上海2024年6月12日 /美通社/ -- 勃林格殷格翰近日宣布，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survodutide(BI 456906)獲得中國國家藥品監(jiān)督管理局（NMPA）藥品審評中心（CDE）突破性療法認定，擬用于代謝功能障礙相關(guān)脂肪性肝炎 (MASH) 的治療。
肝臟在心血管、腎臟和代謝系統(tǒng)中發(fā)揮著重要作用，主導(dǎo)著人體的新陳代謝。[3]MASH是一種進行性疾病，影響全球超過1.15億人，[4]其歸因于肝臟炎癥并導(dǎo)致肝纖維化。[5]肝臟嚴重的組織疤痕（肝硬化）極大地增加終末期肝病和肝癌的風險，[6],[7]肝移植可能是目前唯一的治療選擇。[8]預(yù)計到2030年，MASH將成為肝移植的主要原因，[9]將給醫(yī)療系統(tǒng)帶來巨大的支付壓力。[10],[11]MASH還會影響一個人的生活質(zhì)量、人際關(guān)系和工作能力。[12]患者仍存在巨大的臨床未滿足需求。
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。[13],[14] Survodutide中的胰高血糖素受體激動劑組分能夠增加能量消耗，[15],[16]并且直接對肝臟產(chǎn)生影響，有助于改善肝纖維化。[13]而其GLP-1受體激動劑組分則能有效降低食欲，同時增加飽腹感。[14],[17]
此次突破性療法認定是基于其II期臨床試驗，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，F(xiàn)2，F(xiàn)3期）纖維化成人患者的治療效果。[18]試驗達到其主要、關(guān)鍵次要終點和所有其他終點。研究結(jié)果顯示與安慰劑(18.2%)相比，高達83%接受survodutide (BI 456906) 治療的MASH成人患者實現(xiàn)了具有統(tǒng)計學意義的改善[組間差異：64.8%，(CI 51.1% - 78.6%), p<0.0001]，[13]在使用survodutide 48周后活檢組織學顯著改善且 F1、F2 和 F3 期纖維化（輕度至中度或晚期疤痕）無惡化。[1]關(guān)鍵次要終點結(jié)果顯示，高達52.3%的F1、F2和F3期成人MASH患者的纖維化顯著改善。亞組分析結(jié)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。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。[19],[20]
Survodutide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肝纖維化獲益的該類藥物。此前，survodutide于2021年被美國食品藥品管理局 (FDA) 授予快速審評資格，[21]并于去年11月，被歐洲藥品管理局 (EMA)授予優(yōu)先藥物(PRIME)資格。[22]
勃林格殷格翰大中華區(qū)研發(fā)和醫(yī)學負責人兼勃林格殷格翰中國炎癥免疫治療領(lǐng)域負責人張維博士表示："此次獲得CDE突破性療法認定是survodutide開發(fā)過程中又一個重要里程碑，這也是中國國家藥品監(jiān)督管理局（NMPA）藥品審評中心（CDE）對這款治療代謝功能障礙相關(guān)脂肪性肝炎（MASH）創(chuàng)新藥物突破性臨床價值的認可。上周發(fā)布的survodutide II期臨床試驗的完整數(shù)據(jù)結(jié)果已經(jīng)驗證了其作為同類最佳藥物的潛力，有望為MASH及臨床顯著纖維化的患者人群帶來變革性的治療。我們正在與相關(guān)部門保持緊密合作，推動該創(chuàng)新藥的加速研發(fā)及早日獲批，并加速落地中國，讓中國廣大MASH及纖維化患者盡早從創(chuàng)新藥物治療中獲益。"
[1] Boehringer Ingelheim. Top-line Results From A Study to Test Efficacy of BI456906 in Adults With Non-alcoholic Steatohepatitis (NASH) and Fibrosis (F1-F3). Data on file. |
[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 May 2024 |
[3] Rui L. Energy metabolism in the liver. Compr Physiol. 2014 Jan;4(1):177-97. doi: 10.1002/cphy.c130024 |
[4] "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 |
[5] Ramai D, Facciorusso, et al. Progressive Liver Fibrosis in Non-Alcoholic Fatty Liver Disease. Cells. 2021 Dec 2;10(12):3401. doi: 10.3390/cells10123401. |
[6] 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 |
[7] 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 |
[8] Estes C, Razavi H, Loomba R, et al. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018; 67:123–133. doi: 10.1002/hep.29466. |
[9] ana C, Ballestri S, Ricci F, et al. Cardiovascular Risk in Non-Alcoholic Fatty Liver Disease: Mechanisms and Therapeutic Implications. Int J Environ Res Public Health. 2019; 16. doi: 10.3390/ijerph16173104. |
[10] Khalil A, et al. New Developments and Challenges in Liver Transplantation. J Clin Med. 2023 Aug 27;12(17):5586. doi: 10.3390/jcm12175586. |
[11] Burra P, Becchetti C, Germani G. NAFLD and liver transplantation: Disease burden, current management and future challenges. JHEP Rep. 2020 Oct 9;2(6):100192. doi: 10.1016/j.jhepr.2020.100192. |
[12] Geier, A., et al. Real-World Burden of Nonalcoholic Steatohepatitis. Clin Gastroenterol Hepatol. 2021 19: 1020-29.e7. |
[13] 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 |
[14] 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. |
[15] 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 |
[16] 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. |
[17] 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. |
[18] "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 May 2024 |
[19] 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. |
[20] 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 |
[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 |
