Sustained Action of Imapextide, A Glucagon-Like Peptide-1 Receptor Antagonist, in Healthy Volunteers

作者：Elisa Fabbrini, Anastasiya Koshkina, Michael Hackett, Michael Zhao, Kishore Thalluri, Marcus Hompesch, ALEJANDRA MACIAS, Kristi Schneider, David A D'Alessio, Richard D. DiMarchi, SALOMON AZOULAY · 发表于：The Journal of Clinical Endocrinology & Metabolism · 年份：2025 · DOI：10.1210/clinem/dgaf691 · 被引用次数：1 · 研究领域：Diabetes Treatment and Management、Bariatric Surgery and Outcomes、Diabetes Management and Research

CONTEXT: After weight-loss surgery, some patients experience postbariatric hypoglycemia (PBH). Although PBH is customarily managed by dietary modifications with continuous glucose monitoring, advanced treatment options are needed. Imapextide is a sustained-action, selective, reversible glucagon-like peptide-1 (GLP-1) receptor antagonist designed for once-weekly administration for PBH treatment. OBJECTIVE: This work aimed to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple ascending doses (SAD/MAD) of imapextide in healthy volunteers (HVs). METHODS: This 3-part, phase 1, double-blind study enrolled healthy adults. In the SAD/MAD parts, randomly assigned participants (3:1) received subcutaneous imapextide (SAD, 10-200 mg; MAD, 10-30 mg once weekly, 4 doses) or placebo. The primary end point was safety/tolerability (treatment-emergent adverse events [TEAEs]). PK (SAD/MAD; time-to-maximal concentration [tmax] and half-life [t1/2]) and PD (MAD; GLP-1 and glycemic parameters during a mixed meal tolerance test [MMTT]) were assessed. Imapextide drug-drug interactions (DDIs) of OATP1B1/OATP1B3 inhibition and accelerated gastric emptying were evaluated with coproporphyrin-I, rosuvastatin, and acetaminophen. RESULTS: Overall, 69 HVs were randomly assigned (32 SAD, 23 MAD, 14 DDIs). Imapextide TEAE rates ranged from 33.3% to 50.0% (SAD), 33.3% to 100% (MAD), and 14.3% (DDIs) across cohorts. The most common TEAEs included injection sit...