Regulating calcification in multiple metabolic diseases.
Our lead candidate, INZ-701, is in preclinical development for the potential treatment of patients with a variety of mineralization disorders linked primarily to mutations in the ENPP1 and ABCC6 genes.
INZ-701 is designed to replace the lost enzymatic function of genetically deficient ENPP1 by restoring the normal balance in pyrophosphate, or PPi and adenosine for ENPP1 deficiency and providing therapeutic effect to treat other diseases, like ABCC6 deficiency, involving low PPi levels.
In a properly functioning mineralization pathway, the protein encoded by the ABCC6 gene on the cellular membrane is responsible for transporting adenosine triphosphate, or ATP, from inside a cell to outside the cell. The enzyme encoded by the ENPP1 gene then cleaves ATP into pyrophosphate, or PPi, and adenosine monophosphate, or AMP. PPi is a potent regulator of mineralization and, in particular, controls the rate of calcium crystal deposition in bone. AMP is further metabolized into adenosine, a potent regulator of cellular proliferation that, in particular, modulates a blood vessel’s response to injury and is responsible for preventing neointimal proliferation, or the overgrowth of smooth muscle cells inside blood vessels.
In contrast to native ENPP1, INZ-701 is a soluble protein that is designed to circulate throughout the body and is capable of accessing extracellular ATP and other nucleotide proteins. Like native ENPP1, INZ-701 cleaves ATP into PPi and AMP, a precursor of adenosine. Pharmacologically, INZ-701 is designed to have prolonged distribution and elimination phases, leading to steady-state concentrations in the blood over time and making dosing possible at infrequent intervals, potentially as long as weekly. INZ-701 is formulated for subcutaneous delivery.
The presumed crystal structure of INZ-701 is depicted in the figure below
Preclinical Data in ENPP1 Deficiency and ABBC6 Deficiency
In our preclinical studies conducted in ENPP1-deficient mouse models, dosing with INZ-701 resulted in increased plasma PPi levels, reduction in ectopic calcium deposits in a variety of tissues, prevention of calcification in the heart and aorta, and improvements in overall health and survival. Inozyme’s preclinical work has shown that, by normalizing the amount of PPi, it can directly impact the calcification and avert its adverse consequences.
In ABCC6-deficient mouse models, dosing with INZ-701 also increased plasma PPi levels. Further, overexpressing ENPP1 in an ABCC6-deficient mouse model reduced calcification in key tissues, in addition to normalizing levels of PPi.
Neointimal proliferation resulting from ENPP1 deficiency was also replicated in corresponding animal models. In animal models, neointimal proliferation is accelerated during conditions of injury including ligation of the artery. The exact mechanism linking ENPP1 to neointimal proliferation is under investigation, but is believed to directly involve the adenosine pathway.
A team of researchers led by Dr. Demetrios Braddock published the ground-breaking preclinical proof-of-concept for ENPP1-Fc for the treatment of GACI in a 2015 paper in Nature Communications, ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy. The paper demonstrates the capability of a murine ERT (mERT) in preventing the lethal vascular calcifications of GACI in mouse models of the disease. The dramatic change induced by this ERT in enpp1asj/asj mice is illustrated in the image below. In untreated mice (a), the postmortem high-resolution micro-CT scans revealed the extensive calcifications in the heart, coronary arteries, and ascending and descending aortas. By contrast, there were no calcifications in these organs in the treated mice (b).
Additionally, data presented at the 45th European Calcified Tissue Society Congress in Valencia, Spain in May 2018 demonstrated that the same mERT used in the GACI mouse model is also capable of preventing the bone mineralization deficits in an ARHR2 animal model. Full publication of these ARHR2 data is forthcoming.
For links to relevant scientific publications and abstracts, please see the Publications landing page.