Preclinical Safety Profile of Deg-AZM, a Clinical-Stage New Transgelin Agonist: hERG Inhibition Study In Vitro, Cardiovascular-Respiratory Pharmacology, and Single/Repeated-Dose Toxicity in Beagle Dogs.

Background

Slow transit constipation (STC) represents a refractory gastrointestinal disorder with limited therapeutic options. Deglycosylated azithromycin (Deg-AZM) is a small molecule Transgelin agonist effective against STC, which has been approved for 2024 clinical trials.

Objectives

This study comprehensively evaluated the cardiac safety (hERG inhibition), acute cardiovascular-respiratory effects, and single/repeated-dose toxicity of Deg-AZM in Beagle dogs to de-risk clinical translation.

Methods

Using automated patch-clamp (hERG-HEK293 cells; 0.1-1000 μM), telemetric monitoring in Beagles (3/8/24 mg/kg; Latin square design), and GLP-compliant toxicity studies (single-dose: 150-300 mg/kg; 28-day: 5-50 mg/kg/day), we assessed functional, biochemical, histopathological, and toxicokinetic parameters.

Results

Deg-AZM showed negligible hERG inhibition (maximum 21.3% at 1000 μM). Transient PR prolongation (24 mg/kg; resolved by 4 h) and respiratory rate reduction (8-24 mg/kg; resolved by 2 h) occurred at supratherapeutic doses. Single-dose toxicity revealed one mortality at 300 mg/kg (acute cardiac ischemia), while 28-day studies identified fully reversible myocardial vacuolation at 50 mg/kg. Toxicokinetics demonstrated dose-proportional exposure (AUC and Cmax) and low accumulation (accumulation factors ≤ 1.5). No hematological, coagulation, or hepatic toxicity was observed.

Conclusions

With absent hERG liability and manageable transient physiological effects, Deg-AZM exhibited a favorable preclinical safety profile supporting its clinical development for STC.