Danuglipron

作者：唐立成 美工：何国红 罗真真 排版：马超 ▶ 引言 过去三年，GLP-1类药物彻底改写了全球肥胖治疗的格局。从司美格鲁肽的现象级爆火，到替尔泊肽刷新减重幅度纪录，再到三靶点激动剂冲击30%减重天花板，肠促胰素类药物用一己之力，把肥胖从“生活方式问题”推进到了“精准药物治疗”的时代。 2025年礼来替尔泊肽全年销售额达365亿美元。超过诺和诺德司美格鲁肽361亿美元的销售额，远超默沙东K药的销售额，正式终结了K药的“药王”时代。“药王”的更迭也预示生物药正逐步的从肿瘤、自免等重大疾病向减肥增肌、抗衰等大健康领域迈进，并已经成为新世代的风口浪尖。 ▲ 图1 美国肠促胰素类似物市场 但热潮之下，行业的共识也越来越清晰：GLP-1只是起点，远非终点。 胃肠道副作用始终伴随、瘦体重 (肌肉) 大量流失、停药后体重反弹……这些未被满足的临床痛点，恰恰是下一代抗肥胖药物的机会窗口。 本文基于2026年发表于Pharmaceuticals的最新顶刊综述，系统梳理超越肠促胰素的13个新兴抗肥胖靶点、数十条在研管线，从机制、临床数据到行业趋势，完整拆解抗肥胖药物的新兴赛道。 一、复盘与瓶颈：GLP-1时代的三次进化与天花板 在谈论新兴靶点之前，我们先快速复盘当前主流药物的进化路径——正是因为摸到了天花板，新靶点才有了崛起的土壤。 01 现有药物的三次进化，一路冲向疗效上限 过去五年，GLP-1类药物沿着三条主线持续迭代，本质都是在GLP-1的骨架上做“加法”： ★ 长效化：从每周1次到每月1次 通过脂肪酸修饰、抗体偶联等技术延长半衰期，提升患者依从性。代表如Amgen的MariTide (GLP-1R激动+GIPR拮抗)，每月1次注射，52周最高减重16.2%；辉瑞的PF-06882961，月制剂28周安慰剂校正减重12.3%。超长效剂型正在把肥胖治疗变成“慢病管理式”的长期用药。 ★ 口服化：从注射到吞服，打破肽类药物的口服魔咒 口服司美格鲁肽2025年获批肥胖适应症，首次实现了肽类GLP-1的口服给药；而礼来的orforglipron作为首款非肽类口服GLP-1激动剂获批，更是证明了小分子也能激活肽类受体。口服化的本质，是大幅降低用药门槛，覆盖更广泛的人群。 ★ 多靶点化：从单靶到双靶再到三靶，减重幅度持续冲高 从单靶点GLP-1 (司美格鲁肽68周减重14.9%)，到GLP-1/GIP双靶点 (替尔泊肽72周减重20.9%)，再到GLP-1/GIP/胰高血糖素三靶点 (瑞他鲁肽68周最高减重28.7%)，多受体激动剂一次次刷新减重上限。国内的mazdutide (玛仕度肽) 也已获批，成为首款GLP-1/胰高血糖素双激动剂。 02 绕不开的三大天花板，定义了下一代药物的方向 无论怎么迭代，GLP-1类药物始终有三个难以突破的核心痛点： ① 胃肠道副作用难以根除：恶心、呕吐、腹泻的发生率始终在20%-30%区间，是患者停药的首要原因； ② 瘦体重流失显著：减重中约20%-30%来自肌肉等瘦体重，不仅降低基础代谢，还会影响身体机能，对老年、糖尿病人群风险更高； ③ 停药后反弹与应答差异：停药后体重回升普遍存在，且部分人群对GLP-1应答不佳。 这些痛点，正是新兴抗肥胖靶点的核心破局点。因此接下来药企研发新兴抗肥胖药物的四大方向，正在从不同维度重塑肥胖治疗的逻辑。 ▲ 图2 介导GLP-1疗法益处的直接和间接机制 二、四大方向，13个新兴靶点重塑肥胖治疗 01 方向一：原材料方案中枢食欲调控——直击“想吃”的根源，与GLP-1机制互补 这类靶点的核心逻辑是：从不同于GLP-1的通路调控大脑摄食中枢，既能单药减重，也能和GLP-1联用叠加疗效，进一步拉升减重幅度。 1. 胰淀素受体 (Amylin Receptor)：最成熟的下一代联用方案 胰淀素是和胰岛素共同分泌的多肽激素，通过延缓胃排空、抑制胰高血糖素、中枢降低食欲实现减重，是目前进展最快的非肠促胰素靶点。 • 明星管线CagriSema (卡格列汀+司美格鲁肽)：诺和诺德的联用方案，III期临床在肥胖人群中实现20.4%的减重幅度，和替尔泊肽相当，已提交FDA上市申请，大概率成为下一个获批的新机制肥胖药物。 • 单分子双激动剂Amycretin：诺和诺德自研的GLP-1/胰淀素双激动剂，36周单药减重最高达24.3%，效果超越现有双靶药物，潜力极强。 • 其他管线：礼来的eloralintide (48周减重17.5%)、罗氏的petrelintide、艾伯维的ABBV-295均处于临床阶段，赛道竞争激烈。 行业定位：最有可能快速落地的“GLP-1+”联用方案，是近期最具确定性的新赛道。 2. 黑皮质素4受体 (MC4R)：从罕见病走向大众肥胖 MC4R是中枢能量稳态调控的核心靶点，其功能缺失突变会直接导致早发重度肥胖。 • 代表药物司美诺肽 (Setmelanotide) 早已获批用于遗传性肥胖，减重幅度可达12.5%-25.6%； • 当前研发重点是口服剂型拓展普适性肥胖：Rhythm的口服MC4R激动剂bivamelagonII期已取得阳性结果，同时还有企业在测试MC4R激动剂与替尔泊肽联用的效果。 亮点：机制明确，从罕见病切入大众市场，口服化是核心突破点。 3. 生长激素释放肽受体 (Ghrelin Receptor)：拮抗“饥饿激素”，从源头降食欲 Ghrelin是人体核心的“饥饿激素”，拮抗其受体就能直接降低饥饿感，和GLP-1的“促饱腹”形成完美的双向互补。 • 内源性拮抗剂LEAP2的I期临床显示：静脉输注可使肥胖男性自由进食量减少12%，同时还能改善餐后血糖； • 长效化LEAP2类似物已完成临床前验证，与司美格鲁肽联用显示出叠加减重效果。 4. 肽YY (PYY/Y2R)：疗效明确，耐受性是核心关卡 PYY是肠道L细胞分泌的饱腹激素，作用于下丘脑Y2受体抑制食欲。临床前数据显示，长效PYY类似物与司美格鲁肽联用，不仅减重效果叠加，还能维持瘦体重。 • 但诺和诺德的PYY1875在II期临床中遭遇挫折：虽然联用司美格鲁肽有额外减重收益，但胃肠道耐受性不佳，开发已暂停。 这也提示：中枢食欲类靶点普遍面临胃肠道副作用的共性难题，如何平衡疗效与安全性是关键。 02 方向二：肌肉保护型靶点——减重不掉肌，定义“高质量减重” 这是当前抗肥胖研发最火热的赛道——解决GLP-1“掉肌肉”的核心痛点，把肥胖治疗从“看体重数字”推向“看体成分质量”。 1. II型激活素受体 (ActRIIA/B) 阻断：肌肉保护的“金标准” 通过阻断ActRIIA/B通路抑制肌肉降解，是目前验证最充分的肌肉保护方案。 代表药物Bimagrumab的II期临床数据极具说服力： • 单用Bimagrumab 48周减重9.7%； • 单用司美格鲁肽减重14.8%，同时瘦体重下降7.9%； • 两者联用减重20.2%，瘦体重仅下降2.6%，几乎实现了“纯减脂”的高质量减重。 目前III期临床正在推进，一旦成功，将彻底改写肥胖治疗的评价标准。 2. GDF8 (肌抑素)+Activin A双抗体：更精准的肌肉调控 Bimagrumab是广谱阻断受体，而Regeneron的思路是精准阻断通路里的两个核心配体——GDF8（肌抑素）和Activin A。 • I期临床显示，双抗体联用可显著增加肌肉量、减少脂肪量，效果优于单抗体； • II期临床正在验证其与司美格鲁肽联用的效果，核心优势是精准靶向，副作用更可控。 3. 促肾上腺皮质激素释放激素受体2 (CRHR2)：单药实现 “减重+增肌” 和前两者需要联用GLP-1不同，CRHR2激动剂本身就兼具双重价值：外周作用于骨骼肌促进肌肥大，同时通过迷走神经抑制食欲。 • 代表管线HM17321 (韩美制药) 的食蟹猴实验数据亮眼：12周显著减重的同时，瘦体重增加了8%； • 目前I期临床正在美国进行，是极少数有望单药实现“减脂增肌”的靶点，想象空间巨大。 4. GRK偏向性β2肾上腺素受体激动剂：口服小分子，保肌又降糖 传统β2受体激动剂因心脏副作用无法用于代谢疾病，而新一代GRK偏向性激动剂只激活GRK通路，避开了G蛋白介导的心脏不良反应。 • 代表化合物Compound 15在动物实验中可逆转GLP-1诱导的肌肉萎缩，同时促进肌肉葡萄糖摄取； • I期临床显示安全性良好，口服给药的方式也极具依从性优势。 03 方向三：代谢改善型靶点——减重+治肝病，一药覆盖双适应症 这类靶点主打“代谢综合获益”，核心针对肥胖最高发的并发症——代谢相关脂肪性肝炎 (MASH)，实现“减重+治病”双重价值，也是大厂并购的热门赛道。 1. 成纤维细胞生长因子21 (FGF21)：MASH赛道的核心玩家 FGF21主要由肝脏分泌，能促进脂肪酸氧化、改善胰岛素敏感性、强效降低肝脏脂肪，是MASH治疗的核心靶点，减重是其附加收益。 • 赛道两大龙头均已被大厂收入囊中：诺和诺德收购Akero的efruxifermin，罗氏收购89bio的pegozafermin，两者均处于MASH III期临床； • 单药减重幅度有限（约2-3kg），但与GLP-1联用是明确趋势——既能强化减重效果，又能带来肝脏获益，是肥胖合并MASH人群的理想方案。 2. INHBE基因 (siRNA 疗法)：基因层面优化体脂分布 INHBE基因的功能缺失突变，被基因组学研究证实与良性体脂分布、糖尿病保护相关。其编码的抑制素βE会促进脂肪储存，阻断它就能优化脂肪分布。 • Arrowhead的ARO-INHBE采用siRNA技术，长效沉默肝脏INHBE表达，目前处于I/IIa期临床； • 这类基因疗法有望实现季度甚至半年一次给药，依从性远超肽类药物。 3. A3腺苷受体 (A3AR)：口服小分子，抗炎+减重双获益 A3腺苷受体激活可上调脂联素、改善胰岛素抵抗、减轻肝脏炎症。 • 代表药物Namodenoson是口服小分子，II期临床显示可改善NAFLD，同时带来轻度减重； • 优势是安全性好、口服便捷，适合长期代谢管理。 04 方向四：前沿探索：从临床前走向临床的潜力机制 除了上述进入临床的靶点，还有一批基于基因组学和新机制发现的潜力方向，代表着更远期的未来： • GLP-1/CCK1双激动剂：CCK1受体激活可通过迷走神经抑制食欲、促进胰岛素分泌，和GLP-1联用效果叠加；但需警惕胰腺炎风险，目前处于临床前阶段； • GDF15/GFRAL通路：GDF15通过大脑GFRAL受体抑制食欲、增加能量消耗，但单药临床减重效果有限；国内企业开发的GLP-1/GDF15融合蛋白在动物实验中效果优于司美格鲁肽，有待临床验证； • 基因组学新靶点：GPR75、GPR45、神经激肽2受体、嗅觉受体Or5v1等，均被全基因组关联研究证实与肥胖保护相关，是早期研发的热门方向。 ▲ 图3 现有抗肥胖药物靶点一览 三、2025-2026全球抗肥胖药物最新临床进展 从靶点机制到临床数据，是衡量抗肥胖药物商业价值与临床潜力的核心标尺。结合2025-2026年最新披露的临床试验结果，我们将全球主流在研管线按靶点赛道分为两大类，整理成两份全景对照表：一份聚焦GLP-1、GIP与胰高血糖素受体轴的成熟及迭代药物，完整呈现肠促胰素赛道的最新进化；另一份覆盖肠促胰素以外的新兴靶点候选分子，直观展示新机制的临床转化进度。表格中同步收录了各药物的给药方案、研发阶段、核心减重幅度与不良反应特征，清晰勾勒出当前抗肥胖赛道的临床进度梯队与疗效天花板。 ▲ 表1 针对GLP-1、GIP和胰高血糖素受体的 抗肥胖药物治疗临床进展 ▲ 表2 新兴靶点的潜在抗肥胖候选药物临床进展 四、抗肥胖药物的下一个十年 从无药可用，到GLP-1横空出世，再到今天百花齐放的新兴靶点，肥胖治疗的进化速度远超行业预期。 GLP-1打开了肥胖药物治疗的大门，但它远不是终点。胃肠道副作用、肌肉流失、停药反弹……这些未被满足的需求，正是下一代药物的成长空间。而“高质量减重”这个新标准，也正在重新定义这个百亿级赛道的胜负手。 下一个现象级的抗肥胖药物，大概率就诞生在肌肉保护、多机制联用的赛道上。 梳理完所有靶点和管线，我们可以清晰看到行业演化的四条核心主线： 1. 研发主线分化：“冲减重幅度”和“提减重质量”并行 ① 一条主线继续做多靶点、做联用，冲击30%甚至更高的减重幅度，面向重度肥胖人群； ② 另一条主线聚焦肌肉保护、降低副作用，主打“高质量减重”，面向更广泛的轻中度肥胖、合并代谢疾病的人群。后者的市场空间或许更广阔。 2. 适应症从“单纯减肥”向“代谢全谱疾病”扩张 抗肥胖药物早已不只是“减肥”。当前GLP-1类药物已拓展到心血管疾病、阻塞性睡眠呼吸暂停，而新兴靶点进一步覆盖MASH、慢性肾病、肌肉衰减症等肥胖相关并发症。未来的肥胖药物，本质是“代谢系统疾病的基础用药”。 3. 给药方式持续迭代：长效化、口服化、无创化 从周制剂到月制剂，从注射到口服肽类，再到口服小分子、siRNA长效给药，降低用药门槛始终是行业进化的核心方向。谁能让患者更方便、更愿意长期用药，谁就能占领更大的市场。 4. 联合用药成主流：GLP-1成为“基础骨架”，新靶点做“加法” 未来大概率不会出现单一靶点完全替代GLP-1的局面。更可能的格局是：GLP-1类药物成为肥胖治疗的基础用药，而肌肉保护、肝脏获益、额外减重等需求，通过联用其他靶点药物来满足。“GLP-1+X”将是下一代肥胖治疗的主流方案。 五、三优生物CPO如何助力创新药企抢占先机 面对抗肥胖药物百花齐放的新靶点浪潮，创新药企的核心竞争早已不只是分子本身的疗效，更是早期布局速度、风险控制能力和管线搭建效率。从零搭建药物发现平台、逐个靶点验证，不仅周期漫长，早期研发失败风险也高度集中。三优生物独创的CPO（协同型项目合作）模式，正是为创新药企快速抢占下一代肥胖药物赛道提供了全新解法。 1. 全阶段项目资产，跳过早期高风险环节 基于智能超万亿分子库 (AI-STAL) 和三优智能新药加速器 (SAI-DA)，三优生物内部已孵化225个自研项目，覆盖肿瘤、自身免疫、代谢等核心领域，项目阶段从Binder、Pre-PCC、PCC到IND全覆盖。针对抗肥胖新兴靶点，药企既可以选择创新探索模式从零启动定制化研发，也可以通过开发嫁接模式直接接手已完成阶段性验证的成熟项目资产——跳过风险最高的早期分子发现与验证环节，直接站在已有数据基础上推进管线，大幅压缩研发周期。 2. 风险共担+灵活出资，适配不同管线策略 不同于传统CRO全额外包的固定成本模式，三优CPO支持从“三优全资”到“合作方全资”的梯度出资方案，知识产权与商业权益按投入比例共享。 • 对于GDF15、CRHR2这类早期高风险的前沿靶点，药企可选择低首付的共同开发模式，以少量投入锁定优质资产，风险共担、收益共享； • 对于GLP-1、GIP这类确定性较高的成熟靶点，也可选择全额投入掌握全部权益，快速补全管线拼图。 截至2026年6月，该模式已累计落地108个合作项目，服务68家国内外客户，其中12个项目成功推进至临床阶段，3个进入临床III期。 3. 全链条交付能力，让靶点到临床路径高度可控 三优生物基于智能超万亿分子库 (AI-STAL) 和三优智能新药加速器 (SAI-DA)，可一站式解决创新药源头分子产生问题及一站式解决创新药各类研发问题。从靶点验证、抗体发现、成药性评估到细胞株构建、工艺开发、IND申报，CPO模式覆盖14项全流程研发基准工作，配套明确的里程碑定价与转让分成规则。对于抗肥胖新药项目，从靶点启动到PCC最快6-9个月即可交付，从PCC推进至IND也仅需12-16个月，研发路径与成本高度可控。成熟稳定的交付体系，让药企无需从零搭建全链条研发能力，就能快速完成下一代减重管线的布局。 ▲ 三优生物AI-STAL&SAI-DA双引擎 在抗肥胖药物从“GLP-1时代”迈向“多靶点百花齐放”的关键节点，更快锁定优质靶点、更低风险推进管线，就是药企的核心竞争力。三优生物CPO模式通过“平台+项目+风险共担”的创新合作逻辑，让创新药企能以更轻的资产、更快的速度、更低的风险切入下一代减重赛道，在新一轮行业竞争中抢占先机。 In-Depth Analysis | 2026 Landscape of Emerging Anti-Obesity Targets: Solving the Muscle Loss Dilemma in Weight Loss with Sanyou Bio’s CPO Model ▶ Introduction Over the past three years, GLP-1-based therapies have fundamentally reshaped the global obesity treatment landscape. From the phenomenal success of semaglutide, to tirzepatide setting new benchmarks for weight loss, and now triple agonists pushing toward the 30% weight-loss ceiling, incretin-based therapies have single-handedly moved obesity treatment from a “lifestyle issue” into the era of “precision pharmacotherapy.” In 2025, Eli Lilly’s tirzepatide generated annual sales of $36.5 billion, surpassing Novo Nordisk’s semaglutide sales of $36.1 billion and significantly exceeding the sales of Merck’s Keytruda, officially bringing the “King of Drugs” era of Keytruda to an end. The changing of the pharmaceutical sales crown also signals a broader shift: biologics are increasingly expanding beyond major disease areas such as oncology and autoimmune disorders into high-growth health sectors including weight management, muscle preservation and anti-aging—making these areas the new frontier of biopharmaceutical innovation. ▲ Figure 1. U.S. incretin analog market Yet beneath the hype, one industry consensus is becoming increasingly clear: GLP-1 is only the beginning, not the end. Gastrointestinal side effects, substantial loss of lean body mass (including muscle), and weight regain after treatment discontinuation remain persistent challenges. These unmet clinical needs represent the opportunity window for the next generation of anti-obesity therapies. This article is based on a recent review published in Pharmaceuticals in 2026. It systematically examines 13 emerging anti-obesity targets and dozens of development programs beyond the incretin class, providing a comprehensive analysis of emerging therapeutic approaches from mechanisms of action and clinical data to broader industry trends. I. Looking Back and Looking Ahead: Three Waves of GLP-1 Evolution and the Emerging Ceiling Before exploring emerging targets, let us first take a quick look at the evolution of today’s leading therapies. It is precisely because existing approaches are approaching their limits that new targets are gaining momentum. 01 Three Waves of Innovation: Continuously Pushing the Efficacy Ceiling Over the past five years, GLP-1-based therapies have evolved along three major pathways—essentially adding new capabilities onto the GLP-1 backbone: ★ Longer-Acting Formulations: From Weekly to Monthly Dosing Technologies such as fatty acid acylation and antibody conjugation have been used to extend half-life and improve patient adherence. A representative example is Amgen’s MariTide (GLP-1R agonist + GIPR antagonist), administered once monthly and achieving up to 16.2% weight loss at Week 52. Pfizer’s PF-06882961 achieved 12.3% placebo-adjusted weight loss at Week 28 with a monthly formulation. Ultra-long-acting formulations are gradually transforming obesity treatment into a chronic-disease-management model requiring long-term therapy. ★ Oral Delivery: From Injection to Oral Administration Oral semaglutide was approved for an obesity indication in 2025, marking the first oral formulation of a peptide GLP-1 therapy for obesity. Eli Lilly’s orforglipron, as the first non-peptide oral GLP-1 receptor agonist, further demonstrated that small molecules can activate receptors traditionally targeted by peptide therapies. At its core, oral delivery dramatically lowers the treatment barrier and has the potential to reach a broader patient population. ★ Multi-Target Therapies: From Single to Dual to Triple Agonism From single-target GLP-1 therapy, with semaglutide achieving 14.9% weight loss at 68 weeks, to dual GLP-1/GIP agonism, with tirzepatide achieving 20.9% weight loss at 72 weeks, and then to triple GLP-1/GIP/glucagon receptor agonism, with retatrutide achieving up to 28.7% weight loss at 68 weeks, multi-receptor agonists have repeatedly raised the bar for weight-loss efficacy. In China, mazdutide has also been approved, becoming the first GLP-1/glucagon dual agonist. 02 Three Unavoidable Ceilings That Will Shape the Next Generation Despite continuous innovation, GLP-1-based therapies continue to face three fundamental challenges: ① Gastrointestinal side effects remain difficult to eliminate Nausea, vomiting and diarrhea continue to occur in approximately 20–30% of patients and remain a leading reason for treatment discontinuation. ② Significant loss of lean body mass Approximately 20–30% of weight lost during treatment may come from lean body mass, including muscle. This can reduce basal metabolic rate and impair physical function, posing particular risks for older adults and people with diabetes. ③ Weight regain after discontinuation and variable treatment response Weight regain after treatment discontinuation is common, while some patients respond poorly to GLP-1-based therapies. These unmet needs are precisely where emerging anti-obesity targets can create breakthroughs. As a result, drug developers are increasingly pursuing four major directions that could reshape the treatment paradigm from different angles. ▲ Figure 2. Direct and indirect mechanisms mediating the benefits of GLP-1-based therapies II. Four Strategic Directions and 13 Emerging Targets Reshaping Obesity Treatment 01 Direction 1: Central Appetite Regulation — Targeting the Root Cause of “Wanting to Eat” These targets regulate appetite centers in the brain through pathways distinct from GLP-1. They may work as monotherapies while also complementing GLP-1 therapies, potentially delivering additive or synergistic weight-loss effects. 1. Amylin Receptor: The Most Advanced Next-Generation Combination Strategy Amylin is a gut-derived peptide co-secreted with insulin. It promotes weight loss by delaying gastric emptying, suppressing glucagon secretion and reducing appetite through central mechanisms. It is currently one of the fastest-advancing non-incretin targets. Leading programs CagriSema (cagrilintide + semaglutide): Novo Nordisk’s combination therapy achieved 20.4% weight loss in people with obesity in Phase III trials, comparable to tirzepatide. A U.S. FDA filing has been submitted, making it a strong candidate to become one of the next approved obesity therapies based on a novel mechanism. Amycretin: Novo Nordisk’s internally developed GLP-1/amylin dual agonist achieved up to 24.3% weight loss after 36 weeks as a monotherapy, outperforming existing dual-target therapies and demonstrating significant potential. Other programs: Lilly’s eloralintide achieved 17.5% weight loss at 48 weeks. Roche’s petrelintide and AbbVie’s ABBV-295 are also in clinical development, making this a highly competitive field. Industry positioning: Among the most likely “GLP-1+” combination strategies to reach the market rapidly, this is one of the most clearly defined emerging opportunities in the near term. 2. Melanocortin-4 Receptor (MC4R): From Rare Diseases to Broad Obesity Applications MC4R is a central regulator of energy homeostasis. Loss-of-function mutations in MC4R can directly cause early-onset severe obesity. Setmelanotide has already been approved for monogenic obesity, with weight loss ranging from 12.5% to 25.6%. Current development efforts are focused on expanding MC4R agonists into broader obesity populations through oral formulations. Rhythm’s oral MC4R agonist bivamelagon has generated positive Phase II results, while other companies are evaluating combinations of MC4R agonists with tirzepatide. Key opportunity: A well-validated mechanism moving from rare diseases toward broader obesity indications, with oral delivery representing a major potential breakthrough. 3. Ghrelin Receptor: Blocking the “Hunger Hormone” at Its Source Ghrelin is a key endogenous “hunger hormone.” Blocking its receptor can directly reduce hunger and therefore offers a potentially complementary mechanism to GLP-1’s appetite-suppressing and satiety-enhancing effects. Phase I studies of the endogenous antagonist LEAP2 showed that intravenous infusion reduced ad libitum food intake by 12% in men with obesity while also improving postprandial glucose levels. Long-acting LEAP2 analogs have completed preclinical validation and demonstrated additive weight-loss effects when combined with semaglutide. 4. Peptide YY (PYY/Y2R): Efficacy Is Established, but Tolerability Is the Key Hurdle PYY is a satiety hormone secreted by intestinal L cells. It suppresses appetite by acting on Y2 receptors in the hypothalamus. Preclinical studies suggest that long-acting PYY analogs combined with semaglutide can provide additive weight loss while helping preserve lean body mass. However, Novo Nordisk’s PYY1875 encountered setbacks in Phase II development. Although the combination with semaglutide provided additional weight-loss benefits, gastrointestinal tolerability was poor and development was discontinued. This highlights a common challenge for central appetite-regulating targets: how to balance efficacy with tolerability and safety remains critical. 02 Direction 2: Muscle-Preserving Targets — Weight Loss Without Muscle Loss This is currently one of the hottest areas in anti-obesity drug development. The goal is to address one of the most significant limitations of GLP-1 therapies—muscle loss—and shift obesity treatment from simply monitoring body weight to evaluating body-composition quality. 1. ActRIIA/B Blockade: The “Gold Standard” for Muscle Preservation Blocking the ActRIIA/B pathway suppresses muscle protein degradation and represents one of the most extensively validated approaches to muscle preservation. The Phase II clinical data for bimagrumab are particularly compelling: Bimagrumab monotherapy achieved 9.7% weight loss at 48 weeks. Semaglutide monotherapy achieved 14.8% weight loss, accompanied by a 7.9% reduction in lean body mass. The combination achieved 20.2% weight loss, while lean body mass decreased by only 2.6%—approaching a “fat-loss-only” high-quality weight-loss profile. A Phase III trial is currently underway. If successful, this approach could fundamentally redefine the standards used to evaluate obesity therapies. 2. GDF8 (Myostatin) + Activin A Bispecific Antibody: More Precise Muscle Regulation While bimagrumab broadly blocks the receptor, Regeneron is pursuing a more targeted approach by simultaneously blocking two key ligands in the pathway: GDF8 (myostatin) and Activin A. Phase I studies showed that the bispecific antibody could significantly increase muscle mass while reducing fat mass, with greater effects than single-antibody approaches. Phase II development is evaluating its combination with semaglutide, with the potential advantage of more precise pathway modulation and improved control of adverse effects. 3. Corticotropin-Releasing Hormone Receptor 2 (CRHR2): “Weight Loss + Muscle Gain” as a Monotherapy Unlike the approaches above, which are designed to be combined with GLP-1 therapies, CRHR2 agonists may provide dual benefits as monotherapies. Peripherally, they act on skeletal muscle to promote muscle hypertrophy, while also suppressing appetite through the vagus nerve. The preclinical data for HM17321, developed by Hanmi Pharmaceutical, are particularly encouraging: in cynomolgus monkeys, 12 weeks of treatment produced significant weight loss while increasing lean body mass by 8%. The program is currently in Phase I clinical development in the United States and represents one of the few targets with the potential to deliver fat loss and muscle gain as a monotherapy. 4. GRK-Biased β2-Adrenergic Receptor Agonists: Oral Small Molecules for Muscle Preservation and Glucose Control Traditional β2-adrenergic receptor agonists have not been suitable for metabolic diseases because of cardiovascular side effects. Next-generation GRK-biased agonists selectively activate the GRK pathway while avoiding G-protein-mediated cardiac adverse effects. In animal studies, Compound 15 reversed GLP-1-induced muscle atrophy while promoting glucose uptake in muscle. Phase I studies demonstrated a favorable safety profile, while oral administration provides a significant adherence advantage. 03 Direction 3: Metabolic-Health Targets — Weight Loss Plus Disease Modification These targets focus on broader metabolic benefits, particularly metabolic dysfunction-associated steatohepatitis (MASH), one of the most common obesity-related complications. The goal is to deliver dual value—weight management plus disease treatment—making this one of the most attractive areas for major-pharma investment and M&A activity. 1. Fibroblast Growth Factor 21 (FGF21): A Key Player in the MASH Field FGF21 is primarily secreted by the liver. It promotes fatty-acid oxidation, improves insulin sensitivity and strongly reduces hepatic fat accumulation. It is therefore a key target in MASH treatment, with weight loss representing an additional benefit. Two leading programs have already been acquired by major pharmaceutical companies: Novo Nordisk acquired Akero’s efruxifermin, while Roche acquired 89bio’s pegozafermin. Both programs are in Phase III development for MASH. Weight loss with monotherapy is relatively limited, at approximately 2–3 kg. However, combining FGF21 therapies with GLP-1 is a clear emerging trend, with the potential to enhance weight loss while providing additional liver benefits for patients with obesity and MASH. 2. INHBE Gene — Optimizing Body-Fat Distribution at the Genetic Level Loss-of-function mutations in INHBE have been associated through genomic studies with favorable fat distribution and protection against diabetes. INHBE encodes inhibin beta E, which promotes fat storage. Blocking this pathway may therefore help optimize fat distribution. Arrowhead’s ARO-INHBEuses siRNA technology to achieve long-acting silencing of hepatic INHBE expression and is currently in Phase I/IIa development. Such gene-silencing therapies could potentially enable quarterly or even semiannual dosing, offering a significant adherence advantage over peptide-based therapies. 3. A3 Adenosine Receptor (A3AR): Oral Small Molecules for Anti-Inflammatory and Weight-Loss Benefits Activation of the A3 adenosine receptor can increase adiponectin levels, improve insulin resistance and reduce hepatic inflammation. The representative drug namodenosonis an oral small molecule. Phase II clinical studies demonstrated improvements in NAFLD, accompanied by modest weight loss. Its key advantages include a favorable safety profile and convenient oral administration, making it potentially suitable for long-term metabolic disease management. 04 Direction 4: Frontier Exploration — Emerging Mechanisms Moving Toward the Clinic Beyond the targets already entering clinical development, a number of emerging mechanisms based on genomics and novel biological insights represent longer-term opportunities: GLP-1/CCK1 dual agonists: Activation of CCK1 receptors may suppress appetite through vagal pathways and promote insulin secretion, potentially producing additive effects when combined with GLP-1. However, the risk of pancreatitis requires close attention. These programs remain at the preclinical stage. GDF15/GFRAL pathway: GDF15 suppresses appetite and increases energy expenditure through the brain’s GFRAL receptor. However, clinical weight loss with monotherapy has been limited. GLP-1/GDF15 fusion proteins developed by Chinese companies have shown superior efficacy to semaglutide in animal studies, although clinical validation remains necessary. Emerging genomic targets: GPR75, GPR45, neurokinin-2 receptor and the olfactory receptor Or5v1 have all been linked to protection against obesity through genome-wide association studies and are becoming promising targets for early-stage drug discovery. ▲ Figure 3. Overview of current anti-obesity drug targets III. Global Clinical Development of Anti-Obesity Drugs in 2025–2026 From target biology to clinical data, clinical development progress is a critical benchmark for assessing both the commercial value and therapeutic potential of anti-obesity drugs. Based on clinical trial results disclosed in 2025–2026, leading global development programs can broadly be divided into two categories. The first focuses on established and next-generation therapies targeting the GLP-1, GIP and glucagon receptor axes, providing a comprehensive view of the latest evolution of the incretin field. The second covers candidate molecules targeting emerging mechanisms beyond incretin pathways, illustrating the clinical translation progress of novel therapeutic approaches. The accompanying tables summarize key characteristics including dosing regimens, development stages, weight-loss efficacy and adverse-event profiles, providing a clear picture of the current clinical development landscape and efficacy ceilings across the anti-obesity field. ▲ Table 1. Clinical development of anti-obesity therapies targeting GLP-1, GIP and/or glucagon receptors ▲ Table 2. Clinical development of potential anti-obesity candidates targeting emerging mechanisms IV. The Next Decade of Anti-Obesity Drug Development From an era with virtually no effective pharmacological options, to the breakthrough of GLP-1 therapies, and now to a rapidly expanding landscape of emerging targets, the evolution of obesity treatment has progressed far faster than the industry anticipated. GLP-1 opened the door to modern pharmacological treatment of obesity, but it is far from the endpoint. Gastrointestinal side effects, muscle loss and weight regain after treatment discontinuation represent significant unmet needs—and therefore significant opportunities for the next generation of therapies. At the same time, “high-quality weight loss” is emerging as a new benchmark that could redefine the competitive landscape of this multibillion-dollar market. The next blockbuster anti-obesity therapy is highly likely to emerge from areas such as muscle preservation and multi-mechanism combination therapies. After reviewing the major targets and development programs, four core trends in industry evolution become particularly clear: 1. R&D Strategies Are Splitting: Maximizing Weight Loss vs. Improving Weight-Loss Quality ① One pathway continues to pursue greater weight-loss efficacy. Developers are combining multiple targets and mechanisms to push weight loss toward 30% or even higher, primarily targeting patients with severe obesity. ② The other pathway focuses on muscle preservation and reducing adverse effects. This approach emphasizes “high-quality weight loss” and targets the much broader population of people with mild-to-moderate obesity and obesity-related metabolic diseases. Its market opportunity may ultimately be even larger. 2. Indications Are Expanding from “Weight Loss” to the Full Spectrum of Metabolic Diseases Anti-obesity drugs are no longer simply “weight-loss drugs.” GLP-1 therapies have already expanded into cardiovascular disease and obstructive sleep apnea, while emerging targets are extending into obesity-associated conditions including MASH, chronic kidney disease and muscle wasting. The obesity therapies of the future will essentially become foundational treatments for metabolic-system disorders. 3. Drug Delivery Continues to Evolve: Longer-Acting, Oral and Non-Invasive From weekly to monthly formulations, from injectable to oral peptides, and from oral small molecules to long-acting siRNA therapies, reducing the treatment burden has remained a central driver of industry evolution. Ultimately, the companies that can make long-term treatment more convenient and acceptable for patients will be best positioned to capture a larger share of the market. 4. Combination Therapy Will Become the Norm: GLP-1 as the “Backbone,” Emerging Targets as the “Add-On” A scenario in which a single target completely replaces GLP-1 is unlikely. A more probable future is that GLP-1-based therapies become the foundational treatment for obesity, while additional needs—including muscle preservation, liver benefits and further weight loss—are addressed by combining GLP-1 with therapies targeting other pathways. “GLP-1 + X” is likely to become the dominant model for next-generation obesity treatment. V. How Sanyou Bio’s CPO Model Can Help Innovative Biopharma Companies Capture the Opportunity As the anti-obesity field enters an era of rapidly expanding targets and mechanisms, the core competitive advantage of innovative biopharma companies is no longer simply the efficacy of an individual molecule. It increasingly depends on the speed of early-stage positioning, risk-management capabilities and pipeline-building efficiency. Building a drug discovery platform from scratch and validating each target individually can be time-consuming, while concentrating substantial risk in the earliest stages of R&D. Sanyou Bio’s proprietary CPO (Cooperative Project Organization) model provides an alternative approach for innovative biopharma companies seeking to enter the next generation of obesity therapeutics quickly. 1. Ready-to-Advance Assets Across Development Stages — Bypassing High-Risk Early Discovery Powered by the AI-STAL and the SAI-DA, Sanyou Bio has internally incubated 225 proprietary programs spanning key therapeutic areas including oncology, autoimmune diseases and metabolic disorders. These programs cover the full spectrum from Binder and Pre-PCC to PCC and IND stages. For emerging anti-obesity targets, biopharma companies can either: Choose an innovative exploration model and initiate customized R&D from the ground up; or adopt a development asset bridging model and directly take over mature project assets that have already undergone stage-specific validation. By bypassing the highest-risk stages of early molecular discovery and validation, partners can advance their pipelines on the foundation of existing data, significantly shortening development timelines. 2. Shared Risk + Flexible Capital Deployment to Fit Different Pipeline Strategies Unlike the fixed-cost, full-outsourcing model traditionally associated with CROs, Sanyou Bio’s CPO model supports a flexible range of investment structures—from Sanyou Bio-funded projects to partner-funded projects, with intellectual property and commercial interests shared according to the respective investment contributions. For early-stage, high-risk frontier targets such as GDF15 and CRHR2, companies can opt for a low-upfront-cost co-development model, securing high-quality assets with limited initial investment while sharing both risks and potential returns. For more established targets such as GLP-1 and GIP, companies can choose to fund the program fully and retain the corresponding rights, enabling them to rapidly complete their pipeline portfolios. As of June 2026, this model has been implemented in 108 collaborative projects, serving 68 domestic and international clients. Among them, 12 programs have successfully advanced to clinical stages, with 3 entering Phase III clinical trials. 3. End-to-End Delivery Capabilities for a Highly Controllable Path from Target to Clinical Development Sanyou Bio operates two core engines: the AI-Super trillion antibody/molecule libraries（AI-STAL） and the Sanyou AI-Drug Accelerator (SAI-DA). Together, they provide integrated solutions for both the generation of drug-discovery molecules at the source and the broader range of R&D challenges encountered throughout drug development. From target validation, antibody discovery and developability assessment to cell-line development, process development and IND submission, the CPO model covers 14 standardized R&D activities across the development process, supported by clearly defined milestone-based pricing and transfer/revenue-sharing mechanisms. For anti-obesity programs, projects can reach PCC delivery in as little as 6–9 months from target initiation, while progression from PCC to IND can take only 12–16 months, enabling a highly controllable development timeline and cost structure. With a mature and standardized delivery system, biopharma companies can rapidly build next-generation obesity pipelines without having to establish the entire end-to-end R&D infrastructure from scratch. ▲ Figure 4. Sanyou Bio’s AI-STAL & SAI-DA dual-engine platform At this critical inflection point, as anti-obesity drug development moves from the “GLP-1 era” toward a landscape of multi-target innovation, the ability to identify high-value targets earlier and advance pipelines with lower risk is becoming a key competitive advantage. Through its innovative “Platform + Projects + Risk Sharing” collaboration model, Sanyou Bio’s CPO approach enables innovative biopharma companies to enter the next-generation obesity market with lighter asset requirements, greater speed and lower risk, helping them secure a first-mover advantage in the next wave of competition. 推荐阅读 Peptide-Generator：开启AI多肽从头生成新路径 从180天到14天: 如何重新定义创新药研发速度 AI驱动蛋白质从头设计，加速创新药物发现 兔单抗分子产生系统解决方案 SAI-DA 1.0 | 智优人源化加速器 SAI-DA 1.0 | GEOTA平台 三优CPO为抗衰老生物药研发全程护航 AI-STAL 2.0 | 智能化多肽亲和力成熟解决方案 AI-STAL 2.0 | 全程智能多肽分子产生系统解决方案 Clicklinks | 新药圈你好，我是原创新药创新工场 SAI-DA 1.0 | 创新药你好，我叫智能新药加速器 AI-STAL 2.0 | 做药人你好，我是AI-STAL Click & Go | 结直肠癌的差异化靶点 创新前沿 | OpenClaw化身生物医药智能工匠 Clicklinks | 三优AI-STAL 2.0-14天先导分子发现 浙江大学上海校友会莅临三优生物考察交流 关于三优生物 三优生物是一家以“让天下没有难做的创新药”为使命，致力于透彻解决创新药源头创新问题的生物医药高科技企业。 公司以智能超万亿分子库（AI-STAL）为核心驱动，以智能新药加速器（SAI-DA）为依托，致力于一站式透彻解决创新药各类分子产生和新药研发问题。 公司致力于打造全球顶尖的原创新药创新工场，协同各方共同加速全球创新药的研发进程。 公司总部位于中国上海，在亚洲、北美洲、欧洲等多地建立了业务中心，形成了全球化的业务网络，现有投产及布局的研发及GMP场地20000多平方米。 公司已与全球2000多家药企、生技公司等建立了良好的合作关系，已赋能1200多个新药研发项目；已完成50多个合作研发项目，其中10多个协同研发项目已推至IND及临床研发阶段。 公司已申请170多项发明专利，其中30多项发明专利已获得授权，并获得了国家级高新技术企业、上海市专精特新、ISO9001、ISO27001等10余项资质及体系认证。