Efficacy, tolerability, and safety of Efsubaglutide Alfa in participants with obesity or overweight ( LIGHT 1): A randomized, double‐blind, placebo‐controlled, ascending‐dose phase 2a trial

BACKGROUND: Efsubaglutide Alfa is a novel long-acting glucagon-like peptide-1 receptor agonist developed to promote weight loss and improve metabolic outcomes. This Phase 2a trial evaluated its efficacy, tolerability, safety, and pharmacokinetics (PK) in overweight and obese individuals unresponsive to lifestyle interventions. METHODS: In this multicenter, randomized, double-blind, placebo-controlled, multiple-ascending dose study, 50 participants were randomized (8:2) across five dose cohorts (5, 7.5, 10, 15, and 20 mg) or placebo. Participants received once-weekly subcutaneous injections of Efsubaglutide Alfa or placebo, with individualized dose escalation every 2 weeks, followed by 4 weeks at target doses. Primary endpoints were percentage change in body weight from baseline and the proportion achieving ≥5% weight loss. Secondary endpoints included changes in body composition and a metabolic composite index (BMI, waist circumference, blood pressure, lipid profiles). Tolerability, safety, immunogenicity, and PK were assessed. FINDINGS: . Efsubaglutide Alfa produced a mean weight reduction of 7.16% (95% CI: -8.08 to -6.24) versus 0.86% with placebo. Overall, 82.5% of Efsubaglutide-treated participants achieved ≥5% weight loss (vs. 0% placebo). Fat mass decreased by 4.47 kg, and lean mass also declined by 2.00 kg from baseline; however, the lean-to-fat mass ratio improved by 19.73 percentage points. BMI, waist circumference, and systolic blood pressure significantly decreased. Gastrointestinal adverse events were the most common, mostly mild to moderate, occurring primarily during dose escalation. No treatment-related serious adverse events occurred. Efsubaglutide Alfa showed dose-proportional PK. INTERPRETATION: Efsubaglutide Alfa demonstrated significant weight-loss efficacy, metabolic improvements, and a preferable tolerability and safety profile, supporting further clinical development for obesity and related metabolic disorders.