SNF472 Improves Limb Blood Perfusion and Walking Ability and Inhibits Progression of Calcification in Femoral Arteries in a Rat Model of Peripheral Artery Disease

Peripheral artery disease (PAD) is common in patients with end-stage kidney disease (ESKD) undergoing dialysis. The prominent vascular calcification in these patients is associated with severity of symptoms and adverse outcomes. There are no medical therapies specifically approved for PAD-ESKD. Although cilostazol is approved for PAD, its use is limited in patients with PAD-ESKD. Surgical interventions for these patients are challenging due to vascular calcification, and they often have poor outcomes. This study aims to evaluate the effects of the investigational drug SNF472, a selective inhibitor of vascular calcification, on limb functional recovery and blood perfusion in a Vitamin D3 (VitD)-induced rat model of arterial calcification and limb ischemia. A total of 66 Sprague Dawley rats received three consecutives daily subcutaneous doses of VitD to induce limb ischemia. At day 5 after the start of VitD treatment, rats were randomized into four groups and treated for 9 days with placebo subcutaneously, placebo orally, SNF472 (40 mg/kg/day, subcutaneously), or cilostazol (40 mg/kg/day, orally). An additional control group did not receive VitD (sham). Posterior limb blood perfusion was measured using laser Doppler imaging at baseline, day (D) 4, and D13. Walking ability was evaluated by measuring maximum walking distance (MWD) and maximum walking time (MWT) using a rat treadmill at baseline, D4 and D11. Rats were sacrificed at D13, and heart and femoral arteries were collected for calcium analysis. VitD-induced arterial calcification was associated with decreased blood perfusion and impairment of walking ability (MWT and MWD) compared with sham on D4. SNF472 inhibited calcification progression in heart by 56% and in femoral arteries by 41% compared to placebo. The inhibition of calcification progression in SNF472-treated animals led to a 29% increase in limb blood perfusion (P < .001) and a significant improvement in walking ability (49% in MWD and 43% in MWT; P < .05) compared with placebo. The degrees of calcification inhibition in femoral arteries and MWD in individual animals were positively correlated (P < .001). Cilostazol was not effective under the same conditions in this model. SNF472 produced improvements in vascular calcification, blood perfusion, and the functional parameter walking distance in a rat model of PAD vascular calcification. These results support investigation of SNF472 as a potential therapy for patients with PAD-ESKD who have vascular dysfunction due to a high degree of arterial calcification.