A high incidence of hemangiosarcoma (HSA) was observed in mice treated for 
2 years with siponimod, a sphingosine-1-phosphate receptor 1 (S1P1) functional 
antagonist, while no such tumors were observed in rats under the same treatment 
conditions. In 3-month rat (90 mg/kg/day) and 9-month mouse (25 and 
75 mg/kg/day) in vivo mechanistic studies, vascular endothelial cell (VEC) 
activation was observed in both species, but VEC proliferation and persistent 
increases in circulating placental growth factor 2 (PLGF2) were only seen in the 
mouse. In mice, these effects were sustained over the 9-month study duration, 
while in rats increased mitotic gene expression was present at day 3 only and 
PLGF2 was induced only during the first week of treatment. In the mouse, the 
persistent VEC activation, mitosis induction, and PLGF2 stimulation likely led 
to sustained neo-angiogenesis which over life-long treatment may result in HSA 
formation. In rats, despite sustained VEC activation, the transient mitotic and 
PLGF2 stimuli did not result in the formation of HSA. In vitro, the mouse and 
rat primary endothelial cell cultures mirrored their respective in vivo findings 
for cell proliferation and PLGF2 release. Human VECs, like rat cells, were 
unresponsive to siponimod treatment with no proliferative response and no 
release of PLGF2 at all tested concentrations. Hence, it is suggested that the 
human cells also reproduce a lack of in vivo response to siponimod. In 
conclusion, the molecular mechanisms leading to siponimod-induced HSA in mice 
are considered species specific and likely irrelevant to humans.