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潛在同類最優(yōu)！勃林格殷格翰Survodutide獲CDE突破性療法認(rèn)定

中國,

本文重點(diǎn)

  • 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(rèn)定，擬用于代謝功能障礙相關(guān)脂肪性肝炎 (MASH)?的治療。
  • 突破性療法認(rèn)定是基于survodutide II期臨床試驗(yàn)。試驗(yàn)結(jié)果顯示，與安慰劑（18.2%）相比，高達(dá)83.0%的成人患者在接受survodutide治療后實(shí)現(xiàn)了具有統(tǒng)計(jì)學(xué)意義的MASH顯著改善。[1]關(guān)鍵次要終點(diǎn)結(jié)果顯示，高達(dá)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(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。進(jìn)一步證實(shí)了Survodutide在治療成人MASH及纖維化患者中的巨大潛力。[2]

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(rèn)定，擬用于代謝功能障礙相關(guān)脂肪性肝炎 (MASH)?的治療。

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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。[1]MASH是一種進(jìn)行性疾病，影響全球超過1.15億人，[2]其歸因于肝臟炎癥并導(dǎo)致肝纖維化。[3]肝臟嚴(yán)重的組織疤痕（肝硬化）極大地增加終末期肝病和肝癌的風(fēng)險，[4],[5]肝移植可能是目前唯一的治療選擇。[6]預(yù)計(jì)到2030年，MASH將成為肝移植的主要原因，[7]將給醫(yī)療系統(tǒng)帶來巨大的支付壓力。[8],[9]MASH還會影響一個人的生活質(zhì)量、人際關(guān)系和工作能力。[10]患者仍存在巨大的臨床未滿足需求。

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）雙重激動劑。[11],[12]?Survodutide中的胰高血糖素受體激動劑組分能夠增加能量消耗，[13],[14]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。[15],14

此次突破性療法認(rèn)定是基于其II期臨床試驗(yàn)，試驗(yàn)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。[16]試驗(yàn)達(dá)到其主要、關(guān)鍵次要終點(diǎn)和所有其他終點(diǎn)。研究結(jié)果顯示與安慰劑(18.2%)相比，高達(dá)83%接受survodutide (BI 456906)?治療的MASH成人患者實(shí)現(xiàn)了具有統(tǒng)計(jì)學(xué)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(xué)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(diǎn)結(jié)果顯示，高達(dá)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(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。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)會大會（EASL）上公布，并在《新英格蘭醫(yī)學(xué)雜志》上同步發(fā)表。[17],[18]

Survodutide是首個在為期48周治療的MASH II期臨床試驗(yàn)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，[19]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。[20]

勃林格殷格翰大中華區(qū)研發(fā)和醫(yī)學(xué)負(fù)責(zé)人兼勃林格殷格翰中國炎癥免疫治療領(lǐng)域負(fù)責(zé)人張維博士表示：“此次獲得CDE突破性療法認(rèn)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(rèn)可。上周發(fā)布的survodutide II期臨床試驗(yàn)的完整數(shù)據(jù)結(jié)果已經(jīng)驗(yàn)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。”

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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(guān)重要。14

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(jìn)行了一項(xiàng)分兩部分的I期試驗(yàn)。[21]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)針對超重和肥胖癥患者的III期研究中接受評估。2,[22],[23]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。2SYNCHRONIZE-CVOT研究則針對伴有心血管疾病、慢性腎病或心血管疾病風(fēng)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。24,25SYNCHRONIZE-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(guān)鍵次要終點(diǎn)。25
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[1] Rui L. Energy metabolism in the liver. Compr Physiol. 2014 Jan;4(1):177-97. doi: 10.1002/cphy.c130024

[2] “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

[3] 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.

[4]?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

[5]?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

[6] 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.

[7] 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.

[8] Khalil A, et al. New Developments and Challenges in Liver Transplantation. J Clin Med. 2023 Aug 27;12(17):5586. doi: 10.3390/jcm12175586.

[9] 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.

[10] Geier, A., et al. Real-World Burden of Nonalcoholic Steatohepatitis. Clin Gastroenterol Hepatol. 2021 19: 1020-29.e7.

[11] 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

[12] 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.

[13] 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

[14] 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.

[15] 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.

[16] “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

[17] 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.

[18]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

[19]?“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

[20]?“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

[21]“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

[22]“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

[23]“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