Leukomalacia, Periventricular

在美国影响少于20万人，和在欧盟不到1/2000人患有的疾病被定义为罕见病。由于患者群体规模小，过去针对孤儿药的研发较少。一些主要市场的监管机构已经推出新的法案来鼓励罕见疾病药物的研发，包括美国FDA在1983年推出的孤儿药法案，和日本在1993年以及欧盟在2000年相继推出的法案。更长的市场独占权（美国7年，欧盟10年），以及新技术的进步等激励措施促进了对罕见病的突破性研究和孤儿药研发的增长。截至2023年3月，美国FDA已经批准了6506种孤儿药，其中1144种获得了“孤儿药认定”批准。在研关键孤儿药近年来，孤儿药的开发主要集中在血液、神经系统疾病、传染病、代谢/内分泌、风湿病/免疫、心血管、胃肠病、肺病和眼科等治疗领域。目前有几种关键的在研孤儿药可能成为新的罕见病治疗方案。表1：几种可能成为罕见病关键候选药物的在研孤儿药Momelotinib骨髓纤维化是一种罕见的骨髓疾病，其特征是血细胞产生异常，导致骨髓广泛瘢痕形成，引发严重贫血、疲劳和脾脏肿大。2022年8月17日，美国FDA接受GSK关于Momelotinib（JAK1、JAK2和激活素A受体I型口服抑制剂）的NDA申请，用于治疗中至重度贫血的骨髓纤维化患者。Momelotinib的研发战略侧重于二线治疗，这是一个未被满足临床需求较高的领域，因为大多数骨髓纤维化患者在二线治疗时会贫血。NDA得到了包括MOMENTUM试验在内的关键III期试验数据的支持，该试验表明有25%的使用Momelotinib的患者“总症状评分”减少至少50%，而达那唑对照组为9%。在第24周，40%接受Momelotinib治疗的患者脾脏体积至少缩小了25%，而对照组患者的脾脏体积缩小了6%。此外，Momelotinib组和对照组实现免于输血的患者比例分别为31%和20%，达那唑组贫血患者的发生率高于Momelotinib组（75% vs 61%）。根据PDUFA的预期目标日期，原定今年6月16日FDA对Momelotinib的批准做出监管决定将延期至9月。SRP-9001杜氏肌营养不良症是一种罕见的X连锁进行性遗传疾病，其特征是杜氏肌营养不良症基因的突变，会阻止功能性肌营养不良蛋白的产生，而功能性肌营养不良蛋白是一种参与维持肌肉细胞完整性的结构蛋白。近期在基因治疗方面取得了进展，可以向患者提供功能性缩短形式的肌营养不良蛋白，从而有可能治愈这种使人衰弱的疾病。Sarepta Therapeutics和罗氏的SRP-9001（delandistrogene moxeparvovec）有可能赢得将首个治疗杜氏肌营养不良症的基因疗法推向市场的机会。SRP-9001是一种携带微营养不良蛋白的AAV恒河猴血清型74衣壳，于2022年11月28日在美国获得优先审查，以加速批准用于治疗杜氏肌营养不良症的门诊患者。该申请得到了ENDEAVOR（SRP-9001-103）I期临床试验、SRP-9001-101 I/II期临床试验和SRP-9001-102II期临床试验数据的支持。SRP-9001-102试验第一部分的主要数据显示，治疗后微肌营养不良蛋白表达的主要生物学终点得到满足：接受SRP-9001治疗的患者在第12周的平均微肌营养不良蛋白表达为28.1%。在第48周，与安慰剂组的0.9分相比，SRP-9001患者的North Star动态评估总分比基线提高了1.7分。Exagamglogene autotemcel镰状细胞病和β地中海贫血是由β-珠蛋白基因突变引起的遗传性血液疾病，导致血红蛋白表现异常（减少或缺失）。Vertex和CRISPR Therapeutics正在寻求作为第一个被批准的CRISPR基因编辑疗法的里程碑式批准。Exagamglogene autotemcel是一种体外CRISPR/Cas9基因编辑疗法，旨在编辑患者自身的造血干细胞，在红细胞中产生高水平的胎儿血红蛋白，以消除血管闭塞危险，减轻输血需求。两家公司用于治疗严重镰状细胞病和输血依赖性β地中海贫血的BLA已被美国FDA接受优先审查，并分别为这些适应症指定了2023年12月8日和2024年3月30日的PDUFA日期。该疗法也正在欧盟和英国接受监管审查。Taldefgrobep alfa脊髓性肌萎缩症是一种影响中枢神经系统、周围神经系统和随意肌运动的复杂遗传性疾病。它涉及脊髓运动神经元的丧失，是由SMN1基因突变导致存活运动神经元（SMN）蛋白缺乏引起的。脊髓性肌萎缩有4种类型，其中1型是最常见和最严重的形式。BiohavenPharma的抗肌生长抑制素Taldefgrobep alfa于2023年2月24日获得美国FDA快速通道认定，用于治疗脊髓性肌萎缩症。它被设计与疾病修饰疗法联用，通过阻断肌肉生长抑制素活性来增强肌肉功能。该公司目前正在进行一项III期试验（RESILIENT），评估taldefgrobep α作为辅助治疗对已经服用诺西那生钠（nusinersen）或利司扑兰（risdiplam）的门诊和非门诊脊髓性肌萎缩症患者的安全性和有效性。该试验预计将于2025年1月完成。ACP-101普拉德-威利综合征是一种罕见的遗传性多系统疾病，其特征是婴儿早期出现严重的肌张力低下、食欲不振和喂食困难，随后在儿童早期过度进食并发展为病态肥胖。个体也会出现认知障碍和生殖器发育不全。目前还没有批准的治疗这种疾病的药物。ACADIA的ACP-101是一种后叶催产素受体激动剂卡贝菌素的鼻内制剂，目前正处于普拉德-威利（Prader-Willi）综合征的III期研发阶段。在一项评估ACP-101在普拉德-威利综合征患者中3.2和9.6毫克剂量的安全性、耐受性和有效性的III期试验中，ACP-101是安全且耐受性良好的，并且在3.2毫克剂量下，在统计意义上具有显著疗效。该公司启动了一项额外的III期试验，以评估3.2毫克剂量的ACP-101治疗普拉德-威利综合征的贪食症。截至2023年6月20日，IQVIA Pipeline Link列出了82个正在积极开发的临床项目，用于骨髓纤维化（MF）、原发性玻璃视网膜淋巴瘤（PVL）、杜氏肌营养不良症（DMD）、镰状细胞病/ β地中海贫血（SCD/BT）、脊髓性肌萎缩症（SMA）和普瑞德-威利综合征（PWS）。图1:在IQVIA PipelineLink中分析的82种MF、PVL、DMD、SCD/BT、SMA和PWS的积极研发疗法的开发现状总结在过去四十年中，监管方授予孤儿药认定的数量显著增加，大大鼓励了孤儿药的研发活动、使之日益常态化。孤儿药认定可为研发人员提供财政激励，包括抵免税收、减免处方药使用者费用（目前每种药物近300万美元）和延长市场独占期。技术进步也使罕见疾病靶向成为可能，并对推动孤儿药研发增长发挥了关键作用。然而，罕见病领域仍然是一个高度未被满足临床需求的领域，因为在为小患者群体建立临床试验以及确定孤儿药研发终点的判定指标方面存在挑战。更好地了解罕见病的病理生理学、以及帮助孤儿药获得更大的市场份额，可能会促使药企进一步加大对开发孤儿药的投资。

In experiments using neonatal mice, researchers have identified a fatty molecule in breast milk that triggers a process in which stem cells in the brain produce cells that create new white matter, reversing brain injury. While it's known that the white matter loss will lead to neurological deficits, there is currently no treatment to help these infants avoid the outcome. In experiments using neonatal mice, researchers at Duke Health have identified a fatty molecule in breast milk that triggers a process in which stem cells in the brain produce cells that create new white matter, reversing the injury. The study appears Aug. 3 in the journal Cell Stem Cell. Eric Benner, M.D., Ph.D., is the study's corresponding author and is a distinguished assistant professor in the Department of Pediatrics at Duke University School of Medicine. Benner said further study in a clinical trial is needed, but the finding is promising. "Developing therapies for children -- especially such medically fragile children -- is very difficult to do because there are justifiably strict safety concerns," Benner said. "The fact that this molecule is already found in something that is safe for premature babies -- breast milk -- is extremely encouraging. "It's been known that fats in breast milk benefit a child's brain development, but there are many types of fats in breast milk," Benner said. "This work has identified a lipid molecule in breast milk that promotes white matter development. Now, we can begin to develop a therapy that isolates and delivers this lipid in a way that is safe for the unique challenges of these infants." Benner is a neonatologist at Duke University and one of the co-founders of Tellus Therapeutics, a Duke spinout company developed with the help of the Duke University Office for Translation & Commercialization to bring this therapy from the bench into the neonatal intensive care unit. The fatty molecule identified in the study will be administered intravenously to patients in an upcoming clinical trial. This is significant because many of the infants who are part of this vulnerable population also have gastrointestinal issues and cannot safely be given milk or medication by mouth. The lipid molecule enters the brain and binds with stem cells there, encouraging the stem cells to become or produce a type of cell called oligodendrocytes. The oligodendrocytes are like a hub that allow for the production of white matter in the central nervous system. This newly produced white matter in pre-term infants prevents the neurological damage that would otherwise impact the child's ability to move -- the hallmarks of cerebral palsy. "The timing of brain injury is extremely difficult to predict, thus a treatment that could be safely given to all preterm babies at risk would be revolutionary," said Agnes Chao, M.D., a former fellow in the Division of Neonatology and first author of the paper. "As a neonatologist, I'm so excited that I may be able to offer a treatment to families with babies that are affected by preterm brain injury who would otherwise have no other options," Chao said. In addition to Benner and Chao, study authors include Pavle Matak, Kelly Pegram, James Powers, Collin Hutson, Rebecca Jo, Laura Dubois, J. Will Thompson, P. Brian Smith, Jason R. Gibson, Noelle E. Younge, Blaire Rikard, Simon G. Gregory, Ronald N. Goldberg, Mari L Shinohara, Estefany Y. Reyes, Chunlei Liu. The study was funded by the National Institutes of Health (1R01NS114578, T32HD094671, K12HD043494, T32HD043728, R01AG070826, R01MH127104, P41EB015897, 1UL1-TR002553), Jean and George Brumley Jr. Neonatal Perinatal Research Institute, with additional support from the Duke Scholars Award from the School of Medicine, Duke University Center for In Vivo Microscopy, and the National Center for Advancing Translational Sciences.

The company designed its next-generation TAVR system to treat aortic stenosis. With a unique concave and convex structure, the TAVR system anchors the valve effectively in the aortic annulus. This helps to avoid common complications with TAVR, including implant dislodging or perivalvular leak (PVL) due to improper fit, according to the company. The valve also features differential radial force in different parts, according to a news release. It imparts low or high radial forces to the valve depending on the location within the annulus and aorta. Onecrea said it designed the delivery system with improvements for greater control and accuracy for implantation. About the first-in-human implants for Onecrea Medical Dr. Carlos Calderas supervised a team of surgeons that performed the implantations for the first-in-human effort for the Onecrea valve. The first patient, an 82-year-old woman, had a history of severe shortness of breath and severe symptomatic aortic stenosis. She underwent a giant abdominal aortic aneurysm (AAA) repair recently. Calderas successfully implanted a 26 mm Crea aortic valve through the femoral approach. The patient was discharged from the hospital after three days with a mean gradient of 8 mmHg and no PVL. Onecrea said that the second patient, an 88-year-old-woman, was referred to consider TAVR because of severe symptomatic aortic stenosis. She recently went to the emergency room for heart failure requiring mechanical ventilation. This led to a diagnosis of severe aortic stenosis and shortness of breath. The team implanted a 26 mm Crea valve through the femoral approach with the 18F introducer. At discharge five days later, the patient recorded a mean gradient of 7 mmHg and no PVL. “The design of the Crea Aortic Valve is truly exceptional, revolutionizing the way we approach TAVR procedures,” Calderas said. “The delivery system was remarkably easy to use, increasing the accuracy of valve placement. This means less time operating on the patient while decreasing the risk of paravalvular leaking and implant dislodging. The valve’s innovative engineering ensures optimal hemodynamics and durability, providing patients with a reliable and long-lasting solution.” Onecrea continues to enroll patients in a larger clinical study conducted across multiple centers.