根據(jù)此前發(fā)布的主要終點(diǎn)數(shù)據(jù)顯示，與安慰劑（18.2%）相比，高達(dá)83.0%的成人患者在接受治療后實(shí)現(xiàn)了具有統(tǒng)計(jì)學(xué)意義的MASH顯著改善。

• 最新次要終點(diǎn)的數(shù)據(jù)顯示，高達(dá)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(jié)果顯示，高達(dá)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(jìn)入MASH III期研究；該結(jié)果證實(shí)了其作為成人MASH患者的同類最佳治療藥物的潛力。隨著對(duì)肥胖人群臨床試驗(yàn)的持續(xù)推進(jìn)，²survodutide有望為心血管、腎臟和代謝疾病領(lǐng)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(xiàng)II期臨床試驗(yàn)的突破性結(jié)果，在經(jīng)過48周治療后，高達(dá)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(guān)并發(fā)癥的風(fēng)險(xiǎn)增加。³

該臨床試驗(yàn)的完整數(shù)據(jù)結(jié)果已在2024年歐洲肝臟研究協(xié)會(huì)大會(huì)（EASL）上公布，并在《新英格蘭醫(yī)學(xué)雜志》上同步發(fā)表 。^1,4次要終點(diǎn)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(dá) 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(shí)候，該臨床試驗(yàn)達(dá)成主要終點(diǎn)，并公布了主要終點(diǎn)數(shù)據(jù)⁵。結(jié)果表明，與安慰劑（18.2%）相比，高達(dá)83.0%的成人患者在接受治療后實(shí)現(xiàn)了統(tǒng)計(jì)學(xué)意義的MASH顯著改善，驗(yàn)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(dú)特作用機(jī)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(dòng)劑，也是首個(gè)在為期48周治療的MASH II期臨床試驗(yàn)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(dòng)劑組分能夠增加能量消耗,^7,8并且直接對(duì)肝臟產(chǎn)生影響，有助于改善肝纖維化。⁵而其GLP-1激動(dòng)劑組分則能有效降低食欲，同時(shí)增加飽腹感。^6,9

弗吉尼亞州聯(lián)邦大學(xué)醫(yī)學(xué)院醫(yī)學(xué)、生理學(xué)和分子病理學(xué)教授，同時(shí)也是該試驗(yàn)的主要研究者Arun Sanyal博士表示：“我對(duì)survodutide在II期臨床試驗(yàn)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(dòng)劑外，胰高血糖素激動(dòng)劑同樣具有改善MASH和逆轉(zhuǎn)纖維化進(jìn)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(dòng)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(yàn)中，采用“治療48周后纖維化程度至少減少一個(gè)分期”作為評(píng)估治療改善的指標(biāo)。¹⁰纖維化是用于評(píng)估MASH進(jìn)展程度的指標(biāo)，^11?MASH是一種困擾全球超過1.15億人口健康的進(jìn)行性疾病。^12?MASH源于肝臟炎癥，可導(dǎo)致纖維化，一旦發(fā)展為嚴(yán)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(fēng)險(xiǎn)。^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(jì)負(fù)擔(dān)。¹⁷肝纖維化通常進(jìn)展緩慢，¹⁸如果纖維化尚未達(dá)到廣泛程度，則往往容易被忽視。¹⁹當(dāng)進(jìn)入疤痕晚期階段時(shí)，肝纖維化逆轉(zhuǎn)往往變得極具挑戰(zhàn)性，而對(duì)于肝硬化，逆轉(zhuǎn)的可能性則可能微乎其微。²⁰

在本次II期臨床試驗(yàn)中，經(jīng)過48周的治療后，與安慰劑相比，survodutide對(duì)所有其他次要終點(diǎn)指標(biāo)均實(shí)現(xiàn)了顯著性改善。¹實(shí)際治療結(jié)果顯示，接受survodutide治療后，高達(dá)87%的成人患者實(shí)現(xiàn)了肝臟脂肪含量相對(duì)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(duì)減少高達(dá)64.3%。¹在實(shí)際治療結(jié)果中，非酒精性脂肪肝病活動(dòng)性評(píng)分（NAS，用于衡量MASH的改善情況）與基線相比的絕對(duì)變化，使用survodutide組高達(dá)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(fù)責(zé)人Carinne Brouillon表示，“survodutide在纖維化領(lǐng)域的突破性進(jìn)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(jìn)三期臨床試驗(yàn)。MASH是一種與心血管、腎臟、肥胖和代謝性疾病相關(guān)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(jìn)相關(guān)重要的議題?！?/span>

Survodutide由Zealand Pharma公司授權(quán)給勃林格殷格翰，勃林格殷格翰全權(quán)負(fù)責(zé)其在全球的開發(fā)和商業(yè)化。Zealand Pharma公司在北歐國(guó)家享有共同推廣權(quán)。

在這項(xiàng)試驗(yàn)中，survodutide證實(shí)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(fēng)險(xiǎn)。^1?Survodutie于2021年獲得美國(guó)食品藥品監(jiān)督管理局（FDA）的快速通道資格認(rèn)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(xiàng)針對(duì)超重和肥胖患者的III期試驗(yàn)中展開研究，^2，23，24超重和肥胖都與MASH有關(guān)。²⁵另一項(xiàng)III期臨床試驗(yàn)正在評(píng)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(guān)于代謝功能障礙相關(guān)脂肪性肝炎（MASH）

MASH是一種由肝臟中脂肪堆積引起的慢性進(jìn)行性肝病，^13,27也是代謝功能障礙相關(guān)脂肪性肝病（MASLD）中一種更為嚴(yán)重的類型。²⁸根據(jù)美國(guó)的研究預(yù)測(cè)，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(guān)聯(lián)。^29,30據(jù)統(tǒng)計(jì)，高達(dá)34%的肥胖患者同時(shí)患有MASH。²⁵

MASH?嚴(yán)重程度使用F0至F4范圍內(nèi)的等級(jí)進(jìn)行評(píng)估，評(píng)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(guān)于本次臨床試驗(yàn)（NCT04771273）

這是一項(xiàng)II期、隨機(jī)、雙盲、安慰劑對(duì)照的劑量探索性試驗(yàn)，共納入了295名受試者。該試驗(yàn)旨在評(píng)估每周皮下注射survodutide對(duì)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(yàn)的主要終點(diǎn)是治療48周后，達(dá)到MASH組織學(xué)改善且纖維化無惡化的受試者百分比。¹⁰ MASH的組織學(xué)改善定義為非酒精性脂肪肝病活動(dòng)性評(píng)分（NAS）降低 ≥ 2分（總分為0 - 8分），包括NASH亞評(píng)分（小葉炎癥或氣球樣變）降低 ≥ 1分，同時(shí)確保纖維化分期不增加。¹⁰ NAS評(píng)分代表了脂肪變性（肝脂肪積聚³²）、小葉炎癥（炎癥細(xì)胞³³）和氣球樣變（一種肝細(xì)胞變性³⁴）的得分總和。

次要結(jié)局包括：¹⁰

• 治療48周后，肝臟脂肪含量相較于基線相對(duì)減少至少30%

• 治療48周后，肝臟脂肪含量相較于基線的絕對(duì)和相對(duì)變化

• 治療48周后，纖維化程度至少減少一個(gè)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(duì)變化

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

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關(guān)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(dòng)劑，可同時(shí)激活胰高血糖素受體和GLP-1受體，這對(duì)于控制代謝功能至關(guān)重要。⁶

Zealand Pharma授權(quán)勃林格殷格翰全權(quán)負(fù)責(zé)survodutide的全球開發(fā)與商業(yè)化，保留了在北歐市場(chǎng)的聯(lián)合推廣權(quán)益。Survodutide是勃林格殷格翰在代謝心腎疾病領(lǐng)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(guó)FDA的快速通道認(rèn)定。^21?23年11月，EMA將其納入PRIME計(jì)劃。²²

勃林格針還對(duì)survodutide在肝硬化（F4）及不同程度肝功能障礙人群中進(jìn)行了一項(xiàng)分兩部分的I期試驗(yàn)。³⁵第1部分試驗(yàn)旨在探究肝硬化（F4）以及不同程度肝功能障礙對(duì)survodutide在人體內(nèi)吸收方式的影響。第2部分試驗(yàn)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(xiàng)針對(duì)超重和肥胖癥患者的III期研究中接受評(píng)估。^2,23,24其中，SYNCHRONIZE-1和SYNCHRONIZE-2研究分別針對(duì)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(duì)伴有心血管疾病、慢性腎病或心血管疾病風(fēng)險(xiǎn)因素的亞組人群。²在地域性研究中，日本的SYNCHRONIZE-JP和中國(guó)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(duì)變化，此為關(guān)鍵次要終點(diǎn)。²⁴

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Reference：

1 Sanyal, Arun J. "Glucagon and GLP-1 receptor dual agonist survodutide improved liver histology in people with MASH and fibrosis: Results from a randomized, double-blind, placebo-controlled phase 2 trial”. Oral presentation at European Association for the Study of the Liver Congress, Milan, Italy. 7June 2024. Abstract #LB117, presentation #GS-006.

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

4 Sanyal, Arun J., et al. “A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis.” The New England Journal of Medicine.?June 2024.?doi: 10.1056/NEJMoa2401755

5 Top-line Results From A Study to Test Efficacy of BI456906 in Adults With Non-alcoholic Steatohepatitis (NASH) and Fibrosis (F1-F3).” Boehringer Ingelheim. Data on file

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

12 “International NASH Day June 10, 2021.” Global Liver Institute. June 2021.?https://ecpc.org/wp-content/uploads/2021/09/IND-report-2021-web.pdf Accessed June 2024

13 Ramai, Daryl, et al. “Progressive Liver Fibrosis in Non-Alcoholic Fatty Liver Disease.”?Cells. Vol. 10, no. 12, Dec. 2021, p. 3401.?doi: 10.3390/cells10123401.

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

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