ESPE Yearbook of Paediatric Endocrinology

J Bone Miner Res. 2021 Aug;36(8):1594-1604.Abstract: https://pubmed-ncbi-nlm-nih-gov/33900645/

In Brief: Enzyme replacement therapy with human ENPP1-Fc protein in Enpp1^asj/asj mice, a murine model of ENPP1 deficiency, restored circulating levels of PPi, prevented clinical manifestations and decreased mortality.

Commentary: ENPP1 deficiency causes generalized arterial calcification of infancy (GACI) and autosomal-recessive hypophosphatemic rickets type 2 (ARHR2) and is associated with low serum inorganic pyrophosphate (PPi). It manifests as ectopic calcification of multiple tissues, neointimal proliferation, premature mortality, impaired growth, and bone deformities.

INZ-701, a human ENPP1-Fc protein, is in clinical development as an enzyme replacement therapy for the treatment of ENPP1 deficiency. The pharmacokinetic and pharmacodynamic profiles and therapeutic effects of INZ-701 were investigated in Enpp1^asj/asj mice, a murine model of ENPP1 deficiency. Enpp1^asj/asj mice have undetectable plasma PPi, lower plasma phosphate, and higher FGF23 levels compared with wild-type (WT) mice. Enpp1^asj/asj mice on the acceleration diet, containing high phosphate and low magnesium, quickly develop clinical signs, including dehydration, rough hair coat, pinned ears, stiffed legs, and hunched back. Enpp1^asj/asj mice treated with vehicle had aforementioned clinical signs plus severe ectopic calcification in multiple tissues and bone defects, characteristics of the clinical phenotype observed in GACI and ARHR2 patients.

This study showed a durable PPi response for more than 3 days after a single dose of INZ-701. Treatment of ENPP1-deficient mice every other day with INZ-701 for 8 weeks restored circulating levels of PPi, prevented pathological calcification in all tested organs, restored growth parameters, corrected bone defects, improved clinical signs, and decreased mortality in Enpp1^asj/asj mice, demonstrating the potential of INZ-701 to treat ENPP1 deficiency. These preclinical findings suggest the potential of INZ-701 to treat ENPP1 deficiency, and support normalization of PPi levels as a surrogate marker to predict clinical benefit in the animal model and potentially in patients with ENPP1 deficiency.