A Phase 2b/3 Study to Evaluate the Safety, Tolerability, and Effects of Livoletide (AZP-531), an Unacylated Ghrelin Analogue, on Food-related Behaviors in Patients With Prader-Willi Syndrome

This Phase 2b/3 double-blind, placebo-controlled study will evaluate the safety, tolerability, and effects of livoletide on food-related behaviors in patients with Prader-Willi Syndrome (PWS).

开始日期2019-03-25

申办/合作机构

Millendo Therapeutics SAS

EUCTR2014-001670-34-ES

/ Completed临床2期

A Phase IIa, randomized, double-blind, placebo-controlled, multi-center study to evaluate the safety, tolerability, and effects of AZP-531, an Unacylated Ghrelin analog, on food-related behavior in patients with Prader-Willi Syndrome

开始日期2015-01-26

申办/合作机构

Alizé Pharma SARL

NCT02040012

/ Unknown status临床1期

A Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZP-531 in Healthy Volunteers, Overweight/Obese Volunteers and Patients With Type 2 Diabetes Mellitus

Objectives:
Primary Objectives
* To investigate the safety and tolerability of single ascending doses of AZP- 531 in healthy volunteers.
* To investigate the safety and tolerability of single and multiple ascending doses of AZP-531 in overweight/obese volunteers.
* To investigate the safety and tolerability of single and multiple ascending doses of AZP-531 in patients with type 2 diabetes mellitus.
Secondary Objectives • To determine the plasma pharmacokinetic (PK) profile of AZP-531 after single and multiple doses.
Exploratory Objectives
• To obtain exploratory data on the effects of AZP-531 on the pharmacodynamic (PD) markers of blood glucose, interstitial glucose, insulin, and plasma acylated ghrelin (AG) and unacylated ghrelin (UAG)

开始日期2013-07-01

申办/合作机构

Alizé Pharma SARL

100 项与 Livoletide 相关的临床结果

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100 项与 Livoletide 相关的转化医学

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100 项与 Livoletide 相关的专利（医药）

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项与 Livoletide 相关的文献（医药）

2023-02-28·Intractable & rare diseases research

Hyperphagia in Prader-Willi syndrome with obesity: From development to pharmacological treatment

Review

作者: Jufri, Nurul Farhana ; Rahman, Qaddra Fahada Ab. ; Hamid, Asmah

Prader-Willi syndrome (PWS) is a rare genetic disorder due to lack of genes expression inherited from the paternal chromosome 15q11-q13 region usually from paternal deletions, maternal uniparental disomy 15 or imprinting defect. There are two different nutritional stages reported in an individual with PWS; first stage during infancy marked by feeding and growth difficulties and second stage where hyperphagia starts and leads to development of obesity. However, the exact mechanism of hyperphagia development, from having difficulties in feeding during early years to insatiable appetite after they grow is still unknown and is the focused in this review. The keywords used for literature search such as "Prader-Willi syndrome", "hyperphagia", "obesity", and "treatment" were used to create the search strings by using synonyms in order to retrieve the relevant records from PubMed, Scopus and Science Direct. The possible mechanism of hyperphagia can be classed into hormonal abnormalities such as increase in ghrelin and leptin from infancy to adulthood. Low level of hormones was observed in the thyroid, insulin and peptide YY at certain ages. Neuronal abnormalities contributed by Orexin A and brain structure alteration was documented at 4-30 years old. Treatment in the form of drugs such as livoletide, topiramate, and diazoxide could potentially alleviate these abnormalities and make hyperphagia less prominent in PWS. The approaches are important to regulate the hormonal changes and neuronal involvement as potentially controlling hyperphagia and obesity.

2017-01-01·Basic research in cardiology1区 · 医学

Unacylated ghrelin analog prevents myocardial reperfusion injury independently of permeability transition pore

1区 · 医学

Article

作者: Ferrera, René ; Gharib, Abdallah ; Loufouat, Joseph ; Pillot, Bruno ; Crola Da Silva, Claire ; Gallo-Bona, Noelle ; Allas, Soraya ; Augeul, Lionel ; Abribat, Thierry ; Ovize, Michel ; Delale, Thomas ; Harisseh, Rania

Reperfusion injury is responsible for an important part of myocardial infarct establishment due notably to triggering cardiomyocytes death at the first minutes of reperfusion. AZP-531 is an optimized analog of unacylated ghrelin currently in clinical development in several metabolic diseases. We investigated a potential cardioprotective effect of AZP-531 in ischemia/reperfusion (IR) and the molecular underlying mechanism(s) involved in this protection. In vivo postconditioning with AZP-531 in C57BL6 mouse IR model decreased infarct size. Western blot analysis on areas at risk from the different mouse groups showed that AZP-531 activates Akt, ERK1-2 as well as S6 and 4EBP1, mTORC1 effectors. We also showed an inhibition of caspase 3 cleavage and Bax translocation to the mitochondria. AZP-531 also stimulated the expression of antioxidants and was capable of decreasing mitochondrial H₂O₂ production, contributing to the reduction of ROS accumulation. AZP-531 exhibits cardioprotective effect when administrated for postconditioning in C57BL6 mouse IR model. Treatment with AZP-531 rescued the myocardium from cell death at early reperfusion by stimulating protein synthesis, inhibiting Bax/caspase 3-induced apoptosis as well as ROS accumulation and oxidative stress-induced necrosis. AZP-531 may prove useful in the treatment of IR injury.

2016-09-01·Diabetes, obesity & metabolism2区 · 医学

Safety, tolerability, pharmacokinetics and pharmacodynamics of AZP ‐531, a first‐in‐class analogue of unacylated ghrelin, in healthy and overweight/obese subjects and subjects with type 2 diabetes

2区 · 医学

Article

作者: Julien, M. ; Delale, T. ; Abribat, T. ; Allas, S. ; Ngo, N. ; Sahakian, P. ; van der Lely, A. J. ; Ritter, J.

Aim:

To explore the safety, pharmacokinetics and pharmacodynamics in humans of the unacylated ghrelin analogue AZP ‐531, designed to improve glycaemic control and reduce weight.

Methods:

Assessments, including glucose measurements, were performed in a three‐part randomized study. In P art A , healthy subjects [n = 44, age 18–50 years, body mass index ( BMI ) 20–28 kg/m 2 ] received a single subcutaneous dose of 0.3, 3, 15, 30, 60 or 120 µg/kg AZP ‐531 or placebo. In P art B , overweight/obese subjects (n = 32, age 18–65 years, BMI 28–38 kg/m 2 ) and in P art C , patients with type 2 diabetes [ T2D ; n = 36, age 18–65 years, BMI 20–40 kg/m 2 , glycated haemoglobin ( HbA1c ) 7–10%] received AZP ‐531 or placebo for 14 days (daily doses of 3, 15, 30 or 60 µg/kg and 15, 2 × 30 or 60 µg/kg, respectively).

Results:

AZP ‐531 was well tolerated. Single‐ and multiple‐dose pharmokinetic variables were similar. Maximum AZP ‐531 concentrations were typically reached at 1 h post‐dose. Observed maximum concentration (C max ) and area under the curve were dose‐proportional. The mean terminal half‐life (t 1/2 ) was 2–3 h. In P art B , AZP ‐531 doses of ≥15 µg/kg significantly improved glucose concentrations, without increasing insulin levels, suggesting an insulin‐sensitizing effect. AZP ‐531 decreased mean body weight by 2.6 kg (vs 0.8 kg for placebo). In P art C , glucose variables improved in all groups, including placebo, suggesting a study effect in uncontrolled patients at baseline. Notwithstanding, AZP ‐531 60 µg/kg reduced HbA1c by 0.4% (vs 0.2% for placebo) and body weight by 2.1 kg (vs 1.3 kg for placebo).

Conclusions:

AZP ‐531 was well tolerated in this first‐in‐human study. Its pharmacokinetic profile, suitable for once‐daily dosing, and metabolic effects support further clinical development for T2D .

项与 Livoletide 相关的新闻（医药）

2025-10-29

·中国普外基础与临床杂志

陈亿、万谦益 | 肥胖症药物治疗的进展、挑战及我国研究现状

肥胖症药物治疗的进展、挑战及我国研究现状陈昱橦1，刘丹璐1，许靖豪1，蒲羽杰1，杜强1，FUMPA Mulusa1，侯栋升2，张贵祥2，杜潇2，程中2，万谦益2，陈亿2 1. 四川大学华西临床医学院（成都 610041） 2. 四川大学华西医院普通外科，胃肠外科病房（成都 610041）引用本文：陈昱橦, 刘丹璐, 许靖豪, 蒲羽杰, 杜强, FUMPAMulusa, 侯栋升, 张贵祥, 杜潇, 程中, 万谦益, 陈亿. 肥胖症药物治疗的进展、挑战及我国研究现状. 中国普外基础与临床杂志, 2025, 32(9): 1071-1078. doi: 10.7507/1007-9424.202506018 作者简介陈亿，博士、教授、博士研究生导师，主要从事胃肠外科研究工作，聚焦消化道肿瘤发病机制、营养支持治疗及糖尿病与肥胖症的外科治疗。现任四川省国际医学交流促进会肥胖与糖尿病外科专业委员会主任委员、Gastroenterology & Hepatology Research 等期刊编委。主持国家自然科学基金青年项目、国家自然科学基金重大研究计划子课题、前四川省卫生和计划生育委员会专项基金等多项课题。以第一或通信作者在Immunity、Cell Research、Signal Transduction and Targeted Therapy、Nature Communications、Cell Host & Microbe 等期刊发表20 余篇高水平论文。荣获国家级奖项3 项、省部级奖项4 项；申请发明专利4 项；参加多次国内外学术会议，行8 次特邀报告；参编英文专著Therapeutic Targets for Inflammation and Cancer 并作为香港中文大学教材使用；获得四川省卫生健康委员会学术技术带头人后备人选称号。作者简介万谦益，四川大学华西医院胃肠外科病房医师/代谢与衰老研究室博士后。四川省医学会肠内肠外营养学专业委员会青年委员，四川省医创会胃肠外科分会委员。主要从事代谢综合征及肠道疾病的临床及基础研究。主持国家自然科学基金青年基金、中国博士后科学基金会特别资助项目、四川省自然科学基金青年基金，入选国家资助博士后研究人员计划（C 档）。以第一（共同第一）作者在Nature Communications、Gut、J Cachexia Sarcopeni、Oncoimmunology 等期刊发表SCI 收录论文18 篇，高被引论文1 篇，授权、转化发明专利2 项。研究成果被3 项国际指南共识引用。摘要肥胖症是由遗传易感性、环境因素、神经内分泌系统紊乱等多因素驱动的慢性代谢性疾病。近年来肥胖症在中国的患病率逐年上升，由肥胖引起的一系列疾病严重威胁公众健康。以胰高血糖素样肽-1受体激动剂为代表的新型减重药物通过靶向中枢神经调控食欲、代谢等多途径协同作用，在临床试验中显示出接近减重代谢手术的治疗效果，但在临床实践中仍面临个体疗效差异显著、长期治疗的安全性证据有限、停药后复胖等关键问题。重点对国内批准上市的几种肥胖症药物的作用机制与临床研究证据进行总结，结合国际前沿的多靶点药物研发进展，探讨我国肥胖症药物治疗进展与面临的挑战，以期为肥胖症的临床药物管理提供科学依据，为我国肥胖症药物的研发及临床转化提供思路。目前中国超重及肥胖的流行病学趋势表现为患病人群广泛、增长速度快等特点，成年人超重率为34.3%、肥胖率为16.4%，且呈上升趋势，肥胖已经成为我国亟待解决的公共卫生问题[1]。肥胖症已不再被视为单纯的体质量超标问题。越来越多的研究[1-3]证实，肥胖与2型糖尿病、心血管疾病、代谢相关脂肪性肝病及多种肿瘤的患病风险增加有关，同时可能通过炎症介导等方式加速相关合并症的进展。目前，生活方式的改变如饮食控制、体育锻炼等方法作为肥胖症治疗的基础策略，但单纯通过生活方式的改变往往很难做到可持续性地控制体质量，这与能量平衡调节补偿、个体易感性等因素相关[1]。因此，药物干预成为肥胖症综合治疗的重要组成部分之一。随着肥胖症病理生理机制研究的深入，减重药物研发经历了从单靶点抑制到多通路联合调控的转变。本综述将基于目前临床研究证据，探讨我国肥胖症药物治疗的研究现状、临床治疗中的困境及今后的发展趋势。 1　肥胖症的病理生理机制 1.1 神经内分泌调控网络失衡下丘脑摄食中枢通过促进食欲的神经肽Y（neuropeptide Y，NPY）/刺鼠相关蛋白（agouti-related peptide，AgRP）神经元与抑制食欲的前阿片黑素细胞皮质激素（proopiomelanocortin，POMC）/可卡因-苯丙胺调节转录物（cocaine- and amphetamine-regulated transcript，CART）神经元构成的神经网络维持机体能量稳态[4-6]。然而，肥胖症患者普遍存在瘦素抵抗与胰高血糖素样肽-1（glucagon-like peptide-1，GLP-1）分泌缺陷的双重病理改变：一方面，瘦素受体敏感性下降，使得中枢对其传递的饱腹信号反应减弱；另一方面，肠道L细胞分泌GLP-1的水平下降，致使胃排空速度加快[7-9]，这种异常使进食及饱腹的动态平衡被破坏，进而成为肥胖发生的重要诱因。此外，肠-脑轴通过GLP-1、肽YY（peptide YY，PYY）等肠促激素向中枢神经系统传递外周代谢信息，当此发生功能紊乱时，不仅会抑制下丘脑POMC神经元活性促进摄食，还会进一步引起肝脏糖脂代谢障碍，进一步加剧机体能量失衡[10]。 1.2 脂肪组织功能异常白色脂肪组织中脂肪细胞肥大、异位沉积伴随脂肪组织胰岛素信号异常转导是肥胖的主要病理特征。肥胖状态下，白色脂肪组织从能量储存器官转变为代谢失调的炎症组织，进而分泌各种炎性因子，加剧胰岛素抵抗，引发胰岛素信号转导异常，导致肝脏和肌肉中糖脂代谢异常[11]。棕色脂肪组织通过解偶联蛋白1（uncoupling protein 1，UCP1）介导的线粒体解偶联产热调节能量平衡。然而肥胖患者的UCP1表达低，导致产热能力下降[12-13]。GLP-1受体激动剂（GLP-1 receptor agonists，GLP-1RA）等新型减重药物可通过激活环磷酸腺苷-蛋白激酶A通路诱导UCP1依赖性产热以诱导白脂肪组织棕色化，发挥调节代谢功能的作用[14]。这种外周作用途径揭示了药物减重的关键途径，有望成为肥胖症治疗的重要靶点。 1.3 肠道微生态失调肥胖的发生及发展与肠道微生态紊乱密切相关[15]。研究表明，肥胖症患者肠道菌群呈现厚壁菌门富集-拟杆菌门减少的特征[16]，其中产短链脂肪酸（short-chain fatty acids，SCFAs）的阿克曼菌等有益菌属丰度下降导致SCFAs 水平显著降低[17]。SCFAs在人体代谢中发挥多种功能，一方面，可通过激活肠道L细胞促进GLP-1分泌；另一方面，可通过增强肠道屏障功能抑制炎症反应。当SCFAs不足时，GLP-1依赖的食欲抑制信号减弱，同时肠黏膜屏障被破坏，导致内毒素进入血液循环，激活先天性免疫系统，从而诱发慢性炎症[15-17]，形成肠道菌群失调-代谢紊乱-炎症激活的恶性循环。 1.4 遗传与表观遗传调控已有证据[18]表明，基因在肥胖的易感性方面有部分作用。脂肪量与肥胖相关基因（fat mass and obesity-associated gene，FTO）、黑色素皮质素4受体（melanocortin 4 receptor，MC4R）、过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor γ，PPARγ）等基因遗传变异通过调节能量代谢和脂肪组织功能参与肥胖发生。如FTO（rs9939609多态性）已被证实可增加儿童肥胖的风险，FTO编码的N6-甲基腺苷去甲基酶可通过表观遗传调控脂肪细胞分化过程[19-20]。表观遗传也参与肥胖发病过程。DNA甲基化是表观遗传学重要的调控标志物，肥胖相关代谢途径调控中DNA甲基化异常可引起脂肪生成相关基因的转录失调[21]；组蛋白修饰异常则会影响脂肪细胞分化相关基因（如PPARγ）的转录活性[22]。这些证据表明，环境因素可以通过表观遗传调控参与到肥胖症的疾病过程，为肥胖症发病机制的研究提供了新视角。综上，肥胖症的病理生理机制是多因素、多环节共同作用的结果：神经内分泌调控网络中下丘脑摄食中枢失衡与肠-脑轴功能紊乱构成能量代谢异常的核心环节，表观遗传因素为疾病发生提供易感性基础，与脂肪组织功能异常、肠道微生态失调协同作用，形成复杂的病理网络（图1），为肥胖症的精准干预提供了多维度靶点。图1　肥胖症的病理生理机制与药物靶点示意图注：BAT：棕色脂肪组织；WAT：白色脂肪组织 2　已获得我国批准的减重药物及临床应用我国已批准的减重药物涵盖不同作用机制，其临床应用需结合患者个体特征与药物特点进行选择，见表1。 2.1 胃肠脂肪酶抑制剂—奥利司他（orlistat）奥利司他作为美国食品药品监督管理局批准的胰脂肪酶抑制剂，其作用机制在于，不可逆性抑制胃脂肪酶与胰脂肪酶的活性，通过阻断膳食脂肪消化吸收。该药适用于身体质量指数（body mass index，BMI）≥24 kg/m2患者的长期体质量管理。XENDOS试验数据[23]显示，肥胖患者采用奥利司他120 mg（3次/d）方案治疗1年后体质量平均下降11.4 kg，4年后体质量平均下降6.9 kg。针对我国糖尿病肥胖/超重患者的研究[24]显示，与安慰剂组相比，奥利司他组体质量减轻≥初始体质量5%的患者比例（60.5%）约为安慰剂组（26.8%）的2倍，体质量减轻≥初始体质量10%的患者比例（20.2%）约为安慰剂组（4.9%）的4倍。奥利司他的副作用主要集中于胃肠道反应，如出现油性便、排便次数增多、胃肠排气增多等，这些症状可能导致患者治疗依从性下降[25]。疗效温和的特性及耐受性问题使奥利司他的临床定位局限于轻中度肥胖的辅助治疗，或作为新型药物的联合用药选择[26-27]。 2.2 GLP-1RA GLP-1RA的核心减重机制在于调节肥胖患者失衡的肠-脑轴信号，通过多环节协同改善神经内分泌紊乱；它能刺激肠道L细胞分泌GLP-1、PYY等肠促激素，延缓胃排空，增强饱腹信号向大脑的传递；同时作用于下丘脑，抑制促食欲神经元（如NPY/AgRP）并激活抑食欲神经元（如POMC/CART），实现中枢的双重调控；其延缓胃排空的作用也延长了肠道对营养物质的感应，进一步强化饱腹感[28-29]。这种整合了外周、中枢和胃肠作用的协同机制，不仅解释了其显著的减重效果，也为理解不同制剂的作用特点提供了依据。 2.2.1 利拉鲁肽（liraglutide）利拉鲁肽独特的体质量减轻机制是由中枢和外周共同发挥：一方面，通过激活下丘脑GLP-1受体抑制食欲；另一方面，通过延缓胃排空，增加饱腹感，从而减少食物摄入[30-32]。该药适用于BMI≥30 kg/m2，或BMI≥27 kg/m2且存在至少1种体质量相关合并症的患者，例如高血糖、高血压、血脂异常、阻塞性睡眠呼吸暂停或心血管疾病等。SCALE试验[33]结果显示，非糖尿病肥胖/超重患者采用皮下注射利拉鲁肽3.0 mg（1次/d）剂量治疗56周后，利拉鲁肽组患者较安慰剂组平均减少了自身体质量的8.0%及2.6%；对于2型糖尿病肥胖/超重患者，分别采用皮下注射利拉鲁肽3.0 mg和1.8 mg（均为1次/d）的治疗方案，56周后分别平均减少了自身体质量的6.0%和4.7%，而安慰剂组则为2.0%[34]。LEADER试验[35]进一步证实，使用1.8 mg/d剂量利拉鲁肽皮下注射治疗可以使2型糖尿病患者主要心血管不良事件风险下降13%（与安慰剂组的14.9%相比，优效性P=0.01），具有明显的心血管保护作用。一项在我国开展的前瞻性研究[36]发现，利拉鲁肽1.8 mg/d治疗12周后，所有肥胖/超重受试者的体质量显著下降［从（89.2±16.0）kg降至（83.3±15.4）kg］，血糖得到改善，皮下、内脏脂肪和肝脏脂肪含量显著减少。在安全性方面，利拉鲁肽常见的不良反应多发生在剂量递增期，主要为恶心和腹泻，≥3级严重不良事件发生率较低，且多数症状会随治疗时间延长而逐渐缓解[37-38]。 2.2.2 贝那鲁肽（benaglutide）贝那鲁肽是一种全人源GLP-1类似物，通过中枢抑制食欲及外周调节胃肠动力以降低食物摄入[39-40]。该药物适用于BMI≥28 kg/m2，或BMI≥24 kg/m2伴随至少1种体质量相关合并症的患者。我国开展的3期临床研究[41]数据显示，采用0.2 mg（3次/d）方案治疗16周后，贝那鲁肽组减少自身体质量≥5%的患者比例高于安慰剂组（58.2%比25.4%，P<0.001），同时贝那鲁肽组腰围减少幅度更大（组间差异：–1.81 cm，P<0.01）；贝那鲁肽相关的胃肠道反应多为暂时性，程度轻至中度，为长效制剂依从性差或需快速控制餐后血糖的肥胖患者提供了短效制剂的治疗选择。 2.2.3 司美格鲁肽（semaglutide）司美格鲁肽是长效GLP-1RA，通过C18脂肪酸侧链修饰，可以延长药物半衰期，发挥长效的降糖及减重效用，仅需皮下注射1次/周，治疗依从性高[42]。该药物适用于BMI≥30 kg/m2，或BMI≥27 kg/m2且存在至少1种体质量相关合并症的患者。诸多临床试验已经对司美格鲁肽的有效性进行了充分证实，在全球3期临床试验STEP研究[43]中，非糖尿病超重/肥胖患者使用司美格鲁肽2.4 mg（1次/周）皮下注射68周，减重幅度（16.9%）显著高于安慰剂组（2.4%）；2型糖尿病超重/肥胖患者接受相同剂量治疗68周，平均减重幅度（10.6%）亦优于安慰剂组（3.1%）。在中国人群中试验研究[44]的结果显示，用相同方法治疗44周后发现超重/肥胖患者体质量平均减轻12.8%。安全性方面，尽管啮齿类动物模型出现甲状腺C细胞增生现象，但长期随访监测并未发现人类甲状腺髓样癌病例[45]。此外，司美格鲁肽可引起恶心（相对危险度为2.59）、腹泻（相对危险度为1.77）、便秘（相对危险度为2.07）等胃肠道不适症状风险显著增加[46]，虽然大部分患者的症状是自限性的，但这些个体反应差异提示，需加强用药监测与个体化干预措施，通过精准化治疗策略使药物的优势得到最大程度地发挥。 2.2.4 替尔泊肽（tirzepatide）替尔泊肽是首个获得批准的GLP-1/葡萄糖依赖性促胰岛素多肽（glucose-dependent insulinotropic polypeptide，GIP）受体双激动剂，通过同时激活 GLP-1受体与GIP受体发挥协同作用。GLP-1受体激活后能有效抑制食欲，降低热量摄取；GIP受体激活则可促进胰岛素分泌、促进脂肪氧化。这种双靶点协同作用的替尔泊肽的减重效果优于单靶点药物[47-48]。该药物适用于BMI≥28 kg/m2，或BMI≥24 kg/m2且伴有至少1种体质量相关合并症的患者。在SURMOUNT研究[49]中，非糖尿病超重/肥胖患者接受5、10、15 mg（1次/周）替尔泊肽治疗72周后，体质量降幅分别为16%、21.4%、22.5%，对比安慰剂组的2.4%降幅差异均有统计学意义；对于2型糖尿病超重/肥胖患者，使用10、15 mg（1次/周）剂量替尔泊肽治疗72周后，体质量降幅分别为13.4%和15.7%（对照组为3.3%）[50]。针对非糖尿病超重/肥胖中国患者的分析[51]显示，使用10、15 mg（1次/周）治疗52 周后，患者体质量下降14.4%和19.9%，高于对照组的2.4%。替尔泊肽常见的不良反应集中于治疗起始阶段，包括恶心、呕吐，这些反应多为轻至中度（1～2级）[49-51]。替尔泊肽取得的令人满意的治疗效果，推动肥胖症治疗进入双靶点时代。 2.2.5 玛仕度肽（mazdutide）玛仕度肽是全球首个获批的胰高血糖素（glucagon，GCG）/GLP-1受体双激动剂，通过同时激活 GLP-1 受体以抑制食欲、减少能量摄入、促进胰岛素分泌及调节血脂，激活 GCG受体促进能量消耗、加速脂肪分解并改善肝脏代谢功能，实现对机体食欲、代谢和血糖稳态的综合调控[52-53]。该药物适用于BMI≥28 kg/m2，或BMI≥24 kg/m2且伴有至少1种体质量相关合并症的患者。针对我国超重/肥胖患者的研究[54]显示，使用4、6 mg（1次/周）玛仕度肽治疗32周后，患者体质量分别平均下降10.09%和12.55%，安慰剂组增加0.45%；48周后患者体质量分别平均下降11.00%和14.01%，安慰剂组增加0.30%，且多项代谢指标得到改善。玛仕度肽常见的不良反应是胃肠道反应，严重程度大多为轻度至中度。 3　未获得我国批准的减重药物研发进展 3.1 多靶点受体激动剂瑞他鲁肽（retatrutide）作为GLP-1/GIP/GCG受体三激动剂，它通过抑制食欲、调节外周代谢及增强能量消耗实现减重[55]。Ⅱ期临床试验[56-57]数据显示，12 mg/周剂量瑞他鲁肽治疗48周后体质量平均下降24.2%，肝脏脂肪含量显著降低，目前已进入Ⅲ期临床研究。 3.2 口服GLP-1RA制剂口服司美格鲁肽采用SNAC ［8-（2-羟基苯甲酰胺基）辛酸钠］辅助吸收技术，50 mg/周治疗68周后体质量下降17.4%，胃肠道反应多为轻至中度（发生率为16%～50%），为偏好便捷治疗的患者提供了选择[58-59]。orforglipron作为非肽类小分子制剂，Ⅱ期临床试验数据显示，口服orforglipron后26周时体质量降幅最高达14.7%[60]，Ⅲ期研究进一步验证了其安全性与传统GLP-1RA类药物一致。 3.3 中枢作用药物芬特明（phentermine）及其复方制剂芬特明-托吡酯（phentermine-topiramate）、纳曲酮-安非他酮（naltrexone-bupropion）等中枢作用药物的应用需在疗效与安全性之间谨慎权衡[61-63]。 3.4 新型靶点药物及其机制探索胃饥饿素通路药物（如AZP-531、CYT009-GhrQb疫苗）通过阻断饥饿信号或免疫调节干预摄食[64-66]；线粒体解偶联剂BAM15则通过提升能量消耗减重[67]；生长分化因子15类似物LY3463251在小鼠和非人类灵长类模型中显示抑制食欲作用且耐受性良好[68-69]。此外，PYY类似物与GLP-1RA联用、中枢MC4R激动剂赛特美拉诺肽（setmelanotide）等新型靶点疗法均展现出临床前景，其疗效与安全性仍需更多证据支持[70-71]。以上这些国际前沿及国内创新药物虽然尚未在我国上市，但多靶点精准调控、口服便捷剂型及新型靶点作用机制的探索，推动了肥胖症药物的治疗更加多元化。 4 临床应用面临的挑战与安全性管理 4.1 疗效异质性与个体化治疗需求减重药物治疗肥胖症患者的疗效存在显著个体差异，这种差异可能受遗传、代谢状态、并发症等多因素综合作用[18, 72]。从遗传因素看，单基因肥胖患者（如MC4R突变携带者）与多基因肥胖患者对特定药物反应可能存在差异[72]。患者的基础代谢率、胰岛素敏感性或脂肪分布差异均能对药物疗效产生影响，例如，胰岛素抵抗型肥胖患者使用GLP-1RA的减重效果可能优于其他亚型[73]。此外，肥胖相关并发症（如代谢相关脂肪性肝病）可能通过改变全身炎症状态或器官功能间接影响药物疗效[72]。提示未来肥胖症治疗需结合基因检测、代谢组学分析等综合评估，制定个体化治疗方案，从而实现精准剂量优化及药物选择。 4.2 长期安全性监测与不良反应管理减重药物的安全性问题一直是临床上关注的热点，特别是GLP-1RA类药物，其恶心、呕吐等胃肠道反应较为常见[37-38, 41, 43, 48]，针对此，阶梯式增量的用药策略或许是可行的。甲状腺风险方面，虽然目前尚无人类长期使用GLP-1RA后引发甲状腺髓样癌的相关报道，但对于有甲状腺髓样癌家族史的患者仍建议谨慎使用，并在治疗期间定期监测血清降钙素水平[45]。而以替尔泊肽为代表的双靶点药物，可能会引起患者心率上升[74]。因此，针对心血管高危人群，需密切监测心率、血压等变化情况，建立完善的安全性监测体系对保障患者用药安全、提升治疗依从性具有重要意义。 4.3 停药后体质量反弹机制与维持策略停药后体质量反弹是肥胖症治疗面临的核心挑战。一项荟萃分析[75]结果显示，停止GLP-1RA治疗后，体质量恢复与原始体质量减轻成正比，服用利拉鲁肽的肥胖症患者的体质量恢复了2.20 kg ［95%CI（1.69，2.70）］，服用司美格鲁肽/替尔泊肽的参与者体质量恢复了9.69 kg ［95%CI（5.78，13.60）］。为有效应对体质量反弹，药物治疗结合运动干预、饮食调整、药物序贯治疗等策略被提出[76-77]，这些策略的有效性与安全性尚待更多长期随访的验证。 5 未来方向—从精准医疗到转化创新 5.1 基于生物标志物的精准用药体系构建精准医疗技术为解决疗效异质性提供新路径，通过整合多维度生物信息实现个体化治疗，如MC4R激动剂赛特美拉诺肽对单基因性肥胖症患者的有效治疗为基因精准治疗提供了思路[71]。未来需识别更多肥胖易感基因（如MC4R、POMC）和药物基因组标志物，开发针对特定肥胖亚型的个体化治疗方案，实现肥胖症治疗模式从传统的经验用药向精准定制转变[78]。 5.2 新型分子靶点开发目前肥胖症药物研发在分子靶点与机制上通过多靶点协同和技术创新突破，聚焦于多效肠促胰岛素类似物（如GLP-1/GIP/GCG受体三重激动剂）和口服递送技术[56-60]，中枢神经系统靶点与基因靶点也受到广泛关注[61-71]。未来多通路协同调控、中枢-外周联动等模式的探索将推动多机制治疗。 5.3 多模式联合治疗策略药物治疗与结构化生活方式干预（饮食及运动）结合可提高体质量维持效果，相比单一药物治疗降低体质量反弹风险[70]。手术结合药物序贯治疗可显示协同效应，如减重手术联合药物治疗或司美格鲁肽停药后继续使用二甲双胍可使体质量反弹风险降低[77, 79]。多模式联合治疗并非不同治疗手段的简单叠加，而是通过机制互补构建的长期管理体系。随着GLP-1RA等新型药物的普及和手术技术的进步，未来需进一步通过真实世界研究验证不同联合方案的长期安全性。 6 结论我国肥胖症药物治疗在流行病学压力与科技进步的双重驱动下，正在经历从单靶点到多靶点、从经验用药到精准医疗的转变，GLP-1RA及多靶点激动剂的临床应用显著提升了肥胖及其相关代谢疾病的管理效果，但它们在个体应答差异、长期安全性评估、停药后体质量维持等方面仍面临挑战。未来需构建肥胖症精准医疗管理体系，同时通过药物递送系统创新及多靶点协同机制探索，推动肥胖症从慢性疾病向可防可控的代谢异常转变，实现全人群的体质量健康管理目标。重要声明和参考文献略。推荐阅读： 1.顾岩 | 单孔腹腔镜袖状胃切除术的技术演进与临床规范开展 2.王存川 | 减重代谢手术的演进、突破、挑战与未来 3.陈亿 | 借鉴肿瘤治疗“桥接”策略: 药物联合手术开创肥胖管理新范式长按或扫描二维码关注我们！版权声明：本文为《中国普外基础与临床杂志》首载文章，其他公众号等传播媒体如需转载，需联系本刊编辑部获取授权，并将“本文刊发于《中国普外基础与临床杂志》，年，卷（期）：起止页或本文刊发于《中国普外基础与临床杂志》，年，优先出版”标注于醒目位置，谢谢合作！点击下方 “ 阅读原文” 可查看我刊当期其他文章

临床研究临床申请

2025-03-27

·FiercePharma

Soleno breaks through with FDA nod for Prader-Willi syndrome treatment Vykat XR

The FDA has approved the first treatment for hyperphagia, a condition which causes insatiable hunger and is associated with the rare genetic disorder Prader-Willi Syndrome (PWS). Since 2000, when the FDA approved recombinant human growth hormone (rhGH) for those with the rare genetic disorder Prader-Willi Syndrome (PWS), several companies have come up short in their attempts to develop a more advanced treatment for hyperphagia, an insatiable hunger condition associated with PWS.Wednesday, Soleno Therapeutics broke through with an FDA nod for Vykat XR (diazoxide choline), which becomes the first drug to treat hyperphagia. It is endorsed for those aged 4 years and older with the condition, which leaves patients with low muscle tone, short stature and intellectual and developmental problems.The once-daily extended-release tablet is a potassium channel activator. The channels, which are widespread throughout the body, including in the pancreas, regulate insulin secretion.With the approval, the share price of the 26-year-old Redwood, California, company had soared by 37% on Thursday morning.Based on the average weight of patients in its clinical trials, Soleno will charge $466,200 per year for Vykat XR. The company expects it to be available next month.In a release, Soleno CEO Anish Bhatnagar, M.D., called the approval “a significant milestone” for the company and for the “PWS community who have had no options to treat the most disruptive aspect of this disease.”Jennifer Miller, M.D., of the University of Florida and a principal investigator in the Vykat XR’s clinical development program, added that it will help families of those with PWS who “have been prisoners in their own homes because of the need to provide constant, eyes-on supervision 24/7 with access to food being completely restricted.”The approvel was backed by a phase 3 trial in which patients were observed during a 16-week withdrawal study after receiving Vykat XR for a median period of 3.3 years. Those who switched to placebo for the study period demonstrated a statistically significant worsening of hyperphagia compared to patients who remained on the drug.Over four years of data collected in four open-label studies, Vykat XR has shown a consistent safety profile with the most common adverse reactions—hypertrichosis, edema, hyperglycemia and rash—occurring in roughly 10% of the patients. The Prader-Willi Syndrome Association USA estimates that the disorder occurs in 1 in every 15,000 live births, with more than 300,000 people worldwide affected. Soleno says that claims data show there are 10,000 PWS patients in the U.S. Among the companies that have struck out in their attempts to develop a treatment for hyperphagia are Alize Pharma of France, which succeeded in a 2016 phase 2 study with AZP-531, a first-in-class unacylated ghrelin peptide analog, but failed to progress it further.In 2016, Boston-based Zafgen demonstrated the efficacy of beloranib, a MetAP2 inhibitor, in a phase 3 trial before the treatment was derailed by safety issues. Sweden’s Saniona developed Tesomet, a combination of monoamine reuptake inhibitor tesofensine and beta blocker metoprolol, which gained Orphan Drug designation from the FDA in 2021 before its development was halted a year later because of funding limitations.Acadia Pharmaceuticals of San Diego is developing a treatment, intranasal carbetocin, which the FDA rejected in 2022. Acadia gained the candidate through a $10 million acquisition of Chicago’s Levo Therapeutics.

临床结果临床3期上市批准并购孤儿药

2021-11-04

·Endpoints

FDA adcomm votes 12-1 against Levo Therapeutics' nasal spray for a disorder that causes insatiable hunger

The FDA’s Psychopharmacologic Drugs Advisory Committee on Thursday voted 12 to 1 against approving Levo Therapeutics’ nasal spray for Prader-Willi syndrome, a difficult-to-treat disease that leaves patients with constant, insatiable hunger. Those who voted no raised concerns about a lack of substantial evidence, as a 9.6 mg dose of the drug failed the primary endpoints in a Phase III trial. Looking for a silver lining, Levo turned to a 3.2 mg dose which met the trial’s secondary endpoints. But adcomm members wondered whether Levo could replicate those positive results. “The thing that stuck out to me most was that the 9.6 dose study did not replicate,” committee member Satish Iyengar, chair of the University of Pittsburgh’s statistics department, said after the vote. “And given the fact that the 3.2 dose study didn’t really hold up strongly to the sensitivity analysis that they did, I just have no confidence — I have little confidence — that it will replicate.” Another panel member, UCLA psychiatry professor Walter Dunn, suggested that if the question had asked about “moderate evidence of effectiveness,” he would have reconsidered his vote. “I do think it’s interesting that this is worded this way, because it doesn’t talk at all about any possible risk-benefit trade-off,” said James Troendle, a mathematical statistician at the NIH. Levo’s candidate, dubbed LV-101, is an intranasal form of carbetocin, a drug used outside the US to control bleeding after childbirth. It’s an oxytocin receptor agonist that was originally being developed for PWS by Ferring Pharmaceuticals, until Levo snagged the rights in 2016. Oxytocin is a neurotransmitter that regulates social-emotional and feeding behaviors, and research shows that those with PWS don’t have enough of it. But despite what Ferring celebrated as positive Phase II results, Levo faced an uphill battle. Although the carbetocin arm showed statistically significant improvements over placebo, the FDA called the data weak and the study duration insufficient. Then, last August, Levo announced the 9.6 mg dose failed the primary endpoints in a Phase III study: changes in baseline in either Hyperphagia Questionnaire for Clinical Trials scores (HQ-CT) or Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) scores. Hyperphagia is another term for the extreme hunger experienced by PWS patients. Researchers describe it as a constant feeling of starvation, adding that patients will oftentimes seek food wherever they can get it. As there are no currently approved treatments, patients cope by limiting the type and amount of food they consume, and in some cases even locking refrigerator doors and trash bins. Levo approached the FDA with its 3.2 mg dose, which achieved statistical significance as evaluated by the HQ-CT scores in the Phase III trial. However, there was no meaningful difference seen in CY-BOCS scores. In their briefing ahead of the adcomm, the FDA noted that the secondary endpoint met with the 3.2 mg dose “must be considered in the context of the lack of efficacy of the higher dose (9.6 mg).” Levo suggested that the lack of efficacy seen in the 9.6 mg group may have been due to off-target vasopressin effects emerging with longer treatment duration. However, the FDA wrote: “If that were the case, one would expect to see a nominal difference versus placebo at Week 2 (consistent with the findings from Study 114); however, no difference between groups was observed at that earlier time point.” PWS has proved extremely difficult to treat. Millendo Therapeutics’ lead drug livoletide failed a pivotal trial for the treatment of PWS last April, sending shares plummeting. The drug didn’t improve hyperphagia or other eating-related behaviors. And Zafgen’s ZGN-1258, its second attempt to treat rare cases of obesity brought on by PWS, hit a brick wall after the FDA put a hold on the company’s PWS program in 2018, citing CV safety concerns. Multiple parents of children with PWS tuned in to the adcomm meeting, touting carbetocin as a miracle that has allowed their children to finally sleep through the night, or visit Disney World without obsessing over food. “You have the opportunity to change and possibly save an untold number of lives. Please take it,” one parent said. But multiple others argued against the drug, with one parent calling it “completely useless” and even claiming the treatment worsened her child’s behavior. Alice Shapley, a patient representative and the only adcomm member who voted in support of the drug, said: “In light of the promising safety profile of carbetocin, I’m convinced of the high ratio of benefit to risk for this treatment for the PWS community.” Charles Billington, an endocrinologist and professor of medicine at the University of Minnesota, said he was moved by the compelling stories by family members. But when it comes down to whether there’s substantial evidence to back the drug, the answer is no. “It’s hard to find any evidence of a signal at all,” he said.

100 项与 Livoletide 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15188

研发状态

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
多食症	临床3期	美国	Millendo Therapeutics SAS	2019-03-25
多食症	临床3期	澳大利亚	Millendo Therapeutics SAS	2019-03-25
多食症	临床3期	比利时	Millendo Therapeutics SAS	2019-03-25
多食症	临床3期	法国	Millendo Therapeutics SAS	2019-03-25
多食症	临床3期	意大利	Millendo Therapeutics SAS	2019-03-25
多食症	临床3期	荷兰	Millendo Therapeutics SAS	2019-03-25
多食症	临床3期	西班牙	Millendo Therapeutics SAS	2019-03-25
多食症	临床3期	英国	Millendo Therapeutics SAS	2019-03-25
普拉德-威利综合症	临床3期	美国	Millendo Therapeutics SAS	2019-03-25
普拉德-威利综合症	临床3期	澳大利亚	Millendo Therapeutics SAS	2019-03-25

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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


NCT03790865 (ZEPHYR, CTgov)	临床2/3期	多食症 \| 普拉德-威利综合症	158	Livoletide (Low-Dose Livoletide)	鑰獵淵製網觸淵艱構醖(糧廠積襯範壓廠襯鏇憲) = 鏇廠襯網構膚憲衊襯夢鹽蓋鹽鬱齋醖選夢夢齋 (夢繭壓廠餘鏇願膚膚積, 7.76) 更多	-	2021-02-17
				Livoletide (High-Dose Livoletide)	鑰獵淵製網觸淵艱構醖(糧廠積襯範壓廠襯鏇憲) = 鬱窪醖襯衊憲鹽築範壓鹽蓋鹽鬱齋醖選夢夢齋 (夢繭壓廠餘鏇願膚膚積, 6.08) 更多
Phase 2a trial (ENDO2020)	临床2期	普拉德-威利综合症	47	Livoletide (AZP-531) (Obese participants)	遞鹹襯積憲網範齋繭構(糧壓艱繭鹹齋築選鏇選) = 鑰齋構築衊網鹹艱遞獵顧鹽鏇餘構夢淵餘蓋廠 (廠鹹築繭製觸範獵餘獵 ) 更多	积极	2020-05-08
				Livoletide (AZP-531) (Non-obese participants)	遞鹹襯積憲網範齋繭構(糧壓艱繭鹹齋築選鏇選) = 鏇獵醖壓鏇憲餘膚廠觸顧鹽鏇餘構夢淵餘蓋廠 (廠鹹築繭製觸範獵餘獵 ) 更多
NCT02040012 (Pubmed \| Diabetes Obes Metab) 人工标引	临床1/2期	2型糖尿病 \| 超重 \| 肥胖	44	AZP-531	鹽壓醖顧艱壓膚獵繭選(鏇衊鹹顧鬱築遞蓋襯襯) = 膚糧餘構鹹製夢襯衊糧鑰艱製構壓襯壓獵壓網 (顧憲網簾築範鹹艱憲艱 ) 更多	积极	2016-09-01
				Placebo	鹽壓醖顧艱壓膚獵繭選(鏇衊鹹顧鬱築遞蓋襯襯) = 蓋鑰網襯膚鹽願築壓膚鑰艱製構壓襯壓獵壓網 (顧憲網簾築範鹹艱憲艱 ) 更多