Enicepatide

如果把人体细胞比作一座戒备森严的城堡，G蛋白偶联受体（GPCR）就是城墙上数以千计的智能门锁。它广泛存在于人体组织中，并参与人体内多种生理过程。蛋白质、肽类、小分子、光或机械应力等多种化学和物理刺激均可与GPCR结合，促使受体发生构象变化，从而将细胞外信息传递至细胞内的蛋白质。因此GPCR也是药物研发的热门靶点。34% 的FDA 获批药物靶向 GPCRs，覆盖癌症、心血管、代谢、中枢神经系统等疾病。 之所以称作“智能门锁”，是因为不同配体与之结合后，可诱导GPCR内部产生不同的特异性构象，进而带来不一样的临床效应和风险。以GLP-1受体为例，它作为B类GPCR家族的明星成员，自2005年首个激动剂艾塞那肽上市以来，已成为2型糖尿病和肥胖治疗的基石。然而，一个尴尬的现实始终存在：疗效与副作用如同一对连体婴儿——降糖减重的同时，20%-50%的患者经历着恶心呕吐的折磨，约10%-15%因此停药。这就与配体诱导GLP-1受体内部构象发生变化，进而带来cAMP与β-arrestin双通路的博弈高度相关。 信号通路的"双城记"：cAMP与β-arrestin的博弈 细胞膜上的 GLP-1受体被激活后，会同时招募两类关键蛋白：G 蛋白（Ga，包括 Gαs、Gαi、Gαq）和 β-arrestin（βarr），进而激活以下通路[1]： 图源参考文献[1] Ga/cAMP通路：腺苷酸环化酶激活→cAMP↑→PKA/Epac2激活，带来葡萄糖依赖性胰岛素分泌，食欲抑制，β细胞保护等核心获益。 β-arrestin通路：受体磷酸化→网格蛋白内吞→阻断cAMP信号，受体内化、脱敏、降解。以及带来可能的ERK1/2持续激活，触发中枢厌恶信号，带来恶心、呕吐等不良反应，与耐受性和副作用高度相关。 传统"平衡型"激动剂如度拉糖肽、司美格鲁肽等，像同时踩下油门和刹车：激活cAMP产生疗效，但也招募β-arrestin导致受体快速内化、脱敏，并可能与恶心呕吐相关。如何能增强cAMP作用通路，减少β-arrestin的招募，似乎顺理成章地成了增效减副的研发思路。由此，G蛋白（cAMP）偏向性GLP-1受体激动剂登上历史舞台。 肽类偏向性激动剂 已上市的包括礼来的GLP-1/GIP双受体激动剂替尔泊肽和先为达的GLP-1受体激动剂埃诺格鲁肽。 替尔泊肽集合了GIP/GLP-1双重受体激动+cAMP偏向性激动GLP-1受体的特质，在临床上取得了卓越的降糖和减重效果。在2型糖尿病人群进行的SURPASS-2研究显示，与司美格鲁肽1.0mg相比，替尔泊肽15mg糖化及体重降幅均更优（HbA1c降低2.46%，体重降幅12.4kg ）。在超重肥胖人群进行的SURMOUNT-5研究显示，替尔泊肽15mg体重降幅可达20.2%，显著优于司美格鲁肽2.4mg。 埃诺格鲁肽是中国原研的GLP-1受体激动剂，算是该领域cAMP偏向性激动剂的排头兵。它在人GLP-1的基础上，将第8 位丙氨酸替换为缬氨酸，在第30位赖氨酸上经连接子连接C18 脂肪二酸侧链。通过上述改造，在延长半衰期的同时，实现了cAMP偏向性，显著降低β-arrestin 招募率，抑制受体内化，提升了受体亲和力[2]。在2型糖尿病人群进行的ECOH-1/2研究显示，埃诺格鲁肽1.2mg降低HbA1c 达 2.43%，糖化达标率为80.3%。与度拉糖肽1.5mg头对头研究证实，降糖及减重均显著更优。因副反应停药的人群比例，埃诺格鲁肽1.2g组为4%，度拉糖肽组为3%。其针对肥胖人群的3期SLIMMER研究显示，在主要研究终点，埃诺格鲁肽2.4 mg治疗40周减重达13.2%。在关键次要终点，埃诺格鲁肽2.4 mg治疗48周减重达15.4%，92.8%患者达到临床显著减重效果（≥5%）； 其他肽类偏向性激动剂也在研发中，如罗氏的CT388（GLP-1/GIP双受体激动剂）II期减重达22.5%，安全性和耐受性良好。 小分子偏向性激动剂 与肽类药物不同，口服小分子GLP-1受体激动剂通常不是模拟天然GLP-1的结构，而是通过高通量筛选和计算化学设计，找到能够作用于受体不同结合位点（通常是非经典的变构位点）的全新化学实体 。这些小分子像一把独特的“钥匙”，可以从一个意想不到的角度“撬开”受体，诱导出高度偏向性的信号。 图源参考文献[3] 肽类配体（粉色）：结合模式为「双结构域结合」，肽的 C 端与胞外域 ECD 结合，N 端插入跨膜核心触发构象变化，如 GLP-1、Exendin-4、司美格鲁肽等均属此类。 小分子激动剂（左侧放大分子）：小分子GLP-1受体不依赖细胞外结构域，而是深入跨膜结构域（TMD）的非经典正构口袋，带来口服生物利用度、生产可扩展性和复方制剂潜力。这也是口服小分子 GLP-1受体激动剂（如orforglipron）的关键设计思路。 2026年4月FDA批准orforglipron（Foundayo®）上市用于减重治疗。其在肥胖人群进行的ATTAIN-1研究显示，Orforglipron 36mg/日降低体重达11.2%。其在2型糖尿病人群进行的ACHIEVE-3研究显示，Orforglipron 36mg/日降低HbA1c达1.91%，显著优于口服司美格鲁肽14mg。但是其胃肠道负担及停药率未展现相应优势。 其他口服小分子偏向性激动剂均在研发中，如阿斯利康与诚益生物合作的ECC5004已开始布局3期研究。 局限与展望 尽管理论上偏向性激动剂应在疗效和安全性上优于传统平衡型激动剂，但在目前的临床研究中尚未观察到这一点。机制层面看到的β-arrestin 招募显著减少，并未体现在胃肠道副反应及停药率更优上。疗效方面要么与平衡型激动剂相当，要么难以厘清GIP受体激动剂或者剂型不同在其中起的作用。基于现状，以下问题值得思考： 1. 明确β-arrestin通路功能。β-arrestin不是简单的“反派”。它会呈现一定的组织特异性，比如在β细胞可能表现为抑制凋亡的细胞保护作用，在中枢又会呈现厌食、恶心呕吐的副作用；还有一定的时间特异性，短期可能表现为通过ERK1/2磷酸化促进胰岛素分泌，以及介导抗凋亡信号，保护β细胞。长期可能又表现为受体持续内吞和溶酶体降解，表面受体密度下降，信号脱敏等；另外，β-arrestin表达水平和功能状态还受疾病微环境（如炎症、氧化应激、高糖毒性）的影响。比如正常状态时， β-arrestin可以维持稳态，保护细胞。而在病理状态（如2型糖尿病晚期）则可能变成促凋亡或促纤维化的因素。通过单纯抑制β-arrestin是否能带来预期的获益尚未可知。 2. 胃肠道反应的机制根源： 偏向性激动剂并未展示更优的胃肠道耐受性，不禁让我们产生疑问：β-arrestin通路真的是中枢性恶心呕吐的唯一或主要驱动因素吗？ 如果胃肠道副作用主要由直接刺激迷走神经或通过其他非β-arrestin机制（如直接作用于CCK受体交叉反应）引起，那么单纯追求cAMP偏向性可能无法带来预期的耐受性突破。 3. 疗效平台期： 常规认为与受体脱敏有关。即便受体不脱敏，如果cAMP信号过强，是否会触发其他的负反馈调节机制（如磷酸酶激活、下游信号通路饱和），导致平台期出现？ 除了进一步明确相应机制外，未来如有条件还应进一步完善与现有“金标准”比如司美格鲁肽和替尔泊肽的头对头研究。或设计专门验证"偏向性优势"的试验设计（如比较Gs偏向 vs β-arrestin偏向的GLP-1单受体激动剂）来更直观的验证cAMP偏向性激动剂的临床优势。  结语 cAMP偏向性GLP-1受体激动剂的故事，是现代药物研发从"粗线条"走向"微雕"的缩影。偏向性激动剂未来能否在这片星辰大海中稳定航行下去，还需更精确的罗盘和更勇敢的领航员。 参考文献 [1] Jones B. The therapeutic potential of GLP-1 receptor biased agonism. Br J Pharmacol. 2022;179(4):492-510. [2]  Guo W, Xu Z, Zou H, et al. Discovery of ecnoglutide: A novel, long-acting, cAMP-biased glucagon-like peptide-1 (GLP-1) analog. Mol Metab. 2023;75:101762. [3]Cary BP, Zhang X, Cao J, et al. New Insights into the Structure and Function of Class B1 GPCRs. Endocr Rev. 2023;44(3):492-517. 版权与免责声明 本文版权归作者所有；未经授权，禁止转载、摘编、复制用于商业用途； 本文仅供医学专业人士参考，不构成具体诊疗建议。本文作者及发布平台不对因使用本文信息而产生的任何直接或间接后果承担责任。 本文作者声明无相关利益冲突。

Company announcement – No. 14 / 2026 Zealand Pharma Announces Financial Results for the First Three Months of 2026 A defining start to 2026, marked by pivotal progress for leading obesity assets, petrelintide and survodutide, and strong momentum in driving the next wave of metabolic health innovation. Announced decision to advance petrelintide into Phase 3 trials in H2 2026 following positive topline results from the Phase 2 ZUPREME-1 trial, demonstrating double-digit weight loss with a placebo-like tolerability, supporting its potential to redefine the weight management experience for people living with obesity or overweight. Announced Boehringer Ingelheim’s positive topline results from the SYNCHRONIZE TM -1 Phase 3 trial with survodutide, supporting its potential as a meaningful and differentiated treatment option for people living with obesity or overweight and metabolic dysfunction. Announced the establishment of a new research hub in Cambridge, Massachusetts, and entered into an agreement with DCAI to access a world-leading AI supercomputer, both key pillars to strengthen and accelerate drug discovery in line with Metabolic Frontier 2030 strategy. Announced initiation of a USD 200 million share buy-back program, reflecting financial flexibility and a strengthened financial outlook following positive developments for leading obesity programs. Copenhagen, Denmark, May 7, 2026 – Zealand Pharma A/S (Nasdaq: ZEAL) (CVR-no. 20045078), a biotechnology company transforming the future of metabolic health, today announced the interim report for the three months ended March 31, 2026, and provided a corporate update. A defining quarter Adam Steensberg, President and Chief Executive Officer at Zealand Pharma said: “In this first part of 2026, we leveraged our agility, speed and proven scientific foundation to execute on our Metabolic Frontier 2030 strategy: A new research hub in Cambridge, AI partnerships, Phase 2 topline results with petrelintide followed by confirmation of Phase 3 advancement, and Phase 3 results with survodutide from Boehringer Ingelheim. These advancements not only build on our momentum, but significantly strengthen our long-term financial outlook, enabling a share buy-back program while cementing our commitment to invest heavily in our pipeline.” Key financial results for Q1 2026 DKK million Q1-26 Q1-25 Revenue 34 8 Net operating expenses, excl. OOI 1 -573 -393 Net operating expenses 1 -573 -415 Operating result -539 -407 Net financial items 145 70 DKK million Mar-31, 2026 Dec-31, 2025 Cash position 2 14,468 15,109 Notes: 1. Net operating expenses consist of R&D, S&M, and G&A and Other operating items (OOI). 2. Cash position includes cash, cash equivalents and marketable securities. Q1 2026 Highlights and Recent Developments Obesity Petrelintide, amylin analog. Reached a key milestone in the monotherapy program with the announcement of positive Phase 2 ZUPREME-1 topline results for petrelintide. Petrelintide demonstrated double-digit weight reduction and placebo-like tolerability, supporting its potential as a future foundational, first-choice therapy for chronic weight management. Petrelintide, amylin analog. In April 2026, Zealand Pharma and Roche announced that they will advance petrelintide monotherapy into Phase 3 trials for chronic weight management with planned initiation of the Phase 3 program in the second half of 2026. Survodutide, glucagon/GLP-1 receptor dual agonist. In April 2026, Zealand Pharma and Boehringer Ingelheim reported positive topline results from the 76-week SYNCHRONIZE TM -1 Phase 3 trial with survodutide in people with overweight or obesity without type 2 diabetes. Participants treated with survodutide achieved a significant weight loss of up to 16.6% and delivered meaningful metabolic improvements. Chronic inflammation ZP9830, Kv1.3 Ion Channel Blocker . Zealand Pharma reported positive topline results from the single ascending dose (SAD) part of the combined SAD/multiple ascending dose (MAD) Phase 1a clinical trial with ZP9830. Single doses of ZP9830 were well tolerated with no serious or severe adverse events or dose-limiting safety findings observed at any dose level. ZP9830 exhibited a pharmacokinetic pro line with predictions based on preclinical data, and exploratory pharmacodynamic biomarkers showed robust, dose-dependent activity consistent with Kv1.3 target engagement. Corporate Zealand Pharma announced the establishment of a new research hub in Cambridge, Massachusetts, enhancing the company’s research platform through AI-driven drug discovery, advanced automation, and next-generation molecule creation, accelerating the translation of scientific insights into innovative medicines. Zealand Pharma announced an agreement with the Danish Centre for AI Innovation (DCAI) to strengthen and accelerate drug discovery through access to Gefion, a world leading AI supercomputer. This positions the company to lead the next generation of metabolic health innovation while maintaining the rigorous scientific standards that underpin Zealand Pharma’s leadership in peptide therapeutics. On May 7, 2026, Zealand Pharma launched a share buy-back program of up to USD 200 million / DKK 1.3 billion. For more information on the share buy-back program, refer to Zealand Pharma Company Announcement No. 13/2026, May 7, 2026. Upcoming events next 12 months Obesity Petrelintide, amylin analog. Additional data from the Phase 2 ZUPREME-1 trial will be presented at the American Diabetes Association’s (ADA) 2026 Scientific Session in New Orleans, Louisiana. In the second half of 2026, Zealand Pharma and Roche expect to initiate registrational Phase 3 trials with petrelintide monotherapy. Petrelintide, amylin analog. In the second half of 2026, Zealand Pharma expects to report topline results from the Phase 2 ZUPREME-2 trial in people with overweight or obesity and type 2 diabetes. Petrelintide/enicepatide (CT-388), amylin+GLP-1/GIP fixed-dose combination. Zealand Pharma and Roche expect to initiate Phase 2 in the first half of 2026. Survodutide, glucagon/GLP-1 receptor dual agonist. Boehringer Ingelheim will present the full data from the SYNCHRONIZE TM -1 and SYNCHRONIZE TM -MASLD Phase 3 trials at the ADA 2026 Scientific Sessions in New Orleans, Louisiana. Survodutide, glucagon/GLP-1 receptor dual agonist. Results from the Phase 3 SYNCHRONIZE TM -2 and SYNCHRONIZE TM -CVOT trials are expected to be reported and presented at scientific meetings in 2026. Rare diseases Glepaglutide in SBS. Zealand Pharma expects potential regulatory approval in the EU in the first half of 2026. In parallel, the company is engaging in partnership discussions for future commercialization. Dasiglucagon in CHI. In the second half of 2026, Zealand Pharma expects to resubmit the New Drug Application (NDA) for three weeks of dosing to the U.S. FDA (Part 1 of the original NDA) and to submit the required and detailed analyses from existing continuous glucose monitoring datasets to support the use of dasiglucagon beyond three weeks (Part 2 of the original NDA). Chronic inflammation ZP9830, Kv1.3 Ion Channel Blocker. Zealand Pharma expects to report topline data from the MAD part of the Phase 1a clinical trial with ZP9830 in the second half of 2026 and expand the development program of ZP9830 with initiation of a Phase 1b/2a trial. Financial guidance for 2026 The financial guidance for net operating expenses for 2026, issued on February 19, 2026, is unchanged, and is expected to be between DKK 2.7-3.3 billion. Following the confirmation of Phase 3 progression for petrelintide monotherapy, planned for initiation in the second half of 2026, Zealand Pharma has recognized USD 700 million / DKK 4.5 billion as collaboration revenue in the second quarter of 2026. DKK million 2026 Guidance 3 2025 Actual Collaboration revenue 4.5 9.2 Net operating expenses, excl. OOI 1 2.7-3.3 2.1 Notes: 1. Financial guidance based on foreign exchange rates as of May 6, 2026. Conference call today at 2 PM CET / 8 AM ET Zealand Pharma’s management will host a conference call today at 2:00 PM CET / 8:00 AM ET to present results through the first three months of 2026 followed by a Q&A session. Participating in the call will be Chief Executive Officer, Adam Steensberg; Chief Financial Officer, Henriette Wennicke; and Chief Medical Officer, David Kendall. The conference call will be conducted in English. To receive telephone dial-in information and a unique personal access PIN, please register at .The live listen-only audio webcast of the call and accompanying slides presentation will be accessible at . Participants are advised to register for the call or webcast approximately 10 minutes before the start. A recording of the event will be available following the call on the Investor section of Zealand Pharma’s website at . Financial Calendar for 2026 Q2 2026 August 13, 2026 Q3 2026 November 12, 2026 About Zealand Pharma A/S Zealand Pharma A/S (Nasdaq: ZEAL) is a biotechnology company focused on advancing medicines for obesity and metabolic health. Combining more than 25 years of peptide R&D expertise with a proprietary data platform that leverages advanced data‑driven and AI/ML approaches, Zealand Pharma aims to lead a new era in obesity and metabolic health. To date, more than ten Zealand Pharma‑invented drug candidates have entered clinical development, of which two products have reached the market and three candidates are in late-stage development. The Company has collaborations with global pharmaceutical and biotechnology partners for research, development, and commercialization. Founded in 1998, Zealand Pharma is headquartered in Copenhagen, Denmark, with a U.S. presence in Boston, Massachusetts. Learn more at . Forward-looking Statements This company announcement contains “forward-looking statements”, as that term is defined in the Private Securities Litigation Reform Act of 1995 in the United States, as amended, even though no longer listed in the United States this is used as a definition to provide Zealand Pharma’s expectations or forecasts of future events regarding the research, development, and commercialization of pharmaceutical products, the timing of the company’s clinical trials and the reporting of data therefrom and the company’s significant events and potential catalysts in 2026 and financial guidance for 2026. These forward-looking statements may be identified by words such as “aim,” “anticipate,” “believe,” “could,” “estimate,” “expect,” “forecast,” “goal,” “intend,” “may,” “plan,” “possible,” “potential,” “will,” “would”, and other words and terms of similar meaning. You should not place undue reliance on these statements, or the scientific data presented. The reader is cautioned not to rely on these forward-looking statements. Such forward-looking statements are subject to risks, uncertainties and inaccurate assumptions, which may cause actual results to differ materially from expectations set forth herein and may cause any or all of such forward-looking statements to be incorrect, and which include, but are not limited to, unexpected costs or delays in clinical trials and other development activities due to adverse safety events or otherwise; unexpected concerns that may arise from additional data, analysis or results obtained during clinical trials; our ability to successfully market both new and existing products; changes in reimbursement rules and governmental laws and related interpretation thereof; government-mandated or market-driven price decreases for our products; introduction of competing products; production problems; unexpected growth in costs and expenses; our ability to effect the strategic reorganization of our businesses in the manner planned; failure to protect and enforce our data, intellectual property and other proprietary rights and uncertainties relating to intellectual property claims and challenges; regulatory authorities may require additional information or further studies, or may reject, fail to approve or may delay approval of our drug candidates or expansion of product labelling; failure to obtain regulatory approvals in other jurisdictions; exposure to product liability and other claims; interest rate and currency exchange rate fluctuations; unexpected contract breaches or terminations; inflationary pressures on the global economy; and political uncertainty. If any or all of such forward-looking statements prove to be incorrect, our actual results could differ materially and adversely from those anticipated or implied by such statements. The foregoing sets forth many, but not all, of the factors that could cause actual results to differ from our expectations in any forward-looking statement. All such forward-looking statements speak only as of the date of this press release/company announcement and are based on information available to Zealand Pharma as of the date of this release/announcement. We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof. Information concerning pharmaceuticals (including compounds under development) contained within this material is not intended as advertising or medical advice. Zealand Pharma® is a registered trademark of Zealand Pharma A/S. Contacts Eric Rojas (Investors) Vice President, Head of Investor Relations erojas@zealandpharma.com Adam Lange (Investors) Vice President, Investor Relations alange@zealandpharma.com Neshat Ahmadi (Investors) Manager, Investor Relations neahmadi@zealandpharma.com Rachel James-Owens (Media) Vice President, Corporate Communications & Media Relations Zealand Pharma Email: RJamesOwens@zealandpharma.com Andreas Hylleberg (Media) Director, External Communications Zealand Pharma Email: AHylleberg@zealandpharma.com Amber Fennell, Jessica Hodgson, Sean Leous (Media) ICR Healthcare Email: ZealandPharma@icrhealthcare.com +44 (0) 7739 658 783 Attachment Zealand Pharma Q1 2026 Interim Report