167 INZ-701 prevents ectopic mineralization in an Abcc6 mouse model of pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE), a heritable ectopic mineralization disorder, affects the skin, eyes and the cardiovascular system. PXE is predominantly caused by biallelic inactivating mutations in ABCC6 encoding a putative efflux transporter, ABCC6, expressed primarily in the liver. Recent studies demonstrated that the absence of ABCC6-dependent adenosine triphosphate release from the liver and consequently reduced plasma inorganic pyrophosphate (PPi) levels are critical pathogenic features of PXE. As PPi is a potent mineralization inhibitor, this study examined whether restoration of plasma PPi levels by ENPP1, the principal enzyme that generates PPi from adenosine triphosphate, could prevent ectopic mineralization in ABCC6 deficiency. INZ-701, a recombinant human ENPP1-Fc fusion protein that is being developed as an enzyme replacement therapy for the treatment of ENPP1 deficiency, was tested for prevention of ectopic mineralization in an Abcc6-/- mouse model of PXE. Abcc6-/- mice, at 5-6 weeks of age, the time of earliest stages of ectopic mineralization, were treated with INZ-701 at 2 and 10 mg/kg administered by subcutaneous injection every other day. Administration of INZ-701 showed a dose-dependent increase in plasma ENPP1 activity and plasma PPi level both 2 and 8 weeks after initiation of treatment. Histopathologic examination of vehicle-treated Abcc6-/- mice revealed extensive mineralization in the muzzle skin containing vibrissae, a biomarker of the mineralization process in these mice, while significantly reduced mineralization was detected in mice treated with INZ-701. Quantitative calcium assay demonstrated that the amount of calcium in the muzzle skin biopsies were reduced by 68% and 74% in mice administered with INZ-701 at 2 and 10 mg/kg, respectively. These results suggest that INZ-701 might provide a promising treatment strategy for PXE, a disease with high unmet need and no approved treatment.