Efficacy and safety of Efsubaglutide Alfa in "overrun" patients in the SUPER2 trial: A post-hoc analysis for comprehensive evaluation.

Abstract

Aims: Efsubaglutide Alfa is a novel, long-acting, once-weekly GLP-1 receptor agonist. In the pivotal phase 2b/3 SUPER2 trial, Efsubaglutide Alfa 3 mg plus metformin showed significant efficacy and favourable safety in patients with type 2 diabetes (T2D) inadequately controlled on metformin. This post-hoc analysis evaluated the 1 mg dose.

Materials and methods: In phase 2b, patients with T2D on metformin were randomized (1:1:1) to once-weekly Efsubaglutide Alfa 1 mg, 3 mg, or placebo for 12 weeks. After interim analysis, 3 mg was selected as the phase 3 dose. However, 155 patients already randomized (the "overrun" cohort) completed 24 weeks of double-blind treatment with 1 mg, then entered 28 weeks of open-label 3 mg and 4 weeks of follow-up. This analysis focused on the 1 mg cohort. The primary endpoint was change in HbA1c at week 24; secondary endpoints included fasting plasma glucose (FPG), body weight, HbA1c <7.0%, and subgroup analyses.

Results: At week 24, HbA1c decreased by -1.69% (95% CI -1.91 to -1.47) with Efsubaglutide Alfa 1 mg versus -0.74% (-0.96 to -0.52) with placebo, a placebo-corrected difference of -0.95% (95% CI -1.25 to -0.65; p < 0.0001). FPG decreased by -2.09 mmol/L versus -0.50 mmol/L with placebo (difference - 1.59 mmol/L; p < 0.001). Body weight reduction was modest and not significant (-2.8% vs. -1.3%; LSM -0.72 kg; p = 0.137). HbA1c <7.0% was achieved by 56.3% versus 11.1% with placebo (p < 0.0001; odds ratio 8.3). Gastrointestinal adverse events were most common, generally mild and transient, and no drug-related serious events occurred.

Conclusions: Efsubaglutide Alfa 1 mg provided clinically meaningful glucose lowering with good tolerability but without significant weight loss. These results support a lower-dose strategy for elderly or frail patients, those with low BMI, or individuals sensitive to gastrointestinal effects, and as a possible lead-in step before escalation. Confirmatory trials are warranted to establish long-term outcomes.