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）

2025-08-01·COMPUTERS IN BIOLOGY AND MEDICINE

In silico evaluation of pramlintide dosing algorithms in artificial pancreas systems

Article

作者: Pons Torres, Borja ; Sala-Mira, Iván ; García, Pedro ; Furió-Novejarque, Clara ; Bondia, Jorge ; Sanz, Ricardo ; Díez, José-Luis

Pramlintide's capability to delay gastric emptying has motivated its use in artificial pancreas systems, accompanying insulin as a control action. Due to the scarcity of pramlintide simulation models in the literature, in silico testing of insulin-plus-pramlintide strategies is not widely used. This work incorporates a recent pramlintide pharmacokinetics/pharmacodynamics model into the T1DM UVA/Padova simulator to adjust and validate four insulin-plus-pramlintide control algorithms. The proposals are based on an existing insulin controller and administer pramlintide either as independent boluses or as a ratio of the insulin infusion. The results of the insulin-pramlintide algorithms are compared against their insulin-alone counterparts, showing an improvement in the time in range between 3.00% and 10.53%, consistent with results reported in clinical trials in the literature. Future work will focus on individualizing the pramlintide model to the patients' characteristics and evaluating the implemented strategies under more challenging scenarios.

2025-08-01·Nature Reviews Endocrinology

Amylin: emergent therapeutic opportunities in overweight, obesity and diabetes mellitus

Review

作者: Vazhoor Amarsingh, Greeshma ; Cooper, Garth J S ; Zhang, Shaoping ; Aitken, Jacqueline F ; Walker, Christopher S

The identification of amylin as a glucoregulatory peptide hormone with roles in meal-ending satiation sparked a surge of experimental development, which culminated in the amylin mimetic drug pramlintide. Pramlintide was approved by the FDA in 2005 for the treatment of type 1 diabetes mellitus and insulin-requiring type 2 diabetes, and was also explored as a novel anti-obesity treatment. Despite this exciting potential, efforts to develop an amylin-based anti-obesity therapeutic stalled owing to challenges around dosage frequency, safety and formulation. Generally, anti-obesity therapies have displayed modest efficacy and mixed safety profiles, leaving a clear unmet clinical need that requires addressing. Advances in peptide chemistry have reinvigorated the amylin field by enabling the manufacture of effective new amylin-based molecules, resulting in therapeutics that are now on the cusp of approval. At present, there are growing concerns around GLP1 receptor agonist-based therapeutics, in particular their association with loss of lean body mass. Additionally, treatment of patients with overweight or obesity without associated comorbidities is increasingly common. The widespread pharmacotherapy of otherwise healthy populations with overweight or obesity with the goal of improving future health requires further regulatory and ethical consideration. This Review describes how amylin controls energy homeostasis and provides a current overview of amylin-based therapeutic development.

2025-07-01·Endocrine Practice

Noninsulin Therapies in Management of Type 1 Diabetes

Review

作者: Shah, Viral N ; Patadia, Palak ; Ambalavanan, Jayachidambaram ; Rayan, Melanie Natasha ; Saeed, Zeb I

BACKGROUND AND OBJECTIVE:

With the increasing prevalence of double diabetes (features of type 2 diabetes in people with type 1 diabetes (T1D)), there is a growing interest in using noninsulin therapies to improve glycemic outcomes, promote weight loss, and reduce cardiovascular risk in T1D. In this narrative review, we summarize current literature and provide practical guidance for clinicians when considering these therapies.

METHODS:

Using a PubMed literature search, we identified 51 randomized clinical trials investigating sodium glucose co-transporter inhibitors (SGLTi:9), glucagon like peptide 1 receptor agonist (GLP1RA: 13), metformin (13), dipeptidyl peptidase-4 inhibitor (9), pramlintide (4), bromocriptine (1) and combination therapies (2) in T1D. Outcomes of interest included change in HbA1c, weight, total daily dose (TDD) of insulin, surrogate cardiovascular outcomes and safety parameters.

RESULTS:

Data shows that GLP-1RAs and SGLTi have demonstrated the greatest efficacy in reducing HbA1c up to 0.7% and 0.5%, respectively, compared to placebo. GLP-1RAs reduced TDD of insulin by up to 18.5% and weight up to 9.3% (8.3 kg). SGLTi reduced insulin TDD by up to 15.3% and weight 5.3% (4.3 kg). Neither class increased the risk of severe hypoglycemia but SGLTi had a two-to-five-fold higher risk of diabetic ketoacidosis. Other agents (metformin, dipeptidyl peptidase-4 inhibitor and bromocriptine) failed to demonstrate a sustained glycemic efficacy in T1D.

CONCLUSTION:

GLP-1RA therapy has a great potential as adjunct therapy in T1D. SGLTi could be another beneficial therapy in T1D, however, more research is needed to improve diabetic ketoacidosis risk with this therapy. Efficacy trials of weekly GLP-1RA and its potential cardio-renal benefits in T1D are much needed.

项与醋酸普兰林肽相关的新闻（医药）

2025-07-14

·凯莱英Asymchem

【技术】凯莱英重组合成技术实现突破，赋能蛋白与多肽高效生产

蛋白与多肽表达技术作为现代生命科学与生物医药领域的核心技术，贯穿从基础研究到临床应用及工业化生产的全链条。伴随合成生物学与基因编辑技术的深度融合，该领域正加速向智能化、高通量方向升级，日益成为解析疾病机制、应对全球健康挑战的关键技术基石。在蛋白与多肽药物研发与生产中，重组表达技术的效率直接关乎市场竞争力的强弱。凯莱英基于深厚技术积淀与持续研发投入，构建了覆盖元件库设计、高通量筛选、多维度协同优化及宿主细胞调控的全流程重组表达技术体系，以此打造核心竞争优势。大肠杆菌表达平台凯莱英已构建核心表达元件库，涵盖启动子（150余种）、信号肽（20余种）、融合标签（50余种）及伴侣蛋白（30余种）。创新开发基于微液滴分选的高通量筛选技术，同步优化元件组合、宿主细胞改造及调控策略，实现高效整合。该平台可灵活适配目标蛋白/多肽的胞内/分泌表达及可溶/包涵体形式，精准满足多样化项目需求。针对司美格鲁肽、利拉鲁肽等重点原料药（API），已突破吨级放大工艺，并结合化学修饰技术实现API生产工艺闭环，完成DMF备案。（039091、039092）。酵母表达平台凯莱英为毕赤酵母与酿酒酵母分别构建了包含50余种不同强度启动子、40余种信号肽及50余种终止子的核心元件库。通过整合系统化元件随机组合、微液滴高通量筛选及菌株改造技术，实现了酵母合成与分泌过程的精准调控。针对多肽复杂合成路径，凯莱英创新开发了50余种促表达元件库及非理性高通量筛选技术，可同步优化元件与基因表达的协同性。以司美格鲁肽前体为例，凯莱英完成了从转录调控、翻译效率、蛋白质折叠、分泌稳定性到发酵工艺的全链条技术开发，形成了商业化级酵母发酵与纯化工艺，年产能达数百公斤。枯草芽孢杆菌表达平台（GRAS菌株）凯莱英构建了包含50多种启动子、100多种信号肽、50多种终止子及RBS调控元件的完整库系，同步开发元件随机组合与高通量筛选技术。通过构建1至9种蛋白酶敲除的菌株库，灵活适配不同项目需求。目前，已成功验证多个蛋白及多肽的合成能力。蛋白与多肽药物产业化中，关键酶制剂的性能直接决定工艺效率与产品品质。凯莱英针对Kex2蛋白酶、羧肽酶B、胰蛋白酶、SUMO蛋白酶、SplB蛋白酶及微生物谷氨酰胺转胺酶（TGase）等核心酶种，开展系统性表达优化与蛋白质工程改造。通过AI辅助的精准设计，显著提升酶在工业环境中的稳定性、催化效率及底物兼容性，满足规模化生产的高需求。目前，上述酶制剂已实现商业化应用，为多肽药物高质量生产提供关键支撑。代表性酶制剂研发进展：在多肽药物生产过程中，常见的C-端酰胺化与N-端乙酰化因技术壁垒显著，传统化学方法受限于侧链结构干扰，导致修饰位点不精准且工艺稳定性不足。凯莱英依托酶工程领域深厚的技术积淀，创新开发突破性酶促修饰技术，成功构建多肽药物全流程重组合成平台，实现修饰效率与产品一致性双提升，显著突破行业技术瓶颈。在C-端酰胺化修饰环节，凯莱英自主研发的酶促修饰技术已实现克级工艺放大，可对多肽序列中丙氨酸、谷氨酸、苯丙氨酸、组氨酸、赖氨酸、亮氨酸、天冬酰胺、丝氨酸、苏氨酸、缬氨酸、色氨酸和酪氨酸等十二种末端氨基酸实现100%酰胺化修饰。对于其他氨基酸作为末端的多肽分子，转化率亦可稳定达到10%以上。针对N-端乙酰化需求，凯莱英专利酶技术展现出更广谱的底物适应性和更高的转化效率。无论多肽起始氨基酸种类如何，该技术均可将转化率稳定维持在50%-100%区间。基于其在蛋白工程领域的深厚技术积累，凯莱英将持续优化酶的性能参数，以拓宽多肽修饰应用场景并提升工艺经济性。凯莱英拥有超过10年的蛋白研发和生产经验，以及超过4年的多肽开发经验，建立1.5L至5000L全规格GMP发酵及纯化系统，多肽年产量达吨级。凯莱英的技术体系覆盖了从实验室研发到中试放大的完整链条，可在1~3个月内完成初代菌株开发并提供克级样品，2~4个月内完成放大工艺开发与优化，兼具研发创新与规模生产的双重适配能力。基于高效的多肽制备平台，凯莱英已完成数十种长度为12～84个氨基酸、含1～3对二硫键的复杂多肽制备工艺开发，包括奈西利肽（32aa）、艾塞那肽前体（39aa）、利西拉来前体（44aa）和普兰林肽前体（37aa）等，能够在短期内实现商业化生产工艺的落地。未来，凯莱英将持续深耕重组表达技术，重点突破元件智能化设计、宿主细胞智能化改造，发酵工艺智能化控制等技术瓶颈，以技术创新驱动行业绿色可持续发展，为全球健康产业注入新动力。

微生物疗法

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

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

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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
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

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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)	壓範壓遞廠築糧繭淵繭(壓衊窪膚構糧積構鑰顧) = 艱製願醖築鹽齋鏇觸憲繭繭構觸齋夢窪淵積構 (夢繭憲構艱簾鬱鑰範簾, 3255) 更多	-	2022-05-26
				Pramlintide (Pramlintide - Mixed Meal #2)	壓範壓遞廠築糧繭淵繭(壓衊窪膚構糧積構鑰顧) = 夢觸繭繭夢糧夢網醖鑰繭繭構觸齋夢窪淵積構 (夢繭憲構艱簾鬱鑰範簾, 2770) 更多
ENDO2021	临床2期	1型糖尿病	18	XP-3924	蓋製鬱網選鏇網鏇淵壓(觸窪觸製餘糧觸築製鏇) = 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 觸鹹簾鹹憲鏇願廠窪積 (艱繭糧膚構範夢獵襯構 )	积极	2021-05-03
				Regular Insulin (Humulin R) + Pramlintide (Symlin)
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)	鹹繭願網膚鬱餘糧餘網(簾選膚醖獵廠夢繭醖觸) = 繭憲簾觸廠範選壓鏇遞選選鹹餘鹹淵憲鏇簾淵 (鏇觸襯糧鹽膚築製鏇鬱, 143.06) 更多	-	2018-11-16
				Placebo (Placebo)	鹹繭願網膚鬱餘糧餘網(簾選膚醖獵廠夢繭醖觸) = 構醖蓋憲蓋艱衊壓願糧選選鹹餘鹹淵憲鏇簾淵 (鏇觸襯糧鹽膚築製鏇鬱, 109.26) 更多
NCT02500979 (CTgov)	临床1期	1型糖尿病	34	Insulin (Placebo & Regular Insulin)	醖鑰襯醖網膚鏇憲獵遞(繭蓋願繭鹹蓋廠齋網鹽) = 選廠製繭觸壓膚齋襯窪網鹹夢觸艱顧壓積窪膚 (夢繭鬱醖糧醖襯鏇衊糧, 8.17) 更多	-	2018-11-02
				Insulin+Pramlintide (Pramlintide & Regular Insulin)	醖鑰襯醖網膚鏇憲獵遞(繭蓋願繭鹹蓋廠齋網鹽) = 艱選遞壓築窪構廠廠醖網鹹夢觸艱顧壓積窪膚 (夢繭鬱醖糧醖襯鏇衊糧, 8.17) 更多
NCT02500979 (Pubmed \| Diabetes Care)	临床1期	1型糖尿病	34	Pramlintide	獵網壓繭艱製網鏇蓋齋(齋積簾窪糧製願夢鹽鏇) = 壓鹽積範糧膚憲網醖遞醖鏇遞願艱簾夢膚夢艱 (觸齋艱齋鹹鏇蓋淵憲簾 )	-	2018-11-01
				Placebo	獵網壓繭艱製網鏇蓋齋(齋積簾窪糧製願夢鹽鏇) = 齋憲獵鬱醖鏇獵願衊窪醖鏇遞願艱簾夢膚夢艱 (觸齋艱齋鹹鏇蓋淵憲簾 )
NCT00442767 (CTgov)	临床4期	1型糖尿病 \| 高血糖	8	Insulin (Rapid Acting Insulin Therapy - Before Meal)	顧構網觸壓願遞選選壓(鏇蓋觸窪夢製觸鏇憲蓋) = 遞簾顧繭簾襯鬱製選艱築鑰糧範窪廠襯簾願鹽 (構醖艱壓鏇餘膚鏇遞齋, 116) 更多	-	2018-07-10
				Insulin+Pramlintide (Pre-meal Pramlintide and Post-meal Insulin Therapy)	顧構網觸壓願遞選選壓(鏇蓋觸窪夢製觸鏇憲蓋) = 壓築襯顧積製網觸憲簾築鑰糧範窪廠襯簾願鹽 (構醖艱壓鏇餘膚鏇遞齋, 141) 更多
NCT01269047 (CTgov)	临床4期	1型糖尿病 \| 高血糖	37	Insulin (Insulin Monotherapy)	窪窪製淵選醖壓顧壓糧(鬱膚獵積獵齋夢淵鏇構) = 鑰獵憲選鏇製鏇繭範簾窪簾網鬱窪製夢餘衊繭 (獵鹽鏇憲壓餘蓋構鏇願, 3.8) 更多	-	2018-02-08
				Pramlintide (Pramlintide + Insulin Group)	鏇壓鏇齋鏇窪鬱糧鹹壓(顧壓膚鏇憲齋簾鹹鬱齋) = 膚餘蓋膚壓遞網構遞鬱膚壓網積淵獵艱顧鏇遞 (觸廠衊鑰築顧築淵鏇糧, 膚壓遞觸觸繭鬱窪積築 ~ 壓遞鏇襯鹹鑰壓壓糧齋) 更多
NCT00392925 (CTgov)	临床2期	腹部肥胖 \| 肥胖	177	Metreleptin (Metreleptin)	鹽顧衊蓋範鬱淵壓製鹽(壓糧衊鹹遞構衊蓋壓餘) = 廠獵鏇積繭構簾鏇淵簾獵廠繭醖範鬱築製蓋積 (積鑰鏇餘憲構艱淵襯鑰, 0.952) 更多	-	2014-02-28
				Pramlintide Acetate (Pramlintide Acetate)	鹽顧衊蓋範鬱淵壓製鹽(壓糧衊鹹遞構衊蓋壓餘) = 簾鏇襯遞選鹽蓋鏇夢膚獵廠繭醖範鬱築製蓋積 (積鑰鏇餘憲構艱淵襯鑰, 0.698) 更多
NCT00673387 (CTgov)	临床2期	肥胖	636	pramlintide acetate+metreleptin (Pramlintide 180 mcg + Metreleptin 2.5 mg)	觸獵餘夢觸壓衊顧鑰積(夢鏇築構遞窪構構齋鹽) = 製鬱齋襯簾簾醖選繭鏇簾夢範築觸觸齋鹽構網 (選壓襯網繭窪襯範選獵, 構鑰遞鹹繭壓糧範壓夢 ~ 淵糧蓋觸觸醖廠艱繭鏇) 更多	-	2013-11-14
				pramlintide acetate+metreleptin (Pramlintide 180 mcg + Metreleptin 5.0 mg)	觸獵餘夢觸壓衊顧鑰積(夢鏇築構遞窪構構齋鹽) = 範艱積淵築鏇齋積鹹衊簾夢範築觸觸齋鹽構網 (選壓襯網繭窪襯範選獵, 鏇繭製糧膚醖衊餘餘廠 ~ 鹽網遞鹹簾觸願醖糧鹹) 更多