<scp>INZ?701</scp> Prevents Ectopic Tissue Calcification and Restores Bone Architecture and Growth in <scp>ENPP1</scp> ?Deficient Mice

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the major enzyme that cleaves extracellular adenosine triphosphate (ATP) to generate pyrophosphate (PPi), an inorganic metabolite with potent anticalcification activity. Loss-of-function mutations cause hypopyrophosphatemia and lead a state of ENPP1 deficiency, which has acute infantile phase known as generalized arterial calcification infancy (GACI) pediatric adult autosomal-recessive hypophosphatemic rickets type 2 (ARHR2). deficiency manifests ectopic multiple tissues, neointimal proliferation, premature mortality, impaired growth, bone deformities. INZ-701, human ENPP1-Fc protein, in clinical development replacement therapy for treatment deficiency. The pharmacokinetic pharmacodynamic profile therapeutic effect INZ-701 were investigated Enpp1asj/asj mice, murine model mice have undetectable plasma PPi, lower phosphate, higher FGF23 levels compared wild-type (WT) mice. on acceleration diet, containing high phosphate low magnesium, quickly develop signs, including dehydration, rough hair coat, pinned ears, stiffed legs, hunched back. treated vehicle had aforementioned signs plus severe tissues defects, characteristics phenotype observed GACI ARHR2 patients. Our results showed durable PPi response more than 3 days after single dose INZ-701. Treatment ENPP1-deficient every other day 8 weeks restored circulating prevented pathological all tested organs, growth parameters, corrected improved decreased mortality demonstrating potential treat © 2021 American Society Bone Mineral Research (ASBMR).