GPR119

Full Data Readout Expected in the Second Half of 2024 CAMBRIDGE, Mass., April 1, 2024 /PRNewswire/ -- NeuroBo Pharmaceuticals, Inc. (Nasdaq: NRBO), a clinical-stage biotechnology company focused on transforming cardiometabolic diseases, today announced the completion of enrollment of Part 1 of its two-part, Phase 2a clinical trial evaluating the efficacy and safety, of DA-1241, a novel G-Protein-Coupled Receptor 119 (GPR119) agonist for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Approximately 49 patients with presumed MASH have been randomized into Part 1 with a 1:2:1 ratio into 3 treatment groups: DA-1241 50 mg, DA-1241 100 mg, or placebo. "Enrollment of the final patient in Part 1 our Phase 2a clinical trial of DA-1241, in patients with presumed MASH, is another important event in the clinical development of our cardiometabolic assets," stated Hyung Heon Kim, President and Chief Executive Officer of NeuroBo. "Part 2 of this Phase 2a trial, exploring the efficacy of DA-1241 in combination with sitagliptin, a DPP-4 inhibitor, continues to enroll patients, which we believe will show synergistic effects compared to DA-1241 alone. As previously reported, DA-1241 was well tolerated in healthy volunteers and in patients with type 2 diabetes mellitus (T2DM). Based on the pre-clinical and clinical evidence to date, we believe that the unique mechanism of action of this promising cardiometabolic asset, targeting the inflammation associated with MASH, will translate into a safe and effective treatment for this disease. We look forward to reporting the full trial data expected in the second half of this year." Each of the two-parts of the Phase 2a trial of DA-1241 are designed to be 16-week, multicenter, randomized, double-blind, placebo-controlled, parallel clinical studies to evaluate the efficacy and safety of DA-1241 in subjects with presumed MASH. Part 2, which will explore the efficacy of DA-1241 in combination with sitagliptin versus placebo, is expected to enroll approximately 37 subjects who will be randomized in a 2:1 ratio into 2 treatment groups: DA-1241 100 mg/sitagliptin 100 mg or placebo. For both Part 1 and Part 2, the primary endpoint is the change from baseline in alanine transaminase (ALT) levels at Week 16. Secondary efficacy endpoints include the proportion of subjects with normalization of ALT, absolute change in total cholesterol, low and high-density lipoprotein cholesterol, triglycerides, and free fatty acids from baseline, among others. Safety will be evaluated by monitoring adverse events (AEs) and serious adverse events (SAEs) leading to discontinuation and laboratory abnormalities. For more information on this clinical trial, please visit: NCT06054815. About DA-1241 DA-1241 is a novel G-Protein-Coupled Receptor 119 (GPR119) agonist with development optionality as a standalone and/or combination therapy for both MASH and type 2 diabetes (T2D). Agonism of GPR119 in the gut promotes the release of key gut peptides GLP-1, GIP, and PYY. These peptides play a further role in glucose metabolism, lipid metabolism and weight loss. DA-1241 has beneficial effects on glucose, lipid profile and liver inflammation, supported by potential efficacy demonstrated during in vivo preclinical studies. The therapeutic potential of DA-1241 has been demonstrated in multiple pre-clinical animal models of MASH and T2D where DA-1241 reduced hepatic steatosis, inflammation, fibrosis, and improved glucose control. Furthermore, in Phase 1a and 1b trials, DA-1241 was well tolerated in both healthy volunteers and those with T2DM. About NeuroBo Pharmaceuticals NeuroBo Pharmaceuticals, Inc. is a clinical-stage biotechnology company focused on transforming cardiometabolic diseases. The company is currently developing DA-1241 for the treatment of Metabolic Dysfunction-Associated Steatohepatitis (MASH) and Type 2 Diabetes Mellitus (T2DM), and is developing DA-1726 for the treatment of obesity. DA-1241 is a novel G-protein-coupled receptor 119 (GPR119) agonist that promotes the release of key gut peptides GLP-1, GIP, and PYY. In preclinical studies, DA-1241 demonstrated a positive effect on liver inflammation, lipid metabolism, weight loss, and glucose metabolism, reducing hepatic steatosis, hepatic inflammation, and liver fibrosis, while also improving glucose control. DA-1726 is a novel oxyntomodulin (OXM) analogue that functions as a glucagon-like peptide-1 receptor (GLP1R) and glucagon receptor (GCGR) dual agonist. OXM is a naturally-occurring gut hormone that activates GLP1R and GCGR, thereby decreasing food intake while increasing energy expenditure, thus potentially resulting in superior body weight loss compared to selective GLP1R agonists. For more information, please visit . Forward Looking Statements Certain statements in this release may be considered forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as "believes", "expects", "anticipates", "may", "will", "should", "seeks", "approximately", "intends", "projects," "plans", "estimates" or the negative of these words or other comparable terminology (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. Forward-looking statements are predictions, projections and other statements about future events that are based on current expectations and assumptions and, as a result, are subject to risks and uncertainties. Many factors could cause actual future events to differ materially from the forward-looking statements in this release, including, without limitation, those risks associated with NeuroBo's ability to execute on its commercial strategy; the timeline for regulatory submissions; ability to obtain regulatory approval through the development steps of NeuroBo's current and future product candidates, the ability to realize the benefits of the license agreement with Dong-A ST Co. Ltd., including the impact on future financial and operating results of NeuroBo; the cooperation of our contract manufacturers, clinical study partners and others involved in the development of NeuroBo's current and future product candidates; potential negative interactions between our product candidates and any other products with which they are combined for treatment; NeuroBo's ability to initiate and complete clinical trials on a timely basis; our ability to recruit subjects for its clinical trials; whether NeuroBo receives results from NeuroBo's clinical trials that are consistent with the results of pre-clinical and previous clinical trials; impact of costs related to the license agreement, known and unknown, including costs of any litigation or regulatory actions relating to the license agreement; effects of changes in applicable laws or regulations; effects of changes to NeuroBo's stock price on the terms of the license agreement and any future fundraising; and other risks and uncertainties described in our filings with the SEC. Forward-looking statements speak only as of the date when made. NeuroBo does not assume any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. Contacts: NeuroBo Pharmaceuticals Marshall H. Woodworth Chief Financial Officer +1-857-299-1033 [email protected] Rx Communications Group Michael Miller +1-917-633-6086 [email protected] SOURCE NeuroBo Pharmaceuticals, Inc.

关注并星标CPHI制药在线放射性药品是指用于临床诊断或者治疗的放射性核素制剂或者其标记化合物。正电子发射断层扫描 （Positron emission tomography, PET） 和单光子发射计算机断层扫描 （single-photon emission computed tomography , SPECT）放射性药物可用于诊断和监测神经系统疾病、癌症、心血管疾病和感染等疾病的进展。比较常见的放射性药物有用于磁共振MRI的含钆对比剂(GBCA)。另一方面，由于放射性元素引起的辐射危害，治疗性放射性药物会引起一定的药理作用。在为治疗应用设计放射性药物时，选择适当的放射性核素是主要决定因素。放射性核素如18F、11C是放射性药物中用于治疗应用的核素。125碘、131碘、132碘等10多种核素是我国国家药品标准收载药物常用的元素。近日，诺华公司的 Salvatore Bongarzone等人在ACS Pharmacology & Translational Science发表文章[1]，简单讲述了一系列的放射性药物及其原理。文章链接https://doi.org/10.1021/acsptsci.3c00347。     放射性药物在近期是非常热门的研究方向。2023年12月26日，百时美施贵宝以每股62.50美元的现金收购RayzeBio，价值约为41亿美元的巨额并购引起了热烈的讨论和人们对放射性药物的重新认识。值得注意的是，百时美施贵宝不是首个对放射性药物感兴趣的跨国药企。2023年9月20日，罗氏旗下的基因泰克与PeptiDream达成一项高达10亿美元的合作和许可协议，该协议目的在于开发新型大环肽-放射性同位素（肽-RI）偶联药物；10月3日，礼来宣布将以14亿美元收购Point Biopharma Global，正式向癌症靶向放射治疗（核素偶连药物）领域发起进攻的号角。众多重量级的并购把放射性药物这个不算热门的研究领域放在了聚光灯下。  在国内，“医药一哥”恒瑞，在2024年的新年伊始，手握4款核药进入临床，引起了一个小轰动，并且登上了著名的央视《新闻联播》。虽然放射性药物近期很热门，但并不能掩盖人们对放射性药物认识的贫乏，大众熟悉各类心血管、肠胃、感冒用药等药品，唯独对放射性药物知之甚少。Salvatore Bongarzone等人的文章无疑是一篇扫盲读物，并且提到，现今的放射性药物主要分成以下不同的类型。1  用于脑成像的放射性药物富含亮氨酸的激酶LRRK2是与帕金森病（PD）进展和表现相关的靶标。在非人灵长类动物 （NHP） 中发现了[18F]1的高脑渗透性，并且使用异源阻断对死后 NHP 脑组织进行放射自显影验证了其与 LRRK2 的特异性结合。[11C]2 用于对多系统萎缩 （MSA） 和 PD 中存在的错误折叠聚集形式的 α-突触核蛋白进行成像。[11C]2显示了MSA中α-突触核蛋白成像的几个有前景的特性。在体内，[11C]2迅速代谢为极性代谢产物。值得注意的是，这些代谢物未显示出与α-突触核蛋白原纤维的结合。[18F]4具有已知靶向CB2R的支架、碳硼烷部分和氘代丁基链，以提高代谢稳定性。啮齿动物的动态 PET 扫描显示脾脏和肝脏摄取快，肝脏清除快，脾脏结合不可移位。在保持高亲和力和选择性的同时，代谢稳定性的整体提高是未来优化CB2R PET配体的重要起点。[18F]6靶向亨廷顿病中的突变亨廷顿蛋白（mHTT）聚集体。体外研究表明，[18F]6比领先的临床配体 CHDI-180 具有更高的 mHTT 特异性和人体代谢稳定性。在非人灵长类中，[18F]6 显示出快速的大脑摄取和快速清除特征。图 1 部分用于脑成像的放射性示踪剂结构式[1](图片来源于ACS Pharmacology & Translational Science )2  用于癌症成像和治疗的放射性药物[18F]15用于雌激素受体β（ERβ）成像。啮齿动物的PET成像证实了该化合物对ERβ的特异性。[18F]16和荷瘤小鼠的离体生物分布研究显示出突出的肿瘤摄取和高对比度。[18F]17用于体内BTK表达水平和靶标占有率的PET成像。图2  部分用于癌症成像和治疗的放射性示踪剂结构式[1](图片来源于ACS Pharmacology & Translational Science )3  其他用于成像的放射性药物选择性基质金属蛋白酶-13（MMP-13）PET 放射性示踪剂的合成和临床前评估，用于早期检测作为急性缺血危险因素的不稳定斑块。离体主动脉放射自显影和研究显示，[18F]20特异性结合动脉粥样硬化斑块内的MMP-13，并定位于富含脂质的区域。GPR119是一种G蛋白偶联受体，在胰腺中高度表达，调节胰岛素和肠促胰岛素的分泌，是治疗糖尿病药物开发的靶点。在体内测量GPR119水平可以显着推进基于 GPR119 的药物开发策略，包括靶点参与、占有率和分布。 [18F]21能被胰腺组织选择性吸收。图3用于动脉粥样硬化斑块和胰腺组织成像的放射性示踪剂[1](图片来源于ACS Pharmacology & Translational Science )4  总结无论是出于诊断，还是治疗，放射性药物都是一个活跃的研究领域。从上述的结构式可以看出，大部分化合物是添加18F作为核素，这些设计策略为我们设计药物提供了参考。在众多的报道中，大部分是讲述放射性药物的前景，甚少提及到这类药物的设计和特点，因此，了解相关化合物的结构，有助于提高药物的设计成功率。参考文献[1]Lindsley C W, Müller C E, Bongarzone S. Diagnostic and Therapeutic Radiopharmaceuticals: A “Hot” Topic[J]. ACS Pharmacology & Translational Science, 2023, 7(1): 1-7.https://doi.org/10.1021/acsptsci.3c00347.【智药研习社近期直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

常见代谢性疾病，如肥胖、代谢综合征、高脂血症、高血压、非酒精性脂肪性肝病（NAFLD）、糖尿病等，影响全球超过20%的人口，给社会带来巨大的医疗负担。每年超过1197万人死于这些疾病及其并发症，其中肥胖和高脂血症占死亡率的高位，肥胖和2型糖尿病（T2D）的死亡率仍在持续上升。目前虽然已有高效药物用于降低甘油三酯和胆固醇，胰岛素增敏剂的使用也有效减少、推迟T2D患者对胰岛素的需求，但亟需寻找更有效治疗手段以应对这些发病率高、死亡率日渐增长的代谢性疾病。近期，复旦大学基础医学院病原生物学系、教育部/卫健委医学分子病毒学重点实验室吴健教授团队阐述了G蛋白偶联受体（GPCR）调控代谢性疾病发生和进展的机制，揭示了关键GPCR如GPR55、GPR91、GPR119、GPR109a、GPR142、GPR40、GPR41、GPR43和GPR120在代谢综合征、NAFLD和糖尿病等常见代谢性疾病中的重要作用，为药物干预提供了理论基础。基于这些GPCR的药理学效应、临床前或临床试验结果，该团队还全面描绘了这些GPCR激动剂或拮抗剂药物研发现状，着重分析了小分子化合物的治疗效益和可能的安全性问题。因此，该长篇综述是继先前发表的“治疗非酒精性脂肪性肝炎药物临床试验更新”一文（《中国药理学报Acta Pharmacol Sin》 2022; 43: 1180–1190）的续篇，于2024年2月7日同刊在线发表 （DOI：10.1038/s41401-023-01215-2）。英文版Acta Pharmacol Sin 在JCR分区中定为医学一区，药理学一区。GPCRs是一类重要的跨膜蛋白受体，对维持各种生理活动起着关键作用。它们接收局部或循环系统中的信号配体，参与调控包括代谢、神经传递和免疫反应在内的多种生理反应。已确定大部分GPCRs的天然配体，其中大多数是代谢产物、脂肪酸、肽类或神经递质，包括胺类、氨基酸、离子、脂质、肽类、蛋白质等。尚未确定特定配体的GPCR被称为孤儿受体。GPCR数据库（GPCRdb）记录了800多个人类GPCR的基因，已经捕获和阐明了793个GPCR结构、781个受体-配体复合物结构以及381个活跃状态下的受体结构。目前，GPCR结构生物学已揭示了229个高分辨136个GPCR-配体复合物的结构，这些结构涉及48种GPCR。大部分GPCRs在结构上相似（图1），由一个细胞外N-末端、七个跨膜结构域（TM）和一个细胞内C-末端组成。三个亲水性细胞外环（ECL）连接着七个跨膜结构域，一个高度保守的二硫键连接TM3的顶部和ECL2的中部，这个二硫键形成了配体结合域的底部。此外，还有第二个二硫键连接受体的N-末端和TM7的顶部，并形成一个伪环，即ECL4。TM3、TM5和TM6在配体结合和G蛋白偶联过程中起重要作用。三个细胞内环（ICL）与TMs一起可能引起结构变化，从而暴露用于偶联和触发下游事件的功能性G蛋白亚单位。不同类型的配体结合到静止GPCRs的配体结合域，配体与受体的偶联激活GPCRs，随之GPCRs的空间构象发生改变，导致GTP取代了Gαβγ/GDP复合物上结合在Gα亚基上的GDP，复合物解离为具有活性的Gα和Gβγ亚基，并通过下游信号分子即第二信使分子：如环磷酸腺苷（cAMP）、钙离子、肌醇三磷酸（IP3）或二酰基甘油（DAG）等发挥调节作用。GPCRs的作用是多方面的，可分为两类：（1）生理作用：通过促进葡萄糖依赖型胰岛素分泌，改善血脂异常、胰岛素抵抗和糖尿病状态；（2）病理作用：从增强炎症反应和肝细胞脂质堆积，到血管内膜脂质沉积，进而导致伴有严重代谢紊乱NAFLD和动脉粥样硬化。图1：GPCRs的信号通路及对代谢性疾病的影响GPCR与G蛋白亚单位结合，触发各种第二信使的生成，调节涵盖生理功能和病理状况的各个方面，这些病理状况包括代谢综合征、肥胖、糖尿病、NAFLD等。由于其表面可及性和特定的信号传导机制，GPCRs被认为是许多种疾病的药物干预靶点，目前批准的药物中近30%是它们的激动剂或拮抗剂。因此，针对GPCRs的特异性激动剂或拮抗剂的开发对代谢调节至关重要，可能有助于对代谢性疾病进行药理学的干预。该文概述了GPCR发挥的重要生理功能，包括脂肪和葡萄糖代谢以及胰岛素释放等生理过程。最新发现指出GPCR与其配体相互作用参与了代谢性疾病的病理过程，并且可能成为这些疾病的潜在治疗靶点。本文系统地总结了参与代谢紊乱相关的关键GPCRs及其激动剂/拮抗剂小分子化合物的成药可能性，为这类药物的研发提供了理论基础和临床试验数据（表1）。表中所列GPCRs特异性激动剂或拮抗剂小分子化合物能否成为治疗代谢性疾病的新药取决于受体表征、晶体结构、化合物设计、药理学筛选、临床评估等。这类药物的研发往往耗时费力，只有少数候选化合物最终进入IIb和III期临床试验阶段。部分GPCR19、GPCR109a、GPCR142、GPCR40和GPCR120激动剂/拮抗剂已经进入临床试验阶段；然而，GPR91、GPR55、GPR41和GPR43的激动剂/拮抗剂仍处于临床前阶段。表1：GPCR激动剂和拮抗剂治疗代谢性疾病的研发概况总之，目前已确定特定GPCR生理功能和组织分布，及其参与营养和能量代谢分子机制，已开发出一系列GPCR激动剂和拮抗剂小分子化合物，例如MBX-2982、MK0354、LY3325656、Tak-875等，部分化合物已经进入早期或晚期临床试验，为治疗代谢性疾病如代谢综合征、血脂异常、非酒精性脂肪肝病、糖尿病及其并发症找到后备新药。然而，代谢性疾病作为一类慢性进行性疾病，通常涉及多个器官或系统，且GPCR具有广泛的组织分布和复杂的生理功能，在没有消除病因的情况下，仅依靠特定GPCR的激动剂或拮抗剂难以实现疾病的根治。因此，在研发针对上述GPCR高特异性和高准确性激动剂或拮抗剂小分子化合物的同时，减少疾病的风险因素并维持健康生活方式是预防代谢性疾病最有效且经济的方法。本文第一作者为复旦大学上海医学院8年制临床医学专业金诚同学，通讯作者为复旦大学基础医学院病原生物学系吴健教授与复旦大学附属中山医院消化科刘黎黎医师。吴健教授为复旦大学中山医院消化科双聘教授，现受自然科学基金面上项目资助，曾承担科技部重大研发专项。近30年首款！渤健ALS新药或将将在欧洲获批，如果不是沾了基因疗法的光......14.6亿美元！诺和诺德又有新交易想要加速审批上市的药物退市分几步？高管被捕、试验失败、自愿撤市、专家咨询委员会反对……点击这里，欣赏更多精彩内容！