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。
德國殷格翰2024年6月7日 /美通社/ -- 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(jié)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(guān)并發(fā)癥的風險增加。3
該臨床試驗的完整數(shù)據(jù)結(jié)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(jié)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(zhuǎn)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(dǎo)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(zhuǎn)往往變得極具挑戰(zhàn)性，而對于肝硬化，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(jié)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(jié)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(lǐng)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(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)生部門推進相關(guān)重要的議題。"
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(quán)。
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歐洲藥品管理局（EMA）于去年11月批準了其針對MASH引發(fā)的纖維化的優(yōu)先藥物（PRIME）計劃。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(guān)。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
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
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
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：
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 and chronic 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 Stål. 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.
14 Dyson, 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.
30 Schnell. 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
