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勃林格殷格翰Survodutide MASH适应症获CDE突破性疗法认定

2024-06-17 16:00:38

Survodutide (BI 456906)获得中国国家药品监督管理局（NMPA）药品审评中心（CDE）"突破性疗法"认定，拟用于代谢功能障碍相关脂肪性肝炎 (MASH) 的治疗。
突破性疗法认定是基于survodutide II期临床试验。试验结果显示，与安慰剂（18.2%）相比，高达83.0%的成人患者在接受survodutide治疗后实现了具有统计学意义的MASH显著改善。^[1]关键次要终点结果显示，高达52.3%的F1、F2和F3期成人MASH患者的纤维化显著改善。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。进一步证实了Survodutide在治疗成人MASH及纤维化患者中的巨大潜力。^[2]

上海2024年6月12日 /美通社/ -- 勃林格殷格翰近日宣布，胰高血糖素受体/胰高血糖素样肽-1受体（GCGR/GLP-1R）双重激动剂survodutide(BI 456906)获得中国国家药品监督管理局（NMPA）药品审评中心（CDE）突破性疗法认定，拟用于代谢功能障碍相关脂肪性肝炎 (MASH) 的治疗。

肝脏在心血管、肾脏和代谢系统中发挥着重要作用，主导着人体的新陈代谢。^[3]MASH是一种进行性疾病，影响全球超过1.15亿人，^[4]其归因于肝脏炎症并导致肝纤维化。^[5]肝脏严重的组织疤痕（肝硬化）极大地增加终末期肝病和肝癌的风险，^[6],[7]肝移植可能是目前唯一的治疗选择。^[8]预计到2030年，MASH将成为肝移植的主要原因，^[9]将给医疗系统带来巨大的支付压力。^[10],[11]MASH还会影响一个人的生活质量、人际关系和工作能力。^[12]患者仍存在巨大的临床未满足需求。

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。^[13],[14] Survodutide中的胰高血糖素受体激动剂组分能够增加能量消耗，^[15],[16]并且直接对肝脏产生影响，有助于改善肝纤维化。^[13]而其GLP-1受体激动剂组分则能有效降低食欲，同时增加饱腹感。^[14],^[17]

此次突破性疗法认定是基于其II期临床试验，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。^[18]试验达到其主要、关键次要终点和所有其他终点。研究结果显示与安慰剂(18.2%)相比，高达83%接受survodutide (BI 456906) 治疗的MASH成人患者实现了具有统计学意义的改善[组间差异：64.8%，(CI 51.1% - 78.6%), p<0.0001]，^[13]在使用survodutide 48周后活检组织学显著改善且 F1、F2 和 F3 期纤维化（轻度至中度或晚期疤痕）无恶化。^[1]关键次要终点结果显示，高达52.3%的F1、F2和F3期成人MASH患者的纤维化显著改善。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。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。^[19],[20]

Survodutide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肝纤维化获益的该类药物。此前，survodutide于2021年被美国食品药品管理局 (FDA) 授予快速审评资格，^[21]并于去年11月，被欧洲药品管理局 (EMA)授予优先药物(PRIME)资格。^[22]

勃林格殷格翰大中华区研发和医学负责人兼勃林格殷格翰中国炎症免疫治疗领域负责人张维博士表示："此次获得CDE突破性疗法认定是survodutide开发过程中又一个重要里程碑，这也是中国国家药品监督管理局（NMPA）药品审评中心（CDE）对这款治疗代谢功能障碍相关脂肪性肝炎（MASH）创新药物突破性临床价值的认可。上周发布的survodutide II期临床试验的完整数据结果已经验证了其作为同类最佳药物的潜力，有望为MASH及临床显著纤维化的患者人群带来变革性的治疗。我们正在与相关部门保持紧密合作，推动该创新药的加速研发及早日获批，并加速落地中国，让中国广大MASH及纤维化患者尽早从创新药物治疗中获益。"

[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

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