Terns, Inc.

摘要：礼来公司的口服 GLP-1 药物 Orforglipron 凭借 “首款口服肥胖疗法” 的先发优势，一度被视为肥胖治疗市场的新标杆。但其 III 期临床数据未达预期，为竞争对手留下了可乘之机。目前，五种差异化显著的口服肥胖候选药物正加速推进，它们或靶向全新机制，或优化给药便利性，或在减重效果上展现潜力。这场 “口服争霸战” 不仅将重塑肥胖治疗市场格局，更可能为全球数亿肥胖患者带来更易接受的治疗选择。礼来的 “领跑者” 困局 作为当前临床进展最领先的口服肥胖药，Orforglipron 的 III 期 ATTAIN-1 研究数据曾备受期待：72 周时平均减重 12.4%，近 60% 高剂量组患者减重超 10%。但这一结果并未让分析师满意 —— 其效果不及注射剂型 GLP-1 药物（如诺和诺德的 Wegovy、礼来自身的 Zepbound），被指 “在礼来近乎无懈可击的肥胖药版图上敲出了一道裂痕”。 即便如此，Orforglipron 的 “口服” 属性仍是其核心竞争力。正如威廉・布莱尔分析师 Andy Hsieh 所言，它为 “极度恐针” 或偏好片剂的患者打开了大门，有望扩大肥胖治疗的受众群体。瑞穗证券分析师 Graig Suvannavejh 也指出，口服药物无需患者学习注射技巧，医生更易处方，且小分子制剂更易量产，可能降低成本、提升可及性。 但市场从不缺挑战者。Suvannavejh 强调：“辉瑞的 Lipitor 并非首个他汀类药物，却最终成为市场霸主。” 如今，五种候选药物正从机制、数据、进展等多个维度，向 Orforglipron 发起冲击。五强选手：差异化路径竞逐市场诺和诺德 Amycretin：双机制瞄准 “下一代” 作为诺和诺德押注的核心资产，Amycretin 的独特之处在于同时靶向 GLP-1 受体与胰岛淀粉样多肽（amylin）受体。Amylin 是胰腺分泌的一种激素，与 GLP-1 协同调控食欲与血糖，被分析师视为 “肥胖治疗的新热门机制”。 其注射剂型在 IIa 期研究中展现出惊人潜力：20mg 剂量 20 周减重 22%，36 周时进一步提升至 23.9%；口服剂型 I 期数据也显示，12 周平均减重 13.1%，且安全性良好。目前，诺和诺德已计划将两种剂型推进至 III 期，试图用 “GLP-1+amylin” 的组合拳，复制甚至超越现有注射剂的疗效。Viking VK2735：双受体靶向的 “快速跟进者” Viking Therapeutics 的 VK2735 与礼来的 Zepbound 机制相同，均靶向 GLP-1 和 GIP 双受体，但更聚焦口服剂型的开发。其 I 期数据显示，100mg 剂量 28 天平均减重 8.2%，远超安慰剂组。 目前，VK2735 的 II 期 VENTURE-Oral 研究已完成入组，计划测试每日一次给药方案。分析师预测，其数据可能于下月公布，若结果理想，有望成为 Orforglipron 最直接的竞争对手。罗氏 CT-996：通路 “偏爱” 求突破 罗氏通过收购 Carmot Therapeutics 获得的 CT-996，是一款 “偏向性” GLP-1 类似物 —— 它更倾向于激活特定细胞通路，理论上能在提升疗效的同时降低副作用。I 期数据显示，4 周治疗平均减重 7.3%，远超安慰剂的 1.2%。 不过，其安全性仍需验证：快速加量时 85% 患者出现恶心，而逐步加量耐受性更佳。罗氏已加快推进步伐，计划今年启动 II 期研究，并利用现有小分子生产网络快速扩产，试图凭借 “疗效 - 安全平衡” 后来居上。Terns TERN-601：以 “便利” 取胜 Terns Pharmaceuticals 的 TERN-601 虽未突破 GLP-1 机制，却在给药便利性上做足文章：每日一次给药即可实现 24 小时疗效覆盖，无需严格空腹，且剂量调整最简单，可与其他药物联用。 其 I 期数据显示，最高剂量 28 天减重 5.5%，67% 患者减重超 5%。目前 II 期 FALCON 研究已完成入组，数据预计年底公布。不过，由于肥胖药市场趋饱和，Terns 正为其寻找合作方，自身转向癌症领域。Rhythm Bivamelagon：小众机制的 “差异化奇兵” 与前四种药物不同，Rhythm 公司的 Bivamelagon 瞄准了全新靶点 —— 黑皮质素 - 4 受体（MC4R），该受体调控饥饿感与能量代谢，其功能异常会导致严重肥胖。 在针对下丘脑性肥胖（一种罕见病）的 II 期研究中，600mg 剂量 14 周使患者 BMI 降低 9.3%，远超安慰剂的 2.2%。分析师认为，其独特机制不仅适用于罕见肥胖人群，未来或可与其他药物联用扩大适应症，但直肠出血、局部色素沉着等副作用可能限制其应用。口服时代：市场格局未定 口服肥胖药的崛起被业内视为 “游戏规则改变者”。相比注射剂，它们能提升患者依从性、降低医疗门槛，而量产优势可能推动价格下探，惠及更多人群。 但竞争的核心仍在于 “疗效 - 安全 - 便利” 的平衡。礼来 Orforglipron 虽暂居领先，但后发者可能凭借更优数据或差异化机制实现超越。正如 Suvannavejh 所言：“肥胖治疗市场足够大，容得下多种赢家。” 这场较量的最终受益者，将是全球亟待更优治疗方案的肥胖患者。 参考来源：https://www.biospace.com/drug-development/5-oral-obesity-drugs-challenging-lillys-orforglipron 识别微信二维码，添加生物制品圈小编，符合条件者即可加入 生物制品微信群！ 请注明：姓名+研究方向！ 版 权 声 明 本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观不本站。

Terns Pharmaceuticals\' partnering plan reflects a belief that the resources of a larger company are needed in obesity.\n Terns Pharmaceuticals is planning to stop investing in metabolic disease clinical development by year-end, starting a countdown to potential deals for assets including a midphase oral obesity prospect. California-based Terns has one cancer candidate, the chronic myeloid leukemia (CML) asset TERN-701, and three metabolic disease programs. While the pipeline currently skews toward metabolic disease, the biotech is focusing on TERN-701 in the belief it can take the candidate through a pivotal trial and on to the market without external support. Terns CEO Amy Burroughs set out the plans for the pipeline.“We are focusing the company in oncology and on rapidly advancing TERN-701 towards a pivotal trial, with the goal of ultimately bringing a potential best-in-class therapy to people living with CML,” the CEO said in a statement. “The company seeks to partner our portfolio of potentially best-in-class metabolic assets and does not plan to invest in clinical development in metabolic disease beyond year end 2025.”The metabolic disease pipeline includes the oral small molecule GLP-1 receptor agonist TERN-601. After seeing promise in four-week data, Terns moved the obesity candidate into a longer, larger phase 2 trial that will provide a clearer picture of how TERN-601 compares to Eli Lilly’s oral front-runner orforglipron. William Blair analysts have questioned whether TERN-601 and CML candidate TERN-701 can stand out. Writing in a note to investors on Tuesday, the analysts said “we do not believe a differentiation thesis is clear at the moment, given the increasing competitiveness of both the CML and obesity treatment landscape.”Lilly, which has already shared phase 3 data on orforglipron in diabetes, is set to publish results from its pivotal obesity program soon. Terns is aiming to release 12-week data from a phase 2 trial of TERN-601 early in the fourth quarter. Talking at a Goldman Sachs event in June, Burroughs flagged tolerability and titration as potential strengths of Terns’ candidate. Burroughs and other Terns executives have repeatedly said at investor events that they plan to partner the obesity program for phase 3. The partnering plan reflects a belief that the resources of a larger company are needed to support TERN-601, given that R&D costs could exceed $500 million and commercialization may require a sales force capable of targeting general practitioners.Terns also previously said its two other metabolic programs, TERN-501 and its TERN-800 series, are up for partnering. TERN-501 is the metabolic dysfunction-associated steatohepatitis candidate that Terns put on the back burner last year. The TERN-800 program is focused on oral GIPR modulators that could combine with GLP-1 agonists.

▎药明康德本期看点1. ROS1选择性抑制剂zidesamtinib用于接受过酪氨酸激酶抑制剂（TKI）治疗的晚期ROS1阳性非小细胞肺癌（NSCLC）患者，在一项1/2期临床试验中取得积极结果，其上市申请递交在即。2. 早期数据表明，罗氏（Roche）的在研双特异性抗体NXT007有望使血友病A患者的凝血功能恢复正常。3. 用于治疗慢性乙型肝炎病毒（HBV）感染的下一代衣壳组装调节剂ABI-4334在1b期临床试验中展现强力的抗病毒活性，高剂量组患者接受治疗28天，血浆HBV DNA平均降低3.2 log IU/mL。NXT007：公布1/2期临床试验数据罗氏宣布，其新一代在研双特异性抗体NXT007在治疗血友病A的1/2期临床试验中取得积极数据，将推进至3期临床试验。NXT007由罗氏旗下的Chugai Pharmaceutical公司研发，基于已上市药物Hemlibra的框架优化设计，旨在模拟因子VIII功能，同时延长半衰期，提高疗效和用药便利性。该药通过将凝血因子IXa和X桥接在一起，激活体内自然凝血级联反应，有望使血友病A患者的凝血功能恢复正常，并减少治疗负担。在这项研究中，30名12至65岁、无因子VIII抑制剂，且既往未接受过Hemlibra治疗的血友病A患者在接受了4至6周的负荷剂量后，在维持期每2至4周皮下注射递增剂量的NXT007。结果显示，高剂量组（B-3和B-4）的患者在整个维持期内均保持止血正常化状态，未出现需治疗的出血事件。安全性方面，NXT007的耐受良好，目前未报告血栓栓塞事件。Zidesamtinib：公布1/2期临床试验数据Nuvalent公司公布了其新型ROS1选择性抑制剂zidesamtinib在1/2期临床试验ARROS-1中的关键积极数据。该试验针对接受过TKI治疗的晚期ROS1阳性NSCLC患者。Zidesamtinib是一种具脑渗透性的ROS1抑制剂，设计用以治疗那些对现有ROS1抑制剂具抗性的癌症，包含那些带有G2032R、S1986Y/F、L2026M或D2033N突变的肿瘤。结果显示，在117例曾接受过TKI治疗的ROS1阳性NSCLC患者中（其中50%曾接受过≥2种ROS1 TKI±化疗），由盲态独立中心审查（BICR）评估的客观缓解率（ORR）为44%，初步估计的缓解持续率在12个月时为78%，18个月时为62%。在其中55名曾接受过1种ROS1 TKI（克唑替尼或恩曲替尼）±化疗的患者中，ORR为51%，初步估计的缓解持续率在12和18个月时均为93%。Zidesamtinib还显示出颅内抗肿瘤活性，对携带ROS1 G2032R耐药突变的肿瘤也有作用，整体安全性良好，剂量减少和停药的比例较低，分别为10%和2%。该公司计划于2025年7月启动滚动提交zidesamtinib的新药申请（NDA），目标在2025年第三季度完成。ABI-4334：公布1b期临床试验数据Assembly Biosciences公司公布了其在研下一代衣壳组装调节剂ABI-4334用于治疗慢性HBV感染患者的1b期临床试验数据。此前公布的150 mg剂量组的结果显示，ABI-4334显示出很强的抗病毒活性，在28天的治疗中，血浆HBV DNA平均降低了2.9 log IU/mL。此次公布的400 mg剂量组的结果类似于先前的报道，在28天的治疗中，血浆HBV DNA平均降低了3.2 log IU/mL。此外，在400 mg剂量下继续观察到ABI-4334良好的安全性和耐受性，半衰期支持每日一次口服给药。TERN-601：公布1期临床试验数据Terns Pharmaceuticals公司公布了其每日一次在研减重疗法TERN-601在肥胖或超重健康成年人中进行的1期试验积极结果。TERN-601是一种口服小分子胰高血糖素样肽-1（GLP-1）受体激动剂，由Terns内部研发。TERN-601通过Terns内部基于结构的药物研发技术设计，采用该公司专有的三维定量构效关系（QSAR）模型所开发。此次公布的结果显示，TERN-601在治疗肥胖方面表现出显著的疗效和良好的安全性。在28天内，每日一次给药可实现统计学显著且呈剂量依赖性的体重减轻。在最高剂量组中，有67%的患者体重减轻≥5%。其独特的药代动力学特性使其在24小时内维持平稳的血药浓度曲线，有效半衰期为9-10小时，支持每日一次给药。此外，药物在肠道中的暴露量高于血浆，且游离药物比例低，从而在不牺牲耐受性的前提下实现了有意义的体重减轻。安全性方面，未出现因治疗导致的中断、减量或停药，＞95%的胃肠道不良事件为轻度，患者的肝酶、生命体征和心电图均无明显变化。ENT-03：公布1a期临床试验数据Metabolics Pharma公司公布了其候选药物ENT-03在肥胖和糖尿病患者中开展的1a期临床试验的的初步结果。该研究数据显示，在所有测试剂量下，ENT-03均表现出良好的安全性和耐受性。在较高剂量组中，ENT-03在减轻体重和提高胰岛素敏感性方面呈现出积极趋势。ENT-03是一种新型中枢神经系统作用的氨基类固醇化合物，具有蛋白酪氨酸磷酸酶1B（PTP1B）抑制活性。它通过作用于大脑中调控能量代谢和血糖平衡的神经回路，达到调节葡萄糖水平、改善胰岛素敏感性并促进体重减轻的效果。临床前研究表明，ENT-03作为单药疗法有效，并且在与GLP-1受体激动剂联合使用时表现出累加效应。此外，ENT-03在停药后仍可维持较长时间的体重降低以及血糖和胰岛素水平的正常化。APR-1051：公布联合治疗1期试验的初步数据Aprea Therapeutics公司公布了其下一代口服WEE1抑制剂APR-1051治疗HPV阳性头颈部鳞状细胞癌患者的新临床数据。APR-1051是一种口服、高选择性的WEE1抑制剂，旨在最大限度地减少脱靶活性并优化药理选择性。该疗法目前正在1期临床试验ACESOT-1051中对携带DDR相关通路基因突变（DDR）的晚期实体瘤患者进行评估。该试验中，一名62岁HPV阳性的晚期口咽鳞状细胞癌男性患者，既往接受过三线铂类治疗后进展，在接受每日口服一次70 mg亚治疗剂量的APR-1051后实现疾病稳定，首次影像学评估时肿瘤缩小了5%。该患者对治疗的耐受性良好，未报告剂量限制性毒性。参考资料（可上下滑动查看）[1] LOMOND THERAPEUTICS ANNOUNCES U.S. FDA CLEARANCE OF IND APPLICATION FOR LONITOCLAX, A SELECTIVE BCL2 INHIBITOR WITH LIMITED IMMUNE SUPPRESSION AND IMPROVED SAFETY COMPARED TO VENETOCLAX AND VENETOCLAX- LIKE MOLECULES. Retrieved June 27, 2025, from https://www.prnewswire.com/news-releases/lomond-therapeutics-announces-us-fda-clearance-of-ind-application-for-lonitoclax-a-selective-bcl2-inhibitor-with-limited-immune-suppression-and-improved-safety-compared-to-venetoclax-and-venetoclax--like-molecules-302487020.html[2] Archeus Technologies Receives FDA Clearance of Investigational New Drug Application for ART-101 in Development for the Treatment of Prostate Cancer. Retrieved June 27, 2025, from https://www.businesswire.com/news/home/20250620911569/en/Archeus-Technologies-Receives-FDA-Clearance-of-Investigational-New-Drug-Application-for-ART-101-in-Development-for-the-Treatment-of-Prostate-Cancer[3] Terns Pharmaceuticals Presents Positive Data from Phase 1 Study of TERN-601 Once-daily Oral GLP-1R Agonist for Treatment of Obesity at 85th Annual American Diabetes Association Scientific Sessions. Retrieved June 27, 2025, from https://www.globenewswire.com/news-release/2025/06/23/3103837/0/en/Terns-Pharmaceuticals-Presents-Positive-Data-from-Phase-1-Study-of-TERN-601-Once-daily-Oral-GLP-1R-Agonist-for-Treatment-of-Obesity-at-85th-Annual-American-Diabetes-Association-Sci.html[4] Forte Biosciences Announces Positive Data in FB102 Celiac Disease Phase 1B Study. Retrieved June 27, 2025, from https://www.fortebiorx.com/investor-relations/news/news-details/2025/Forte-Biosciences-Announces-Positive-Data-in-FB102-Celiac-Disease-Phase-1B-Study/default.aspx[5] Nuvalent Announces Positive Pivotal Data from ARROS-1 Clinical Trial of Zidesamtinib for TKI Pre-treated Patients with Advanced ROS1-positive NSCLC. Retrieved June 27, 2025, from https://investors.nuvalent.com/2025-06-24-Nuvalent-Announces-Positive-Pivotal-Data-from-ARROS-1-Clinical-Trial-of-Zidesamtinib-for-TKI-Pre-treated-Patients-with-Advanced-ROS1-positive-NSCLC[6] Cellarity Initiates Phase 1 Clinical Study of CLY-124, a First-in-Class Globin-Switching Oral Medicine for the Treatment of Sickle Cell Disease. Retrieved June 24, 2025 from https://www.prnewswire.com/news-releases/cellarity-initiates-phase-1-clinical-study-of-cly-124-a-first-in-class-globin-switching-oral-medicine-for-the-treatment-of-sickle-cell-disease-302492168.html[7] Contineum Therapeutics Provides Update on Phase 1b Positron Emission Tomography (PET) Trial of PIPE-791. Retrieved June 24, 2025 from https://www.businesswire.com/news/home/20250625697950/en/Contineum-Therapeutics-Provides-Update-on-Phase-1b-Positron-Emission-Tomography-PET-Trial-of-PIPE-791[8] Sangamo Therapeutics Announces Positive Topline Results From Registrational STAAR Study in Fabry Disease. Retrieved June 24, 2025 from https://www.businesswire.com/news/home/20250624043784/en/Sangamo-Therapeutics-Announces-Positive-Topline-Results-From-Registrational-STAAR-Study-in-Fabry-Disease[9] Immutep Announces Positive Update from Phase I Study of IMP761, a First-in-Class LAG-3 Agonist Antibody for Autoimmune Diseases. Retrieved June 24, 2025 from https://www.immutep.com/detail/immutep-announces-positive-update-from-phase-i-study-of-imp761-a-first-in-class-lag-3-agonist-antibody-for-autoimmune-diseases.html#:~:text=SYDNEY%2C%20AUSTRALIA%2C%20June%2023%2C%202025%20--%20Immutep%20Limited,a%20first-in-class%20LAG-3%20agonist%20antibody%20for%20autoimmune%20diseases.[10] Aclaris Therapeutics Initiates Phase 1a/1b Program for its Novel Bispecific Antibody ATI-052. Retrieved June 24, 2025 from https://www.globenewswire.com/news-release/2025/06/23/3103239/37216/en/index.html[11] Early data suggest Roche’s NXT007 may have the potential to provide haemostatic normalisation in people with haemophilia A. Retrieved June 24, 2025 from https://www.globenewswire.com/news-release/2025/06/23/3103084/0/en/Early-data-suggest-Roche-s-NXT007-may-have-the-potential-to-provide-haemostatic-normalisation-in-people-with-haemophilia-A.html[12] Verdiva Bio to Present New Data Highlighting Once-Weekly Potential of Its Investigational Oral Obesity Candidates at the ADA 85th Scientific Sessions. Retrieved June 24, 2025 from https://www.businesswire.com/news/home/20250620108098/en/Verdiva-Bio-to-Present-New-Data-Highlighting-Once-Weekly-Potential-of-Its-Investigational-Oral-Obesity-Candidates-at-the-ADA-85th-Scientific-Sessions[13] Plus Therapeutics Announces FDA Clearance of its Investigational New Drug Application using REYOBIQTM for the Treatment of Childhood Brain Cancer. Retrieved June 24, 2025 from https://www.globenewswire.com/news-release/2025/06/25/3104980/0/en/Plus-Therapeutics-Announces-FDA-Clearance-of-its-Investigational-New-Drug-Application-using-REYOBIQTM-for-the-Treatment-of-Childhood-Brain-Cancer.html[14] Assembly Biosciences Reports Positive Topline Results from Phase 1b Clinical Trial of Next-Generation Investigational Capsid Assembly Modulator ABI-4334 in Chronic Hepatitis B. Retrieved June 24, 2025 from https://www.globenewswire.com/news-release/2025/06/25/3105003/16259/en/Assembly-Biosciences-Reports-Positive-Topline-Results-from-Phase-1b-Clinical-Trial-of-Next-Generation-Investigational-Capsid-Assembly-Modulator-ABI-4334-in-Chronic-Hepatitis-B.html[15] Biogen to Advance Investigational Spinal Muscular Atrophy Asset to Registrational Studies Based on Positive Interim Phase 1 Results. Retrieved June 24, 2025 from https://www.globenewswire.com/news-release/2025/06/25/3104985/0/en/Biogen-to-Advance-Investigational-Spinal-Muscular-Atrophy-Asset-to-Registrational-Studies-Based-on-Positive-Interim-Phase-1-Results.html[16] Blue Earth Therapeutics: SNMMI Presentation of Results from Lutetium (177Lu) rhPSMA-10.1 Injection Phase 1 Clinical Trial. Retrieved June 24, 2025 from https://www.prnewswire.com/news-releases/blue-earth-therapeutics-snmmi-presentation-of-results-from-lutetium-177lu-rhpsma-10-1-injection-phase-1-clinical-trial-302490153.html[17] Metabolics Pharma Announces Positive Top-Line Results from Phase 1a Clinical Trial of ENT-03 in Obese and Diabetic Subjects. Retrieved June 24, 2025 from https://www.businesswire.com/news/home/20250625436712/en/Metabolics-Pharma-Announces-Positive-Top-Line-Results-from-Phase-1a-Clinical-Trial-of-ENT-03-in-Obese-and-Diabetic-Subjects[18] Aprea Reports Anti-Proliferative Results and Promising Early-Stage Clinical Data for Next-Generation WEE1 Inhibitor, APR-1051, in HPV+ Head and Neck Squamous Cell Carcinoma (HNSCC) in Collaboration with MD Anderson Cancer Center. Retrieved June 24, 2025 from https://www.globenewswire.com/news-release/2025/06/25/3105158/0/en/Aprea-Reports-Anti-Proliferative-Results-and-Promising-Early-Stage-Clinical-Data-for-Next-Generation-WEE1-Inhibitor-APR-1051-in-HPV-Head-and-Neck-Squamous-Cell-Carcinoma-HNSCC-in-C.html[19] CRISPR Therapeutics Reports Positive Additional Phase 1 Data for CTX310™ Targeting ANGPTL3 and Provides Update on In Vivo Cardiovascular Pipeline. Retrieved June 24, 2025 from https://www.globenewswire.com/news-release/2025/06/26/3105698/0/en/CRISPR-Therapeutics-Reports-Positive-Additional-Phase-1-Data-for-CTX310-Targeting-ANGPTL3-and-Provides-Update-on-In-Vivo-Cardiovascular-Pipeline.html免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新