Recombinant ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) decreases vascular calcification and prevents osteomalacia in a rat model of chronic kidney disease.

Chronic kidney disease (CKD) impacts a large percentage of the global population. Chronic kidney disease-mineral bone disorder (MBD) is the broad term describing alterations in key circulating factors involved in mineralization, ectopic calcification, and bone abnormalities. Cardiovascular complications, involving vascular calcification are one of the leading causes of death in this patient population. Plasma levels of pyrophosphate, a potent inhibitor of ectopic mineralization, are low in CKD and end-stage kidney disease patients. These data suggest that the correction of pyrophosphate levels could stand out as a crucial therapeutic goal to mitigate vascular calcifications and reduce cardiovascular mortality. The primary enzyme responsible for the generation of plasma pyrophosphate is ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We therefore evaluated INZ-701, a recombinant human ENPP1-Fc fusion protein, in an adenine-induced rat model of CKD. Our investigation revealed that INZ-701 administration resulted in significantly lower levels of calcification in the vasculature and soft tissues. Moreover, INZ-701 treatment significantly prevented the osteoid volume increase observed in vehicle-treated rats, addressing another critical clinical manifestation of CKD-MBD. These results underscore the potential of INZ-701 to reduce vascular calcification and bone mineralization abnormalities in CKD.