Roginolisib (IOA-244) is a novel, non-ATP competitive phosphoinositide-3-kinase (PI3K) delta inhibitor that regulates Akt/mTOR signaling. Roginolisib was administered once daily to rats and dogs in dose-range finding (DRF) and 4-week GLP toxicology studies. Free plasma levels of roginolisib exceeded the cellular target engagement IC90 for PI3Kδ for ≥12 hours at doses of 5 mg/kg, the IC90 for PI3Kβ for ≥2 hours at doses ≥15 mg/kg, and the IC50 for PI3Kα for ≥2 hours at dose levels ≥45 mg/kg. Toxicity in rats occurred at doses ≥100 mg/kg. In dogs, we observed dose-dependent skin and gastrointestinal toxicity and doses ≥30 mg/kg had a greater incidence of mortality. Lymphoid tissue toxicity occurred in both species. Toxicities in dogs observed at the ≥15 mg/kg dose, affecting the digestive mucosa, liver, and skin, cleared after treatment cessation. Doses ≤75 mg/kg were tolerated in rats and the no-observed-adverse-effect-level (NOAEL) in rats was 15 mg/kg. Due to mainly epithelial lesions of the skin at 5 mg/kg and necrotizing damage of the intestinal epithelia at ≥15 mg/kg, no NOAEL was determined in dogs. However, the adverse effects observed in dogs at 5 mg/kg were considered monitorable and reversible in patients with advanced malignancies. Furthermore, the PK profile subsequently proved to be a decisive factor for achieving selective PI3Kδ inhibition without the toxicities observed in dogs. As the result of the unique PK profile of roginolisib, patients were able to take daily roginolisib without dose modification and showed pharmacodynamic PI3Kδ inhibition over several months without gastrointestinal or dermatologic toxicities.
Keywords: PI3Kδ; phosphoinositide-3 kinase delta; phosphoinositide-3 kinase inhibitors; roginolisib; toxicology.