Biopharmaceutical company Inozyme Pharma (“Inozyme”) has become a leader at the forefront of developing innovative therapies for rare diseases such as ENPP1 deficiency (the childhood form is known as generalized arterial calcification of infancy, or GACI, type 1) and ABCC6 deficiency (GACI type 2). These progressive lifelong diseases can lead to early death, with 50% of children diagnosed with ENPP1 deficiency in utero dying within six months following birth and significant percentages of those with ABCC6 deficiency not surviving past the first year of life. Those with GACI who survive may develop symptoms such as autosomal-recessive hypophosphatemic rickets type 2, reduced or absent pulse, soft bones, pain, mobility issues, high blood pressure, hearing loss, vascular calcification and stenosis, congestive heart failure, and dental issues. There is no cure for ENPP1 deficiency or ABCC6 deficiency, leaving adolescents and adults with this condition without support and dealing with a significant disease burden. Pediatric patients with GACI type 2 also have a heightened risk of ischemic stroke.

To address this, and provide a novel therapeutic option to this community, Inozyme developed INZ-701. Inozyme explains that ENPP1 and ABCC6 mutations result in low levels of adenosine and inorganic pyrophosphate (PPi), which can cause abnormal mineralization and calcification. With INZ-701, the company explains:

Native ENPP1 is bound to the cell membrane with the active enzymatic portion of the protein outside of the cell [so] we fused this domain with an antibody Fc fragment to construct INZ-701. In contrast from native ENPP1, INZ-701 is a soluble protein designed to circulate through the body and cleave extracellular ATP into PPi and AMP, a precursor of adenosine.

The Clinical Space

In early April 2024, Inozyme shared positive topline efficacy, safety, pharmacodynamic, and pharmacokinetic data from ongoing Phase 1/2 clinical studies evaluating INZ-701 for adults with ENPP1 deficiency and ABCC6 deficiency. The study includes 10 adults with ABCC6 deficiency, as well as thirteen adults with ENPP1 deficiency.

Participants with ABCC6 deficiency have both cardiovascular and retinal disease; these individuals were split into three groups which received 0.2mg/kg, 0.6mg/kg, or 1.8mg/kg respectively. The therapy was administered subcutaneously two times each week. While the first portion of the trial aimed to identify the ideal dose for further clinical study and drug development, the Phase 2 portion is looking at pharmacokinetics, pharmacodynamics, and safety over a 48-week period or longer. So far, findings from the study include:

• Adults with ABCC6 deficiency have a higher risk of stroke and cardiovascular disease than the general population, which can be tracked using the biomarker carotid intima-media thickness (cIMT). After being treated with INZ-701, patients’ cIMT levels either fell or stabilized, highlighting its potential to benefit patients’ cardiovascular health.
• Adults with ABCC6 deficiency can also have visual disturbances and vision loss caused by retinal degeneration. INZ-701 helped thicken the choroid and improve visual function and acuity.
• The highest INZ-701 dose contributed to significant increases in PPi that were sustained over time.
• Researchers found the treatment to be tolerated nicely by participants, as well as safe for use.

Moving forward, Inozyme plans to continue developing INZ-701 for GACI type 2 in both the pediatric and adult subsets, contributing to better outcome. While the current study focuses on adults with ABCC6 deficiency, Inozyme hopes to begin a pediatric trial by early 2025.

ENPP1 Deficiency Results

Those with ENPP1 deficiency were also split into the above three cohorts, as well as a fourth cohort evaluating once-weekly 1.2mg/kg INZ-701. Data from this portion of the study shows that:

• ENPP1 deficiency often appears with elevated fibroblast growth factor-23 (FGF-23), but INZ-701 helped to reduce levels of this biomarker when given at the highest dose. Since high FGS-23 levels are linked to hypophosphatemia, or low levels of phosphate in the blood, these levels contribute to weakened bones. By reducing these levels, INZ-701 can maintain bone strength and encourage mineralization.
• In the groups receiving treatment twice per week, researchers noticed lower levels of pain and fatigue.
• For the group receiving INZ-701 once per week, their PPi levels were raised and sustained at normal levels.
• Similarly to the safety data seen in ABCC6 deficiency, INZ-701 was safe and nicely tolerated in adults with ENPP1 deficiency.