Gefapixant Citrate

罗氏在10月23日更新其第三季度管线的时候，将进入Ⅱ期临床试验的咳嗽候选药物RG6341从其新药管线中移除。 RG6341是瞬时受体电位通道锚蛋白1(TRPA1)拮抗剂，由罗氏旗下的基因泰克公司发现的这款咳嗽候选药物，并于去年将其纳入Ⅱ期临床试验。 TRPA1是一种非选择性钙离子通道，在初级感觉神经元中高度表达，作为外源性和内源性刺激的多模式传感器，与神经性疼痛和呼吸系统疾病有关。因此，TRPA1拮抗剂具有治疗与哮喘、慢性肺阻塞性疾病(COPD)、特发性肺纤维化(IPF)或病毒后咳嗽相关的咳嗽或慢性特发性咳嗽以及敏感患者咳嗽的潜力。 基因泰克研究团队在解决了凝血问题后，发现了RG6341，并认为可以成为first-in-class的止咳药。 罗氏对RG6341这一希望未能通过临床疗效的关键早期测试。在RG6341的Ⅱ期试验中，慢性咳嗽或患者感知的咳嗽严重程度没有出现有临床意义的改善。尽管耐受性良好，没有安全问题，这表明基因泰克克服了毒性研究中发现的问题，但缺乏疗效却成了RG6341致命一击。 罗氏对RG6341的放弃意味着这一first-in-class靶点在咳嗽新药开发前景中更加扑朔迷离。 而TRPA1拮抗剂治疗咳嗽新药开发者中，勃林格殷格翰可能是最快的追逐者。其开发的BI 1839100用于治疗特发性肺纤维化咳嗽也于近期进入Ⅰ期临床试验研究中。 如今行业对于慢性咳嗽新药开发可能会再次转向P2X3靶点。 默沙东的Gefapixant是首个发现对难治性慢性咳嗽（RCC）患者有显著疗效的P2X3拮抗剂新型疗法。尽管该药已日本和欧盟获批准上市，却在美国确连续两次遭到FDA拒绝！ 延伸阅读：默沙东慢性咳嗽新药gefapixant二次遭FDA拒绝，已无领先优势 默沙东的Gefapixant治疗难治性慢性咳嗽疗效在美国遭遇FDA质疑，且难以克服的味觉障碍不良反应高发生率，正在让葛兰素史克看到机会。 葛兰素史克在2023年4月以20亿美元收购BELLUS Health获得Camlipixant以赶超默沙东，而且在充分对竞争对手进行分析后对Camlipixant的Ⅲ期临床试验进行精心设计： 首先，确保试验中的患者确实患有慢性难治性咳嗽。 其次，试验只招募病情最严重的慢性难治性咳嗽患者。 第三，Ⅲ期研究设有为期六周的安慰剂清除期，在此期间患者停止使用任何其他咳嗽治疗药物，以获得真正的安慰剂效应。 此外，Camlipixant对P2X3靶点的选择性更高，这意味着其不良反应会更少，因此，葛兰素史克可以使用更大剂量。 Gefapixant（45mg）味觉障碍不良反应发生率达到了65%，14%的患者因此提前停药。而Camlipixant显示出较低的味觉障碍发生率，且没有停药。 在国内，目前也有多家企业在开发P2X3拮抗剂，如朗来科技的QR-052107B、豪森的HS-10383、恒瑞医药的HRS-2261都已进入到Ⅱ期临床试验，还有多几个争对手处于更早期开发中。 此外，也有一些其他新靶点探索在咳嗽领域的应用前景。 本文由「新药前沿」微信公众号根据公开资料整理编辑，欢迎个人转发至朋友圈。媒体或机构转载授权请在「新药前沿」微信公众号留言公众号名称，审核通过后开通白名单获取转载授权，转载请标识来源。 免责声明：本文仅作信息交流之目的，非投资建议或者治疗方案推荐，「新药前沿」微信公众号不对任何主体因使用本文内容而导致的任何损失承担责任。 限于作者水平和专业知识所限，如有谬误，欢迎指正

Expands Adrenergic Pipeline to Address Neurogenic Orthostatic Hypotension and Major Depressive Disorder in Older Adults SAN CARLOS, Calif.--(BUSINESS WIRE)--CuraSen Therapeutics, Inc., a clinical-stage biopharmaceutical company developing oral, rapid onset, small molecule drugs to treat psychiatric and neurodegenerative diseases, announced today that it has appointed Kathleen Sereda Glaub, MBA, formerly executive chair, as chief executive officer. Dr. Anthony Ford will move to the role of president and chief scientific officer, and continue to lead research and development. Patrick Enright, managing director of Longitude Capital, will become chair of the board. Along with these executive changes, the company announced clinical program updates for its drug candidates that are each designed to restore adrenergic stimulus that declines with age or disease. CuraSen’s most recent development candidate is CuraAX (CST-3056), an alpha-1A adrenoceptor (α 1A -AR) agonist being developed as a treatment for neurogenic orthostatic hypotension (nOH). The company is planning to submit an investigational new drug (IND) application this quarter. A significant orphan indication affecting approximately 120,000-150,000 patients in the U.S., nOH is a dysfunction in the autonomic nervous system common in Parkinson’s disease (PD) and related diseases that causes sudden drops in blood pressure upon standing. This can lead to debilitating dizziness, weakness, cognitive decline and dangerous falls. CuraAX is a selective, CNS-penetrant, α 1A -AR agonist designed to provide cognitive benefit as well as control harmful blood pressure deviations. CuraCN (formerly known as CST-103/CST-107), a beta2 adrenoceptor (β 2 -AR) agonist combination, is targeted for a Phase 2b study in major depressive disorder in adults 65 and older, many of whom also suffer from cognitive decline. These plans are based on the company’s previous Phase 2 clinical study in patients that revealed compelling evidence of anti-depressant efficacy and improvements in cognition tests. CuraXN (formerly known as CST-2032/CST-107), a second β 2 -AR agonist combination, is in development for Alzheimer’s disease (AD) to address both cognitive symptoms and disease progression. All three drug candidates work by restoring adrenergic function that declines with age and, in particular, is lost early in neurodegenerative diseases such as AD & PD. CuraSen’s development candidates have strong potential to improve cognitive function and mood, in addition to addressing specific aspects of disease pathobiology. “We are thrilled to have Ms. Glaub assume the role of chief executive officer as CuraSen seeks to capitalize on the company’s adrenergic platform and clinical data to develop a broad pipeline of drugs for psychiatric and neurodegenerative diseases. These include opportunities for a significant, fast-to-market, orphan opportunity in neurogenic orthostatic hypotension,” said Mr. Enright, board chair. “CuraSen will benefit from the collective and complementary executive experience of both Ms. Glaub and Dr. Ford, both co-founders of the company.” Ms. Glaub brings more than 30 years of experience in biopharmaceutical corporate development, strategy, financing and company-building. She serves on the board of directors of IO Biotech, and previously served on the boards of Codexis, Aligos Pharmaceuticals and Escient Pharmaceuticals. Ms. Glaub was previously chief executive officer of Afferent Pharmaceuticals, which was acquired by Merck in 2016 for $1.25 billion. Under her leadership, the company advanced gefapixant to Phase 3 readiness for the treatment of chronic cough and raised $80 million in additional private funding for Afferent. Previously, she served as president of Plexxikon, and helped develop two FDA-approved drugs, Zelboraf® for metastatic melanoma and Turalio® for tenosynovial giant cell tumor (TGCT). She led Plexxikon’s business and financing strategy, negotiated multimillion-dollar partnerships, and led the sale of the company to Daiichi Sankyo for nearly $1 billion. She previously held positions as senior vice president and chief financial officer of Cell Genesys, treasurer of Genentech, and various finance and treasury roles with Intel Corporation. Ms. Glaub received her BA from the University of California, Berkeley, and her MBA from Northwestern University. “CuraSen’s expertise in adrenergic pharmacology, chemistry and clinical development has led to the discovery of three promising drug candidates focused on some of the most debilitating and common neurodegenerative and psychiatric diseases affecting patients and their families. Our adrenergic target mechanisms are already validated by approved drugs in a range of indications, and we have confirmed the ability to develop CNS-penetrant compounds with a unique approach to safety,” said Glaub. “Given the strong and rapid-onset efficacy signals pointing to an anti-depressant effect in our past studies and our understanding of adrenergic deficits in older adults, we believe there is a unique opportunity to address depression in these patients with CuraCN. With CuraXN, we hope to deliver a transformational treatment for Alzheimer’s disease with our holistic approach to restoring brain functionality and health. Lastly, with CuraAX, we believe we can offer major advantages over current treatments for nOH, including durability of efficacy and cognitive benefit, dosing convenience and improved safety.” About CuraSen Therapeutics CuraSen is focused on the development of new treatments for psychiatric and neurodegenerative diseases, including neurogenic orthostatic hypotension, major depressive disorder and Alzheimer’s disease. CuraSen’s drugs are small molecule, oral tablets designed to activate certain receptor populations in the brain to compensate for decline of the adrenergic system driven by aging and disease. The company has evaluated two β 2 -AR agonist candidates, CuraCN and CuraXN, in multiple Phase 2 clinical studies for effects on memory, attention, executive function and mood, as well as safety and tolerability. CuraSen is planning to submit an IND application by the end of 2024 for its third drug candidate CuraAX, an α 1A -AR agonist, for the treatment of nOH. For more information, please visit . Contacts Susan Kinkead Kinkead Communications susan@kinkeadcomm.com 415-509-3610