根據(jù)此前發(fā)布的主要終點數(shù)據(jù)顯示，與安慰劑（18.2%）相比，高達83.0%的成人患者在接受治療后實現(xiàn)了具有統(tǒng)計學意義的MASH顯著改善。

• 最新次要終點的數(shù)據(jù)顯示，高達52.3%的F1、F2和F3期成人MASH患者的纖維化改善。¹
• 額外的亞組分析結果顯示，高達64.5%的F2和F3期纖維化（中度至晚期疤痕）成人患者的纖維化改善，且MASH無惡化。¹
• Survodutide將進入MASH III期研究；該結果證實了其作為成人MASH患者的同類最佳治療藥物的潛力。隨著對肥胖人群臨床試驗的持續(xù)推進，²survodutide有望為心血管、腎臟和代謝疾病領域帶來具有重大臨床意義的獲益。

勃林格殷格翰今日宣布了survodutide的一項II期臨床試驗的突破性結果，在經(jīng)過48周治療后，高達64.5%的F2和F3期纖維化（中度至晚期疤痕）成人患者的纖維化得到改善且MASH無惡化，而安慰劑組為 25.9%? [組間差異: 38.6% (95% CI 18.1% - 59.1%), p=0.0005]。^1?F2?和 F3?患者群體發(fā)生肝臟相關并發(fā)癥的風險增加。³

該臨床試驗的完整數(shù)據(jù)結果已在2024年歐洲肝臟研究協(xié)會大會（EASL）上公布，并在《新英格蘭醫(yī)學雜志》上同步發(fā)表 。^1,4次要終點數(shù)據(jù)顯示，在使用 survodutide (BI 456906)?治療48周治療后，與安慰劑組（25.8%）相比，高達 52.3%?的 F1、F2?和 F3?期（輕度至中度或晚期疤痕）成人患者的纖維化取得了顯著改善 [組間差異: 26.5% (95% CI 8.37%?– 44.66%), p<0.01]?。¹

今年早些時候，該臨床試驗達成主要終點，并公布了主要終點數(shù)據(jù)⁵。結果表明，與安慰劑（18.2%）相比，高達83.0%的成人患者在接受治療后實現(xiàn)了統(tǒng)計學意義的MASH顯著改善，驗證了survodutide作為同類最佳藥物的潛力[組間差異：64.8%（95%CI 51.1%-78.6%），p<0.0001]。⁵

Survodutide是一種具有獨特作用機制的胰高血糖素受體/胰高血糖素樣肽-1受體（GCGR/GLP-1R）雙重激動劑，也是首個在為期48周治療的MASH II期臨床試驗中取得如此顯著纖維化獲益的該類藥物。^5,6? Survodutide中的胰高血糖素激動劑組分能夠增加能量消耗,^7,8并且直接對肝臟產(chǎn)生影響，有助于改善肝纖維化。⁵而其GLP-1激動劑組分則能有效降低食欲，同時增加飽腹感。^6,9

弗吉尼亞州聯(lián)邦大學醫(yī)學院醫(yī)學、生理學和分子病理學教授，同時也是該試驗的主要研究者Arun Sanyal博士表示：“我對survodutide在II期臨床試驗中的發(fā)現(xiàn)倍感振奮。這些研究發(fā)現(xiàn)充分證明，除了GLP-1激動劑外，胰高血糖素激動劑同樣具有改善MASH和逆轉纖維化進程的巨大潛力。這些數(shù)據(jù)指出，survodutide作為一種前沿的胰高血糖素受體/胰高血糖素樣肽-1受體（GCGR/GLP-1R）雙重激動劑，有望為MASH及臨床顯著性纖維化的患者人群帶來變革性的治療方案。”

在本次臨床試驗中，采用“治療48周后纖維化程度至少減少一個分期”作為評估治療改善的指標。¹⁰纖維化是用于評估MASH進展程度的指標，^11?MASH是一種困擾全球超過1.15億人口健康的進行性疾病。^12?MASH源于肝臟炎癥，可導致纖維化，一旦發(fā)展為嚴重的組織疤痕（肝硬化），¹³將顯著增加終末期肝病和肝癌的風險。^14,15目前，肝移植可能是終末期肝病和肝癌患者唯一的治療手段，¹⁶但這無疑給醫(yī)療系統(tǒng)帶來了沉重的經(jīng)濟負擔。¹⁷肝纖維化通常進展緩慢，¹⁸如果纖維化尚未達到廣泛程度，則往往容易被忽視。¹⁹當進入疤痕晚期階段時，肝纖維化逆轉往往變得極具挑戰(zhàn)性，而對于肝硬化，逆轉的可能性則可能微乎其微。²⁰

在本次II期臨床試驗中，經(jīng)過48周的治療后，與安慰劑相比，survodutide對所有其他次要終點指標均實現(xiàn)了顯著性改善。¹實際治療結果顯示，接受survodutide治療后，高達87%的成人患者實現(xiàn)了肝臟脂肪含量相對減少了至少30%，顯著優(yōu)于安慰劑組的19.7%。¹此外，與安慰劑組的7.3%相比，接受survodutide治療的患者中，肝臟脂肪含量相對減少高達64.3%。¹在實際治療結果中，非酒精性脂肪肝病活動性評分（NAS，用于衡量MASH的改善情況）與基線相比的絕對變化，使用survodutide組高達3.3，而安慰劑組僅為0.4。¹

勃林格殷格翰全球人用藥品負責人Carinne Brouillon表示，“survodutide在纖維化領域的突破性進展再次證明了其作為MASH患者同類最佳治療方案的卓越潛力。我們將快速推進三期臨床試驗。MASH是一種與心血管、腎臟、肥胖和代謝性疾病相關的疾病，亟需新的療法，我們很高興能繼續(xù)與醫(yī)療衛(wèi)生部門推進相關重要的議題?！?/span>

Survodutide由Zealand Pharma公司授權給勃林格殷格翰，勃林格殷格翰全權負責其在全球的開發(fā)和商業(yè)化。Zealand Pharma公司在北歐國家享有共同推廣權。

在這項試驗中，survodutide證實了與基于GLP-1的分子具有一致的安全性數(shù)據(jù)，沒有新的安全性數(shù)據(jù)風險。^1?Survodutie于2021年獲得美國食品藥品監(jiān)督管理局（FDA）的快速通道資格認定，²¹去年11月，被歐洲藥品管理局（EMA）授予了優(yōu)先藥物（PRIME）資格。²²

Survodutide也在五項針對超重和肥胖患者的III期試驗中展開研究，^{2，23，24}超重和肥胖都與MASH有關。²⁵另一項III期臨床試驗正在評估survodutide是否有助于超重或肥胖的人（確診或可能診斷為MASH）減少肝臟脂肪和減重。²⁶

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關于代謝功能障礙相關脂肪性肝炎（MASH）

MASH是一種由肝臟中脂肪堆積引起的慢性進行性肝病，^13,27也是代謝功能障礙相關脂肪性肝?。?/span>MASLD）中一種更為嚴重的類型。²⁸根據(jù)美國的研究預測，從2015年至2030年，MASH的病例數(shù)將激增63%，從1650萬例攀升至2700萬例。¹⁶ MASH與心血管、腎臟及多種代謝疾病之間存在著密切關聯(lián)。^29,30據(jù)統(tǒng)計，高達34%的肥胖患者同時患有MASH。²⁵

MASH?嚴重程度使用F0至F4范圍內的等級進行評估，評估纖維化（疤痕）的水平：³¹?????

• F0-F1：表示無纖維化或輕度纖維化
• F2-F3：表示中度或晚期纖維化
• F4：表示肝硬化

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關于本次臨床試驗（NCT04771273）

這是一項II期、隨機、雙盲、安慰劑對照的劑量探索性試驗，共納入了295名受試者。該試驗旨在評估每周皮下注射survodutide對伴有或未伴有2型糖尿病的MASH及（F1，F2，F3期）纖維化成人患者的治療效果。¹⁰

本次臨床試驗的主要終點是治療48周后，達到MASH組織學改善且纖維化無惡化的受試者百分比。¹⁰ MASH的組織學改善定義為非酒精性脂肪肝病活動性評分（NAS）降低 ≥ 2分（總分為0 - 8分），包括NASH亞評分（小葉炎癥或氣球樣變）降低 ≥ 1分，同時確保纖維化分期不增加。¹⁰ NAS評分代表了脂肪變性（肝脂肪積聚³²）、小葉炎癥（炎癥細胞³³）和氣球樣變（一種肝細胞變性³⁴）的得分總和。

次要結局包括：¹⁰

• 治療48周后，肝臟脂肪含量相較于基線相對減少至少30%

• 治療48周后，肝臟脂肪含量相較于基線的絕對和相對變化

• 治療48周后，纖維化程度至少減少一個分期的（纖維化改善的定義）

• 治療48周后，NAS總分相較于基線的絕對變化

本次試驗采用劑量遞增的設計，包括2.4 mg、4.8 mg和6.0 mg三個治療組，劑量遞增階段持續(xù)24周，隨后進入為期24周的劑量維持階段。¹⁰

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關于Survodutide（BI456906）

Survodutide是一種胰高血糖素受體/胰高血糖素樣肽-1受體（GCGR/GLP-1R）雙重激動劑，可同時激活胰高血糖素受體和GLP-1受體，這對于控制代謝功能至關重要。⁶

Zealand Pharma授權勃林格殷格翰全權負責survodutide的全球開發(fā)與商業(yè)化，保留了在北歐市場的聯(lián)合推廣權益。Survodutide是勃林格殷格翰在代謝心腎疾病領域研發(fā)組合的組成部分。

2021年5月，survodutide用于MASH和纖維化治療成功獲得美國FDA的快速通道認定。^21?23年11月，EMA將其納入PRIME計劃。²²

勃林格針還對survodutide在肝硬化（F4）及不同程度肝功能障礙人群中進行了一項分兩部分的I期試驗。³⁵第1部分試驗旨在探究肝硬化（F4）以及不同程度肝功能障礙對survodutide在人體內吸收方式的影響。第2部分試驗則旨在探究在肝硬化（F4）及不同程度肝功能障礙的超重和肥胖人群中，survodutide治療28周的耐受性。

Survodutide還正在五項針對超重和肥胖癥患者的III期研究中接受評估。^2,23,24其中，SYNCHRONIZE-1和SYNCHRONIZE-2研究分別針對有合并癥但不伴和伴有2型糖尿病的亞組患者。^2?SYNCHRONIZE-CVOT研究則針對伴有心血管疾病、慢性腎病或心血管疾病風險因素的亞組人群。²在地域性研究中，日本的SYNCHRONIZE-JP和中國的SYNCHRONIZE-CN研究正致力于探索survodutide在肥胖癥患者亞人群中的治療效果。^23,24?SYNCHRONIZE-JP研究探索survodutide與安慰劑相比，肝臟脂肪含量從基線到第76周的相對變化，此為關鍵次要終點。²⁴

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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

3 Sanyal, Arun J., et al. “Prospective Study of Outcomes in Adults with Nonalcoholic Fatty Liver Disease.” The New England Journal of Medicine. Vol. 385, no. 17, 2021, pp. 1559-1569. doi: 10.1056/NEJMoa2029349

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6 Zimmerman, Tina, et al. “BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy.” Molecular Metabolism. Vol. 66, Dec. 2022, p. 101633. doi: 10.1016/j.molmet.2022.101633.

7 Tan, Tricia M., et al. “Coadministration of glucagon-like peptide-1 during glucagon infusion in humans results in increased energy expenditure and amelioration of hyperglycemia.” Diabetes.?Vol. 62, no. 4, Mar. 2013, pp. 1131-36. doi: 10.2337/db12-0797

8 Salem, V., et al. “Glucagon increases energy expenditure independently of brown adipose tissue activation in humans.” Diabetes, Obesity and Metabolism. Vol. 18, no. 1, Nov. 2015, pp. 72-81. doi: 10.1111/dom.12585.

9 Shah, Meera, and Adrian Vella. “Effects of GLP-1 on appetite and weight.” Reviews in Endocrine and Metabolic Disorders. Vol. 15, no. 3, May 2014, pp. 181 – 87. doi: 10.1007/s11154-014-9289-5.

10?“A Study to Test Efficacy of BI456906 in Adults With Non-alcoholic Steatohepatitis (NASH) and Fibrosis (F1-F3).” ClinicalTrials.gov.?classic.clinicaltrials.gov/ct2/show/NCT04771273. Accessed June 2024

11 St?l. Per. “Liver fibrosis in non-alcoholic fatty liver disease - diagnostic challenge with prognostic significance.” World Journal of Gastroenterology. Vol. 21, no. 39, Jan. 2015, p. 11077. doi: 10.3748/wjg.v21.i39.11077

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¹⁴Dyson, Jessica, et al.?“Hepatocellular cancer: The impact of obesity, type 2 diabetes and a multidisciplinary team.”?Journal of Hepatology. Vol. 60, no. 1, Jan. 2014, pp. 110–17. doi: 10.1016/j.jhep.2013.08.011.

^15?Adams, Leon A., et al. “Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases.” Gut. Vol. 66, no. 6, Mar. 2017, pp.1138-53. doi: 10.1136/gutjnl-2017-313884

¹⁶ Estes. Chris, et al. “Modelling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease.” Hepatology. Vol 67, no. 1, Dec. 2017, pp. 123-33. doi: 10.1002/hep.29466.

^17?Khalil, Amjad, et al. “New Developments and Challenges in Liver Transplantation.” Journal of Clinical Medicine.?Vol 12, no. 17, Aug. 2023, pp 5586. doi: 10.3390/jcm12175586.

^18?Kumar, Rahul, et al. “A practical clinical approach to liver fibrosis.” Singapore Medical Journal.?Vol. 59, no. 12, Dec. 2018, pp 628-633. doi: 10.11622/smedj.2018145. PMID: 30631885; PMCID: PMC6301869.

^19?Pinzani, Massimo, et al. “Fibrosis in chronic liver diseases: diagnosis and management.” Journal of Hepatology. Vol. 42, no. 1, April 2005, S22-36. doi: 10.1016/j.jhep.2004.12.008

^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

²⁴“A Study to Test Whether BI 456906 Helps Japanese People Living With Obesity Disease (SYNCHRONIZE?JP).” Clinicaltrials.gov.?clinicaltrials.gov/study/NCT06176365. Accessed June 2024

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.

²⁷? “Nonalcoholic Fatty Liver Disease (NALFD) and NASH.” National Institute of Diabetes and Digestive and Kidney Diseases.? www.niddk.nih.gov/health-information/liver-disease/nafld-nash. Accessed June 2024

^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.

³¹?Kleiner, David E., et al.?“Nonalcoholic Steatohepatitis Clinical Research Network.?Design and validation of a histological scoring system for nonalcoholic fatty liver disease.” Hepatology. Vol. 41, no. 6, June 2005, pp. 1313-21. doi: 10.1002/hep.20701.

^32??“Non-alcoholic fatty liver disease (NAFLD).” NHS. www.nhs.uk/conditions/non-alcoholic-fatty-liver-disease. Accessed June 2024

³³?Vanderbeck, Scott, et al. “Automatic quantification of lobular inflammation and hepatocyte ballooning in nonalcoholic fatty liver disease liver biopsies.” Human Pathology. Vol. 46, no. 5, May 2015, pp. 767-75. doi: 10.1016/j.humpath.2015.01.019.

³⁴ Caldwell, Stephan, et al. “Hepatocellular ballooning in NASH.” Journal of Hepatology. Vol. 53, no. 4, Oct. 2010, pp 719-23. doi: 10.1016/j.jhep.2010.04.031.

^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