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

Efsubaglutide alfa, a novel long-acting GLP-1RA, was developed for sustained glycaemic management.

Efsubaglutide alfa是一种新型长效GLP-1RA，已被开发用于持续的血糖管理。

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.

本研究旨在确认其推荐的临床剂量，并评估其在通过生活方式干预措施未能充分控制的2型糖尿病初治患者中的疗效和安全性。

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.

这项两阶段的IIb/III期试验采用了操作无缝的自适应设计，并招募了新诊断为2型糖尿病且通过饮食和运动未能充分控制糖尿病的成年人。

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.

在第二阶段b期，参与者按照2:2:2:1的比例随机接受每周一次的efsubaglutide alfa（1、2或3毫克）或安慰剂皮下注射，持续12周。

Based on an interim analysis, two recommended Phase III doses (RP3Ds) were selected by an independent data monitoring committee.

基于中期分析，独立数据监测委员会选择了两个推荐的第三阶段剂量（RP3Ds）。

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.

在第三阶段，参与者以2:2:1的比例随机分配接受efsubaglutide alfa的两个RP3D之一或安慰剂。

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.

在整个试验过程中，参与者、研究人员和赞助商对药物/安慰剂的分配情况均不知情。主要终点是从基线到第24周HbA1c的变化。

Secondary endpoints included changes in body weight and metabolic parameters at weeks 24 and 52.

次要终点包括第24周和第52周体重及代谢参数的变化。

Safety was monitored throughout.

安全性在整个研究过程中得到监测。

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).

在 IIb 期阶段，140 名参与者被随机分配到 efsubaglutide alfa（1 毫克，n=41；2 毫克，n=39；3 毫克，n=41）或安慰剂（n=19）。

Based on interim analysis, 1 and 3 mg were selected as the RP3Ds.

基于中期分析，1 毫克和 3 毫克被选为 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).

在III期临床试验阶段，297名参与者被随机分配到efsubaglutide alfa组（1毫克，n=118；3毫克，n=117）或安慰剂组（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.

在第24周时，与基线相比，1毫克剂量组的HbA1c降低了-18.91毫摩尔/摩尔（1.73%）（95%置信区间-20.98, -16.83），而3毫克剂量组的HbA1c降低了-23.50毫摩尔/摩尔（2.15%）（95%置信区间-25.68, -21.31）。

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.

与安慰剂相比，1毫克剂量的估计治疗差异为-13.71毫摩尔/摩尔（-1.26%）（95%置信区间-17.39至-10.06），而3毫克剂量的估计治疗差异为-18.36毫摩尔/摩尔（-1.68%）（95%置信区间-22.08至-14.64）。

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%).

此外，接受1毫克剂量的参与者中有56%达到了HbA1c<53.0毫摩尔/摩尔（7.0%）（95%置信区间47至65；p<0.001），而接受3毫克剂量的参与者中有68%达到了HbA1c<53.0毫摩尔/摩尔（7.0%）（95%置信区间59至76；p<0.001）。

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).

与基线相比，空腹血浆葡萄糖显著降低：1毫克剂量组为2.04毫摩尔/升（95%置信区间-2.40, -1.68），3毫克剂量组为2.49毫摩尔/升（95%置信区间-2.87, -2.11）（与安慰剂相比估计治疗差异：1毫克剂量组为-1.71毫摩尔/升[95%置信区间-2.34, -1.07]，3毫克剂量组为-2.16毫摩尔/升[95%置信区间-2.80, -1.52]）。

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).

与基线相比，2小时餐后血浆葡萄糖也有显著降低：1毫克剂量组为3.7毫摩尔/升（95%置信区间-4.42, -3.03），3毫克剂量组为4.6毫摩尔/升（95%置信区间-5.36, -3.86）（与安慰剂相比估计治疗差异：1毫克剂量组为-3.2毫摩尔/升[95%置信区间-4.41, -1.98]，3毫克剂量组为-4.1毫摩尔/升[95%置信区间-5.28, -2.88]）。

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).

体重减轻了0.97%（95% 置信区间-1.76, -0.18）使用1毫克剂量，以及减轻了3.14%（95% 置信区间-3.98, -2.31）使用3毫克剂量（与安慰剂相比估计治疗差异：1毫克剂量为0.97% [95% 置信区间-0.41, 2.35]，3毫克剂量为-2.18% [95% 置信区间-3.30, -1.05]）。

Gastrointestinal symptoms, including nausea, vomiting, diarrhoea and decreased appetite, were the most common adverse events, and were mostly mild to moderate in severity.

胃肠道症状，包括恶心、呕吐、腹泻和食欲减退，是最常见的不良事件，且大多数为轻度至中度。

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.

Efsubaglutide alfa 显著改善了未用药的2型糖尿病患者的血糖管理并促进了体重减轻，具有良好的安全性。

These results establish efsubaglutide alfa as a promising therapeutic option for type 2 diabetes and related metabolic disorders.

这些结果确立了 Efsubaglutide alfa 作为2型糖尿病及其相关代谢紊乱的有希望的治疗选择。

trial_registration

ClinicalTrials.gov NCT04994288 FUNDING: This study was sponsored by Innogen Pharmaceutical Co. Ltd.

ClinicalTrials.gov NCT04994288 资助信息：本研究由Innogen制药有限公司赞助。