Science defines our company and guides our work.
INZ-701
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 ATP-Binding Casette, subfamily C, member 6 (ABCC6) efflux transporter, belonging to the multidrug resistance-associated protein (MRP) subfamily of ATP-binding cassette (ABC) transmembrane transporters, transports 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
Pipeline
Inozyme’s goal is to develop and commercialize safe and effective therapies for the treatment of patients suffering from a broad range of genetic and non-genetic diseases of abnormal mineralization that result that can be life-threatening and debilitating.
The critical components of our strategy to achieve this goal include:
- Efficiently advance clinical development for our lead product candidate, INZ-701, with an initial focus on ENPP1 and ABCC6 Deficiencies.
- Expand our research and development efforts for INZ-701 in additional diseases of abnormal mineralization and for other therapies beyond INZ-701.
- Continue to expand our scientific understanding of abnormal mineralization, our related intellectual property portfolio and our rights to complementary technologies.
| Program |
|
Next Anticipated Milestone | ||||||
| Genetic Diseases | ||||||||
| ENPP1 Deficiency |
|
Enrollment in Ph. 1/2 Q4 2021 |
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| ABCC6 Deficiency |
|
Enrollment in Ph. 1/2 Q4 2021 |
||||||
| Diseases of abnormal mineralization |
|
Manufacturing and preclinical tox. testing | ||||||
| Non-Genetic Diseases | ||||||||
| Calciphylaxis |
|
Preliminary regulatory interactions | ||||||
| Diseases of neointimal proliferation |
|
Generate preclinical proof-of-concept | ||||||
Genetic Diseases
Program: ENPP1 Deficiency
Asset: INZ-701
Stage of Development: IND-Enabling
Anticipated Milestone:
Enrollment in Ph. 1/2
Q4 2021
Program: ABCC6 Deficiency
Asset: INZ-701
Stage of Development: IND-Enabling
Anticipated Milestone:
Enrollment in Ph. 1/2
Q4 2021
Program: Diseases of abnormal mineralization
Asset: Gene Tx
Stage of Development: IND-Enabling
Anticipated Milestone: Manufacturing and preclinical tox. testing
Non-Genetic Diseases
Program: Calciphylaxis
Asset: INZ-701
Stage of Development: IND-Enabling
Anticipated Milestone: Preliminary regulatory interactions
Program: Diseases of Neointimal Proliferation
Asset: INZ-701
Stage of Development: Research
Anticipated Milestone: Generate preclinical proof-of-concept
New Therapeutics
Program: ENPP1 Protein Delivery
Asset: AAV construct
Stage of Development: Research
Anticipated Milestone: Select development candidate
INZ-701 is directed at ENPP1 Deficiency and ABCC6 Deficiency which diseases represent an area of high unmet medical need.
ENPP1 Deficiency results in low plasma levels of PPi and AMP, a precursor of adenosine, and neointimal proliferation, and is a disease with high mortality and morbidity. The spectrum of manifestations of ENPP1 Deficiency includes an infantile phase, a pediatric phase and an adult phase, formerly described as Generalized arterial calcification of infancy (GACI)/Autosomal-recessive hypophosphatemic rickets type 2 (ARHR2).
ABCC6 Deficiency results in low plasma levels of PPi and is associated with pathological mineralization in blood vessels and soft tissues throughout the body, resulting in significant morbidity, including blindness, potentially life-threatening cardiovascular complications and skin calcification. ABCC6 Deficiency can lead to a vascular calcification condition resembling the acute infantile form of ENPP1 Deficiency in infants and pseudoxanthoma elasticum (PXE) in older patients.
INZ-701 is designed to correct a defect in the mineralization pathway caused by ENPP1 and ABCC6 Deficiencies and targets the restoration of a normal balance of PPi and adenosine.
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.
Future Research
We believe that INZ-701 has the potential to bring therapeutic benefit to patients beyond those with monogenic defects in the ENPP1 or ABCC6 gene. We intend to explore the potential of INZ-701 as a therapy for calciphylaxis, a manifestation of chronic kidney disease.
Calciphylaxis, a manifestation of chronic kidney disease, is associated with low levels of PPi and is characterized by pathological calcification of the vasculature in the skin and fat leading to blood clots and skin ulcers. This disease has a reported one-year survival rate of approximately 50%. Calciphylaxis affects between 1% and 4% of patients with end stage renal disease. The estimated incidence of calciphylaxis is at least 1,800 new patients per year in the United States. There are currently no approved therapies for calciphylaxis, although use of sodium thiosulfate, a chelating agent intended to lower calcium content in the blood, reportedly ameliorates symptoms. Patients also are often advised to maintain a low phosphate diet.
We have an ongoing collaboration with the laboratory of Demetrios Braddock at Yale University to further characterize disorders of aberrant calcification. This translational research program potentially opens a number of additional indications to drug therapy.
Building on the foundation of the research conducted at Yale, we have invested in our own internal lab capabilities with more than 3,500 square feet of research facilities located in the heart of Boston’s Longwood Medical Area.
Earlier Research
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.
