Preclinical Evaluation of the Oral Toxicity, Genotoxicity, and Safety Pharmacology of LPM4870108 , a Novel Potent Tropomyosin Receptor Kinase Inhibitor

ABSTRACT Tropomyosin receptor kinase (Trk) inhibitors are an essential class of anticancer drugs treating NTRK gene fusions‐positive cancer. However, the potential for the emergence of on‐target resistance suggests newer Trk inhibitors with low drug resistance risk are needed. LPM4870108 is a novel Trk inhibitor with robust anticancer efficacy in preclinical studies. To support future clinical development, this study systematically evaluated the acute and subacute (4‐week) toxicity, toxicokinetic, genotoxic, and safety pharmacology of LPM4870108. The acute toxicity study revealed the maximum tolerated dose of LPM4870108 was 300 mg/kg, whereas subacute studies determined its STD10 in rats was 10 mg/kg/day. The toxicological effects of LPM4870108 were consistent with its pharmacodynamic efficacies as a Trk inhibitor, including corneal inflammation, splenic lymphocytopenia, hepatocyte vacuolar degeneration, scab formation, and increased food consumption and body weight. These changes were partially or fully recovered after 4 weeks of recovery. In rats treated with 10 or 20 mg/kg/day, 2/30, or 6/30 rats died or were moribund, and the primary organs affected by treatment‐related toxicity included the eyes, liver, and skin. Rat toxicokinetic findings were consistent with a dose‐dependent effect of LPM4870108. There was no evidence of LPM4870108‐related genotoxicity, nor did it affect respiratory function or neurobehavioral activity in rats or blood pressure or electrocardiogram results in rhesus monkeys. The IC50 of LPM4870108 for hERG current inhibition was 18.2 μM. Together, these results demonstrate that LPM4870108 exhibits a satisfactory safety profile which is appropriate for further clinical development.