S746 Pharmacogenomic Analysis of the GLP-1 Receptor in a Phase 2 Trial of Survodutide, a Glucagon/GLP-1 Receptor Dual Agonist, in Adults With Obesity

Introduction: Survodutide is a glucagon/glucagon-like peptide-1 (GLP-1) receptor (R) dual agonist in clinical development for the treatment of obesity, and metabolic dysfunction-associated steatohepatitis. Studies have shown that genetic variants, such as single nucleotide polymorphisms (SNPs), may influence inter-individual therapeutic responses to GLP-1R agonists. We present data from a prespecified pharmacogenomic analysis of GLP-1R variants in a phase 2 trial population to investigate their possible effect on therapeutic responses to survodutide. Methods: In a phase 2 clinical trial (NCT04667377), 387 adults (≥18 to <75 years) with body mass index ≥27 kg/m2 without diabetes were randomized to once-weekly subcutaneous survodutide (0.6, 2.4, 3.6, or 4.8 mg) or placebo for 46 weeks; an initial rapid dose-escalation period of up to 20 weeks (option to adjust dose for gastrointestinal tolerability), followed by dose-maintenance for the remaining trial duration. Blood samples were obtained from participants at visit 2, prior to start of treatment. Following DNA extraction, 5 ng of DNA was used for genotyping the 3 most common GLP-1R SNPs; rs6923761, rs10305420, and rs2268640. Mixed models for repeated measurements were fitted to data of 6 endpoints to test treatment effect heterogeneity after 46 weeks across genotypes of each of the SNPs. Treatment group referred to actual dose and only on-treatment data were analyzed. P-values from F-tests of heterogeneity at Week 46 across genotypes; considered nominally significant at 5%. Results: Whole blood samples were available from 344 participants; of these, 337 samples were available for analysis following DNA extraction and quality checks. Genotyping analysis revealed no statistically significant treatment effect heterogeneity between these genetic variants and the observed changes in bodyweight (rs6923761 P = 0.44; rs10305420 P = 0.69; rs2268640 P = 0.48), waist circumference (rs6923761 P = 0.89; rs10305420 P = 0.38; rs2268640 P = 0.44), and selected protein biomarkers; blood HbA1c (rs6923761 P = 0.94; rs10305420 P = 0.38; rs2268640 P = 0.61); fasting plasma glucagon (rs6923761 P = 0.85; rs10305420 P = 0.95; rs2268640 P = 0.40), and fasting plasma glucose (rs6923761 P = 0.82; rs10305420 P = 0.63; rs2268640 P = 0.19); and fasting serum insulin (rs6923761 P = 0.32; rs10305420 P = 0.97; rs2268640 P = 0.55). Conclusion: The GLP-1R variants investigated here were not associated with changes in survodutide efficacy in this phase 2 trial population. Encore: Originally presented at ECO 2025.