The two main aims of this clinical study is;
1. To investigate if the results from a series of physiological tests and questionnaires prior to treatment, can be used to predict the treatment response to obesity medication
2. To investigate the effect of combining semaglutide and pramlintide on various aspects of appetite, food preference and eating habits.
The study is planed as a 26 week, double blinded, randomized, placebo controlled trial. The goal is to include N=40. They will all receive weekly semaglutide injections. After 24 weeks they will be randomized to receive either an amylin analog (pramlintide) or placebo as a continuous infusion for two weeks, in addition to weekly semaglutide.
The results from this study will contribute to identifying possible predictors of treatment response, enabling optimal individualized medical weight loss treatment. As well as providing knowledge on the complex interplay between incretin hormones and their effects on appetite and eating habits.

开始日期2025-09-01

申办/合作机构-

NCT06186063

/ RecruitingN/AIIT

The Role of Amylin in Bone Metabolism

The clinical study aims to investigate the effect of the intravenously administrated amylin analogue (pramlintide) on the circulating levels of C-terminal telopeptide of type I collagen (CTX-1) (a marker of bone resorption) and N-terminal propeptide of type I procollagen (P1NP) (a marker of bone formation) in individuals with type 1 diabetes and matched healthy controls during fasting euglycemic conditions.

开始日期2024-02-12

申办/合作机构-

NCT06046417

/ Recruiting临床2/3期IIT

A Randomized, Controlled, Crossover Trial to Assess a Fully Automated, Dual-hormone (Insulin-and-pramlintide) Delivery System Without Carbohydrate Counting in Regulating Glucose Levels in Adults With Type 1 Diabetes.

The aim of this clinical trial is to investigate whether a fully automated Lyumjev-and-pramlintide delivery system improves glycemic outcomes in adults with type 1 diabetes. The main question we aim to answer is whether a Lyumjev-pramlintide fully closed loop system improves time in range compared to a hybrid closed loop system with carbohydrate counting. We also aim to find the optimal insulin to pramlintide ratio for glycemic control in the fully automated system.
In this cross-over study, patients will undergo the following three interventions in a random order:
(i) fully automated Lyumjev insulin-and-pramlintide (8 μg/u) (ii) fully automated Lyumjev insulin-and-pramlintide (10 μg/u) (iii) rapid automated Lyumjev insulin-and-placebo with carbohydrate-matched boluses
For all interventions, participants will be required to wear two Ypsomed pumps programmed by our developed EuGlide system.

开始日期2023-11-30

申办/合作机构

McGill University Health Centre

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100 项与醋酸普兰林肽相关的临床结果

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100 项与醋酸普兰林肽相关的转化医学

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100 项与醋酸普兰林肽相关的专利（医药）

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项与醋酸普兰林肽相关的文献（医药）

2025-06-01·Diabetes Therapy

Amylin: From Mode of Action to Future Clinical Potential in Diabetes and Obesity

Review

作者: Janež, Andrej ; Muzurović, Emir ; Koceva, Andrijana ; Jensterle, Mojca ; Volčanšek, Špela

Precision diabetology is increasingly becoming diabetes phenotype-driven, whereby the specific hormonal imbalances involved are taken into consideration. Concomitantly, body weight-favorable therapeutic approaches are being dictated by the obesity pandemic, which extends to all diabetes subpopulations. Amylin, an anorexic neuroendocrine hormone co-secreted with insulin, is deficient in individuals with diabetes and plays an important role in postprandial glucose homeostasis, with additional potential cardiovascular and neuroprotective functions. Its actions include suppressing glucagon secretion, delaying gastric emptying, increasing energy expenditure and promoting satiety. While amylin holds promise as a therapeutic agent, its translation into clinical practice is hampered by complex receptor biology, the limitations of animal models, its amyloidogenic properties and pharmacokinetic challenges. In individuals with advanced β-cell dysfunction, supplementing insulin therapy with pramlintide, the first and currently only approved injectable short-acting selective analog of amylin, has demonstrated efficacy in enhancing both postprandial and overall glycemic control in both type 2 diabetes (T2D) and type 1 diabetes (T1D) without increasing the risk of hypoglycemia or weight gain. Current research focuses on several key strategies, from enhancing amylin stability by attaching polyethylene glycol or carbohydrate molecules to amylin, to developing oral amylin formulations to improve patients' convenience, as well as developing various combination therapies to enhance weight loss and glucose regulation by targeting multiple receptors in metabolic pathways. The novel synergistically acting glucagon-like peptide-1 (GLP-1) receptor agonist combined with the amylin agonist, CagriSema, shows promising results in both glucose regulation and weight management. As such, amylin agonists (combined with other members of the incretin class) could represent the elusive drug candidate to address the multi-hormonal dysregulations of diabetes subtypes and qualify as a precision medicine approach that surpasses the long overdue division into T1DM and T2DM. Further development of amylin-based therapies or delivery systems is crucial to fully unlock the therapeutic potential of this intriguing hormone.Graphical abstract available for this article.

2025-05-09·ENDOCRINE REVIEWS

Insulin Resistance in Type 1 Diabetes: Pathophysiological, Clinical, and Therapeutic Relevance

Review

作者: Lambadiari, Vaia ; Dimitriadis, George D ; Roden, Michael ; Apostolopoulou, Maria

Abstract:

People with type 1 diabetes (T1D) are usually considered to exclusively exhibit β-cell failure, but they frequently also feature insulin resistance. This review discusses the mechanisms, clinical features, and therapeutic relevance of insulin resistance by focusing mainly on human studies using gold-standard techniques (euglycemic–hyperinsulinemic clamp). In T1D, tissue-specific insulin resistance can develop early and sustain throughout disease progression. The underlying pathophysiology is complex, involving both metabolic- and autoimmune-related factors operating synergistically. Insulin treatment may play an important pathogenic role in predisposing individuals with T1D to insulin resistance. However, the established lifestyle-related risk factors and peripheral insulin administration inducing glucolipotoxicity, hyperinsulinemia, hyperglucagonemia, inflammation, mitochondrial abnormalities, and oxidative stress cannot always fully explain insulin resistance in T1D, suggesting a phenotype distinct from type 2 diabetes. The mutual interaction between insulin resistance and impaired endothelial function further contributes to diabetes-related complications. Insulin resistance should therefore be considered a treatment target in T1D. Aside from lifestyle modifications, continuous subcutaneous insulin infusion can ameliorate insulin resistance and hyperinsulinemia, thereby improving glucose toxicity compared with multiple injection insulin treatment. Among other concepts, metformin, pioglitazone, incretin-based drugs such as GLP-1 receptor agonists, sodium-glucose cotransporter inhibitors, and pramlintide can improve insulin resistance, either directly or indirectly. However, considering the current issues of high cost, side effects, limited efficacy, and their off-label status, these agents in people with T1D are not widely used in routine clinical care at present.

2025-05-01·Clinical Spine Surgery

Fusion Outcomes of GLP-1 Agonist Therapy in Multilevel Cervical Spinal Fusion

Article

作者: Levidy, Michael F ; Meister, Andrew S ; Bible, Jesse E ; Rowe, Nicholas D ; Vatsia, Sohrab K

Study Design::

Retrospective analysis.

Objective::

To evaluate the effects of GLP-1 agonist therapy upon the incidence of pseudarthrosis in patients undergoing multilevel cervical spinal fusion

Summary of Background Data::

The rising prevalence of obesity and diabetes mellitus has rendered the usage of glucagon-like peptide-1 receptor (GLP-1) agonists increasingly commonplace since their introduction in 2005. However, there is a dearth of evidence to suggest whether outcomes of multilevel cervical spinal fusion differ in patients treated with GLP-1 agonists. This study assesses rates of pseudarthrosis in patients who underwent multilevel cervical spine fusion with and without concurrent GLP-1 agonist therapy.

Methods::

The TriNetX, LLC Diamond Network database was queried utilizing CPT codes for patients undergoing both anterior and posterior multilevel cervical spinal fusion from 2005 to 2024. Patients prescribed liraglutide, pramlintide, tirzepatide, semaglutide, lixisenatide, or dulaglutide within 1 year of surgery were propensity matched to patients without GLP-1 agonist prescriptions. Cohort balancing was achieved categorically according to age at procedure, race, sex, and nicotine dependence. Cohort balancing was performed continuously to account for body mass index and hemoglobin A1C at the time of procedure. CPT diagnosis codes for pseudarthrosis after attempted fusion were concomitantly utilized to assess pseudarthrosis rates at 6-months, 1-year, and 2-years postoperatively using the Fisher exact test. Statistical significance was set at P<0.05.

Results::

In consideration of anterior multilevel cervical fusion, 1204 patients utilized GLP-1 agonist therapy, while 1204 patients did not use GLP-1 agonists. With respect to posterior multilevel cervical fusion, 1378 patients utilized GLP-1 agonist therapy, and 1378 patients did not have a GLP-1 agonist prescription. Anterior postoperative pseudarthrosis rates were significantly decreased in the GLP-1 agonist cohort versus the non-GLP-1 agonist cohort at 6-months (10.71% vs. 17.61%; P<0.001), 1-year (12.04% vs. 18.52%; P<0.001), and 2-years (12.87% vs. 19.19%; P<0.001). Posterior postoperative pseudarthrosis rates were also significantly decreased in the GLP-1 agonist cohort versus the non-GLP-1 agonist cohort at 6-months (13.21% vs. 22.28%; P<0.001), 1-year (14.37% vs. 24.45%; P<0.001), and 2-years (16.87% vs. 24.43%; P<0.001).

Conclusion::

Our findings demonstrate a statistically significant lower incidence of pseudarthrosis among patients treated with GLP-1 agonist therapy at all timepoints within this study—from 6-months to 2-years postoperatively, suggesting a potentially beneficial effect of GLP-1 agonist therapy in promoting fusion success in multilevel cervical spine surgery. Fundamentally, this aligns with the pharmacodynamic nature of GLP-1 agonists: as compounds that enhance osteoblastic activity and suppress osteoclastic activity, thereby facilitating bone formation and attenuating bone resorption. Further investigation into the mechanistic underpinnings of GLP-1 agonists’ effects on bone metabolism may pave the way for enhancing the success of cervical spine surgery.

项与醋酸普兰林肽相关的新闻（医药）

2025-03-11

·peplib.cn

靶蛋白非肿瘤特异性因素对靶向药疗效的影响

细胞膜作为细胞与外界环境交流的重要通道，其上的膜蛋白在细胞的生理功能中发挥着至关重要的作用。正常细胞和肿瘤细胞的细胞膜蛋白存在显著差异。肿瘤细胞为实现不受控制的生长、侵袭和转移，会在其表面表达一些特殊的膜蛋白。这些蛋白有的参与细胞生长信号的传递，比如表皮生长因子受体（Epidermal growth factor receptor， EGFR）；有的帮助肿瘤细胞逃避免疫系统的监视，像程序性死亡配体 - 1（Programmed cell death ligand 1，PD-L1）；还有的在肿瘤血管生成过程中起关键作用，例如血管内皮生长因子受体（Vascular endothelial growth factor，VEGFR）。这些独特的细胞膜蛋白，成为了抗肿瘤药物精准打击的理想靶点。细胞膜的脂质双层结构如同一个天然屏障，分隔了细胞外和细胞内的物质，使其无法自由交换和直接沟通。因此，环境中的分子或细胞内分子不得不遵循细胞固有法则，借助特异受体、离子通道、转运体、黏附蛋白等完成各自的功能。与传统的细胞毒性化疗不同，靶向细胞表面蛋白的疗法提供了一种提高癌细胞特异性，同时最大限度地减少毒性的策略。许多治疗性靶向药物（如抗癌药）的主要治病机制是通过特异性高表达的靶抗原或膜上受体将非靶向药物递送到肿瘤细胞内，从而达到特异性肿瘤杀伤的效果。目前，已经开发了多种类型的细胞表面蛋白靶向疗法，具有不同的作用机制。科研人员已对75 种候选的细胞表面蛋白进行了深入研究，但在美国或欧盟，仅有25个治疗相关的细胞表面蛋白被批准用于癌症疗法[1]。尽管抗体-药物偶联物（Antibody-drug conjugate，ADC）和放射性药物疗法（Radiopharmaceutical therapy，RPT）等几类细胞表面靶向疗法已经获得了美国食品药品监督管理局（FDA）的批准，得以应用于临床实践，但不得不承认的是，这些疗法的许多疗效机制至今尚未完全明晰，仍存在着诸多待解之谜。临床抗肿瘤疗效的评估是一个复杂的系统工程，靶点蛋白的肿瘤特异性毋庸置疑是公认的重要指标，但并非唯一的决定因素，还需要考虑其他多种因素，如表达水平（临床常用免疫组织化学（Immunohistochemistry，IHC）和荧光原位杂交（Fluorescence in situ hybridization，FISH）的阳性分数以及生物学特征的丰度）、靶点蛋白的分布特性和肿瘤组织中靶点异质性等。这些因素同样对疗效、毒性以及成药性起着决定性作用。本文将围绕以上几点，对这些因素与靶向药的临床疗效关系逐一进行阐述。膜蛋白表达水平通常采用临床常用的IHC和FISH的阳性分数，以及生物学特征的丰度这两种方法进行研究。1）靶点高表达：是指在细胞或组织中，某个特定的靶点（如基因、蛋白质等）的表达水平呈现显著高于正常状态的现象，这可能是由于基因突变、染色体异常、转录调控机制的改变或其他因素所导致。值得注意的是，过表达是一个相对的概念，通过与正常生理状态下的表达情况进行对比后得出，强调的是表达水平的异常增高，这一现象往往与疾病的发生、发展密切相关，例如在许多肿瘤细胞中，某些癌基因会出现过表达，进而促进肿瘤的生长和增殖。2）表达丰度：是指在特定细胞、组织或生物样本中，某种基因或蛋白质的实际含量或数量。它是一个更侧重于量化的概念，主要用来描述靶点在样本中的具体表达量，并不涉及与正常状态的比较，仅仅单纯地反映该靶点在某个环境中的丰富程度。表达丰度可以借助多种技术手段进行测量。在基因层面，可采用PCR、RNA 测序实时定量；在蛋白质层面，可运用蛋白质免疫印迹法（Western blot）、酶联免疫吸附测定（Enzyme-linked immunosorbent assay，ELISA）等方法，得到具体的拷贝数、浓度、相对含量等数值。这二者的区别在于：高表达反映肿瘤组织中阳性细胞的占比情况，属于相对参数，多用于临床研究中的病人筛选。而表达量体现单个细胞内的蛋白个数，如HER-2受体最高表达量可达106，当小于103则被认为是低表达，这是一个定量参数，多用于药物机制研究。在临床实践中，医生通常会通过 IHC 和 FISH 等方法来检测肿瘤细胞的 HER-2 阳性水平，以指导治疗方案的选择并预测患者的预后。一般而言， IHC 检测为 3 + 或 FISH 检测显示基因扩增的患者，被认为是 HER-2 高表达，这类患者更有可能从 HER-2 靶向治疗中获益[2]（如下表）。 Orforglipron‌（LY3502970）是由礼来开发的口服GLP-1受体激动剂，一日一次。该小分子能够刺激GLP-1R诱导的cAMP积累，未检测到GLP-1R介导的β-arrestin蛋白的募集‌作用。II期临床试验结果显示[3]，在第26周时，Orforglipron剂量组（12, 24, 36,或45 mg）的体重与基线相比的平均变化范围为-8.6%至-12.6%，安慰剂组为-2.0%。在第36周，Orforglipron的平均变化范围为-9.4%至-14.7%，显示显著的减重效果。目前Orforglipron已经进入III期临床试验阶段，预计2026年上市。该药的上市将冲击注射型司马格鲁肽及替尔泊肽的市场份额。 CT-388原由Carmot Therapeutics公司开发，属于GLP-1/GIP受体双重调节剂，可以一周一次注射给药。2023年12月罗氏收购Carmot Therapeutics公司，继续进行开发。I期临床试验显示，健康肥胖成人每周皮下注射一次CT-388，24周后，平均体重可减少18.8%。该肽对β-arrestin的作用弱，可减少药物对心肌方面的副作用，目前正处于II期临床试验阶段（Roche官网）。目前发现激活素受体ACVR、肌肉生长抑素MSTN、Apelin受体APJ、‌甲状腺激素受体β(THR-β)、选择性雄性激素受体（SARM）调节剂、瘦素leptin、黑色素受体MC4R、GDF-15、Gherin受体等具有发展减肥增肌或减肥不减肌药潜力，一些重要的单靶药物或与GLP-1激动剂多靶点药物或联合用药已进入I-III期临床试验（表1）。下面对几个重要的靶点及药物研发进展进行简要介绍。激活素受体ActR2包括激活素受体ACVR2A及ACVR2B，是转化生长因子β（TGF-β）受体超家族中的两个重要成员，其在细胞生长、分化和组织修复等多种生理过程中发挥关键作用[4]。肌肉生长和发育是一个复杂的过程，受到多种因素的调控，其中ACVR2A和ACVR2B作为关键受体，扮演着重要角色。研究表明，抑制这两种受体可以促进肌肉生长并防止肌肉萎缩，这种双重作用使其成为治疗肥胖和相关代谢疾病有吸引力的靶点。目前，ACVR2A及ACVR2B融合蛋白用于治疗肺动脉高压、地中海贫血、骨髓增生异常综合征抑郁症等，如默沙东Sotatercept、BMS的Luspatercept已上市，一些也进入临床II-III期[5]。近期发现，靶向该受体的抗体药物具有显著的减重增肌活性。靶向ActR2A/B单抗Bimagrumab（礼来研发）的II期试验(NCT03005288)结果显示，75名体重指数介于28和40之间的2型糖尿病患者在48周内接受了bimagrumab治疗后，脂肪减少超过20.5%，而安慰剂组体重仅减少0.5%。除促进脂肪减少外，受试者瘦体重增加了3.6%，而安慰剂组瘦体重降低了0.8%[6]。此外，Alnylam、Arrowhead Pharmaceuticals等开展了Activin E、ActRIc(ALK7)的siRNA单药及与GLP-1联合用药用于减肥增肌的临床前研究（数据来源于公司网站），具有减肥不减肌活性。国内来凯医药的对ActRIIA的单克隆抗体LAE102，与GLP-1受体激动剂联用可进一步减少脂肪，并显著降低GLP-1受体激动剂导致的肌肉流失。2024年6月，LAE102已开始临床I期试验。该公司的LAE-103（靶标ACVR2B）、LAE-123（靶标ACVR2AxACVR2B）也正在积极推进中。此外，宜明昂科的IMC-003（靶标ACVR2A）及一个双靶抗体（IMC-004）也在研发中。肌肉生长抑制素（MSTN）(也称生长分化因子8（GDF8）)也属TGF-β家族成员，在骨骼肌中广泛表达，基因突变或敲除MSTN会导致肌肉质量显著增加。该靶点在肌肉萎缩症和肌肉衰减综合征等疾病治疗中具有显著疗效[7]。Trevogrumab是再生元开发的一款MSTN单抗，目前正在联合garetosmab（抗激活素A单抗）针对肥胖适应症开展临床Ⅱ期研究。2024年11月，再生元披露了Trevogrumab联合garetosmab的Ⅰ期临床结果。在单剂量研究中，设置了Trevogrumab （6 mg/kg, N=6）、garetosmab (10 mg/kg，N=6），Trevogrumab （6mg/kg）联合garetosmab（1 mg/kg、3 mg/kg、10 mg/kg）或安慰剂（N=12）组。结果显示，Trevogrumab（6 mg/kg）联合garetosmab（10 mg/kg）给药8周后，女性大腿肌肉体积较基线增加7.7%，而总脂肪量和腹部脂肪量较基线出现下降（-4.6%和-6.7%），显示联用疗法具有显著的减脂增肌效果。 Apitegromab 由Scholar Rock研发，其选择性地靶向MSLN的前体或非活性形式，阻断其在肌肉中的激活，主要适应症为脊髓性肌萎缩症。Apitegromab 的III期临床研究达到了主要终点，显著改善了患者的运动功能[8]。今年1月Scholar Rock已向美国FDA提交了Apitegromab上市申请。2024年5月，Apitegromab与GLP-1R药物（semaglutide或tirzepatide）联合使用治疗肥胖症的II期临床试验申请也获得FDA批准（来自Scholar Rock公司网站）。甲状腺激素受体β（THR-β）通过甲状腺激素的多种代谢作用对肝脏稳态起着至关重要的作用，其激动剂可以改善脂质代谢。针对该靶点的ASC47（歌礼制药）已在澳大利亚完成Ib临床试验。结果显示，ASC47在LDL-C偏高的健康受试者(10毫克、30毫克、90毫克)和肥胖症患者(90 毫克)中单次皮下注射后，经安慰剂校准的LDL-C降幅为22%，总胆固醇(TC)降幅为16%。在与司美格鲁肽治疗的DIO小鼠比较试验中，低剂量ASC47联合司美格鲁肽显示显著减重增肌效果（表2），单剂量ASC47(9 mg/kg)的减重幅度不大（1.55%），但低剂量ASC47（3 mg/kg或9 mg/kg）联合司美格鲁肽（30 nmol/kg，皮下注射，每日一次）用药使体重下降36%，显著高于司美格鲁肽单药疗法（体重下降23%），且肌肉总量/总体重显著提高。 Apelin受体（APJ）属于孤儿G蛋白偶联受体，Apelin及其受体在多种器官和组织中表达，包括中枢神经系统、心脏、肺、脂肪组织和胃肠道等[9]。APJ的内源性配体包括Apelin和Elabela两类多肽。Apelin对APJ受体的激活触发细胞内G蛋白依赖性信号传导途径，增加心肌收缩性和血管舒张，而机械拉伸激活APJ介导的β-arrestin信号传导，导致心脏肥大。因此，G蛋白偏向的APJ激动剂可以用于心力衰竭的治疗。此外，APJ介导的β-arrestin信号传导的丧失可以缓解饮食诱导的代谢功能障碍等。 BioAge（AMG占股）开发的Azelaprag(AMG986)激动剂，可预防肌肉萎缩。2024年6月启动了与替尔泊肽联用治疗肥胖的临床II期试验，最近的结果显示患者出现转氨酶升高副作用，而单独的替尔泊肽无类似副作用，目前已终止临床试验。类似的激动剂还有BMS公司的BMS-986224[10]。总的来说，目前的APJ激动剂偏向性不高。最近APJ激动剂与APJ受体复合物结构被解析[10]，发现了完全偏向的激动剂，但活性仅为100 nM [11]。瘦素单药减重效果不显著，但与pramlintide的联合使用后，可使超重者的体重减轻更多。再生元的瘦素单抗激动剂REGN4461，在全身性脂肪营养不良的小鼠模型中，REGN4461缓解了高食欲、高血糖、胰岛素抵抗、血脂异常和肝脂肪变性。I期临床结果显示，用REGN4461治疗超重或肥胖的人，在循环瘦素浓度低（<8 ng/ml）的人中，体重在12周内有所下降，但对基线瘦素水平较高的人的体重没有影响[12]。最近诺和诺德公司开展了GLP-1R/LepR双重激动剂研发，该多肽在leptin缺乏的肥胖小鼠模型中表现出显著的减少进食量和降低体重的效果（图3）[13]。 MC4R是公认的治疗肥胖的靶点，但目前还缺乏高选择性和安全的MC4R激动剂[14，15]。Palatin Technologies公司将上市的MC4R bremelanotide与替尔泊肽联合使用，小鼠试验显示，MC4R激动剂可增强GLP-1激动剂利拉鲁肽的药效[16], 2024年已开展II期临床试验。笔者认为一些潜在的新靶点，如受体蛋白酪氨酸激酶Mer (MERTK)、GPR75、Irisin、Dysferlin、ANGPTL8、脂肪酸受体4（Ffar4）以及一些新发现多肽、蛋白质还未找到确切受体的靶点（表3）可能在减肥增肌中发挥作用[17-26]。BRP是最近发现的一种全新、非胰岛素促分泌素类的抗肥胖多肽，在小鼠和小型猪模型中，BRP单次给药即可显著降低食物摄入量，效果持续数小时。此外，BRP不会引起低血糖或恶心等GLP-1药物常见的不良反应，且减脂不减肌（图4）。其作用机制与GLP-1等不同，主要通过激活大脑下丘脑区域特定神经元中的cAMP-PKA-CREB-FOS信号通路来抑制食欲[18]。目前已发现的减肥增肌靶点不少，但单独用药减肥效果不及GLP-1R激动剂及其多靶药激动剂，联合用药后的效果高于GLP-1R激动剂或具有显著的减肥增肌效果。一些原来只用于肿瘤患者恶质病的肌肉增强剂，与GLP-1R激动剂联合用药后，获得减肥增肌效果。从进展来看，一些改进型的GLP-1R单靶点及多靶点激动剂将率先获得批准，如GLP-1/葡萄糖依赖性促胰岛素多肽和胰高血糖素受体激动剂（Retatrutide）、口服的GLP-1R小分子体激动剂（Orforglipron）等。新的GLP-1迭代产品预期在减少副作用、减少停药后体重反弹、使用方便方面发挥作用。在减肥增肌方面，激活素受体ACVRII、肌肉生长抑素MSTN抗体类拮抗剂可能跟进获批，靶向Apelin受体APJ、选甲状腺激素受体β、瘦素leptin、黑色素受体MC4R分子还需更多的临床试验，验证其减肥增肌或不减肌效果。近期出现的新靶点可能在减肥增肌中发挥作用，显示诱人的发展潜力，但需进一步的动物实验及临床研究证实其效果。 1.Dolgin E. Dozens of new obesity drugs are coming: these are the ones to watch. Nature. 2025 Feb;638(8050):308-310. doi: 10.1038/d41586-025-00404-9. 2.Kokkorakis M, Chakhtoura M, Rhayem C, et al. Emerging pharmacotherapies for obesity: A systematic review. Pharmacol Rev. 2025, 77(1):100002. 3.Wharton S, Blevins T, Connery L, et al. Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. N Engl J Med. 2023, 389(10):877-888. 4.Morvan F, Rondeau JM, Zou C, et al. Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy. Proc Natl Acad Sci U S A. 2017, 114(47):12448-12453. 5.Nunn E, Jaiswal N, Gavin M, et al. Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism. Mol Metab. 2024, 101880. 6.Heymsfield SB, Coleman LA, Miller R, et al. Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity: A Phase 2 Randomized Clinical Trial. JAMA Netw Open. 2021, 4(1):e2033457. 7.Stefanakis K, Kokkorakis M, Mantzoros CS. The impact of weight loss on fat-free mass, muscle, bone and hematopoiesis health: Implications for emerging pharmacotherapies aiming at fat reduction and lean mass preservation. Metabolism. 2024, 161:156057. 8.Crawford TO, Darras BT, Day JW, et al. Safety and Efficacy of Apitegromab in Patients With Spinal Muscular Atrophy Types 2 and 3: The Phase 2 TOPAZ Study. Neurology. 2024, 102(5):e209151. 9.Hu G, Wang Z, Zhang R, et al. The Role of Apelin/Apelin Receptor in Energy Metabolism and Water Homeostasis: A Comprehensive Narrative Review. Front Physiol. 2021, 12:632886. 10.Gargalovic P, Wong P, Onorato J, et al. In Vitro and In Vivo Evaluation of a Small-Molecule APJ (Apelin Receptor) Agonist, BMS-986224, as a Potential Treatment for Heart Failure. Circ Heart Fail. 2021, 14(3):e007351. 11.Wang WW, Ji SY, Zhang W, et al. Structure-based design of non-hypertrophic apelin receptor modulator. Cell. 2024, 187(6):1460-1475.e20. 12.Altarejos JY, Pangilinan J, Podgrabinska S,et al. Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency. Sci Transl Med. 2023, 15(723):eadd4897. 13. Polex-Wolf J, Deibler K, Hogendorf WFJ, et al. Glp1r-Lepr coexpressing neurons modulate the suppression of food intake and body weight by a GLP-1/leptin dual agonist. Sci Transl Med. 2024, 16(776):eadk4908. 14.Müller TD, Blüher M, Tschöp MH, DiMarchi RD. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov. 2022, 21(3):201-223.] 15.Liu Z, Hruby VJ. MC4R biased signalling and the conformational basis of biological function selections. J Cell Mol Med. 2022, 26(15):4125-4136. 16.Dahir NS, Gui Y, Wu Y, et al. Subthreshold activation of the melanocortin system causes generalized sensitization to anorectic agents in mice. J Clin Invest. 2024, 134(14):e178250. 17.Deaton AM, Dubey A, Ward LD, et al. Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity. Nat Commun. 2022, 13(1):4319. 18.Coassolo L, B Danneskiold-Samsøe N, et al. Prohormone cleavage prediction uncovers a non-incretin anti-obesity peptide. Nature. 2025 Mar 5. doi: 10.1038/s41586-025-08683-y. 19.Shi X, Hu X, Fang X, et al. A feeding-induced myokine modulates glucose homeostasis. Nat Metab. 2025 Jan;7(1):68-83. doi: 10.1038/s42255-024-01175-9. Epub 2025 Jan 2. Erratum in: Nat Metab. 2025 Feb 11. doi: 10.1038/s42255-025-01231-y. 20.Akbari P, Gilani A, Sosina O, et al. Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity. Science. 2021, 373(6550): eabf8683. 21.Kumagai H, Coelho AR, Wan J, et al. MOTS-c reduces myostatin and muscle atrophy signaling. Am J Physiol Endocrinol Metab. 2021, 320(4):E680-E690. 22.Wang YT, Zheng SY, Jiang SD, et al. Irisin in degenerative musculoskeletal diseases: Functions in system and potential in therapy. Pharmacol Res. 2024, 210:107480. 23.Cho H, Lai CC, Bonnavion R, et al. Endothelial insulin resistance induced by adrenomedullin mediates obesity-associated diabetes. Science. 2025, 387(6734):674-682. 24.Paulke NJ, Fleischhacker C, Wegener JB, et al. Dysferlin Enables Tubular Membrane Proliferation in Cardiac Hypertrophy. Circ Res. 2024, 135(5):554-574. 25.Hu L, Wei J, Zhang Y, et al. ANGPTL8 is a negative regulator in pathological cardiac hypertrophy. Cell Death Dis. 2022, 13(7):621. 26.Kiepura A, Stachyra K, Wiśniewska A, et al. The Anti-Atherosclerotic Action of FFAR4 Agonist TUG-891 in ApoE-Knockout Mice Is Associated with Increased Macrophage Polarization towards M2 Phenotype. Int J Mol Sci. 2021, 22(18):9772.

抗体药物偶联物放射疗法

2025-03-05

·echemi

AbbVie Invests $2.2 Billion to Develop Best-in-Class Obesity Drug

On March 3, 2025, AbbVie and Gubra announced a significant licensing agreement to collaboratively develop GUB014295, a promising long-acting amylin analogue aimed at treating obesity. This partnership marks AbbVie’s strategic entry into the obesity treatment market. As part of the agreement, AbbVie will oversee the global development and commercialization of GUB014295. Gubra is set to receive an upfront payment of $350 million and could earn up to $1.875 billion in milestone payments related to development, commercialization, and sales, along with tiered royalties on global net sales. Currently, GUB014295 is undergoing Phase I clinical trials. This innovative drug specifically activates amylin and calcitonin receptors, helping regulate appetite and promote satiety. Initial results from a single ascending dose trial indicated that GUB014295 was well-tolerated, with mild and transient gastrointestinal side effects. The drug exhibited favorable pharmacokinetic properties, with a half-life of 11 days, supporting weekly dosing. During the six-week trial, patients in the high-dose group (3.5 - 6.0 mg) experienced an average weight loss of about 3%, while those on placebo saw an increase of approximately 1%. A multiple ascending dose trial is currently underway, with mid-term results expected in the first half of 2025. Amylin, a 37-amino acid hormone, plays a critical role in glucose control and appetite regulation. Its potential as a therapeutic target for obesity is underscored by existing amylin analogues like Symlin, which has been on the market since 2005 for diabetes management. AbbVie’s investment in GUB014295 highlights the growing interest in effective obesity treatments, reflecting a broader trend in the pharmaceutical industry to address the rising global obesity epidemic. With this collaboration, AbbVie aims to leverage Gubra's innovation in the hope of bringing a groundbreaking obesity therapy to market.

临床1期引进/卖出临床结果

2025-01-12

·药时代

全网寻找Amylin口服产品 | 药时代BD项目

正文共： 3000字 3图预计阅读时间： 8分钟 Amylin作为针对肥胖和超重的新药研发热门靶点之一，正吸引着全球制药行业的高度关注。MNC公司、欧美biotech公司、欧美基金公司委托药时代帮助寻找靶向Amylin受体的小分子新药产品或可口服的多肽产品等其他分子实体，目前所处阶段最好是PCC已经确定。我们诚挚邀请感兴趣的公司推荐更多靶向Amylin受体的小分子新药产品或可口服的多肽产品等其他分子实体。如果您有相关产品或信息，请速速联系药时代BD团队，邮箱：BD@drugtimes.cn 让我们共同推动Amylin靶点新药的研发，为肥胖和超重患者带来更多的治疗选择。以下内容仅供参考，欢迎批评指正！衷心感谢！~ Amylin作为肥胖新药研发的靶点的作用机理 Amylin（胰淀素）是一种由37个氨基酸组成的多肽激素，由胰岛β细胞分泌，与胰岛素一起在餐后被释放到血液中。它在代谢调节中发挥重要作用，特别是在控制食欲和能量平衡方面。以下是Amylin作为肥胖新药研发靶点的主要作用机理：抑制食欲： Amylin通过作用于大脑中的食欲调节中枢，减少食欲，增加饱腹感，从而减少食物摄入。这种作用机制有助于控制过度饮食，减少能量摄入。延缓胃排空： Amylin能够抑制肠胃蠕动，延缓胃排空速度。这不仅增加了饱腹感，还减少了食物在胃中的停留时间，从而进一步控制食物摄入。抑制胰高血糖素分泌： Amylin可以抑制胰高血糖素的分泌，从而减少肝脏中的葡萄糖生成，帮助调节血糖水平。这一机制对于控制餐后血糖升高尤为重要。增加能量代谢： Amylin通过多种机制增加机体的能量代谢，包括促进脂肪氧化和减少脂肪组织重量。这有助于减少体内脂肪积累，从而达到减重的效果。改善瘦素应答： Amylin可以改善瘦素的应答，增强瘦素在调节能量平衡和体重管理中的作用。瘦素是一种重要的食欲调节激素，通过改善瘦素应答，Amylin进一步增强了减重效果。抑制胃酸分泌： Amylin能够抑制胃酸分泌，减少胃部不适，从而间接影响食欲和食物摄入。这一机制有助于减少因胃部不适引起的过度进食。Amylin的代谢调节功能主要通过胰淀素受体（Amylin receptors, AMYRs）介导完成。胰淀素受体是一类特殊的蛋白异二聚体，由降钙素受体（Calcitonin receptor, CTR）和受体活性修饰蛋白（Receptor-Activity Modifying Protein, RAMPs）形成。RAMPs分为三种亚型：RAMP1、RAMP2和RAMP3，分别与CTR形成AMY1、AMY2和AMY3三种亚型的受体。临床应用主要包括以下方面。 Pramlintide： Pramlintide是首个获批用于糖尿病管理的合成胰淀素类似物，具有类似于GLP-1受体激动剂的减肥效果。它通过模拟天然胰淀素的作用机制，参与调控食欲、减缓胃排空速度以及改善血糖控制。然而，其疗效有限且与恶心和低血糖等副作用相关，妨碍其在临床上的广泛使用。 Cagrilintide： Cagrilintide是一种新型长效胰淀素类似物，在二期临床试验中，每周一次给药方案下的Cagrilintide呈现出剂量依赖性的体重减轻作用，其效果介于6%至10.8%之间。相比之下，同样为3毫克剂量的利拉鲁肽带来的体重减轻为9%，而安慰剂组则只有3%的减轻幅度。 Amycretin： Amycretin是一款GLP-1R和胰淀素受体的长效协同激动剂，正在开发皮下注射（每周一次）和口服（每天一次）两种剂型，目前拟开发适应症为肥胖。一项包含16位患者的口服Amycretin小型1期试验表明，患者在接受治疗12周后其体重下降幅度达13.1%，相较之下，安慰剂组患者的体重下降幅度仅为1.1%。此外，Amycretin展现良好的药代动力学特性，以及与其所开发的GLP-1类疗法类似的良好安全性、耐受性以及不良反应。Amylin通过多种机制调节食欲、延缓胃排空、抑制胰高血糖素分泌、增加能量代谢和改善瘦素应答，从而在肥胖和糖尿病治疗中发挥重要作用。随着对Amylin受体的深入研究，靶向Amylin的新药研发正在快速推进，未来有望为肥胖和糖尿病患者提供更有效的治疗选择。 Amylin新药相关交易简介 1. 百时美施贵宝收购Amylin Pharmaceuticals 2012年，百时美施贵宝以50亿美元的价格收购了Amylin Pharmaceuticals。Amylin Pharmaceuticals是一家专注于糖尿病诊断和治疗产品的生物制药公司，其新药Bydureon（每周注射一次的糖尿病治疗用药）具有年销售额15亿美元的潜力。2. 诺和诺德的Amycretin 2024年3月7日，诺和诺德在投资者日活动上汇报了其减重管线的布局和进展，特别引人注目的是口服Amycretin。这是一种GLP-1R和Amylin受体激动剂，一期临床中治疗12周减重13.1%，远优于司美格鲁肽治疗12周减重6%的效果。这一数据推动了诺和诺德股价盘前涨近6%，市值逼近6000亿美元。3. Zealand Pharma的Petrelintide 2024年6月21日，丹麦制药公司Zealand Pharma公布了其减肥注射剂Petrelintide的积极试验结果，引发市场热烈反响，股价飙升20%。Petrelintide属于长效Amylin类药物，在减重和稳定血糖方面显示出良好前景。1B期MAD试验结果显示，接受高剂量Petrelintide治疗的参与者平均体重下降了8.6%，而安慰剂组体重仅下降了1.7%。4. 礼来与KeyBioscience的合作 2024年10月10日，瑞士KeyBioscience和礼来公司宣布扩大在开发双胰淀素（Amylin）和降钙素（Calcitonin）受体激动剂（DACRA）方面的合作。DACRA是一种新型的双受体激动剂，旨在通过双重机制增强食欲抑制，实现更好的减重效果。5. 先为达生物与Verdiva Bio的合作 2025年1月10日，先为达生物宣布与Verdiva Bio达成了一项全球开发和商业化许可与合作协议，涉及每周一次口服GLP-1受体激动剂伊诺格鲁肽等3款产品组合，总金额高达24.7亿美元。Verdiva Bio是一家专注于开发针对肥胖和其他心血管代谢紊乱的创新疗法的公司，刚刚完成4.11亿美元A轮融资。此次合作的产品组合包括：口服伊诺格鲁肽（Ecnoglutide Oral, XW004）：处于II期临床试验准备阶段的潜在同类首创的每周一次口服GLP-1受体激动剂。口服胰淀素受体激动剂（Amylin RA）：处于临床前阶段的潜在同类首创的每周一次口服胰淀素受体激动剂，可用作单药治疗或与GLP-1受体激动剂联合使用。皮下注射胰淀素受体激动剂（Amylin RA）：处于临床前阶段的潜在同类最佳的长效皮下注射胰淀素受体激动剂，可用作单药治疗或与GLP-1受体激动剂联合使用。这些交易和合作表明，Amylin作为肥胖和糖尿病治疗的新靶点，正在吸引越来越多的制药公司的关注和投资。通过这些合作和收购，制药公司希望利用Amylin的多重机制，开发出更有效的减重和降糖药物，满足市场对创新疗法的迫切需求。如果您有相关产品或信息，请速速联系药时代BD团队，邮箱：BD@drugtimes.cn 让我们共同推动Amylin靶点新药的研发，为肥胖和超重患者带来更多的治疗选择。参考资料：各家公司官网药时代数据库其它公开信息推荐阅读美国上市公司寻找创新性ADC、双抗，您感兴趣吗？| 药时代BD项目 2024-07-25 诺和、礼来看好的ADC payload，您感兴趣吗？| 药时代BD项目 2024-07-22 药时代BD-030项目 | IND ready阶段月制剂减重药物GDF15融合蛋白寻求合作 2024-06-25 药时代BD需求 | 顶级MNC寻找优质项目：炎症性肠病、哮喘、慢阻肺、特发性肺间质纤维化 2024-05-03 版权声明/免责声明本文为汇编文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢! 药时代官方网站:www.drugtimes.cn 联系方式: 电话:13651980212 微信:27674131 邮箱:contact@drugtimes.cn 点击这里，查看更多精彩内容！

100 项与醋酸普兰林肽相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D05595	醋酸普兰林肽	A10BX05	DB01278

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
1型糖尿病	美国	AstraZeneca AB	2005-03-16
2型糖尿病	美国	AstraZeneca AB	2005-03-16

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
胰岛素依赖型糖尿病2	临床3期	美国	AstraZeneca PLC	2003-04-01
腹部肥胖	临床2期	美国	AstraZeneca PLC	2006-10-01
肥胖	临床2期	美国	AstraZeneca PLC	2004-08-01

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01841359 (CTgov)	临床4期	低血糖 \| 胃病	22	Pramlintide (Baseline (Prior to Pramlintide Treatment) Mixed Meal #1)	憲襯獵簾獵鬱鬱廠壓鏇(壓築餘獵鏇製鏇願窪膚) = 願鏇積窪醖簾窪網鬱獵窪醖淵鑰壓衊網憲築網 (糧築簾範鏇膚製築廠願, 3255) 更多	-	2022-05-26
				Pramlintide (Pramlintide - Mixed Meal #2)	憲襯獵簾獵鬱鬱廠壓鏇(壓築餘獵鏇製鏇願窪膚) = 膚簾淵築網顧廠網鹹網窪醖淵鑰壓衊網憲築網 (糧築簾範鏇膚製築廠願, 2770) 更多
ENDO2021	临床2期	1型糖尿病	18	XP-3924	淵夢選艱築鑰繭憲憲構(繭鬱襯製顧選範窪鏇網) = The incidence and severity of treatment emergent adverse events (e.g., injection site reactions, minimal nausea and vomiting) was comparable across all treatment arms with no drug-related serious adverse events 淵壓繭鏇夢願製衊衊鹽 (淵觸齋顧繭鹽築製網蓋 )	积极	2021-05-03
				Regular Insulin (Humulin R) + Pramlintide (Symlin)
ADA2019	N/A	1型糖尿病	24	BCPramIns	選鑰積觸憲淵願願醖艱(範觸顧遞壓製繭壓願遞) = Hypoglycemia during dosing visit days were balanced between the three treatment groups (4-3-3) 願構鹽鬱網淵繭衊蓋餘 (鑰夢廠顧網鹹積顧範窪 ) 更多	-	2019-06-01
				PRAM+INS
SAT-LB028 (ENDO2019)	N/A	胰岛素抵抗	111	U-500 insulin only	構壓顧獵獵夢範淵糧繭(蓋製鏇鏇選鏇醖獵糧網) = 遞憲膚憲觸夢鏇廠鹹壓鏇襯鑰衊壓窪範願獵憲 (製選餘範廠壓窪網窪製, 1.73) 更多	积极	2019-04-30
				U-500 insulin with pramlintide	構壓顧獵獵夢範淵糧繭(蓋製鏇鏇選鏇醖獵糧網) = 窪範選製襯糧顧鏇範觸鏇襯鑰衊壓窪範願獵憲 (製選餘範廠壓窪網窪製, 1.24) 更多
NCT00690235 (CTgov)	临床4期	糖尿病 \| 分裂情感性障碍 \| 精神分裂症 ... 更多	33	Pramlintide (Pramlintide)	鏇願觸選鏇蓋觸憲鏇築(鬱廠鑰齋餘淵願夢淵餘) = 遞鑰衊鏇簾鏇製壓夢鹹齋窪廠醖膚鬱願範糧獵 (製糧艱淵蓋廠壓繭艱繭, 143.06) 更多	-	2018-11-16
				Placebo (Placebo)	鏇願觸選鏇蓋觸憲鏇築(鬱廠鑰齋餘淵願夢淵餘) = 願憲醖襯獵獵鑰齋夢選齋窪廠醖膚鬱願範糧獵 (製糧艱淵蓋廠壓繭艱繭, 109.26) 更多
NCT02500979 (CTgov)	临床1期	1型糖尿病	34	Insulin (Placebo & Regular Insulin)	鹹願觸願觸構襯壓築餘(鹹廠製醖淵膚膚鹽餘膚) = 鬱構廠膚夢醖鹽繭襯願顧顧憲鹽積願餘蓋憲繭 (窪衊餘壓衊夢鏇觸壓構, 8.17) 更多	-	2018-11-02
				Insulin+Pramlintide (Pramlintide & Regular Insulin)	鹹願觸願觸構襯壓築餘(鹹廠製醖淵膚膚鹽餘膚) = 襯廠鹹膚範鏇壓構鹽鏇顧顧憲鹽積願餘蓋憲繭 (窪衊餘壓衊夢鏇觸壓構, 8.17) 更多
NCT02500979 (Pubmed \| Diabetes Care)	临床1期	1型糖尿病	34	Pramlintide	範鹹襯夢衊膚蓋鑰製夢(顧鹹壓築鹽選齋簾蓋壓) = 壓獵餘艱網願壓鏇廠願壓遞願齋構鑰鏇廠選淵 (顧繭窪鹹網鏇鹹鬱醖夢 )	-	2018-11-01
				Placebo	範鹹襯夢衊膚蓋鑰製夢(顧鹹壓築鹽選齋簾蓋壓) = 鑰顧夢築築糧艱積壓壓壓遞願齋構鑰鏇廠選淵 (顧繭窪鹹網鏇鹹鬱醖夢 )
EASD2018	N/A	-	-	BC Pram Ins	夢膚鹹廠淵獵觸蓋選醖(齋網衊獵願願繭壓憲壓) = 0.45 [0.20; 1.05] 構糧構簾壓醖淵膚蓋膚 (鹽築築餘築餘鏇觸憲積 ) 更多	积极	2018-10-02
				Humulin
NCT00442767 (CTgov)	临床4期	1型糖尿病 \| 高血糖	8	Insulin (Rapid Acting Insulin Therapy - Before Meal)	遞鏇壓鏇觸鹹鹽夢選願(製積網衊築壓願淵糧獵) = 鬱鑰網選鑰憲鑰淵繭艱蓋觸窪鹹製蓋積鑰鹹獵 (醖網憲淵簾淵窪膚鑰淵, 116) 更多	-	2018-07-10
				Insulin+Pramlintide (Pre-meal Pramlintide and Post-meal Insulin Therapy)	遞鏇壓鏇觸鹹鹽夢選願(製積網衊築壓願淵糧獵) = 獵網鏇憲網繭鹹衊積淵蓋觸窪鹹製蓋積鑰鹹獵 (醖網憲淵簾淵窪膚鑰淵, 141) 更多