Indacaterol acetate

关注新药，直击前沿！ 近年来，与创新型新药相比，改良型新药因研发周期短、投入低和风险低等特点，备受追捧。但改良型新药可能面临着因创造性不足难以获得专利保护也是不争的事实。 海思科开发的HL231吸入溶液是对诺华开发的杰润（茚达特罗格隆溴铵吸入粉雾剂）改剂型品种（2.2类创新药），杰润于2017 年 12 月 28 日在中国获批用于成人慢性阻塞性肺疾病（包括慢性支气管炎和肺气肿）患者维持性支气管舒张治疗以缓解症状，是中国首个获批的 LAMA/LABA 复方吸入制剂。 HL231吸入溶液使用雾化吸入装置吸入，相比干粉吸入器（DPI），雾化吸入对病人的呼吸协调能力和吸气流速要求较低，患者可保持平静呼吸，不需要刻意配合，操作较为简单。 目前海思科在国内正在进行Ⅲ期研究，评估HL231吸入溶液相比阳性对照药物（杰润）治疗慢性阻塞性肺疾病（COPD）的有效性，同时也在对该药的长期安全性进行观察。 专利布局分析 海思科于2019年7月3日直接向中国国家知识产权局（受理局）提交一份PCT国际申请（PCT/CN2019094486），并于2020年1月30日公布（WO2020019952A1）。 该件国际申请专利于2020年9月29日进入中国（申请号201980023670.6），并于2020年11月13日公布（CN111936124A），2020年11月19日进入实审阶段。 经过2轮审查答复，国家知识产权局2022年11月16日作出“驳回决定”，海思科针对该驳回决定未要求复审。 驳回决定的主要要点： 审查员认为：权利要求1保护的气雾剂组合物（格隆溴铵/茚达特罗），仅仅是对对比文件（KR 20030065509A）已公开的含有噻托溴铵/沙美特罗吸入剂在COPD治疗领域相同作用机制药物（LAMA/LABA）的简单替换，效果类似；而且用量也仅仅根据常规给药剂量可以确定，PH限定非常接近，属于常规调整范围内，本申请也没有证明这一调整带来了何种预料之外的技术效果。因此不符合专利法第22条第3款关于创造性的规定。 申请人认为：本申请的剂量小于对比例，效果却更好。本申请的毒副作用更小，雾化时间更小。 审查员认为：本申请所述的改善肺部有效成分占比、提高沉积率、无推进剂等均不是由于活性成分的改变而带来的，也就是说，这些技术问题并非是因为活性成分的改变而得到了解决，而是因为其使用如对比文件1、2或3所述的雾化装置带来的。另外，从辅料看，本申请与D1使没有证明且解决了稳定性、溶解性问题，并不能因此具备创造性。本申请没有记载任何关于副作用的技术内容，也就是说，本申请并没有证明调整了含量后能够缓解副作用这一技术效果。另外，针对说明书中描述的副作用，其也仅是因为没有使用乳糖等添加剂带来的，而对比文件1已经公开了该特征，相应的技术效果也是可以预期的。因此，申请人的意见陈述没有说服力。 海思科随后于2023年2月14日提交了分案申请（202310107966.4），公布号CN116173025A，2023年6月2日提出实质审查时请求延迟审查，期限为2年。 有意思的是，海思科提交的分案申请专利权利要求却与原申请的权利要求完全相同，获得授权的前景似乎同样渺茫，或许仅仅是为了“迷惑或者威慑”竞争者，为自己的产品上市后获得较长市场独占机会创造条件。 “新药前沿”格言 创新通常不会沿着直线路径进行，乐观和勇气可以帮助我们度过难关。 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！

In this article, we will focus on Sosei Heptares, a leading company in the field of GPCR new drug development, and its GPCR research and development pipeline. For more details, please follow the link below. GPCR Targets and Pipeline at the JP Morgan Healthcare Conference 2024 (1)GPCR Targets and Pipeline at the JP Morgan Healthcare Conference 2024 (2)GPCR Targets and Pipeline at the JP Morgan Healthcare Conference 2024 (3)GPCR Targets and Pipeline at the JP Morgan Healthcare Conference 2024 (4)Sosei Heptares in JPM 2024Sosei Heptares is a biopharmaceutical company based in Japan with operations spanning the Asia-Pacific region, focused on structure-based drug design (SBDD), particularly in the area of G protein-coupled receptors (GPCRs). The company has over 30 active research and development projects involving central nervous system disorders, immunology, gastrointestinal diseases, and various other therapeutic areas. Its marketed product, PIVLAZ®, is widely used in Japan and South Korea, where it has been approved for use. Over the past 20 years, Sosei has undergone several rounds of acquisitions and restructurings and completed a significant transformation in 2023, including the acquisition of Idorsia Pharmaceuticals' operations in Japan and the Asia-Pacific region and securing significant investments from government funds. Additionally, the company has collaborated with several top global pharmaceutical companies, making clinical advancements in the treatment of metabolic and neuropsychiatric disorders such as insomnia. Daridorexant is expected to be launched in Japan by the end of 2024. In 2023, Sosei Heptares has implemented a series of corporate actions and investments to drive future growth. The company's internal research projects, including PIVLAZ®, daridorexant, HTL-149 (a GPR52 agonist), and HTL-723, have achieved milestone progress. Moreover, Sosei Heptares and its partners launched multiple clinical programs in 2023, involving the research and development of several innovative therapies for metabolic and neuropsychiatric disorders. This includes a range of novel cholinergic M4 and M1/M4 agonists being developed in collaboration with Neurocrine for the study of schizophrenia and other neuropsychiatric diseases, with some drugs nearing or having entered the late clinical phase. The company's first commercially available medicine, PIVLAZ® (a selective ETA receptor antagonist), has made a significant impact on stroke treatment in Japan and has been accumulating evidence in the real world. PIVLAZ® is recommended by the Japan Stroke Society and has proven to have a definitive therapeutic effect on subarachnoid hemorrhage (SAH), preventing delayed cerebral ischemia and adverse outcomes with a high level of evidence, thus strengthening the confidence of neurosurgeons in prescribing the medication. Additionally, the drug has received market approval in Korea and is planned to start sales to patients at the beginning of 2025. By the end of 2023, the company has submitted a New Drug Application (NDA) in Japan for daridorexant for the treatment of insomnia, with an anticipated launch in the Japanese market in the fourth quarter of 2024. The drug is expected to make a significant contribution to Japanese society. Insomnia causes an estimated annual economic loss of up to 15 trillion yen in Japan (approximately 3% of GDP), and results in the loss of 604,000 working days due to absenteeism and medical leave. Moreover, individuals averaging less than 6 hours of sleep per night face an increased mortality risk by 10%. Daridorexant, a dual orexin receptor antagonist, is already on the market in the United States and Europe under the brand name QUVIVIQ™. Joint development and co-marketing plans for daridorexant in Japan are currently underway, with expectations to effectively address the issue of insomnia. Sosei Heptares employs Artificial Intelligence (AI) and Machine Learning (ML) technologies in various drug development processes to enhance the efficiency of drug discovery, including receptor preparation technology (StaR®), protein structure, molecular design, and translational medicine. Utilizing the StaR® technology in combination with AI/ML algorithms, the company mines datasets rich in GPCR mutations to predict and accelerate the generation of StaR® variants conducive to stabilizing GPCR structures, thereby hastening the drug discovery process. Additionally, AI technology is used to analyze GPCR binding sites and patterns, enhancing the accuracy of GPCR homology models to support drug molecule optimization and virtual screening efforts. Hit identification is conducted based on internal and external structural databases, while drug molecule designs are optimized using ML QSAR models derived from internal and public datasets. Moreover, AI is applied to analyze large patient datasets to identify biomarkers and stratify patients, ensuring more precise and effective clinical trial designs. The application of these advanced technologies not only aids in the identification of new chemical series but also enhances the optimization of existing chemical series, improving drug properties with the goal of developing more life-changing medicines. The company possesses several internally researched and collaboratively developed GPCR (G protein-coupled receptor) new drug development pipelines, which are at various stages of research and development. These pipelines encompass multiple therapeutic areas including metabolic diseases, inflammatory bowel disease, schizophrenia and neuropsychiatric disorders, as well as solid tumors. PIVLAZ® (Clazosentan) is a potent, selective endothelin ETA receptor antagonist indicated for the prevention of cerebral vasospasm, vasospasm-related cerebral infarction, and ischemic symptoms following aneurysmal subarachnoid hemorrhage (aSAH). Pivlaz® successfully launched in Japan in April 2022 for the treatment of cerebral vasospasm. Sosei Heptares holds the rights to sell Pivlaz® in Japan and the Asia-Pacific region, excluding China. Ultibro Breezhaler is a pioneering inhaled dual bronchodilator (long-acting β2-adrenergic receptor agonist or long-acting muscarinic antagonist, LAMA/LABA), approved in more than 90 countries including the European Union and Japan. It is a once-daily fixed-dose combination formulation of indacaterol and glycopyrronium bromide, indicated in the European Union for the maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Daridorexant is a dual orexin receptor antagonist that blocks the binding and activity of the wakefulness-promoting neuropeptide orexin. In October 2022, daridorexant achieved positive Phase 3 clinical trial results among patients with insomnia in Japan. The success of the trial paved the way for regulatory submission in Japan in the second half of 2023. Daridorexant is approved in the United States and Europe and is marketed by Idorsia under the brand name QUVIVIQ™ in these regions. Sosei Heptares has the rights to sell daridorexant in Japan and the Asia-Pacific region (excluding China). Cenerimod is an S1PR1 modulator currently under Phase 3 clinical investigation for the treatment of systemic lupus erythematosus (SLE). Cenerimod aims to reduce autoimmune responses and control disease activity in patients with SLE by affecting lymphocyte migration. In its collaboration with Idorsia, Sosei Heptares has obtained not only the two key products, PIVLAZ® and daridorexant, but also exclusive options to license cenerimod and lucerastat, as well as selection rights for five additional projects in Idorsia's global pipeline. HTL0016878 is a selective oral small-molecule muscarinic M4 receptor agonist currently in Phase II clinical development for the treatment of schizophrenia. The mechanism of action of HTL0016878 differs from existing antipsychotic medications, and its high selectivity compared to previous non-selective muscarinic receptor agonists offers the potential for improved safety. The GPR52 agonist program is currently in Phase I clinical research, targeting schizophrenia as an indication. GPR52 is an orphan GPCR expressed in the central nervous system, implicated in neural development and regulation of the dopaminergic system. As a potential therapeutic approach, GPR52 agonists aim to ameliorate schizophrenia-related psychopathological symptoms by targeting this receptor. HTL0039732 is a novel, highly selective, and potent EP4 receptor antagonist intended for the clinical treatment of advanced solid tumors by mediating the immunosuppressive effects of PGE2 within the tumor microenvironment. In July 2022, Sosei Heptares signed an agreement with Cancer Research UK to bring Sosei Heptares' cancer immunotherapy candidate into its first human trials. Lotiglipron (PF-07081532) is an oral small-molecule GLP-1R agonist co-developed by Sosei Heptares and Pfizer. Initiated by its partner Pfizer, the Phase I clinical trial of this once-daily oral GLP-1 receptor agonist is expected to improve the metabolic status of patients with diabetes and obesity. At the end of 2022, Sosei Heptares and Pfizer announced the advancement of Lotiglipron (PF-07081532) to Phase II clinical trials. However, in June 2023, Pfizer announced the discontinuation of the clinical development of PF-07081532. At the end of November 2023, Pfizer announced the inclusion of another GLP-1R agonist, PF-06954522, developed in collaboration with Sosei Heptares, into Phase I clinical research. PF-07054894 is a selective small molecule antagonist targeting CCR6 for clinical treatment of inflammatory bowel disease (IBD). This project is also part of a collaborative research program developed with Pfizer. PF-07258669 is a selective antagonist targeting the MC4R receptor co-developed by Sosei Heptares and Pfizer, and is being clinically developed for the treatment of cachexia associated with cancer. NBI-1117570 is a dual agonist product selectively targeting the M1/M4 receptors, intended for the treatment of a variety of psychiatric disorders in the neuropsychiatric field, including but not limited to diseases related to cognition, mood, and behavior. This drug is currently in a Phase 1 clinical development study in collaboration with Neurocrine. NBI-1117569 is a selective small molecule agonist targeting the M4 receptor, while NBI-1117567 is a selective small molecule agonist targeting the M1 receptor. Both different cholinergic receptor agonists were developed using Sosei Heptares' structure-based drug design platform and are involved in neuropsychiatric indications at different stages of research. The former is in a Phase 1 clinical trial, and the latter is ready to enter Phase 1 clinical study; both drugs are being co-developed with Neurocrine. HTL0014242 (TMP-301) is a potent, selective negative allosteric modulator of the mGlu5 receptor discovered by Sosei Heptares, used for the treatment of certain neurological disorders. It is currently in a Phase 1 collaborative development by Tempero Bio for the treatment of substance abuse issues. The EP4 agonist project is currently in the preclinical research phase with indications for inflammatory bowel disease (IBD). The drug is an oral, once-daily small molecule formulation designed to modulate the prostaglandin E2 EP4 receptor subtype within the gastrointestinal tract. By activating the EP4 receptor, the medication may help to regulate immune responses and inflammation processes, thereby alleviating the symptoms of IBD patients. GSK4381406 is a GPR35 receptor agonist co-developed by Sosei Heptares and GSK for the clinical treatment of inflammatory bowel disease, currently in phase 1 clinical research. In November last year, Sosei Heptares announced that, due to GSK's strategic realignment, the company would independently continue the research on the GPR35 receptor agonist project returned by GSK. This orally administered, gut-restricted new drug has the potential to improve intestinal barrier function and reduce visceral pain sensitivity, with plans to re-initiate entry into phase 1 clinical trials.