Obicetrapib

过去一年，血脂领域在基础研究、临床实践、药物研发和患者管理等方面开展了一系列研究，取得了显著成果。这不仅更新并完善了我们对血脂异常的认知，同时也为心血管疾病防治提供了新思路和新方法。本文将从临床血脂管理的角度，重点回顾2025年血脂领域的指南共识和临床试验。此外，随着去年欧洲动脉粥样硬化性学会（EAS）提出“系统性代谢紊乱（SMD）”这一概念，血脂异常与代谢异常之间的联系愈发受到关注。因此，本文也将对在2025年美国心脏病学会（ACC）年会、欧洲心脏病学会（ESC）年会和美国心脏协会（AHA）年会上发布并被评为重要研究的代谢相关药物的临床试验做初步点评。 北京大学人民医院 陈红教授 壹 血脂管理相关的指南共识 2025年，新发布/更新的主要血脂管理指南共识共10项，（表1），其中有2项分别聚焦高甘油三酯血症和高龄老人（>75岁）高胆固醇血症管理。过去1年没有发布专门针对脂蛋白（a）[Lp(a)]水平管理的指南和共识，部分原因可能与相关的3期临床研究尚未完成有关。 这些指南在诸多观点上保持一致，均认同低密度脂蛋白胆固醇（LDL-C）是动脉粥样硬化（AS）和动脉粥样硬化性心血管疾病(ASCVD)防治的首要靶点，他汀类药物是降低LDL-C的基石和首选药物，同时也都肯定了非他汀类降脂药物在ASCVD中的作用。然而，也存在值得讨论的差异，其中最重要的差异在于LDL-C治疗目标值的设定。尽管降低LDL-C可带来获益已成共识，但不同专业组织的推荐目标不尽相同。2025年ESC/EAS血脂异常管理指南延续了2019年指南的推荐, 即低、中、高、极高和超高危人群LDL-C的目标值分别为<3.0、<2.6、<1.8、<1.4和<1.0mmol/L，其中对低危和超高危人群LDL-C的推荐仍是Class IIb。大部分指南与ESC/EAS指南的推荐相似，要求ASCVD患者LDL-C的靶目标<1.4mmol/L（ Class Ia），对发生过多次ASCVD事件等的超高危人群，可以考虑<1.0mmol/L。美国内分泌医师协会(ACCE)的去年发布的指南则极具“个性”。2017年ACCE率先将不稳定、早发或合并DM的ASCVD患者的LDL-C目标值由<1.8mmol/L下调为<1.4mmol/L，但AACE今年发布的2个指南又将针对这一人群的LDL-C目标值上调回<1.8 mmol/L，理由是支持<1.4mmol/L获益的证据尚不充分。 心血管风险评估是ASCVD防治的重要举措，有助于量化未来风险、识别高危人群、指导个体化治疗及优化医疗资源配置。然而，由于人群差异、预测终点定义及所用参数不同，加之方法学的局限性，各指南的风险评估模型在适用人群、预测因子和风险分层标准上存在差异。 表1 2025年由主要学术机构新发布或更新的血脂管理指南与共识 贰 2025年获批上市的降脂药物 2025年中国、美国和欧盟陆续有多款新型降脂药物获批上市（表2），涵盖寡核苷酸、单抗和小分子化合物等，提示血脂管理进入更多元化和精准化的新阶段。 表 2 2025年获批在中国、美国和欧盟上市的主要降脂药物 Lerodalcibep-liga是Adnectin与人血清白蛋白结合形成的融合蛋白，是第3代前蛋白转化酶枯草溶菌素9 （PCSK9）抑制剂，有半衰期长（12-15天）、使用便利且无需冷藏的特点。2025年普乐司兰在美国获批用于治疗家族性乳糜微粒血症综合征，该药已于2026年1月获批在中国上市，适应症同美国。 叁 2025年完成的降脂治疗相关的主要临床试验 2025年，血脂临床领域完成了许多临床干预研究，限于篇幅，在此主要汇总在去年ACC, ESC和AHA年会发布并被评为重要研究的临床试验（表3），并分类简介如下 （一） 降低Lp(a)的临床干预研究 去年发布的Lp(a)相关临床干预研究较少，3个重要的3期临床研究（HORIZON研究、OCEAN(a)–Outcomes 研究和ACCLAIM-Lp(a)研究）均处于随访阶段。目前以小干扰RNA（如olpasiran、lepodisiran）、反义寡核苷酸（如pelacarsen）、小分子抑制剂（如muvalaplin）乃至基因编辑（如CTX320）为代表的新型降低Lp(a)的疗法正在研发中，展现出巨大潜力。 ALPACA研究 研究简介：该研究的目的旨在评估Lepodisiran对Lp(a)增高患者的疗效和安全性。Lepodisiran（LY3819469）是靶向apo(a) mRAN的小干扰RNA（siRNA）,可以抑制肝脏合成Lp(a)蛋白的。有包括中国在内的10个国家66个中心参加的随机双盲安慰剂对照的2期临床研究，共入选320例年龄>40岁，且Lp(a)浓度Lp(a) ≥175 nmol/L的患者，主要终点为与安慰剂相比，治疗组第60-180天（即第2次注射前）Lp(a)变化幅度（%）。分别于入组第一天和第180天皮下注射给药。研究提示经安慰剂校正后，Lepodisiran治疗180天后Lp(a)浓度明显降低。观察致540天，未发现严重不良事件，注射部位的反应较轻，主要见于最高剂量组。该研究提示Lp(a)增高的成人，单次注射Lepodisiran可显著降低Lp(a)浓度。 其它：Lp(a)浓度有明显的种族差异，但该研究只有2%的黑人参与。该研究为正在招募中的Lepodisiran 3 期心血管结局试验提供了剂量和给药间隔依据 临床意义： Lepodisiran可能为管理升高的Lp(a)提供一种疗效确切更长效的治疗选择，有望通过较少的给药频率提高依从性 （二）降低LDL-C相关的临床干预研究 过去一年，降胆固醇领域的重要临床研究主要集中于PCSK9抑制剂，形成压倒性主导态势，体现了长效化，口服化的特点 PURSUIT研究 研究简介：本研究旨在评估AZD0780对已接受他汀治疗的高胆固醇血症患者的疗效和安全性。AZD0780 是一种有较高的生物利用度的小分子PCSK9抑制剂，它与PCSK9蛋白C端结构域‌特异性结合，防止 PCSK9 诱导的 LDLR 降解。有8个国家55个中心参加了该随机双盲安慰剂对照的2期临床研究，共入选428例高胆固醇血症的患者，所有患者均服用他汀类，且在试验过程中继续按原方案服用。经口服给药，每日1次。主要终点为治疗12周后LDL-C变化的幅度(%)。研究发现，经安慰剂校正后，口服AZD0780 12周后LDL-C水平明显降低， 1、3、10和30mg组的下降幅度分别为35.3%、37.9%、45.2%和50.7%（p均<0.001）。安全性良好。 其他：可以与他汀类药物合用，其长期疗效、安全性，以及是否可以和其他降胆固醇药物联合使用，还有于进一步研究 临床意义：AZD0780有成为可及性好，安全有效的PCSK9抑制剂的潜力 VESALIUS-CV试验 研究简介：该研究旨在对AS或AS的高危患者早期使用依洛优单抗是否能降低心血管风险。依洛优单抗是抑制PCSK9的单克隆抗体。该研究在33个国家的774个研究中心进行，是一项随机、双盲、安慰剂对照的3期临床研究。。共入选12257例LDL-C未达标的既往无MI或脑卒中的AS患者或病程≥10年的糖尿病患者，所有患者必须接受优化稳定的降脂治疗至少2周，且在试验过程中继续按原方案服用。研究预设两个主要终点：（1） 3点主要不良心血管事件：冠心病死亡、心肌梗死或缺血性卒中；（2）4点主要不良心血管事件：冠心病死亡、心肌梗死、缺血性卒中或缺血驱动的血运重建。皮下注射给药，每2周1次。经4.6年的随访，与安慰剂组相比， 依洛优单抗组的心血管风险明显减低，其中3点主要不良心血管事件风险降低25%，4点主要不良心血管事件降低19%（p均小于0.001）。依洛优单抗组基线时LDL-C 116mg/dL，治疗48周后降至45mg/dL，较安慰剂组降低55.3%.研究结果于2025年的AHA年会上发布。 其它：该随机对照研究平均随访4.6年，是目前随访时间最长的PCSK9抑制剂终点事件研究。该研究的结果是依洛优单抗联合他汀类药物治疗的效果，单独使用依洛优单抗是否能够获得同样的结果还有待进一步的研究。 临床意义：无心血管重大事件的动脉粥样硬化和高危糖尿病患者，应尽早在常规降脂治疗的基础上加用依洛优单抗，以进一步降低心血管风险 CORALreef脂质试验 研究简介：本研究旨在评估 Enlicitide（(MK-0616 ）对高胆固醇血症成年患者的有效性、安全性和耐受性。Enlicitide是一种小分子大环肽类口服PCSK9抑制剂，它与PCSK9结合，竞争性阻断PCSK9与肝细胞表面‌的低密度脂蛋白受体（LDLR）结合。这项随机、双盲、安慰剂对照的3期临床研究在包括中国在内的14个国家和地区的168个研究中心开展，共入选2904例既往有ASCVD事件或ASCVD的高危患者。除他汀不耐受者外，绝大部分患者（95%）均已接受包括他汀在内的稳定的降脂治疗，且在试验过程中继续按原方案服用。口服给药，每天1次。主要终点有三个：（1）第24周时LDL-C的变化幅度（%）；（2）60周内不良事件的发生率（%）；（3）52周内因不良事件而停药的比例（%）。研究结果提示：经安慰剂校正后，24周时Enlicitide组LDL-C下降55.8%（ p < 0.001）。Enlicitide与安慰剂组不良事件的发生率分别为64.3%和62.1%，因不良事件终止治疗的比例分别为3.2%和4.0%。安全性和耐受性良好。研究结果于2025年AHA年会上发布。 其它：包括该研究在内的一项延展性研究将进一步评估该药的长期安全性和有效性，同时有两项将开展的3期临床将分别评估该药联合瑞舒伐他汀后的有效性，以及对主要心血管不良事件的影响。 临床意义：口服Enlicitide能够产生与注射类PCSK9抑制剂相似的降LDL-C效果，为需降LDL-C的患者提供了潜在的便捷新选择。 CORALreef HeFH研究 研究简介：该研究旨在评价Enlicitide对成年HeFH患者的疗效和安全性。有包括台湾在内的17个国家和地区的59个研究中心参加了该随机双盲的3期临床研究。共入选303例年龄≥18岁的HeFH患者。所有患者均稳定接受他汀治疗，且在试验过程中继续按原方案服用。口服给药，每天1次。主要终点为第24周时LDL-C的变化幅度（%）。研究提示，与安慰剂相比，第24周时Enlicitide显著降低LDL-C, 降幅达−59.4%（P < 0.001），耐受性和安全性良好。 其它：为改善胃肠道的吸收，Enlicitide的功能性赋型剂辛酸钠具有渗透增强作用，安慰剂中不含辛酸钠，但两组间的安全性、耐受性，以及空腹服药的依从性均相似。计划开展2/3期临床试验，探索该药对儿童和青少年HeFH的影响。 临床意义：可能为HeFH患者LDL-C达标带来新的选择和希望 BROADWAY研究 研究简介：该研究旨在确定Obicetrapab对LDL-C水平的影响及安全性。Obicetrapab是一种抑制胆固醇酯转移蛋白（CETP）的小分子化合物。这项随机、双盲、安慰剂对照的3期临床研究在中国、欧洲、日本和美国的188个研究中心开展，共入选 2530例65岁左右的ASCVD或HeFH患者，所有患者均已接受最大耐受剂量的降脂治疗，且在试验过程中继续按原方案服用。基线LDL-C 浓度为98mg/dL（2.54mmol/L）。主要终点为第84天LDL-C的变化幅度（%）。口服给药，每天一次。研究发现，经安慰剂组校正，Obicetrapab治疗84天后LDL-C明显降低，降幅为32.6%（P<0.001），同时HDL-C、apoB和Lp（a）浓度变化分别为+136.3%、−18.9%和−33.5%。两组包括血压在内的安全结局（59.7% vs 60.8%）以及最常见的不良事件的发生率相似。这些发现表明，Obicetrapab在已经接受强化降脂治疗的高风险人群中，能能进一步降低LDL-C水平。 其它：尽管在随访的第365天时，一些亚临床终点（如apoB, non-HDL-C等）的变化与期望相符，但其长期安全性仍需进一步了解。计划将开展的一项大型长期心血管结局试验将进一步评估安全性和对心血管疾病预后的影响。另外在2025年的阿尔茨海默病协会国际会议（AAIC）上，发布了BROADWAY试验预设亚组分析的结果，提示Obicetrapib有‌显著延缓阿尔茨海默病生物标志物进展的作用。‌ 临床意义：可能为心脑血管疾病防治增添新的靶点和思路 （二）降低甘油三酯的临床干预研究 2025年，降低甘油三酯相关的临床研究成果显著，靶向‌APOC3‌的siRNA类药物普乐司兰不但完成了3期临床研究，而且在美国和中国获批上市，用于家族性乳糜微粒血症综合征。同时新靶点和新方法在高甘油三酯血症的管理上也崭露头角。 PROLONG-ANG3研究 研究简介：本研究旨在评估Solbinsiran（LY3561774）对混合性血脂异常成年患者致动脉粥样性脂蛋白，特别是apo B浓度的影响。Solbinsiran是一种靶向肝脏血管生成素样蛋白3（ANGPTL3） mRAN的siRNA, 通过N-乙酰半乳糖胺（GalNAc）特异性递送致肝细胞表面，与去唾液酸糖蛋白受体（ASGPR）结合后抑制肝脏合成ANGPTL3，从而增加脂蛋白酯酶的活性。有7个国家的41个临床中心参加了该随机双盲安慰剂对照的2期临床研究，共入选了205例混合型高脂血症的成年患者，所有患者在入选前至少服用了2个月的他汀类药物，且在试验过程中继续按原方案服用。主要终点为第180天apoB的变化幅度（%）。分别于研究的0天和90天经皮下注射给药。研究发现，与安慰剂组相比，尽管Solbinsiran显著降低了ANGPTL3浓度，但只有400mg组在180天时apoB浓度明显下降，降幅为14.3%;（p=0.008），同时LDL-C和甘油三酯浓度分别降低16.8%和50.3%。至270天时Solbinsiran 400mg组降低apoB的疗效依然存在（-11.3%，p=0.033）。药物不良反应总体与安慰剂组相似，但Solbinsiran组血糖出现了短暂变化，氨基转移酶浓度暂时升高的人数多于安慰剂组（7人vs 1人） 其它：尽管研究跨越四大洲，但以西班牙裔为主。在第180天时，通过MRI测量获得的肝脏脂肪分数，无论时400毫克（-27.6%）还是800毫克（-21.1%）均显著降低，但仍需进一步观察期长期的安全性和疗效 临床意义：靶向ANGPTL3的Solbinsiran除降低TG外，还可以通过降低apoB为混合型血脂异常治疗提供另一个可能的靶点。‌也可能对减少肝脏脂肪有益处 CORE-TIMI 72研究 研究简介：该研究包括两项3期临床研究，即：CORE-TIMI 72a和CORE 2-TIMI 72b，旨在评估Olezarsen对严重高甘油三酯血症的疗效。Olezarsen是靶向apo C3 mRNA的反义寡核苷酸，已于2024年底被FDA批准用于治疗家族性乳糜微粒血症综合征（FCS）。有33个国家和地区的293个研究中心参与这该随机双盲安慰剂对照的3期临床研究。共入选1061例基线时空腹TG水平≥ 500 mg/dL (5.65 mmol/L)的患者。所有患者在筛选前应优化并稳定降脂药物至少 4 周，且在试验过程中继续保留原降脂方案。主要终点为治疗6周后TG水平的变化幅度（%）。急性胰腺炎的发生率（至第53周）是次要终点之一。皮下注射给药，每周1次，共49周。治疗6周后Olezarsen 50mg和80mg组分别降低甘油三酯49.2-62.9%和54.5-72.2%（P均小于0.001）。约86%的接受治疗患者达到了甘油三酯水平<500 mg/dL的目标（而安慰剂组为35%；p < 0.001）。和安慰剂组相比，急性胰腺炎的风险降低85%，对基线TG ≥ 880 mg/dL的胰腺炎高危患者，获益更大，NNT为每年4例（p < 0.001）。各治疗组间的总体不良事件相似，但80 mg剂量组中轻度肝酶升高、肝脂肪增加和血小板减少的发生频率较高。 其它：为评价长期的安全性和疗效，计划基于该试验开展名为CORE-OLE研究的开放标签扩展研究。 临床意义：有助于扩展Olezarsen的适应症，为高甘油三酯血症患者提供有效安全的治疗 PALISADE研究 研究简介：本研究旨在评估普乐司兰（Plozzasiran）对持续性乳糜微粒血脂患者的疗效和安全性。普乐司兰是靶向apoC3 mRNA的siRNA，通过抑制甘油三酯代谢路径中的重要蛋白apoC3的合成，降低循环甘油三酯水平。有21个国家的53个研究中心参加了该随机双盲安慰剂对照的3期临床研究。共入选75例经标准降脂治疗后至少3次空腹TG均大于1000mg，且基因或临床诊断为FCS的成人患者。主要终点为治疗10个月后甘油三酯水平变化的幅度（%），急性胰腺炎发生率为次要终点之一。经皮下注射给药，每3个月1次。患者基线甘油三酯水平为2044mg/dL。治疗1个后甘油三酯明显下降，此后基本维持该水平，至第10个月时普乐司兰25mg和50mg组甘油三酯浓度下降的幅度分别为80%和78%，与安慰剂组（-17%）相比，均明显下降（P<0.001），普乐司兰治疗也极大的降低了急性胰腺炎的风险，降幅达83%（P=0.03）。各组间的药物不良反应风险相似。 其它：该研究的部分患者后续被纳入一个开放标签的3期临床研究，以进一步观察该药长期安全性。该研究中近一半的人是经基因检测确诊的FCS患者，按预先设定的亚组，研究了该药对有或无基因诊断患者疗效的影响，发现试验患者对Plozasiran的反应（apoC3，或TG水平）与其确诊的遗传特征无关。一项正在进行的3期临床正在探索该药对严重高甘油三酯血症（有急性胰腺炎病史）患者的疗效和安全性，以期扩大适应症。 临床意义：目前严重高甘油三酯血症和其并发症的治疗手段非常有限且疗效欠佳。该研究为这部分患者带来了曙光，同时由于这种新的降甘油三酯方法的出现，有助于破解甘油三酯和AS关系这一难题。 DR10624的2期临床研究 研究简介：本研究旨在评估DR10624对严重高甘油三酯血症的影响。DR10624 是由中国研发的全球首个三靶点激动剂，是一种 Fc 融合蛋白。该药通过激动胰高血糖素样肽-1受体（GLP-1R）、胰高血糖素受体（GCGR）和成纤维细胞生长因子21受体(FGF21R)，调节代谢，降低甘油三酯水平。中国的35个中心参加了这项随机、双盲、安慰剂对照的2期临床试验，共入选79例甘油三酯水平500-2000mg/dL（中位数水平832.5mg/dL）的患者。主要终点为 12 周时空腹血清甘油三酯水平的变化幅度（%）。皮下注射给药，每周1次，共12周。结果显示，治疗2周后DR10624组的甘油三酯水平基本达最低水平，并持续至治疗12周。12周时DR10624组较安慰剂组的甘油三酯水平明显降低，降幅分别为68.9%和8%（p<0.001）。同时DR10624在所有剂量组均显著降低了肝脏脂肪含量。影像学研究显示，治疗12周后，许多患者的肝脏脂肪含量<5%。总体耐受性良好。最常见的不良反应包括轻度至中度恶心事件（治疗组23.7%，安慰剂组5.0%）、食欲减退（22.0%对5.0%）以及注射部位红斑（13.6%对5.0%）。 其它：后续需进一步探索该药对不同种族人群的影响。评估DR10624对不同类型脂肪性肝病的作用。该药拟定适应症是重度高甘油三酯血症，已被国家药品监督管理局药品审评中心（CDE）纳入“突破性治疗品种”， 其临床试验的申请也于去年10月获得FDA的批准，这为3期临床研究的开展奠定了基础 临床意义：这些发现为管理严重甘油三酯血症，以及降低胰腺炎、代谢功能障碍相关脂肪性肝病（MASLD）和心血管疾病等长期并发症提供了新的希望，有助于‌推动中国创新药发展‌ CTX310的1期临床试验 研究简介：该研究旨在评估CTX310的安全性。CTX310是含有‌编码CRISPR-Cas9内切酶mRNA‌和‌靶向ANGPTL3基因的向导RNA（gRNA）的脂质纳米颗粒（LNP）。LNP将mRNA和gRNA递送至肝细胞，mRNA在细胞内翻译成Cas9蛋白，与gRNA结合形成复合物，切割并敲除ANGPTL3基因。这项在澳大利亚、新西兰和英国的6个研究中心开展的开放标签、单次递增剂量的1期临床研究，共入选15例经最大耐受剂量的降脂疗法后仍为未控制的高胆固醇血症、中重度高甘油三酯血症或混合性血脂异常的成年患者。主要终点是不良事件发生率，包括限制剂量的毒性效应（主要指持续的肝氨基转移酶和胆红素严重升高，以及达到不良事件通用术语标准3-4级的任何实验室结果）。次要终点为ANGPTL3、LDL-C浓度等。单次静脉输注给药，给药前所有参与者均接受了糖皮质激素和抗组胺药的预治疗。结果提示，未发生与CTX310相关的剂量限制性毒性效应。发生“任何严重的不良事件”2例，一例为死亡（0.1mg/kg组），另一例为椎间盘突出住院（0.3mg/kg组），分别发生于治疗后6和7个月。与CTX310相关的特殊不良事件主要为输液相关反应、过敏反应和转氨酶升高，严重程度均小于3级。0.8mg/kg组ANGPTL3水平降低73%，LDL-C降低49% 。0.6mg/kg组甘油三酯水平降幅最大，达62% 其它：尽管研究者认为试验中1例有心血管疾病的51岁男性的死亡与治疗无关，但因在转甲状腺素蛋白淀粉样变性心肌病的转基因治疗（nexiguran ziclumeran） 3 期试验中也报告了死亡事件，2项研究采用的基因编辑技术（CRISPR-Cas9）和递送系统（脂质纳米颗粒）相同，故其安全性还有待进一步评估。CTX310的II期临床研究计划将于今年启动。 临床意义：1期临床的安全性数据支持可以进一步研究基于CRISPR-Cas9基因编辑技术靶向ANGPTL3的CTX310，给打一针“一劳永逸”的降脂梦想带来了希望 肆 代谢相关的心血管临床研究 2025年代谢领域完成了多项临床试验，但在此仅就SOUL研究和SURMOUNT-5试验及事后分析进行简述，选择理由如前述。DR10624的2期临床研究见“降低甘油三酯的临床干预研究”，不再赘述。这些研究进一步深化了对代谢疾病的分子机制认知，推动了代谢疾病防治从单一血糖控制向综合风险管理的范式转变，为临床实践提供了更精准的干预策略。 SOUL研究 研究简介：该研究旨在评估口服司美格鲁肽对患有ASCVD、慢性肾病或两者兼有的2型糖尿病患者的心血管影响。司美格鲁肽是GLP-1R激动剂，通过激活GLP-1R调控血糖，并抑制食欲。有33个国家的444个研究中心参加了该随机、双盲事件驱动的3b期临床试验，共入选9650例有ASCVD、慢性肾病或两者兼有的2型糖尿病患者，平均随访47.5个月。主要研究终点为主MACE（包括心血管死亡、非致命MI或非致命性卒中）。口服司美格鲁肽从3mg开始，最终加量为14mg，每日1次。研究提示口服司美格鲁肽可以明显降低MACE风险14% (p=0.006),其心血管保护作用与年龄、性别、体质指数、心血管病史、eGFR及基线用药情况无关。严重不良事件较安慰剂组低。 其它：在司美格鲁肽组和安慰剂组中，约有28%的受试者发生了随机分配药物的过早永久停药。口服司美格鲁肽组172名参与者（3.6%）和安慰剂组253名（5.2%）开具了开放标签GLP-1RA。对肾脏的影响还有待进一步观察 临床意义：口服司美格鲁肽也可以降低糖尿病患者的心血管事件，有望和注射类司美格鲁肽共同用于糖尿病患者的管理。 SURMOUNT-5试验及事后分析     研究简介 1.SURMOUNT-5试验：这是一个“头对头”的临床研究，旨在比较替尔泊肽和司美格鲁肽对无糖尿病的肥胖患者体重的影响。‌与司美格鲁肽不同，替尔泊肽是全球首个双受体激动剂，可以同时激活葡萄糖依赖性胰岛素释放多肽（GIP）受体和GLP-1R，实现双靶点协同效应，有更强的代谢调节能力。美国和波多黎各的32个研究中心参加了该随机对照开放标签的3b期临床试验，共入选751例肥胖但无DM的成年患者。主要终点是替尔泊肽与司美格鲁肽相比，72周后体重的变化幅度（%）。每周皮下注射替尔泊肽（10或15 mg）或司美格鲁肽（1.7或2.4 mg），持续72周。结果提示：72周时替尔泊肽组体重下降20.2%，较司美格鲁肽组有更好的减轻体重的效果（13.7%，P<0.001）。治疗期间发生或恶化的不良事件替尔泊肽和司美格鲁肽分别为76.7%和49.0%，最常见的是轻-中度的胃肠道症状 2.SURMOUNT-5试验事后分析：旨在比较替尔泊肽和司美格鲁肽减轻肥胖患者体重对10年心血管疾病风险的影响。入选上述参加SURMOUNT-5试验，但基线无心血管疾病的576例患者。这是一个事后分析，基于美国国家健康与营养检查调查数据，采用用D’Agostino等人提出的基于BMI的性别特异性风险方程评估心血管风险，比较替尔泊肽和司美格鲁肽治疗组之间从基线到72周时预测10年CVD风险的变化。治疗前所有患者的预测10年CVD风险为9.3%。治疗72周后，替尔泊肽和司美格鲁肽组的预测10年CVD风险分别下降2.4% 和1.4%（P < 0.001），替尔泊肽较司美格鲁肽能更显著降低预测10年CVD风险。这种差异在治疗12周时已体现。 其它：相比于替尔泊肽，司美格鲁肽的心血管获益已获得包括SELECT试验和‌SOUL试验‌的证实，但替尔泊肽对心血管风险影响3期正在评估中（SURMOUNT-MMO研究） 临床意义：对肥胖的非糖尿病患者替尔泊肽有更好的减肥效果，该效应在肥胖患者的一级预防中有可能转化为心血管获益 总之，过去一年是血脂管理领域成果丰硕的一年。 从指南共识的细化与更新，到以siRNA、基因编辑为代表的革命性疗法在临床研究中的卓越表现，再到口服PCSK9抑制剂、多靶点激动剂等新药的不断涌现，都深刻表明血脂管理正加速迈向多靶点协调，更精准、更长效、更便捷的新时代。 表3 2025年降血脂相关的主要临床试验 作者简介 陈红 北京大学人民医院（点击查看专家详细简历） 延伸阅读 向上滑动阅览 年度盘点丨赵强：2025年冠脉外科进展 年度盘点丨潘湘斌：2025年二尖瓣介入治疗领域重要进展 年度盘点丨张抒扬&田庄：2025年肥厚型心肌病药物治疗进展 年度盘点丨葛雷：2025年冠状动脉慢性完全闭塞病变（CTO）介入治疗进展 年度盘点丨余江涛&白元：2025年经导管左心耳封堵国际视野 年度盘点丨秦永文&张玉顺&白元&朱霓：2025年卵圆孔未闭（PFO）诊疗新进展 年度盘点丨李小梅：2025年植入型心律转复除颤器（ICD）的临床应用进展——EV-ICD 年度盘点丨张静：2025年心脏重症救治进展——理念深化、路径完善与能力提升 年度盘点丨张运&刘艳：2025年超声心动图领域重要进展 年度盘点丨邹建刚：2025年心脏生理性起搏领域重要临床研究进展 年度盘点｜荆志成&蒋鑫&吴文汇：2025年肺栓塞领域研究年度进展 年度盘点丨杨杰孚&王华：2025年心力衰竭进展——治疗突破、全程管理与中国数据揭示的防治新路径 年度盘点丨崔勇：2025年肥厚型心肌病外科治疗进展——myectomy 的机制化与路径再定位 年度盘点丨陶凉：2025年小主动脉根部手术治疗进展 年度盘点丨居维竹&陈明龙：2025年室性心律失常诊疗进展——策略演进与技术创新 年度盘点丨窦克非：2025年介入式心室辅助装置（pVAD）进展——新的器械和新的证据 年度盘点丨张澄&杨建民：2025年急性失代偿心衰治疗进展——指南更新、技术革新与实践优化 年度盘点丨侯晓彤：2025年体外生命支持领域研究进展 年度盘点丨陆方林：高分子材料心脏瓣膜进展——从材料创新走向临床验证 年度盘点丨蔡军：高血压2025年度诊疗进展  年度盘点丨王焱：2025年度三尖瓣介入进展——从“被遗忘”到“多策略干预”的范式重塑 年度盘点丨赵世华：心血管磁共振与人工智能2025年度诊疗进展——从“生成式重建”到“多模态精准诊疗” 年度盘点丨陈绍良：2025年肺高压诊疗进展——从血管重构机制到新型药物与肺动脉去神经术的综合管理 · END · 版权及免责声明：严道医声网旨在搭建学术传播及媒体发声平台，文内信息版权属于持有人，我们只提供传递信息之用。如有侵权，请联系我们删除。 点击 “阅读原文” 进入 “2025 年度盘点”专栏

-- Approval decisions from EMA, UK and Switzerland regulators for obicetrapib and obicetrapib/ezetimibe fixed dose combination expected in 2H26 -- -- Phase 3 PREVAIL CVOT blinded event rate tracking in line with observed event rate in BROADWAY-- -- Topline data from RUBENS Phase 3 trial in patients with type 2 diabetes and metabolic syndrome expected by year-end 2026 -- -- $728.9 million in cash, cash equivalents and marketable securities at December 31, 2025 -- NAARDEN, the Netherlands and MIAMI, Feb. 18, 2026 (GLOBE NEWSWIRE) -- NewAmsterdam Pharma Company N.V. (Nasdaq: NAMS or “NewAmsterdam” or the “Company”), a late-stage, clinical biopharmaceutical company developing oral, non-statin medicines for patients at risk of cardiovascular disease (“CVD”) with elevated low-density lipoprotein cholesterol (“LDL-C”), for whom existing therapies are not sufficiently effective or well-tolerated, today announced financial results for the full year ended December 31, 2025 and provided a corporate update. “2025 marked a year of meaningful clinical and regulatory progress for NewAmsterdam, as we advanced our mission to bring a potentially transformative therapy with obicetrapib to cardiometabolic disease patients who continue to struggle to reach their LDL-C goals,” said Michael Davidson, M.D., Chief Executive Officer of NewAmsterdam. “Marketing Authorization Applications for obicetrapib and the fixed dose combination were accepted for review by the European Medicines Agency (“EMA”), Switzerland, and United Kingdom regulators, and we anticipate a decision from each in the second half of 2026. In parallel, together with our partner Menarini, we are actively preparing for a potential commercial launch in Europe. In the United States, we continue to expand our commercial capabilities with the notable hiring of Steve Albers, former senior vice president of market access and public affairs at Novo Nordisk, who will now lead our market access and public affairs efforts, further strengthening our established team.” “At the same time, we remain focused and well positioned to execute our clinical development strategy, including the advancement of obicetrapib in our three ongoing Phase 3 trials: PREVAIL, REMBRANT and RUBENS. In December 2025, we initiated the RUBENS trial, which will evaluate obicetrapib alone and in combination with ezetimibe in patients with type 2 diabetes or metabolic syndrome that require additional lowering of LDL-C despite treatment with available therapy, with topline data expected by year-end 2026. Our PREVAIL cardiovascular outcomes trial continues to progress well, where the overall blinded MACE event rate in PREVAIL through the initial 12-months was in line with what we observed in BROADWAY. NewAmsterdam continues to operate from a position of financial strength, with cash runway expected to be sufficient to fund operations through the PREVAIL readout and, if approved, support the subsequent U.S. commercial launch. Additionally, following positive biomarker results from the Alzheimer’s disease analysis in the BROADWAY trial, we plan to initiate a new clinical trial evaluating obicetrapib in early Alzheimer’s disease patients this year.” Clinical Development and Regulatory Updates NewAmsterdam is developing obicetrapib, an oral, low-dose and once-daily, highly-selective cholesteryl ester transfer protein (“CETP”) inhibitor, as a monotherapy and in fixed-dose combination with ezetimibe, as the preferred LDL-C lowering therapy to be used in patients at risk of CVD for whom existing therapies are not sufficiently effective or well-tolerated. In August 2025, NewAmsterdam announced acceptance of MAAs for review by the EMA for obicetrapib 10 mg monotherapy and 10 mg obicetrapib plus 10 mg ezetimibe FDC for patients with primary hypercholesterolemia, both heterozygous familial (“HeFH”) and non-familial or mixed dyslipidemia. Subsequently, MAAs were also submitted to regulators in UK and Switzerland and accepted for review. The MAAs were submitted by NewAmsterdam’s partner, A. Menarini International Licensing S.A. (“Menarini”), who is responsible for communications with regulatory authorities in Europe and for the commercialization and local development of obicetrapib in Europe and other collaborative activities pursuant to an exclusive License Agreement (the “Menarini License”). NewAmsterdam is entitled to tiered double-digit percentage royalties ranging from the low double-digits to mid-twenties on net sales in the European countries covered by the Menarini License and up to an additional €833 million upon the achievement of various clinical, regulatory and commercial milestones. In August 2025, NewAmsterdam presented pooled data from its pivotal Phase 3 BROADWAY and BROOKLYN trials on the impact of obicetrapib on major adverse cardiovascular events at the European Society of Cardiology Congress (“ESC”) 2025, along with the simultaneous publication in the Journal of the American College of Cardiology, highlighting obicetrapib’s performance across diverse lipid-lowering backgrounds observed in these trials. The presentation and publication underscore the Company’s continued momentum in advancing obicetrapib as a differentiated oral therapy for patients with elevated LDL-C. In June and July 2025, NewAmsterdam announced positive data from the prespecified AD biomarker analysis in the BROADWAY clinical trial and presented at the 2025 Alzheimer’s Association International Conference (“AAIC”). The pre-specified analysis was conducted to assess the effect of obicetrapib on plasma biomarkers of AD in both the full analysis set and in patients carrying the apolipoprotein E4 (“ApoE4”) gene, based on phenotypic analysis. NewAmsterdam observed statistically significant reductions in p-tau217, a key biomarker of AD pathology, in both the full analysis set (p<0.002, n=1,515) and in ApoE4 carriers (p=0.0215, n=367), which NewAmsterdam believes support an emerging link between CETP-inhibition and neurodegeneration. In ApoE4/E4 carriers, the highest risk category for Alzheimer’s disease, obicetrapib was observed to reduce p-tau217 levels by 20.5%, over 12 months, compared to placebo (p=0.010, n=29). In October 2025, the data was published in the Journal of Prevention of Alzheimer's Disease. NewAmsterdam observed statistically significant reductions in p-tau217, a key biomarker of AD pathology, in both the full analysis set (p<0.002, n=1,515) and in ApoE4 carriers (p=0.0215, n=367), which NewAmsterdam believes support an emerging link between CETP-inhibition and neurodegeneration. In ApoE4/E4 carriers, the highest risk category for Alzheimer’s disease, obicetrapib was observed to reduce p-tau217 levels by 20.5%, over 12 months, compared to placebo (p=0.010, n=29). In October 2025, the data was published in the Journal of Prevention of Alzheimer's Disease. Upcoming Milestones and Ongoing Trials: Following the successful completion and positive topline results of the Phase 3 BROADWAY, TANDEM, and BROOKLYN trials, NewAmsterdam plans to announce additional data from these trials relating to obicetrapib and the FDC of obicetrapib plus ezetimibe during 2026. The following Phase 3 trials are currently ongoing: PREVAIL Phase 3 trial: PREVAIL is a CVOT evaluating obicetrapib in patients with a history of ASCVD, whose LDL-C is not adequately controlled despite being on maximally tolerated lipid-lowering therapy. NewAmsterdam completed enrollment of over 9,500 patients in April 2024. REMBRANDT Phase 3 trial: The REMBRANDT trial utilizes coronary computed tomography angiography imaging to evaluate the effect of obicetrapib plus ezetimibe FDC on coronary plaque burden. The placebo-controlled, double-blind, randomized, Phase 3 trial is being conducted in adult participants with high-risk ASCVD with evidence of coronary plaque who are not adequately controlled by their maximally tolerated lipid-modifying therapy, to assess the impact of the obicetrapib 10 mg plus ezetimibe 10 mg FDC daily on coronary plaque and inflammation characteristics. The trial is expected to complete enrollment of approximately 300 patients in 2026. RUBENS Phase 3 trial: Initiated in December 2025, the RUBENS trial will evaluate obicetrapib alone or in combination with ezetimibe in patients with type 2 diabetes or metabolic syndrome that require additional lowering of LDL-C despite treatment with available therapy. The trial is expected to enroll approximately 300 patients, with topline data expected by year end 2026. Additionally, NewAmsterdam expects to initiate a new clinical trial evaluating obicetrapib in early Alzheimer’s disease patients in 2026. Full Year 2025 Financial Results Cash Position: As of December 31, 2025, NewAmsterdam reported cash, cash equivalents and marketable securities of $728.9 million, compared to $834.2 million as of December 31, 2024. The decrease was primarily driven by cash outflows related to research and development costs as the Company continues development of obicetrapib and spending on selling, general and administrative expenses to support the Company’s ongoing operations, partially offset by cash inflows from the exercise of options and warrants. Revenue: NewAmsterdam recognized $22.5 million in revenue for the year ended December 31, 2025, compared to $45.6 million in the year ended December 31, 2024. The decrease in revenue related to clinical development milestones pursuant to the Menarini License was partially offset by an increase in the amount of revenue recognized in the current period related to the development cost contributions under the Menarini License. Research and Development (“R&D”) Expenses: R&D expenses were $141.8 million for the year ended December 31, 2025, compared to $151.4 million in the year ended December 31, 2024. The decrease was primarily driven by a decrease in clinical expenses mainly due to the completion of several Phase 3 clinical trials in the second half of 2024 and cost phasing in ongoing clinical trials, partially offset by increases in non-clinical expenses, manufacturing expenses, personnel expenses and regulatory expenses. Share-based payment expenses included within R&D expenses totaled $19.6 million in the year ended December 31, 2025, compared to $13.3 million in the year ended December 31, 2024. Selling, General and Administrative (“SG&A”) Expenses: SG&A expenses were $106.4 million for the year ended December 31, 2025, compared to $70.4 million in the year ended December 31, 2024. This increase was primarily due to increases in personnel expenses, marketing and communication expenses and costs related to our intellectual property. Share-based payment expenses included within SG&A expenses totaled $39.9 million in the year ended December 31, 2025, compared to $20.3 million in the year ended December 31, 2024. Net loss: Net loss for the year ended December 31, 2025, was $203.8 million, compared to net loss of $241.6 million in the year ended December 31, 2024. The individual components of the change are described above in addition to non-cash losses related to changes in the fair value of our derivative liabilities and foreign exchange gains/(losses). About Obicetrapib Obicetrapib is a novel, oral, low-dose CETP inhibitor that NewAmsterdam is developing to overcome the limitations of current LDL-lowering treatments. In each of the Company’s Phase 2 trials, ROSE2, TULIP, ROSE, and OCEAN, as well as the Company’s Phase 3 BROOKLYN, BROADWAY and TANDEM trials, evaluating obicetrapib as monotherapy or combination therapy, the Company observed statistically significant LDL-lowering combined with a side effect profile similar to that of placebo. The Company commenced the Phase 3 PREVAIL cardiovascular outcomes trial in March 2022, which is designed to assess the potential of obicetrapib to reduce occurrences of MACE. The Company completed enrollment of PREVAIL in April 2024 and randomized over 9,500 patients. Commercialization rights of obicetrapib in Europe, either as a monotherapy or as part of a fixed-dose combination with ezetimibe, have been exclusively granted to the Menarini Group, an Italy-based, leading international pharmaceutical and diagnostics company. About Cardiovascular Disease Cardiovascular disease remains the leading cause of death globally, despite the availability of lipid-lowering therapies (“LLTs”). By 2050 more than 184 million U.S. adults are expected to be affected by CVD and hypertension, including 27 million with coronary heart disease and 19 million with stroke. In the United States from 2019 through 2022, CVD age-adjusted mortality rates increased by 9%, reversing the trend observed since 2010 and undoing nearly a decade of progress. Despite the availability of high-intensity statins and non-statin LLTs, LDL-C target level attainment remains low, contributing to residual cardiovascular risk, and underscoring a significant clinical need for improved therapeutic regimens. Even with 269 million LLT prescriptions written over the last 12 months, 30 million under-treated US adults are not at their risk-based LDL-C goal, of which 13 million have ASCVD. Less than 1 in 4 patients with ASCVD achieve an LDL-C goal of less than 70 mg/dL and only 10% of very high risk ASCVD patients achieve the goal below 55 mg/dL. In addition to the 30 million under-treated U.S. adults, there are 10 million patients diagnosed with elevated LDL-C who are not taking any LLTs including statins. Beyond LDL-C, additional factors are at play, such as lifestyle choices, tobacco use, and obesity, as well as inflammation, thrombosis, triglyceride levels, elevated Lp(a) levels, and type 2 diabetes. Alzheimer’s Analysis In BROADWAY, a pre-specified analysis was designed to assess plasma biomarkers of Alzheimer’s disease (“AD”) in patients enrolled in the BROADWAY trial and evaluated the effects of longer duration of therapy (12 months) with a prespecified ApoE population, based on phenotypic analysis. The analysis included 1,535 patients, including 367 ApoE4 carriers (ApoE3/E4 or ApoE4/E4), whose ApoE status was able to be determined. Because this analysis was based on a subset of patients from BROADWAY (which was designed to evaluate LDL-C reductions in an ASCVD and/or HeFH population), the AD analysis was not controlled for baseline differences between the treatment and placebo populations, but statistical analyses were adjusted for baseline biomarker values and age. The absolute and percent change over 12 months in p-tau217, a key biomarker of AD pathology, was measured among patients with baseline and end of study datapoints above the lower limit of quantitation. Additional outcome measures included NFL, GFAP, p-tau181, and Aβ42/40 ratio absolute and percent change over 12 months. NewAmsterdam observed statistically significant lower absolute changes in p-tau217 compared to placebo over 12 months in both the full analysis set (p=0.002; n= 1,535) and in ApoE4 carriers (p=0.02; n=367) as well as favorable trends in the other AD biomarkers. Although a safety analysis was not performed in the AD analysis population, in BROADWAY obicetrapib was observed to be well-tolerated, with safety results comparable to placebo. About NewAmsterdam NewAmsterdam (Nasdaq: NAMS) is a late-stage biopharmaceutical company whose mission is to improve patient care in populations with metabolic diseases where currently approved therapies have not been adequate or well tolerated. We seek to fill a significant unmet need for a safe, well-tolerated and convenient LDL-lowering therapy. In multiple phase 3 trials, NewAmsterdam is investigating obicetrapib, an oral, low-dose and once-daily CETP inhibitor, alone or as a fixed-dose combination with ezetimibe, as LDL-C lowering therapies to be used as an adjunct to statin therapy for patients at risk of CVD with elevated LDL-C, for whom existing therapies are not sufficiently effective or well tolerated. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995 and are subject to the “safe harbor” provisions created thereunder. All statements that are not historical facts are hereby identified as forwarding-looking statements for this purposes and include, among others, statements relating to: expectations regarding the timing of potential approval decisions from the EMA, UK and Switzerland regulators with respect to MAAs for obicetrapib and the FDC of obicetrapib plus ezetimibe, and preparations for commercial launch, if approved; the initiation of a new clinical trial evaluating obicetrapib in early Alzheimer disease in 2026; the therapeutic potential of the Company’s product candidates; the timing for commencing trials, enrolling patients and completing trials, and the timing and forums for announcing data; expected milestones and business objectives for 2026 and beyond; the Company’s expectation that its cash runway will be sufficient to fund operations through the PREVAIL readout and, if approved, support the subsequent U.S. commercial launch; and other statements regarding the Company's future operations, financial performance, financial position, prospects, objectives, strategies and other future events. These forward-looking statements are based upon management’s current expectations and assumptions, and are subject to a number of risks, uncertainties and other factors that could cause actual results and events to differ materially and adversely from those indicated by such forward-looking statements including, among others: uncertainties and delays regarding the initiation, enrollment and completion of the Company’s clinical trials; uncertainties regarding the outcome of the Company’s clinical trials, and whether such outcomes will be adequate to support regulatory review and approval of its product candidates; whether topline, initial or preliminary results or analyses from a particular clinical trial will be predictive of the final results of that trial and whether results of early clinical trials and analyses will be indicative of the results of later clinical trials and analyses, or whether projections regarding clinical outcomes will reflect actual results in future clinical trials or clinical use of the Company’s product candidates; the potential for varying interpretation of the results of clinical trials and analyses; risks related to the Company’s ability to achieve its business plans, objectives and milestones, including approval of the Company’s product candidates and potential commercialization; unanticipated costs and expenses impacting the Company’s cash runway; the Company’s ability to continue to source the raw materials for its product candidates and ensure adequate supply of product for clinical trials and, if approved, commercialization; the impact of competing product candidates on the Company’s business; risks and uncertainties relating to intellectual property and regulatory exclusivities; changes in domestic and foreign business, market, financial, political, and legal conditions; and those risks, uncertainties and other factors discussed under the caption “Item 1A. Risk Factors” and elsewhere in the Company’s most recent Form 10-K, Form 10-Q and other public filings with the Securities and Exchange Commission, which are available at www.sec.gov. As a result, you should not place undue reliance on any forward-looking statements. The forward-looking statements made in this press release speak only as of the date of this press release, and the Company undertakes no obligation to update such forward-looking statements, whether as a result of new information, future developments or otherwise. Company ContactMatthew PhilippeP: 1-917-882-7512matthew.philippe@newamsterdampharma.com Media ContactReal Chemistry on behalf of NewAmsterdamChristian EdgingtonP: 1-513-310-6410cedgington@realchemistry.com Investor ContactPrecision AQ on behalf of NewAmsterdamAustin MurtaghP: 1-212-698-8696austin.murtagh@precisionaq.com