Xpovio

“Rats were chosen as the rodent species and cynomolgus monkeys as the non-rodent species.”

“Based on available data, both species were determined to be pharmacologically relevant for toxicology studies.”

“Thirteen-week repeat-dose oral toxicity and toxicokinetic studies were conducted in the rat (0, 0.25, 1, or 4 mg/kg selinexor; 5 total doses given every 2-week period) and monkey (0, 0.1, 0.3, 1 mg/kg selinexor; 2 to 3 times/week) to support the NDA.”

“Thirteen-week repeat-dose oral toxicity and toxicokinetic studies were conducted in the rat (0, 0.25, 1, or 4 mg/kg selinexor; 5 total doses given every 2-week period) and monkey (0, 0.1, 0.3, 1 mg/kg selinexor; 2 to 3 times/week) to support the NDA.”

“Thirteen-week repeat-dose oral toxicity and toxicokinetic studies were conducted in the rat (0, 0.25, 1, or 4 mg/kg selinexor; 5 total doses given every 2-week period) and monkey (0, 0.1, 0.3, 1 mg/kg selinexor; 2 to 3 times/week) to support the NDA.”

“Thirteen-week repeat-dose oral toxicity and toxicokinetic studies were conducted in the rat (0, 0.25, 1, or 4 mg/kg selinexor; 5 total doses given every 2-week period) and monkey (0, 0.1, 0.3, 1 mg/kg selinexor; 2 to 3 times/week) to support the NDA.”

“Selinexor was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay in human lymphocytes or in the in vivo rat micronucleus assay.”

“Carcinogenicity studies were not conducted to support the use of selinexor for the proposed indication.”

“Adverse developmental outcomes occurred at ≥ 0.75 mg/kg/day and included alterations to growth (e.g., fetal weights in the 0.75 and 2 mg/kg/day groups were 13.5% and 32.4% lower than controls) and structural abnormalities (such as incomplete or delayed ossification of sternebra(e) and/or vertebral arches, and/or unossified and bent ribs).”

“Selinexor was evaluated for its ability to inhibit the hERG channel (IC50 = 20.6 μM) using whole cell patch clamp in stably-transfected HEK293 cells (Study: KS-0055).”

“Study treatment on Arm 1 during the dose escalation phase followed a standard 3+3 design with a starting dose of selinexor 3 mg/m2.”

“Rats exhibited toxicological sequalae due to hematopoietic/lymphoid hypoplasia and male/female reproductive organ effects. Female rats also exhibited higher liver weights and/or centrilobular hepatocellular hypertrophy and/or increased mitotic figures. Monkeys exhibited gastrointestinal effects and lymphoid/hematologic depletion.”

“Selinexor was also identified as non-phototoxic and to induce mild-grade II dermal contact sensitivity response at 24 and 48 hours.”

“The highest concentrations of radioactivity were observed in the kidneys, liver, and small intestine. There was no specific binding to pigmented tissues.”

“Non-clinical safety program revealed a high toxicity of selinexor. Some tissues were mainly affected (reproductive systems, CNS-mediated gastrointestinal system…) and clinical findings reported (food consumption and body weight reduction, mortality).”