MAR-001

SOUTH SAN FRANCISCO, CA, USA I July 14, 2025 I Marea Therapeutics, Inc., a clinical-stage biotechnology company harnessing the latest advances in human genetics to develop first-in-class, next-generation medicines for cardioendocrine diseases, today announced the presentation of preclinical data on MAR002, a novel growth hormone receptor (GHR) antagonist antibody for the treatment of acromegaly, at the 2025 Annual Meeting of the Endocrine Society (ENDO). The oral presentation, titled “Development of a Novel Growth Hormone Receptor Antagonist Antibody for the Treatment of Acromegaly,” highlights the significant potential of MAR002 to address critical unmet needs in patients suffering from this rare and highly morbid disease. Presentation highlights include: Marea Therapeutics has completed a GLP-toxicology study to assess MAR002’s safety. The preclinical pharmacology data strongly support advancing MAR002 into clinical development; a Phase 1 first-in-human study is expected to begin in the third quarter of 2025. Marea’s development strategy aims for rapid advancement into acromegaly patients after achieving proof of mechanism in healthy volunteers, with a clear path to approval guided by FDA guidance for IGF-1 normalization. “The preclinical data presented at ENDO 2025 underscore the potential of MAR002 to meaningfully transform the treatment landscape for acromegaly,” said Ethan Weiss, M.D., chief scientific officer of Marea Therapeutics. “With its strong potency, enhanced durability, and favorable developability profile, MAR002 is uniquely positioned to overcome the limitations of current therapies and offer a more effective, targeted approach for patients. We are excited to advance MAR002 into clinical development and bring forward a next generation and potential best-in-class GHR antagonist.” Marea Therapeutics believes MAR002 represents a significant opportunity to replace and expand the market for existing growth hormone receptor antagonists (GHRAs) and could also be used in combination with somatostatin receptor ligands (SRLs), offering a more effective and convenient treatment option for patients with acromegaly. About MAR002 MAR002 is a novel, potent and selective half-life-extended, allosteric, human monoclonal GHRA antibody being developed for the treatment of acromegaly. The PK and PD properties of MAR002 are predictable and typical of a half-life extended human antibody, showing a long duration of action compatible with infrequent subcutaneous dose administration in humans. These characteristics support its potential to offer an effective and convenient treatment for patients with acromegaly. About Acromegaly Acromegaly is an orphan disease characterized by the excess secretion of growth hormone (GH) from a benign pituitary adenoma. Acromegaly affects approximately 30,000 patients in the U.S. If left untreated, acromegaly is highly morbid, leading to significant comorbidities such as GH-induced insulin resistance and diabetes, and serious cardiovascular pathology. The median lifespan of patients can be shortened by 10 years without effective therapy, and incomplete IGF-1 normalization is associated with increased mortality. Despite its severity, acromegaly is often under or misdiagnosed, with an average time from symptom onset to diagnosis of approximately eight years. The current treatment paradigm for acromegaly often involves surgery, performed in over 90% of patients, which achieves remission in about 50% of cases, though this can degrade over time. Medical therapy is required for approximately 65% (around 20,000 in the U.S.) of patients during their disease journey, regardless of their surgical history. Current medical treatments include somatostatin receptor ligands (SRLs) and growth hormone receptor antagonists (GHRAs), such as pegvisomant. However, many patients do not achieve biochemical control with existing therapies. About Marea Therapeutics Marea Therapeutics is a clinical-stage biotechnology company harnessing the latest advances in human genetics to develop first-in-class, next-generation medicines for cardioendocrine diseases. The company’s lead therapy, MAR001, is in Phase 2 clinical development for adults with metabolic dysfunction and high risk for atherosclerotic cardiovascular disease. The company is also advancing MAR002 for the treatment of acromegaly. To learn more, please visit www.mareatx.com and follow us on LinkedIn and X . SOURCE: Marea Therapeutics

血管生成素样蛋白4（ANGPTL4）是血管内皮生长因子家族成员，主要在脂肪和肝脏表达，其可通过抑制脂蛋白脂肪酶活性而调节脂质代谢。遗传学研究已明确，ANGPTL4是甘油三酯代谢的关键调节因子，也是降低动脉粥样硬化心血管疾病（ASCVD）风险的具有前景的靶点。MAR001是一种潜在“first-in-class”的单克隆抗体，靶向在脂肪组织中高度表达的ANGPTL4蛋白。MAR001可通过抑制ANGPTL4，优先增强脂肪组织中的脂蛋白脂肪酶活性，降低残余胆固醇水平，改善脂肪组织和代谢功能，并减少心血管事件。近日，《柳叶刀》（The Lancet）发表的一项研究结果表明，在代谢功能障碍参与者中[高甘油三酯血症、2型糖尿病病史或胰岛素抵抗稳态模型（HOMA-IR）＞2.2且腹部肥胖]，450 mg MAR001用药12周后，可将甘油三酯水平显著降低52.7%、残余胆固醇水平降低52.5%。研究结果支持MAR001是一种具有前景的潜在降脂疗法，有待进一步开发和研究，以造福更多的患者。截图来源：The Lancet本次公布了1期研究和1b/2a期研究结果。1期试验是MAR001的首次人体、随机、安慰剂对照、单次剂量递增研究，共分为1a（健康人群）、1b[高体重指数（BMI）人群]和1c（高血脂人群）三个部分，所有参与者（56例）均随机接受MAR001或安慰剂治疗，主要目的是评估单次皮下注射MAR001至用药后141天的安全性和耐受性。1a部分纳入体重≥50 kg且BMI在18~30 kg/m2、年龄18~65岁的成人健康参与者32例，其中各有6例参与者分别接受15 mg、50 mg、150 mg和450 mg的MAR001，以及各有2例参与者分别接受匹配的安慰剂；1b部分纳入体重≥70 kg且BMI在30~40 kg/m2成人参与者12例，其中9例接受450 mg的MAR001，3例接受匹配的安慰剂；1c部分纳入体重≥59 kg、空腹甘油三酯水平在200~500 mg/dL的参与者12例，其中8例参与者接受450 mg的MAR001，4例接受匹配的安慰剂。研究结果显示，在1c（高血脂人群）参与者中，用药后第2天参与者的空腹甘油三酯水平即明显降低，且在第15天达到最大降幅。▲高血脂人群使用MAR001（蓝色）和安慰剂（红色）后，空腹甘油三酯水平变化情况（图片来源：参考文献[1]）用药后第15天时，在1c（高血脂人群）参与者中，空腹甘油三酯水平相较于基线降低了47.2%（90%CI：-61.0%~-33.4%）。校正安慰剂影响后，MAR001可使甘油三酯水平和残余胆固醇水平分别降低68.6%（90%CI：-97.4%~-39.8%）和65.5%（90%CI：-94.2%~-36.9%）。▲高血脂人群使用MAR001（蓝色）和安慰剂（红色）后，残余胆固醇水平变化情况（图片来源：参考文献[1]）此外，由于1a（健康人群）和1b（高BMI人群）参与者基线时空腹甘油三酯水平均正常，因此，使用450 mg MAR001在降低空腹甘油三酯水平方面的作用较弱，也未降低餐后甘油三酯水平。所有剂量的MAR001安全性均可控且患者耐受性良好。研究未报告有死亡病例、严重不良事件。所有56例参与者中，有19例（34%）至少发生一起不良事件，其中17例（30%）共发生23起轻度不良事件、2例（3.6%）共发生3起中度不良事件。随后，研究人员在一项针对代谢功能障碍参与者的随机、双盲、安慰剂对照1b/2a研究中，评估MAR001的用药安全性和耐受性。该研究纳入高甘油三酯血症（甘油三酯水平≥151 mg/dL且≤496 mg/dL）、2型糖尿病病史或HOMA-IR＞2.2且腹部肥胖成人参与者55例。其中10例参与者接受了150 mg MAR001、9例参与者接受300 mg MAR001、17例参与者接受450 mg MAR001，以及19例参与者接受安慰剂治疗，治疗期为12周（每2周皮下注射一次，共注射7次），而后是为期12周的安全随访。基线时，接受MAR001治疗的患者甘油三酯水平在169.9 mg/dL~219.2 mg/dL。研究结果显示，治疗第12周时，使用MAR001的参与者甘油三酯水平和残余胆固醇水平呈现剂量依赖性降低，且用药第一周即可观察到明显降幅，高剂量MAR001在用药后第6周可达到最大降幅。校正安慰剂影响后，接受150 mg MAR001、300 mg MAR001、450 mg MAR001的参与者甘油三酯水平分别较基线降低40.6%（90%CI：-70.1%~-11.2%）、50.3%（90%CI：-88.0%~-12.7%）和52.7%（90%CI：-77.0%~-28.3%）；残余胆固醇水平分别较基线降低37.4%（90%CI：-66.1%~-8.8%）、49.3%（90%CI：-85.8%~-12.8%）和52.5%（90%CI：-76.1%~-28.9%）。▲150 mg MAR001组（蓝色）、300 mg MAR001组（紫色）、450 mg MAR001组（绿色）和安慰剂组（红色）甘油三酯（图A）和残余胆固醇（图B）水平变化趋势（图片来源：参考文献[1]）此外，校正安慰剂影响后，治疗第12周，450 mg MAR001参与者非高密度脂蛋白胆固醇（non-HDL-C）水平降低7.1%（90%CI：-14.7%~-0.6%），高密度脂蛋白胆固醇（HDL-C）水平升高了19%（90%CI：10.2%~27.8%）。安全性方面，MAR001安全性可控且患者耐受性良好，未观察到有严重不良事件或致命不良事件的发生，发生不良事件的参与者比例也未表现出剂量依赖性增加趋势。仅有1例参与者（安慰剂组）因不良事件停止参与研究，多数不良事件均为1级或2级，可自行缓解。MAR001未引发新的肠系膜炎症，也无患者出现腹水。《柳叶刀》发表的同期社论指出，该研究探索了新型疗法在降低甘油三酯和残余胆固醇方面的作用。在此之前，医学界已经探索了载脂蛋白C3（APOC3）和血管生成素样蛋白3（ANGPTL3）抑制剂的作用，可分别用于治疗家族性乳糜微粒血症和纯合子家族性高胆固醇血症，但ANGPTL4抑制剂在人体中的作用研究始终较少，部分原因是在小鼠实验中观察到ANGPTL4抑制剂的安全耐受性有待提升。本次研究未观察到接受MAR001治疗的参与者有可检测到的肠系膜淋巴数量增多或淋巴结增大问题。未来仍需开展大型随机对照试验，来明确使用ANGPTL4抑制剂后患者的临床获益情况，获益不仅包含降低脂质水平，还应涵盖ASCVD风险和糖尿病风险是否有所降低。总之，本次研究结果显示，在基线高甘油三酯水平的人群中使用MAR001，可有效降低甘油三酯水平和残余胆固醇水平，且整体用药安全性可控，患者耐受性良好。点击文末“阅读原文/Read more”，即可访问The Lancet官网阅读完整论文。推荐阅读欢迎投稿：学术成果、前沿进展、临床干货等主题均可，点此了解投稿详情。参考资料[1] Beryl B Cummings, Mark P Joing, Page R Bouchard, et al. Safety and efficacy of a novel ANGPTL4 inhibitory antibody for lipid lowering: results from phase 1 and phase 1b/2a clinical studies. Published Online May 15, 2025. The Lancet. http://doi.org/10.1016/S0140-6736(25)00825-6.[2] Anders B Wulff. Safely lowering triglycerides through ANGPTL4 inhibition. Published Online May 15, 2025. The Lancet. https://doi.org/10.1016/S0140-6736(25)00988-2. 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「医学新视点」微信公众号留言联系。如有其他合作需求，请联系wuxi_media@wuxiapptec.com分享，点赞，在看，传递医学新知