Xpovio: genotox, carcinogenicity and repro: done or skipped?

“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).”

“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.”

“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.”

“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.”

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

“The IC50 for the inhibitory effect of selinexor on hERG potassium current was 20.6 µM (Hill coefficient=1.1). The Applicant estimated >250 times safety margins based on the human free unbound Cmax following an 80 mg dose”