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Non-clinical and first-in-human characterization of ECC5004/AZD5004, a novel once-daily, oral small-molecule GLP-1

Amina Z Haggag1, Jianfeng Xu2, Laurie Butcher2

  • 1Anaheim Clinical Trials LLC, Anaheim, California, USA.

Diabetes, Obesity & Metabolism
|November 4, 2024
PubMed
Abstract

Insights

ECC5004, an oral small-molecule GLP-1 RA, effectively targets the GLP-1 receptor, showing promise for type 2 diabetes and obesity. The first-in-human study demonstrated good tolerability and dose-dependent reductions in glucose and body weight.

Area of Science:

  • Pharmacology and Endocrinology
  • Metabolic Diseases
  • Drug Development

Background:

  • Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are established treatments for type 2 diabetes mellitus (T2DM) and obesity.
  • ECC5004/AZD5004 is an orally available small-molecule GLP-1 receptor agonist.

Purpose of the Study:

  • To evaluate the non-clinical and first-in-human (FIH) safety and efficacy of ECC5004.
  • To assess the pharmacokinetic and pharmacodynamic profile of ECC5004.

Main Methods:

  • In vitro assays using cell lines overexpressing human GLP-1R and glucose-stimulated insulin secretion (GSIS) assays.
  • Non-human primate (NHP) studies for safety and efficacy, including a 9-month oral administration toxicity study.
  • A Phase I, double-blind, placebo-controlled FIH study in healthy volunteers and patients with T2DM.

Main Results:

  • ECC5004 demonstrated high affinity for the hGLP-1R, potentiated GSIS, and augmented cAMP signaling without promoting β-arrestin-2 recruitment or receptor internalization.
  • NHP studies showed dose-dependent body weight changes, and the FIH study indicated ECC5004 was well-tolerated with no serious adverse events.
  • Dose-dependent reductions in glucose and body weight were observed in T2DM patients, with dose-proportional exposure.

Conclusions:

  • ECC5004 effectively engages the GLP-1 receptor within the tested therapeutic dose range.
  • The drug exhibits a safety and tolerability profile comparable to existing GLP-1 RAs, with pharmacokinetics suitable for once-daily oral administration.
  • These findings support the continued development of ECC5004 for T2DM and overweight or obesity management.
Keywords:
AZD5004ECC5004GLP‐1GLP‐1 RAobesityoverweightsmall moleculetype 2 diabetes mellitus

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