Non-Clinical Toxicology Evaluation of the Novel Non-ATP Competitive Oral PI3 Kinase Delta Inhibitor Roginolisib

Abstract

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.

Figure 1.

Heat map shows the histopathological findings including the severity grades of sites of toxicity in rats in a 4-week DRF study. Females that received 100 mg/kg of roginolisib resulted in premature mortality due to either clinical symptoms or euthanasia due to welfare concerns on Days 7-9. Male findings are represented in the upper colored triangles and female findings in the lower colored triangles. Coloring is matched with the severity grade assigned to the finding with increasing intensity of red being associated with severe grade toxicity.

Figure 2.

Observed hematology and clinical chemistry changes in 4-week dog toxicity study. Graphs show combined data for male and female animals. Data is presented as boxes with whiskers for min to max values. WBC = white blood cells; PLT = platelets; NEU = neutrophils; LYMPH = lymphocytes; ALAT = alanine aminotransferase; ASAT = aspartate aminotransferase; AP = alkaline phosphatase; GLDH = glutamate dehydrogenase; TP = total protein; ALB = albumin; CHOL = cholesterol.

Figure 3.

Bar graph shows inhibition of pAkt in whole blood rat B cells 1 hour after treatment with roginolisib.

Figure 4.

Heat map shows the histopathological findings including the severity grades in the liver and hematopoietic and lymphoid tissues of rats in a 4-week oral toxicology study. No histopathological findings were present in the digestive system or skin of any of the rats in this study. Male findings are represented in the upper colored triangles and female findings in the lower colored triangles. Coloring (i.e., increasing intensity of red) is matched with the severity grade assigned to the finding.

Figure 5.

Heat map shows the nature and severity of histopathological findings in the digestive system, liver, skin, and hematopoietic and lymphoid tissues of dogs during a 12-week oral toxicology study. Male findings are represented in the upper colored triangles and female findings in the lower colored triangles. Coloring (i.e., increasing intensity of red) is matched with the severity grade assigned to the finding. ^aThe treatment dose for this group was lowered on Day 15 from the original 45 mg/kg to 30 mg/kg; ^bThese animals were "recovery" animals and were investigated after an 8-week, treatment-free recovery period; ^cThis animal died/was prematurely euthanized.

Figure 6.

Graphs show the free concentration of roginolisib (ng/mL) in plasma at each measured timepoint following daily administration, as calculated for rat A and dog B at escalating doses (5, 15, 50, and 75 mg/kg for rat and 5, 15, and 45/30 mg/kg for dog) based on plasma protein binding data (24% for rat and 56% for dog). IC₅₀ thresholds for PI3Kα, PI3Kß, and PI3Kδ and IC₉₀ threshold PI3Kδ, based on intracellular target engagement measured in Jurkat cell lysate (Kinativ®), are depicted with dotted lines. For comparison the free concentration of roginolisib as measured in patients at the 80 mg dose is depicted in Figure 6B as well.