降糖减重领域中，自2005年FDA批准首款靶向GLP-1R药物上市以来^[1]，同靶点产品逐个获批上市，尤其是2017年和2021年经FDA批准上市的治疗2型糖尿病（T2DM）及治疗肥胖的司美格鲁肽[1]，以其良好的疗效及安全性，已成为降糖减重领域的明星产品。随之而来的是同类单靶点（GLP-1R）、双靶点（GLP-1R/GIPR和GLP-1R/GCGR）及三靶点（GLP-1R/GIPR/GCGR）激动剂的大量涌现。在竞争激烈的当下，如何做好此类产品的临床开发策略，助力产品临床开发，建立各自产品的差异化竞争优势，是正处在临床开发阶段的产品亟待解决的核心问题。

“以患者为中心”的药物研发理念已成为当前药物研发的核心指导思想。“以患者为中心”的药物研发是指以患者需求为出发点，视患者为主动参与者，以临床价值为最终目的。

自美国FDA于2022年2月25日《以患者为中心的药品研发：识别对患者重要的方法》指南发布，到2022年7月31日中国国家药品监督管理局药品审评中心（CDE）发布了《以患者为中心的临床试验获益—风险评估技术指导原则（征求意见稿）》《以患者为中心的临床试验设计技术指导原则（征求意见稿）》和《以患者为中心的临床试验实施技术指导原则（征求意见稿）》，可见新药研发已进入以患者为中心的新时代。

本文将以患者为中心，从未被满足的临床需求为出发点，基于有效性、安全性、方便性以及适应症拓展的四个方面讨论靶向GLP-1R的单靶点、双靶点和三靶点产品的差异化开发策略。本期介绍以上四个方面中的有效性差异化开发策略，后续的安全性、方便性以及适应症拓展的三个方面将于下期讨论。

一、有效性

1.针对2型糖尿病（T2DM）的降糖作用

现有已上市的GLP-1R单靶点激动剂——司美格鲁肽，包括注射剂和口服剂两种剂型均获批用于降糖治疗。其中注射用司美格鲁肽的降糖适应症的获批是基于其在T2DM人群开展的SUSTAIN系列临床试验^[2-12]，口服制剂的降糖适应症的获批是基于PIONEER 1-8全球性临床试验^[12]。

其中SUSTAIN系列研究（SUSTAIN 1-11），患者总例数超过1.1万例，试验组药物是司美格鲁肽单药或联合用药，对照组为安慰剂和/或阳性对照，主要终点指标为HbA1c降幅(%)。这些关键的III期临床研究（SUSTAIN 1-5、7-11）验证了司美格鲁肽单药或联合用药的良好降糖疗效，总体HbA1c降幅为0.9%-1.8%，可用于既往接受或未接受降糖治疗的2型糖尿病患者（详见表1）。

表1 注射用司美格鲁肽降糖的SUSTAIN系列临床研究汇总

于2022年5月13日经美国FDA获批上市的GLP-1R/GIPR双靶点激动剂的替尔泊肽注射液（Tirzepatide，商品名为Mounjaro）作为饮食和运动的辅助用药，用以改善成人2型糖尿病的血糖控制。该适应症的获批是基于其在2型糖尿病人群中开展的全球关键III期注册试验——SURPASS系列临床试验^[13-19]。

SURPASS 1-5研究，患者总例数超过6000例，试验组药物是替尔泊肽单药，对照组为安慰剂或阳性对照，主要终点指标为HbA1c降幅(%)。这些关键的III期临床研究验证了替尔泊肽单药较安慰剂和司美格鲁肽更优的降糖疗效，总体HbA1c降幅为1.87%-2.59%，可用于既往接受或未接受降糖治疗的2型糖尿病患者（详见表2）。

表2 注射用替尔泊肽降糖的SURPASS系列临床研究汇总

上述两款已上市的GLP-1R单靶点和GLP-1R/GIPR双靶点产品在针对2型糖尿病适应症的降糖作用明显，同类同靶点产品的同适应症的临床开发需满足与上述产品在有效性方面的非劣性，甚至是优效性，才能有竞争力。

2.针对超重和肥胖人群的减重作用

司美格鲁肽的注射剂型主要依据STEP系列III期临床研究于2021年6月获美国FDA批准用于减重，口服剂型主要依据OASIS系列III期临床研究，于2023年5月获美国FDA批准用于减重。STEP系列临床研究[20-27]，试验组药物是司美格鲁肽单药，对照组为安慰剂或阳性对照，主要终点指标为体重减轻降幅(kg)或体重减轻≥5%的受试者比例。

这些关键的III期临床研究说明司美格鲁肽单药较安慰剂和阳性对照（利拉鲁肽）具有更优的减重疗效，总体体重较基线降幅约为7.9kg-16.1kg，体重减轻≥5%的受试者比例约为68.8%-86.6%，可用于肥胖患者（详见表3）。

表3 注射用司美格鲁肽用于肥胖人群的III期临床试验汇总

于2023年11月经美国FDA获批上市的GLP-1R/GIPR双靶点激动剂的替尔泊肽注射液（Tirzepatide，商品名为Zepbound）用于减重治疗。该适应症的获批是基于SURMOUNT系列III期临床试验结果^[28-32]。

此系列研究患者总例数超5000例，试验组药物是替尔泊肽单药，对照组为安慰剂或阳性对照，主要终点指标为体重降幅(%)。这些关键的III期临床研究验证了替尔泊肽单药较安慰剂和司美格鲁肽更优的减重疗效，总体体重降幅为15.7%-22.2%（10mg及15mg），可用于超重和肥胖患者（详见表4）。

表4 注射用替尔泊肽降糖的SURMOUNT系列临床研究汇总

靶向GLP-1R/GIPR/GCGR三靶点激动剂的Retatrutide，目前已经完成的一项减重II期临床，研究结果显示，12mg Retatrutide组受试者在给药24周后体重降幅达17.5%（安慰剂组为1.6%），给药48周后，体重降幅达到24.2%（安慰剂组为2.1%）。

上述两款已上市的GLP-1R单靶点激动剂和GLP-1R/GIPR双靶点激动剂，以及处于关键临床研究阶段的GLP-1R/GIPR/GCGR三靶点激动剂，在超重和肥胖患者中减重效果明显，同类同靶点产品在同适应症的临床开发中可以考虑单药以及联合治疗。同类同靶点产品的同适应症的临床开发需满足与上述产品在有效性方面的非劣性，甚至是优效性，才能有竞争力。

四、总结

基于GLP-1R靶点产品的开发，以患者为本，从临床未被满足的需求出发，做好差异化的临床开发策略，才能在靶向GLP-1R单靶点、双靶点和三靶点产品竞争中，建立产品的独特竞争优势。本期暂基于有效性讨论同类产品的差异化开发策略，下期将继续讨论安全性、方便性以及适应症拓展三个方面的差异化开发策略。

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[32] https://trials.lilly.com/en-US/trial/399775