SAT-559 Population PK (PopPK) and Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis of Avexitide in Individuals with Post-Bariatric Hypoglycemia

Abstract Disclosure: C. Craig: Amylyx Pharmaceuticals, Inc. K. Fox: Amylyx Pharmaceuticals, Inc. M. Manuel: Amylyx Pharmaceuticals, Inc.. Background: Post-bariatric hypoglycemia (PBH) is a condition characterized by hyperinsulinemic hypoglycemia in individuals who have undergone bariatric surgery. PBH is thought to be driven by an excessive glucagon-like peptide-1 (GLP-1) response due to altered nutrient transit after surgery. Avexitide is an investigational, first-in-class GLP-1 receptor antagonist designed to competitively inhibit GLP-1-mediated insulin secretion and stabilize glucose levels. Avexitide has been investigated across 5 PBH clinical trials and 7 toxicity studies including assessment of effect on embryofetal development. Results have demonstrated that avexitide is well tolerated and may have the potential to prevent GLP-1-mediated hyperinsulinemia as well as the resultant symptomatic hypoglycemia that characterizes PBH. The efficacy and safety of avexitide 90 mg once daily will be further evaluated in the phase 3 LUCIDITY trial based in part on supporting evidence from a phase 2b study that demonstrated reductions in the rates of Levels 1-3 hypoglycemia with avexitide 90 mg daily. Objective: Develop a population pharmacokinetic (PopPK) model for avexitide in people with PBH and evaluate the PK/PD relationship describing the effect of avexitide on hypoglycemia responses in individuals with PBH. Methods: The PK of avexitide in plasma was evaluated in 58 individuals with 1,473 samples from two studies. A nonlinear mixed effects modeling approach with the first-order conditional estimation (FOCE) method in NONMEM 7, version 7.3 (ICON, Maryland) was used for the PopPK analysis. The relationship between avexitide PK and glucose concentrations was evaluated using graphical and modeling approaches to determine the potential potency of avexitide effect on glucose. Results: Postprandial glucose nadirs observed during mixed meal tolerance testing (MMTT) were evaluated against PopPK model-predicted avexitide trough concentrations (Cmin). PK/PD data were fitted to an Emax model. Model fitting results established a half maximal effective concentration (EC50) of 90.1 ng/mL (Standard Error [SE]: 1.53) for Cmin. Model-predicted typical steady-state avexitide Cmin at 90 mg once daily was 96.1 ng/mL. Based on model-predicted parameters, avexitide Cmin above 50 ng/mL corresponds to glucose readings above 54 mg/dL. Conclusions: Mechanistically, Cmin is expected to be a primary driver of avexitide efficacy. Avexitide 90 mg once daily resulted in Cmin above EC50 for 24 hours, providing evidence that this dose can have continued biological effect between daily doses and further supporting the rationale for and appropriateness of the 90 mg once daily dosing regimen in the Phase 3 LUCIDITY trial. Presentation: Saturday, July 12, 2025