Smith-Magenis Syndrome

The FDA flashed a red light on Vanda Pharmaceuticals’ experimental treatment for a gastrointestinal condition that disrupts the digestion process. The agency rejected tradipitant in gastroparesis on Wednesday, the Washington-based company said Thursday morning. The biotech said it will keep seeking approval and will still support the expanded access program for the “several dozen patients” currently using that pathway. Vanda offered a stinging rebuke of the agency’s actions, complaining that the FDA’s decision was delayed by more than 185 days and failed to “satisfy the requirements specified by the Food Drug and Cosmetic Act (FDCA).” The company was also miffed that the regulator didn’t grant an advisory committee hearing, which Vanda wanted. The company submitted two placebo-controlled studies of part of its application package. Signs did not seem to be pointing in Vanda’s favor after the company said in its second-quarter earnings update that “deficiencies” precluded the regulator from having discussions with Vanda about the drug’s label. The FDA told the company that its response then should not be considered a teaser of a decision on the full application. “If you see it from the patient need, I think it is very important that tradipitant makes it to the armamentarium of drugs for gastroparesis,” CEO Mihael Polymeropoulos said. There has been “no effective treatment approved by the FDA in over 40 years” for the condition, the company added. The latest rejection follows the FDA’s decision earlier this year not to tack on insomnia to the label of Vanda’s Hetlioz. The drug is approved to treat non-24-hour sleep-wake disorder and a rare behavioral condition called Smith-Magenis syndrome, but the FDA was dissatisfied by the package informing the insomnia ask. Patients treated with tradipitant have filed a citizen petition with the FDA, requesting the agency approve it for gastroparesis, Vanda said Thursday. The company added it will also submit a different NDA for the drug for vomiting prevention in motion sickness by year’s end. Vanda’s stock price $VNDA dropped about 12% before the opening bell.

▎药明康德内容团队报道 炎热的夏季，失眠也变得更加常见或加重。失眠是一种不容易自然地进入睡眠状态的症状，可能是短期的，也可能长期持续。长期失眠会伴随白天精神不佳、嗜睡、易怒、甚至抑郁等症状，严重影响人们的健康、工作和生活质量。根据《中国成人失眠诊断与治疗指南（2023版）》数据，中国普通人群有临床意义的失眠患病率约为15%。本文根据公开资料整理全球十多款正在进行失眠症临床开发的在研药物，其中6款在中国已迈入临床开发阶段。 图片来源：123RF 先声药业、Idorsia公司：达利雷生 作用机制：双食欲素受体拮抗剂 盐酸达利雷生片是Idorsia公司开发的抗失眠药，为一款双食欲素受体拮抗剂。先声药业此前通过一项5000万美元的合作获得了该产品在大中华地区开发和商业化的独家权利。目前，达利雷生已在美国、英国、欧盟等地获批上市。今年7月，盐酸达利雷生片新药上市申请已获得NMPA受理。 食欲素受体拮抗剂是一类经过临床检验的、安全有效的新型抗失眠药。食欲素是存在于大脑特定部位的一种神经递质，通常向身体传递各种保持清醒的讯息，是导致失眠的罪魁祸首之一。根据先声药业公开资料，与传统镇静催眠药物通过镇静大脑来促进睡眠的疗法不同，达利雷生通过阻断食欲素神经肽与其受体的结合，降低过度活跃的中枢觉醒。由于其仅阻断食欲素受体的启动，因此可减少唤醒驱动，诱导睡眠发生，而不改变睡眠阶段的比例，且没有次日残留效应。在针对中国失眠患者的3期临床研究中，服用达利雷生的患者每周相当于可增加近一整晚的睡眠。 卫材（Eisai）：莱博雷生 作用机制：双重食欲素受体拮抗剂 根据卫材公开资料，莱博雷生片（lemborexant）是一款双重食欲素受体拮抗剂，此前已经在中国香港地区获批上市，用于治疗成人失眠，特别是入睡困难和/或睡眠维持困难。2024年1月，该产品在中国内地的上市申请获NMPA受理。 莱博雷生是一款小分子药物，其通过竞争性结合两种食欲素受体亚型OX1R和OX2R，抑制食欲素神经传递，调节睡眠-觉醒节律。作为一种竞争性拮抗剂，莱博雷生对OX2R具有更强的抑制作用，可抑制REM和非REM睡眠驱动，从而可以为患者提供更快的睡眠开始、更好的睡眠维持。 扬子江药业：YZJ-1139片 作用机制：双重食欲素受体拮抗剂 根据扬子江药业公开资料，YZJ-1139片是一款双重食欲素受体拮抗剂，能够同时抑制食欲素受体1型和2型，加快睡眠速度，延长深睡时间。该产品于2017年在中国获批临床。根据中国药物临床试验登记与信息公示平台，扬子江药业已经完成一项YZJ-1139片治疗失眠症的3期临床试验，针对的适应症为以入睡困难/睡眠维持障碍为特征的失眠症。 YZJ-1139治疗原发性失眠症的2期临床试验结果曾发表于2021年亚洲睡眠医学会第三届睡眠大会。试验结果表明，YZJ-1139可剂量相关地改善睡眠效率，各剂量组均可以改善受试者睡眠效率至健康水平。与安慰剂组相比，YZJ-1139未出现明显的中枢神经系统副作用，第二日残留效应低。 翰森制药：HS-10506 作用机制：化药1类新药 根据中国药物临床试验登记与信息公示平台，翰森制药正在开展一项1b/2期临床研究，评价HS-10506在中国成人失眠障碍患者中多次给药的安全性和耐受性。根据中国国家药监局药品审评中心（CDE）公示的受理号信息，HS-10506是一款1类化药新药，拟开发用于抑郁症及失眠。目前翰森制药尚未披露该产品的具体作用机制。 中国医学科学院药物研究所：YZG-331 作用机制：新型腺苷类衍生物 公开资料显示，YZG-331是一款1类化学新药，是中国医学科学院药物研究所以天麻为起点，通过药物化学和药理学紧密结合研究，深入发掘天麻中微量有效成分，并经过进一步结构修饰得到的新型腺苷类衍生物。研究表明，该产品具有潜在的镇静和催眠作用，其作用机制涉及A1R/A2aR的激活和Ca2+-CaMKII信号通路的下调。今年8月4日，YZG-331片在中国获批临床，拟用于失眠的治疗。 布瑞迅药业：BrP-01096 作用机制：选择性食欲素受体（OX2R）拮抗剂 2023年8月，布瑞迅药业申报的1类新药BrP-01096在中国获批IND，拟用于失眠症的治疗。根据公开资料，BrP-01096是一款口服小分子选择性食欲素受体（OX2R）拮抗剂，通过选择性地抑制OX2R而改善睡眠，包括加快入睡速度和延长睡眠时间，具有潜在起效快、药效优异、耐受性好、长期服用耐药风险低、停药不反弹等特点。根据中国药物临床试验登记与信息公示平台，该产品正在开展针对失眠症的1期临床研究。 除了前述在研产品，还有一些在研产品在国际领域已经获批治疗失眠症，或正在开展失眠症的治疗研究，但从公开信息尚未查询到在中国的注册进展。 默沙东（MSD）：suvorexant 根据默沙东公开资料，suvorexant是一款双重食欲素受体拮抗剂，此前已经于2014年获美国FDA批准用于治疗入睡困难和/或睡眠质量不佳的成人失眠症患者。 百时美施贵宝/Vanda Pharmaceuticals：他司美琼（tasimelteon） Tasimelteon是一款褪黑素受体激动剂。2014年，它曾得到FDA的批准，治疗“非24小时睡醒周期障碍”（Non-24-hour sleep–wake disorder）。2020年，Vanda宣布FDA批准Hetlioz胶囊和口服混悬液上市，用于治疗史密斯-马吉利综合征成人和儿童患者夜间睡眠障碍。 盐野义制药/Purdue Pharma:sunobinop Sunobinop（V117957/IMB-115）是一种伤害感受器受体小分子激动剂。它用于治疗失眠的2期临床研究正在进行中。 Servatus biopharmaceuticals：SVT-4A1011 公开信息显示，SVT-4A1011是一款微生物调节剂。该产品正在开展2期临床研究，用于入睡和睡眠障碍。 芬兰奥利安集团：tasipimidine（ODM-105） Tasipimidine是一款口服选择性α2A-肾上腺素受体激动剂，正在开展2期临床试验，旨在研究其治疗失眠的效果。 20多年来，中国已经有一些药物获批上市，用于失眠症状的治疗，例如褪黑素产品美洛托宁（melatonin）、GABAAR激动剂酒石酸唑吡坦（zolpidem），佐匹克隆（zopiclone），以及地达西尼（dimdazenil）等。期待更多新机制的药物取得突破，为失眠症患者带来更好的生活改善。 参考资料： [1]各公司官网和公开资料 本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权及其他合作需求，请联系wuxi_media@wuxiapptec.com。 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

TEL-AVIV, Israel, July 30, 2024 /PRNewswire/ -- Neurim Pharmaceuticals ("Neurim") announces that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion, recommending an extension to the existing indication to include the treatment of Insomnia in children with Neurogenetic disorders (NGDs). Slenyto® is a child appropriate prolonged release melatonin formulation that was approved in the EU in 2018 for the treatment of insomnia in children with autism spectrum disorder (ASD) and/ or Smith-Magenis Syndrome. Slenyto® is the only authorised medication for insomnia in these disorders. The adopted recommended wording for the extended indication is: "Slenyto® is indicated for the treatment of insomnia in children and adolescents aged 2-18 with autism spectrum disorder (ASD) and/or neurogenetic disorders with aberrant diurnal melatonin secretion and /or nocturnal awakenings, where sleep hygiene measures have been insufficient". "The positive CHMP opinion on Slenyto® represents a significant milestone in addressing an unmet need for children with NGDs, who suffer severely from impaired sleep. Upon approval, Slenyto® would be the only medicinal product approved for sleep disorders in this unique paediatric population, allowing treatment initiation at an early age," said Prof. Nava Zisapel, CEO of Neurim Pharmaceuticals. Paul Gringras, Professor of paediatric Sleep Medicine, London, England commented: "Melatonin deficiency or misalignment is a common pathophysiological mechanism for insomnia in neurogenetic disorders. Slenyto® is a prolonged-release formulation of melatonin that delivers melatonin over the course of the night, mimicking the endogenous release profile in healthy subjects. Therefore, Slenyto® has the potential to treat the pathophysiology of insomnia in this population improving sleep latency, sleep continuity and total nighttime sleep duration. Slenyto® has been specifically formulated for use in children and has a favorable safety profile. The treatment will address a significant need in the medical management of many children and adolescents with NGDs". ABOUT INSOMNIA IN CHILDREN WITH NEUROGENETIC DISORDERS (NGDs) Sleep impairment is a common comorbidity in neurogenetic disorders, with up to 86% of children reported to experience disrupted sleep, starting at an early age. During early childhood, sleep plays an essential role in healthy cognitive and psychosocial brain development, influencing learning memory, emotional regulation, and brain structure. Children with neurogenetic disorders tend to develop insomnia and other sleep disorders at an early age. Insomnia has a significant impact on these children, aggravating disease symptoms and reducing quality of life in both patients and caregivers. Current practices recommend parent-directed behavioral sleep interventions as first-line treatment for pediatric insomnia in NGDs, with a 25% response rate. Slenyto® will be the first approved pharmacological treatment for insomnia in children and adolescents with NGDs. ABOUT SLENYTO ® Slenyto® is an age-appropriate prolonged-release formulation of melatonin, a hormone involved in the regulation of circadian clock and sleep. The mini-tablet innovative formulation was specifically designed to facilitate ease of swallowing without resistance in pediatric ASD and NGD population, in response to the unmet medical need in the field of paediatric insomnia. Slenyto® delivers melatonin over the night to mimic the endogenous melatonin release profile in healthy subjects. In a Phase III study in ASD and SMS children and adolescents, Slenyto® improved sleep latency, sleep continuity and total nighttime sleep duration. The positive effect on sleep maintenance and duration was associated with an improvement in externalizing behavior, which correlated with an improvement in parents' well-being. The mechanism of action of Slenyto® on sleep latency, sleep maintenance and total sleep time is independent of the background disorder. Therefore, any patient with a neurogenetic disorder with sleep disturbances associated with aberrant diurnal melatonin secretion patterns and/or insufficient nighttime melatonin secretion will benefit from Slenyto®. ABOUT NEURIM PHARMACEUTICALS Neurim Pharmaceuticals Ltd. () is a neuroscience drug discovery and development company. Its first approved drug, CIRCADIN®, is approved for patients over the age of 55 who are suffering from insomnia and is commercially available in 45 countries around the world, including Europe, Asia-Pacific, Latin America, Africa and the Middle East. Neurim has a strong and innovative product pipeline targeting central nervous system (CNS) disorders. Contact: Guy Manor VP Commercial Operations [email protected]