PRECLINICAL TOXICOLOGY EVALUATION OF ISM5411: 13-WEEK ORAL ADMINISTRATION IN RATS AND BEAGLE DOGS

Abstract INTRODUCTION ISM5411 is a novel gut-restricted, small-molecule inhibitor of PHD1/2, intracellular oxygen sensors that catalyze the degradation of HIF-1α. In the context of inflammatory bowel disease (IBD), stabilization of HIF-1α promotes expression of intestinal mucosal protective genes, restoring the integrity and function of the intestinal barrier and alleviating inflammation. We previously demonstrated promising efficacy and safety in 28-day treatment of mouse models of IBD. Further 13-week preclinical toxicology studies were conducted in rats and dogs to assess the potential toxicity and toxicokinetics of ISM5411 after repeated oral administration and to determine the reversibility of any effects following a recovery period. METHODS ISM5411 was administered to 7–9-week-old Sprague-Dawley rats once daily via oral gavage at 0, 100, 300, and 1000 mg/kg for 13 weeks, followed by a 28-day recovery period (n = 15/sex/dosage). ISM5411 was administered to ∼7-month-old Beagle dogs once daily via oral gavage at 0, 25, 80, and 1000 mg/kg for 13 weeks, followed by a 28-day recovery period (n = 6/sex/dosage). Toxicological endpoints included clinical observations, body weight, food consumption, ophthalmology, hematology, serum chemistry, coagulation, urinalysis, organ weights, gross necropsy, histopathology, and toxicokinetics. Toxicokinetics (Cmax, Tmax, AUC0-24h) were evaluated on Days 1 and 91. Electrocardiographic parameters and body temperature were also assessed in the dog safety studies. RESULTS ISM5411 was well tolerated in both species with no test article-related adverse findings. Test article-related changes were limited to erythroid parameters in dogs, with a moderate increase ( ≤ +30.34%) in erythrocyte count, hemoglobin, and hematocrit. All changes fully resolved after the 28-day recovery period. Erythroid changes were not considered adverse based on the lack of any associated changes in other clinical pathology parameters or histopathological findings. The NOAEL was determined to be the maximum dose of 1000 mg/kg/day in both species. In rats, systemic exposure increased less than dose-proportionally, with higher exposure in females; no significant accumulation was observed. In dogs, exposure also increased less than dose-proportionally, with no sex differences or accumulation. CONCLUSIONS The 13-week oral administration of ISM5411 in both rats and Beagle dogs demonstrated a favorable safety profile, with no observed adverse effects at the highest tested doses of 1000 mg/kg. These results support clinical advancement of ISM5411 and inform dose selection and safety monitoring in human trials.