勃林格殷格翰survodutide的研究结果显示，64.5%的F2和F3期纤维化患者的肝纤维化得到突破性改善且MASH无恶化

根据此前发布的主要终点数据显示，与安慰剂（18.2%）相比，高达83.0%的成人患者在接受治疗后实现了具有统计学意义的MASH显著改善。

• 最新次要终点的数据显示，高达52.3%的F1、F2和F3期成人MASH患者的纤维化改善。¹
• 额外的亚组分析结果显示，高达64.5%的F2和F3期纤维化（中度至晚期疤痕）成人患者的纤维化改善，且MASH无恶化。¹
• Survodutide将进入MASH III期研究；该结果证实了其作为成人MASH患者的同类最佳治疗药物的潜力。随着对肥胖人群临床试验的持续推进，²survodutide有望为心血管、肾脏和代谢疾病领域带来具有重大临床意义的获益。

勃林格殷格翰今日宣布了survodutide的一项II期临床试验的突破性结果，在经过48周治疗后，高达64.5%的F2和F3期纤维化（中度至晚期疤痕）成人患者的纤维化得到改善且MASH无恶化，而安慰剂组为 25.9%  [组间差异: 38.6% (95% CI 18.1% - 59.1%), p=0.0005]。¹ F2 和 F3 患者群体发生肝脏相关并发症的风险增加。³

该临床试验的完整数据结果已在2024年欧洲肝脏研究协会大会（EASL）上公布，并在《新英格兰医学杂志》上同步发表 。^1,4次要终点数据显示，在使用 survodutide (BI 456906) 治疗48周治疗后，与安慰剂组（25.8%）相比，高达 52.3% 的 F1、F2 和 F3 期（轻度至中度或晚期疤痕）成人患者的纤维化取得了显着改善 [组间差异: 26.5% (95% CI 8.37% – 44.66%), p<0.01] 。¹

今年早些时候，该临床试验达成主要终点，并公布了主要终点数据⁵。结果表明，与安慰剂（18.2%）相比，高达83.0%的成人患者在接受治疗后实现了统计学意义的MASH显著改善，验证了survodutide作为同类最佳药物的潜力[组间差异：64.8%（95%CI 51.1%-78.6%），p<0.0001]。⁵

Survodutide是一种具有独特作用机制的胰高血糖素受体/胰高血糖素样肽-1受体（GCGR/GLP-1R）双重激动剂，也是首个在为期48周治疗的MASH II期临床试验中取得如此显著纤维化获益的该类药物。^5,6  Survodutide中的胰高血糖素激动剂组分能够增加能量消耗,^7,8并且直接对肝脏产生影响，有助于改善肝纤维化。⁵而其GLP-1激动剂组分则能有效降低食欲，同时增加饱腹感。^6,9

弗吉尼亚州联邦大学医学院医学、生理学和分子病理学教授，同时也是该试验的主要研究者Arun Sanyal博士表示：“我对survodutide在II期临床试验中的发现倍感振奋。这些研究发现充分证明，除了GLP-1激动剂外，胰高血糖素激动剂同样具有改善MASH和逆转纤维化进程的巨大潜力。这些数据指出，survodutide作为一种前沿的胰高血糖素受体/胰高血糖素样肽-1受体（GCGR/GLP-1R）双重激动剂，有望为MASH及临床显著性纤维化的患者人群带来变革性的治疗方案。”

在本次临床试验中，采用“治疗48周后纤维化程度至少减少一个分期”作为评估治疗改善的指标。¹⁰纤维化是用于评估MASH进展程度的指标，¹¹ MASH是一种困扰全球超过1.15亿人口健康的进行性疾病。¹² MASH源于肝脏炎症，可导致纤维化，一旦发展为严重的组织疤痕（肝硬化），¹³将显著增加终末期肝病和肝癌的风险。^14,15目前，肝移植可能是终末期肝病和肝癌患者唯一的治疗手段，¹⁶但这无疑给医疗系统带来了沉重的经济负担。¹⁷肝纤维化通常进展缓慢，¹⁸如果纤维化尚未达到广泛程度，则往往容易被忽视。¹⁹当进入疤痕晚期阶段时，肝纤维化逆转往往变得极具挑战性，而对于肝硬化，逆转的可能性则可能微乎其微。²⁰

在本次II期临床试验中，经过48周的治疗后，与安慰剂相比，survodutide对所有其他次要终点指标均实现了显著性改善。¹实际治疗结果显示，接受survodutide治疗后，高达87%的成人患者实现了肝脏脂肪含量相对减少了至少30%，显著优于安慰剂组的19.7%。¹此外，与安慰剂组的7.3%相比，接受survodutide治疗的患者中，肝脏脂肪含量相对减少高达64.3%。¹在实际治疗结果中，非酒精性脂肪肝病活动性评分（NAS，用于衡量MASH的改善情况）与基线相比的绝对变化，使用survodutide组高达3.3，而安慰剂组仅为0.4。¹

勃林格殷格翰全球人用药品负责人Carinne Brouillon表示，“survodutide在纤维化领域的突破性进展再次证明了其作为MASH患者同类最佳治疗方案的卓越潜力。我们将快速推进三期临床试验。MASH是一种与心血管、肾脏、肥胖和代谢性疾病相关的疾病，亟需新的疗法，我们很高兴能继续与医疗卫生部门推进相关重要的议题。”

Survodutide由Zealand Pharma公司授权给勃林格殷格翰，勃林格殷格翰全权负责其在全球的开发和商业化。Zealand Pharma公司在北欧国家享有共同推广权。

在这项试验中，survodutide证实了与基于GLP-1的分子具有一致的安全性数据，没有新的安全性数据风险。¹ Survodutie于2021年获得美国食品药品监督管理局（FDA）的快速通道资格认定，²¹去年11月，被欧洲药品管理局（EMA）授予了优先药物（PRIME）资格。²²

Survodutide也在五项针对超重和肥胖患者的III期试验中展开研究，^2，23，24超重和肥胖都与MASH有关。²⁵另一项III期临床试验正在评估survodutide是否有助于超重或肥胖的人（确诊或可能诊断为MASH）减少肝脏脂肪和减重。²⁶

关于代谢功能障碍相关脂肪性肝炎（MASH）

MASH是一种由肝脏中脂肪堆积引起的慢性进行性肝病，^13,27也是代谢功能障碍相关脂肪性肝病（MASLD）中一种更为严重的类型。²⁸根据美国的研究预测，从2015年至2030年，MASH的病例数将激增63%，从1650万例攀升至2700万例。¹⁶ MASH与心血管、肾脏及多种代谢疾病之间存在着密切关联。^29,30据统计，高达34%的肥胖患者同时患有MASH。²⁵

MASH 严重程度使用F0至F4范围内的等级进行评估，评估纤维化（疤痕）的水平：³¹     

• F0-F1：表示无纤维化或轻度纤维化
• F2-F3：表示中度或晚期纤维化
• F4：表示肝硬化

关于本次临床试验（NCT04771273）

这是一项II期、随机、双盲、安慰剂对照的剂量探索性试验，共纳入了295名受试者。该试验旨在评估每周皮下注射survodutide对伴有或未伴有2型糖尿病的MASH及（F1，F2，F3期）纤维化成人患者的治疗效果。¹⁰

本次临床试验的主要终点是治疗48周后，达到MASH组织学改善且纤维化无恶化的受试者百分比。¹⁰ MASH的组织学改善定义为非酒精性脂肪肝病活动性评分（NAS）降低 ≥ 2分（总分为0 - 8分），包括NASH亚评分（小叶炎症或气球样变）降低 ≥ 1分，同时确保纤维化分期不增加。¹⁰ NAS评分代表了脂肪变性（肝脂肪积聚³²）、小叶炎症（炎症细胞³³）和气球样变（一种肝细胞变性³⁴）的得分总和。

次要结局包括：¹⁰

• 治疗48周后，肝脏脂肪含量相较于基线相对减少至少30%

• 治疗48周后，肝脏脂肪含量相较于基线的绝对和相对变化

• 治疗48周后，纤维化程度至少减少一个分期的（纤维化改善的定义）

• 治疗48周后，NAS总分相较于基线的绝对变化

本次试验采用剂量递增的设计，包括2.4 mg、4.8 mg和6.0 mg三个治疗组，剂量递增阶段持续24周，随后进入为期24周的剂量维持阶段。¹⁰

关于Survodutide（BI456906）

Survodutide是一种胰高血糖素受体/胰高血糖素样肽-1受体（GCGR/GLP-1R）双重激动剂，可同时激活胰高血糖素受体和GLP-1受体，这对于控制代谢功能至关重要。⁶

Zealand Pharma授权勃林格殷格翰全权负责survodutide的全球开发与商业化，保留了在北欧市场的联合推广权益。Survodutide是勃林格殷格翰在代谢心肾疾病领域研发组合的组成部分。

2021年5月，survodutide用于MASH和纤维化治疗成功获得美国FDA的快速通道认定。²¹ 23年11月，EMA将其纳入PRIME计划。²²

勃林格针还对survodutide在肝硬化（F4）及不同程度肝功能障碍人群中进行了一项分两部分的I期试验。³⁵第1部分试验旨在探究肝硬化（F4）以及不同程度肝功能障碍对survodutide在人体内吸收方式的影响。第2部分试验则旨在探究在肝硬化（F4）及不同程度肝功能障碍的超重和肥胖人群中，survodutide治疗28周的耐受性。

Survodutide还正在五项针对超重和肥胖症患者的III期研究中接受评估。^2,23,24其中，SYNCHRONIZE-1和SYNCHRONIZE-2研究分别针对有合并症但不伴和伴有2型糖尿病的亚组患者。² SYNCHRONIZE-CVOT研究则针对伴有心血管疾病、慢性肾病或心血管疾病风险因素的亚组人群。²在地域性研究中，日本的SYNCHRONIZE-JP和中国的SYNCHRONIZE-CN研究正致力于探索survodutide在肥胖症患者亚人群中的治疗效果。^23,24 SYNCHRONIZE-JP研究探索survodutide与安慰剂相比，肝脏脂肪含量从基线到第76周的相对变化，此为关键次要终点。²⁴

Reference：

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2 “Phase III studies to investigate survodutide for people living with obesity and overweight, with and without diabetes, cardiovascular disease andchronic kidney disease.” Boehringer Ingelheim. www.boehringer-ingelheim.com/phase-3-studies-survodutide-obesity-and-overweight. Accessed June 2024

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²⁰ Zhang, Chun-Ye, et al. “Treatment of liver fibrosis: Past, current, and future.” World Journal of Hepatology. Vol. 15, no. 6, June 2023, pp. 755-74. doi: 10.4254/wjh.v15.i6.755.

²¹  “Boehringer Ingelheim and Zealand Pharma Received FDA Fast Track Designation for Investigational Treatment for NASH.” Boehringer Ingelheim. www.boehringer-ingelheim.com/us/press-release/boehringer-ingelheim-and-zealand-pharma-receive-fda-fast-track-designation. Accessed June 2024

²² “List of medicines currently in PRIME scheme.” European Medicines Agency. December 2023. www.ema.europa.eu/en/documents/other/list-medicines-currently-prime-scheme_en.xlsx. Accessed June 2024

²³ “A Study to Test Whether BI 456906 Helps Chinese People Living With Overweight or Obesity to Lose Weight.” Clinicaltrials.gov. clinicaltrials.gov/study/NCT06214741. Accessed June 2024

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²⁵ Quek, Jingxuan, et al. ”Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis.” The Lancet Gastroenterology & Hepatology. Vol. 8, no. 1, Jan. 2023, pp. 20-30.https://doi.org/10.1016/S2468-1253(22)00317-X

²⁶ “A Study to Test Whether Survodutide Helps People Living With Obesity or Overweight and With a Confirmed or Presumed Liver Disease Called Non-alcoholic Steatohepatitis (NASH) to Reduce Liver Fat and to Lose Weight”. Clinicaltrials.gov. https://clinicaltrials.gov/study/NCT06309992. Accessed June 2024.

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²⁸ “Nonalcoholic steatohepatitis (NASH): Symptoms & complications (2023).” American Liver Foundation. liverfoundation.org/liver-diseases/fatty-liver-disease/nonalcoholic-steatohepatitis-nash/. Accessed June 2024

²⁹ Musso, Giovanni, et al. “Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis.” PLoS Medicine. Vol. 11, no. 7, July 2014, p. E1001680. doi: 10.1371/journal.pmed.1001680.

³⁰Schnell. Oliver, et al. “CVOT Summit Report 2023: new cardiovascular, kidney, and metabolic outcomes.”  Cardiovascular Diabetology. Vol. 23, no. 1, Mar. 2024. doi: 10.1186/s12933-024-02180-8.

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³⁵ “A Study to (1) Compare How BI 456906 is Taken up in the Body of Healthy People and People With Liver Problems and (2) Find Out How People With Overweight and Obesity, With and Without Liver Problems, Tolerate Different Doses of BI 456906.” Clinicaltrials.gov. clinicaltrials.gov/study/NCT05296733. Accessed June 2024