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Aims/hypothesis <p>Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have become an important option in clinical use for type 2 diabetes due to their dual benefits of glycaemic management and metabolic improvements. Efsubaglutide alfa, a novel long-acting GLP-1RA, was developed for sustained glycaemic management. This study aimed to confirm its recommended clinical dose and evaluate its efficacy and safety in drug-naive individuals with type 2 diabetes that was inadequately managed through lifestyle interventions.</p> Methods <p>This two-stage Phase&#xa0;IIb/III trial employed an operationally seamless adaptive design and enrolled adults who had been newly diagnosed with type 2 diabetes and whose diabetes was inadequately managed by diet and exercise. In the Phase&#xa0;IIb stage, participants were randomised in a 2:2:2:1 ratio to receive once-weekly subcutaneous injections of efsubaglutide alfa (1, 2 or 3 mg) or placebo for 12 weeks. Based on an interim analysis, two recommended Phase&#xa0;III doses (RP3Ds) were selected by an independent data monitoring committee. In the Phase&#xa0;III stage, participants were randomised in a 2:2:1 ratio to receive efsubaglutide alfa at one of the two RP3Ds or to receive placebo. Participants, investigators and sponsors were masked to drug/placebo allocation throughout the trial. The primary endpoint was the change in HbA<sub>1c</sub> from baseline to week 24. Secondary endpoints included changes in body weight and metabolic parameters at weeks 24 and 52. Safety was monitored throughout.</p> Results <p>In the Phase&#xa0;IIb stage, 140 participants were randomised to efsubaglutide alfa (1 mg, <i>n</i>=41; 2 mg, <i>n</i>=39; 3 mg, <i>n</i>=41) or placebo (<i>n</i>=19). Based on interim analysis, 1 and 3 mg were selected as the RP3Ds. In the Phase&#xa0;III stage, 297 participants were randomised to efsubaglutide alfa (1 mg, <i>n</i>=118; 3 mg, <i>n</i>=117) or placebo (<i>n</i>=62). At week 24, the HbA<sub>1c</sub> reductions from baseline were −18.91 mmol/mol (1.73%) (95% CI −20.98, −16.83) with the 1 mg dose, and −23.50 mmol/mol (2.15%) (95% CI −25.68, −21.31) with 3 mg. The estimated treatment difference vs placebo was −13.71 mmol/mol (−1.26%) (95% CI −17.39, −10.06) for the 1 mg dose and −18.36 mmol/mol (−1.68%) (95% CI −22.08, −14.64) for 3 mg. Additionally, 56% of participants receiving the 1 mg dose (95% CI 47, 65; <i>p</i>&lt;0.001) and 68% of participants receiving the 3 mg dose (95% CI 59, 76; <i>p</i>&lt;0.001) achieved an HbA<sub>1c</sub> &lt;53.0 mmol/mol (7.0%). There were significant reductions of fasting plasma glucose from baseline: 2.04 mmol/l (95% CI −2.40, −1.68) for the 1 mg dose, and 2.49 mmol/l (95% CI −2.87, −2.11) for 3 mg (estimated treatment difference vs placebo: −1.71 mmol/l [95% CI−2.34, −1.07] for the 1 mg dose, and −2.16 mmol/l [95% CI −2.80, −1.52] for 3 mg). There were also significant reductions in 2&#xa0;h postprandial plasma glucose compared with the baseline: 3.7 mmol/l (95% CI −4.42, −3.03] for the 1 mg dose, and 4.6 mmol/l (95% CI −5.36, −3.86) for 3 mg (estimated treatment difference vs placebo: −3.2 mmol/l [95% CI −4.41, −1.98] for the 1 mg dose, and −4.1 mmol/l [95% CI −5.28, −2.88] for 3 mg). Body weight decreased by 0.97% (95% CI −1.76, −0.18) with the 1 mg dose and by 3.14% (95% CI −3.98, −2.31) with 3 mg (estimated treatment difference vs placebo: 0.97% [95% CI −0.41, 2.35] for the 1 mg dose, and −2.18% [95% CI −3.30, −1.05] for 3 mg). Gastrointestinal symptoms, including nausea, vomiting, diarrhoea and decreased appetite, were the most common adverse events, and were mostly mild to moderate in severity.</p> Conclusions/interpretation <p>Efsubaglutide alfa significantly improved glycaemic management and promoted weight loss in drug-naive individuals with type 2 diabetes, with a favourable safety profile. These results establish efsubaglutide alfa as a promising therapeutic option for type 2 diabetes and related metabolic disorders.</p> Trial registration <p>ClinicalTrials.gov NCT04994288</p> Funding <p>This study was sponsored by Innogen Pharmaceutical Co. Ltd</p> Graphical Abstract <p></p>

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Efficacy and safety of efsubaglutide alfa in individuals with type 2 diabetes (SUPER1): a randomised, double-blind, placebo-controlled, Phase IIb/III trial

  • 期刊论文

  • 发表日期：

    2025年11月21日

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  • Dalong Zhu,
  • Jianhua Ma,
  • Weimin Wang,
  • Bimin Shi,
  • Xiaolin Dong,
  • Fang Bian,
  • Qingju Li,
  • Yihua Wang,
  • Chengyan Jiang,
  • Xueying Wang,
  • Kun Wang,
  • Hongwei Ling,
  • Xiaoxia Shi,
  • Zhifeng Cheng,
  • Guoyue Yuan,
  • Liping Li,
  • Xiuhai Su,
  • Yibing Lu,
  • Weihong Song,
  • Yawei Zhang,
  • Wen Hu,
  • Xin Zhang,
  • Haifang Wang,
  • Yu Liu,
  • Jifang Li,
  • Lili Zhang,
  • Yan Liu,
  • Xiaokun Sun,
  • Xiaoyue Wang,
  • Keqin Zhang,
  • Yongcai Zhao,
  • Lili Zhang,
  • Tianrong Pan,
  • Ping Li,
  • Shu Li,
  • Haifeng Zhou,
  • Chengxia Jiang,
  • Xin Zheng,
  • Lin Ni,
  • Bo Feng,
  • Feng Li,
  • Lianshan Piao,
  • Hongwei Jin,
  • Yang Liu,
  • Hongyi Cao,
  • Yufeng Li,
  • Hanqing Cai,
  • Hong Mao,
  • Yongqian Liang,
  • Jianchao Guo,
  • Yangang Wang,
  • Yan Li,
  • Ning Xu,
  • Jinan Zhang,
  • Qiu Zhang,
  • Wuyan Pang,
  • Jianxin Yu,
  • Yulong Xu,
  • Yue Zhou,
  • Yiming Li,
  • Qinghua Wang

摘要

Aims/hypothesis

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have become an important option in clinical use for type 2 diabetes due to their dual benefits of glycaemic management and metabolic improvements. Efsubaglutide alfa, a novel long-acting GLP-1RA, was developed for sustained glycaemic management. This study aimed to confirm its recommended clinical dose and evaluate its efficacy and safety in drug-naive individuals with type 2 diabetes that was inadequately managed through lifestyle interventions.

Methods

This two-stage Phase IIb/III trial employed an operationally seamless adaptive design and enrolled adults who had been newly diagnosed with type 2 diabetes and whose diabetes was inadequately managed by diet and exercise. In the Phase IIb stage, participants were randomised in a 2:2:2:1 ratio to receive once-weekly subcutaneous injections of efsubaglutide alfa (1, 2 or 3 mg) or placebo for 12 weeks. Based on an interim analysis, two recommended Phase III doses (RP3Ds) were selected by an independent data monitoring committee. In the Phase III stage, participants were randomised in a 2:2:1 ratio to receive efsubaglutide alfa at one of the two RP3Ds or to receive placebo. Participants, investigators and sponsors were masked to drug/placebo allocation throughout the trial. The primary endpoint was the change in HbA1c from baseline to week 24. Secondary endpoints included changes in body weight and metabolic parameters at weeks 24 and 52. Safety was monitored throughout.

Results

In the Phase IIb stage, 140 participants were randomised to efsubaglutide alfa (1 mg, n=41; 2 mg, n=39; 3 mg, n=41) or placebo (n=19). Based on interim analysis, 1 and 3 mg were selected as the RP3Ds. In the Phase III stage, 297 participants were randomised to efsubaglutide alfa (1 mg, n=118; 3 mg, n=117) or placebo (n=62). At week 24, the HbA1c reductions from baseline were −18.91 mmol/mol (1.73%) (95% CI −20.98, −16.83) with the 1 mg dose, and −23.50 mmol/mol (2.15%) (95% CI −25.68, −21.31) with 3 mg. The estimated treatment difference vs placebo was −13.71 mmol/mol (−1.26%) (95% CI −17.39, −10.06) for the 1 mg dose and −18.36 mmol/mol (−1.68%) (95% CI −22.08, −14.64) for 3 mg. Additionally, 56% of participants receiving the 1 mg dose (95% CI 47, 65; p<0.001) and 68% of participants receiving the 3 mg dose (95% CI 59, 76; p<0.001) achieved an HbA1c <53.0 mmol/mol (7.0%). There were significant reductions of fasting plasma glucose from baseline: 2.04 mmol/l (95% CI −2.40, −1.68) for the 1 mg dose, and 2.49 mmol/l (95% CI −2.87, −2.11) for 3 mg (estimated treatment difference vs placebo: −1.71 mmol/l [95% CI−2.34, −1.07] for the 1 mg dose, and −2.16 mmol/l [95% CI −2.80, −1.52] for 3 mg). There were also significant reductions in 2 h postprandial plasma glucose compared with the baseline: 3.7 mmol/l (95% CI −4.42, −3.03] for the 1 mg dose, and 4.6 mmol/l (95% CI −5.36, −3.86) for 3 mg (estimated treatment difference vs placebo: −3.2 mmol/l [95% CI −4.41, −1.98] for the 1 mg dose, and −4.1 mmol/l [95% CI −5.28, −2.88] for 3 mg). Body weight decreased by 0.97% (95% CI −1.76, −0.18) with the 1 mg dose and by 3.14% (95% CI −3.98, −2.31) with 3 mg (estimated treatment difference vs placebo: 0.97% [95% CI −0.41, 2.35] for the 1 mg dose, and −2.18% [95% CI −3.30, −1.05] for 3 mg). Gastrointestinal symptoms, including nausea, vomiting, diarrhoea and decreased appetite, were the most common adverse events, and were mostly mild to moderate in severity.

Conclusions/interpretation

Efsubaglutide alfa significantly improved glycaemic management and promoted weight loss in drug-naive individuals with type 2 diabetes, with a favourable safety profile. These results establish efsubaglutide alfa as a promising therapeutic option for type 2 diabetes and related metabolic disorders.

Trial registration

ClinicalTrials.gov NCT04994288

Funding

This study was sponsored by Innogen Pharmaceutical Co. Ltd

Graphical Abstract