A39-06 Inhaled Rentosertib (INS018_055) Exhibits High Safety and Tolerability in Animal Models

Rationale Rentosertib (INS018_055) is a novel, potent inhibitor of TNIK developed using generative AI platforms currently in clinical testing for the treatment of idiopathic pulmonary fibrosis (IPF). An aerosolized, inhalable formulation of rentosertib has been developed, which exhibits substantially higher exposure in lung compared to plasma. Preclinical toxicology studies were conducted to assess potential toxicity, toxicokinetics, and reversibility after repeated dosing. Methods Toxicities were investigated in Sprague-Dawley rats receiving 0 mg/kg, 2 mg/kg, 6 mg/kg, or 20 mg/kg aerosolized rentosertib administered once-daily for 28 days (n = 15/sex/group). Animals were monitored for toxicological endpoints including clinical observations, hematology, urinalysis, and histopathology. Samples were collected at the end of the dosing period and after a four-week recovery phase. Central nervous system (CNS) safety pharmacology was assessed in rats after one dose of aerosolized rentosertib (n = 5/sex/group). Functional observational battery (FOB) tests were conducted at multiple timepoints to assess behavioral, sensory, motor, and physiological parameters. Additional toxicity assessment was carried out in Beagle dogs receiving 0 mg/kg, 1 mg/kg, 3 mg/kg, or 10 mg/kg aerosolized rentosertib administered once-daily for 28 days (n = 5/sex/group). Samples were collected on day 1 pre- and post-dosing, at the end of the dosing period, and after a four-week recovery phase. Toxicological endpoints included clinical observations, hematology, urinalysis, and histopathology. Cardiovascular and respiratory safety pharmacology was assessed in Beagle dogs after one dose of aerosolized rentosertib (n = 4/sex/group) using a crossover study design with a three-day interval. Parameters such as electrocardiogram, blood pressure, respiratory function, and body temperature were monitored over an extended period. Results Inhaled rentosertib was well-tolerated in both species with no drug-related adverse findings observed. Mild macrophage infiltration was noted in the lungs, which was reversible after the recovery period. In dogs, mild to moderate nasal mucosal changes were observed, which also resolved after treatment cessation. No accumulation was observed in either species. Conclusions Four-week administration of inhaled rentosertib in both rats and dogs demonstrated a favorable safety profile. The no-observed-adverse-effect-level (NOAEL) was established at the highest doses tested of 20 mg/kg/day in rats and 10 mg/kg/day in dogs, with safety margins exceeding 100-fold systemically and 40-fold locally. These results support an improved safety compared to oral administration. This abstract is funded by: Insilico Medicine