The Genetic and Embryo–Fetal Developmental Toxicity Profile of the Novel Transgelin Agonist Deg-AZM: Ames, Micronucleus, Chromosomal Aberration, and Rat EFD Studies

TL;DR

A new drug for constipation, Deg-AZM, was tested and found to be safe in terms of genetic and fetal development risks.

Contribution

Deg-AZM's safety profile is established through genetic and developmental toxicity studies, supporting its clinical use.

Findings

Deg-AZM showed no mutagenic or clastogenic effects in genetic toxicity tests.

No maternal or fetal toxicity was observed at doses up to 600 mg/kg in rat studies.

Deg-AZM has a favorable safety profile for potential use in treating slow-transit constipation.

Abstract

Background: Slow-transit constipation (STC) lacks durable and safe prokinetics. Deglycosylated-azithromycin (Deg-AZM), a novel small-molecule transgelin agonist that restores colonic motility in STC, has been approved for clinical trials in 2024. Objectives: This study aimed to assess the genetic toxicity and embryo–fetal development (EFD) toxicity of Deg-AZM through a series of standardized non-clinical safety studies. Methods: We conducted Ames, in vivo micronucleus, and chromosomal aberration tests to evaluate genotoxicity. Acute and 28-day repeated-dose oral toxicity studies were performed in Sprague-Dawley rats. EFD toxicity was assessed in pregnant rats administered Deg-AZM from gestation day (GD) 6 to 15. Toxicokinetic analyses were integrated into repeated-dose and EFD studies. Results: Deg-AZM demonstrated no mutagenic potential in the bacterial reverse-mutation assay at concentrations up to 2500 µg/plate (with metabolic activation) or 150 µg/plate (without metabolic activation). No clastogenic effects were observed in micronucleus or chromosomal aberration assays. The median lethal dose (LD50) exceeded 1600 mg/kg in acute oral toxicity. In the 28-day study, no adverse effects were observed at doses up to 600 mg/kg, though mild hematological and hepatic changes were noted at high doses, all of which were reversible. In the EFD study, Deg-AZM did not induce maternal toxicity, teratogenicity, or adverse fetal outcomes at doses up to 600 mg/kg. Conclusions: Deg-AZM demonstrates a favorable safety profile with no evidence of genetic toxicity or developmental harm at pharmacologically relevant doses, supporting its further development as a therapeutic agent for STC.

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