime procedure, because valves implanted in older people are less likely to calcify, he said. Sanofi is planning a larger late-stage trial of ataciguat that could be used to seek regulatory approval. Hidden lung problems discovered in children with long covid An advanced type of magnetic resonance imaging has revealed significant - and previously unrecognized - lung abnormalities in children and adolescents with long COVID, researchers reported on Tuesday in Radiology. Conventional exams in young patients with suspected long COVID - such as pulmonary function tests, echocardiography and reviews of medical history - often show normal lung and cardiac function, the researchers said. "Parents should understand that their children's persistent symptoms after COVID-19 may have a measurable physiological basis, even when standard medical tests appear normal," study leader Dr. Gesa Pohler of Hannover Medical School in Germany said in a statement. The advanced technology, known as a phase-resolved functional lung (PREFUL) MRI, showed that children and adolescents with long COVID had significantly reduced blood flow in the lungs compared with healthy counterparts. In addition to poor blood flow, a subgroup of long COVID patients with cardiopulmonary symptoms, such as shortness of breath, also showed a reduction of air movement and reach in the lungs. PREFUL MRI is particularly suitable for use in children because it doesn't involve radiation or intravenous contrast agents and can be done while the patient breathes freely, the researchers noted. The tool may become a useful means of classifying and monitoring the severity of long COVID in youngsters going forward, Pohler said. (Reporting by Nancy Lapid; editing by Bill Berkrot)

从阿司匹林到青霉素，从奥司他韦到阿帕替尼。一个多世纪以来，小分子一直在为人类医学疾病带来新突破。近年来，随着抗体、基因疗法、细胞疗法、ADC、溶瘤病毒的等众多创新生物技术的出现，小分子药物的研发数量有进一步缓慢下降的趋势。但在常用药物中，小分子药物的数量仍可占总量的98%。相对于大分子药物而言，小分子在研发成本和工艺难度上都有很大的优势，依然是新药研发的主战场。据统计，2020年FDA批准的53个新药中化学药有40个。小分子药物仍然方兴未艾。尽管小分子药物存在研发成功率低、半衰期短、特异性不高等问题，仍有许多初创公司投身于这一领域，致力开发减缓钙化性主动脉瓣狭窄（CAVS）疾病药物的RSF Bio便是其中一家。  赛诺菲、妙佑医疗国际、NCATS共同开发RSF Bio，全名为Rancho Santa Fe Bio，是一家创立于2019年的临床阶段心血管药物研发公司，总部位于加利福利亚。目前，RSF Bio与赛诺菲、妙佑医疗国际以及美国国家推进转化科学中心（NCATS）达成协议，获得继续开发创新药物Ataciguat的独家许可。Laura Lewerentz-Juziuk是RSF Bio的创始人，她拥有超过20年的临床催化剂和企业家经验，能够科学成果与商业化战略联系，帮助临床成果顺利转化。担任RSF Bio首席科学官的是Leonard Miller，同时在妙佑医疗国际从事专注于CAVS钙积聚的研究——完成了Ataciguat临床前、Ⅰ期、Ⅱ期试验。他拥有超过20年的生物技术经验，在Gensia Pharma、Metabasis担任高级科学调查员，Targazyme担任研究副总裁。Leonard拥有超过17年的CAVS钙积聚研究经验，发表了65篇同行评审并担任三本生物技术书籍的主编。Ataciguat：有望减缓主动脉瓣钙化进程CAVS即钙化性主动脉瓣狭窄，是主动脉瓣钙化的其中一种类型。CAVS是发达国家最常见的进行性瓣膜疾病，主要困扰老年人群，55岁以上人群患病率为2%，65岁以上人口患病率达到3%。在75岁人群中，其患病率随着年龄的增长而增加至12%或更高。据统计，患病人数在美国约为200万人，欧洲超过300万人，具有较高的发病率和死亡率。患者在代偿期可能无症状，重度患者大多有伴随倦怠、呼吸困难、心绞痛、晕厥等症状。由于钙在主动瓣膜上逐渐积累，造成主动脉瓣硬化。如果不治疗，CAVS通常在症状发作几年内导致死亡。目前CAVS的病理生理机制尚不清楚，尚无药物来阻止或减缓疾病进展。只有对具有换瓣指征的患者，可以进行外科开胸主动瓣膜置换术（SAVR）或经导管瓣膜置换术（TAVR）。RSF Bio正在开发的Ataciguat，是一种一氧化氮非依赖性可溶性鸟苷酸环化酶活化剂，也是RSF Bio正在开发中有望减缓CAVS进展的小分子药物。在正常的生理条件下，身体中保存的一氧化氮（NO）会刺激可溶性鸟苷酸环化酶（sGC）产生cGMP（NO-sGC-cGMP信号通路），cGMP作为各种蛋白激酶的调节剂，控制细胞内Ca++的分布并减弱下游促骨和促纤维化信号传导。 正常NO-sGC-cGMP信号通路，来源：RSF Bio官网然而，在CAVS患者的主动脉瓣中，由超氧化物（O3）和过氧化氢（H2O2）等活性氧（ROS）在钙化区域显著升高，而负责ROS代谢的抗氧化酶（如SOD、过氧化氢酶等）减少，导致主动脉瓣氧化应激升高。主动脉瓣中氧化应激升高会导致sGC转化为对NO不敏感的氧化形式，间接导致cGMP水平降低，也就是NO-sGC-cGMP通路受损而导致细胞内钙的积累和瓣膜钙化。Ataciguat是氧化形式的sGC的高效活化剂，可重新激活下游NO靶标，修复有缺陷的NO-sGC-cGMP信号通路。在CAVS的临床前动物模型中，Ataciguat通过激活氧化可溶性且对NO不敏感的sGC，导致BMP2诱导的转录反应减弱，从而减缓瓣膜钙积累。 Ataciguat作用原理 来源：RSF Bio官网  已开展广泛临床试验，探索Ataciguat其他适应症最开始由赛诺菲进行了一项药物临床试验，召集1000名涵盖稳定性心绞痛、外周动脉疾病和神经性疼痛疾病患者，确定了Atacigua研发渠道的优先级。此后赛诺菲将Atacigua提供给美国国立卫生研究院国家转化科学促进中心（NCATS）的新治疗用途（NTU）计划——鼓励将该药物用于其他临床试验。妙佑医疗国际Jordan Miller（已被聘为RSF Bio首席科学官）实验室在获得NCATS资助后，先后展开Ataciguat用于CAVS的临床前、Ⅰ期和Ⅱ期研究。2021年，通过与赛诺菲和秒佑医疗国际达成协议，RSF Bio已获得继续开发Ataciguat的全球独家许可。RSF Bio希望能够继续探索开发Ataciguat的其他适应症（包括罕见适应症）、发现能够识别CAVS早期迹象的生物标志物以及在心血管和其他领域内其他小分子药物的研究与开发。目前，已有针对修复有缺陷的NO-sGC-cGMP信号通路机制的上市药物Vericiguat，主要适应症为心衰。Vericiguat由医药巨头默沙东和拜耳开发，2021年通过FDA批准，现已多国提交上市申请，已于2022年5月年获批成为国内该机制首个上市药物。左右滑动查看更多近期推荐声明：动脉网所刊载内容之知识产权为动脉网及相关权利人专属所有或持有。未经许可，禁止进行转载、摘编、复制及建立镜像等任何使用。动脉网，未来医疗服务平台