INZ-701 for Metabolic Bone Disease

(ENERGY Trial)

Recruiting at 6 trial locations

Age: < 18

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Inozyme Pharma

Disqualifiers: Uncontrolled thyroid disease, Malignancy, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

The primary purpose of Study INZ701-104 (the ENERGY study) is to assess the safety and tolerability of INZ-701 in infants with ENPP1 Deficiency or with ABCC6 Deficiency.

Will I have to stop taking my current medications?

The trial information does not specify whether participants must stop taking their current medications. However, if you are participating in another study or have recently taken another investigational drug, you may need to wait before joining this trial.

What data supports the effectiveness of the treatment INZ-701 for Metabolic Bone Disease?

Research shows that INZ-701, a treatment for ENPP1 deficiency, helped restore bone structure and growth in mice with this condition. It prevented abnormal tissue calcification and improved overall health, suggesting it could be effective for similar bone diseases. ^{1 2 3 4 5}

How is the drug INZ-701 different from other treatments for metabolic bone disease?

INZ-701 is unique because it acts as an enzyme replacement therapy specifically targeting ENPP1 deficiency, which is a root cause of certain metabolic bone diseases. Unlike conventional treatments that may not address low bone mineral density and can lead to complications like nephrocalcinosis, INZ-701 restores normal levels of pyrophosphate, preventing abnormal calcification and improving bone health without these risks. ^{1 2 4 5 6}

Research Team

Alex Lai, MD

Principal Investigator

Inozyme Pharma

Eligibility Criteria

The ENERGY study is for infants weighing at least 0.5 kg with a genetic diagnosis of ENPP1 Deficiency, which can cause rickets and other related conditions. Infants must be between 1 month to less than 1 year old and able to complete the study procedures. Caregivers must consent and provide medical records access.

Inclusion Criteria

In the opinion of the Investigator, the subject must be able to complete all aspects of the study

Caregiver(s) must provide written or electronic consent after the nature of the study has been explained, and prior to any research-related procedures, per International Conference on Harmonisation (ICH) Good Clinical Practice (GCP).

I have a confirmed genetic diagnosis of ENPP1 Deficiency.

Exclusion Criteria

I have been diagnosed with cancer.

According to the doctor, you have a serious disease or abnormal test results that could affect your participation in the study or make it hard to understand the study results. This includes uncontrolled thyroid disease or other unrelated bone, muscle, or tissue diseases.

I am not in another drug study or haven't taken any experimental drugs recently.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

8 weeks

Treatment

Participants receive INZ-701 for safety, tolerability, pharmacokinetics, and pharmacodynamics assessment

52 weeks

Twice weekly visits for dosing

End of Treatment (EOT)

Participants have a final visit 30 days after the last dose of INZ-701

4 weeks

Extension

Participants may continue to receive INZ-701 until it is commercially available or an alternative study is available

Follow-up

Participants are monitored for survival outcomes at least quarterly through the end of the study

Treatment Details

Interventions

• INZ-701 (Enzyme Replacement Therapy)

Trial Overview This trial tests the safety and tolerability of a medication called INZ-701 in infants diagnosed with ENPP1 Deficiency, which affects bone development and can lead to rickets or vascular calcification.

Participant Groups

Group I: INZ-701 Experimental Treatment 1 Intervention

The first 2 study participants will receive 1 dose of 0.2 mg/kg on Day 1 and start at Dose Level A (0.2 mg/kg twice weekly) on Day 8. The Data Review Committee (DRC) comprised of representatives of the Sponsor, the study Investigators, and a physician who is a subject matter expert not affiliated with the study or Sponsor, will review the safety data of the first study participant through Day 8. Contingent upon this review, the Sponsor will decide if additional study participants can begin receiving INZ-701. After the second study participant completes Day 32, the DRC will perform a cumulative review of safety and PK/PD data and will make dosing recommendations, for example, modifying the dose of the ongoing study participants and/or changing the starting dose for future participants. Dose Level A: 0.2 mg/kg twice weekly Dose Level B: 0.6 mg/kg twice weekly Dose Level C: 0.2 mg/kg once weekly Dose Level D: 0.6 mg/kg once weekly Dose Level E: 1.8 mg/kg once weekly

Who Is Running the Clinical Trial?

Inozyme Pharma

Lead Sponsor

Trials

10

Recruited

1,400+

Findings from Research

Heterozygous mutations in the ENPP1 gene can lead to early onset osteoporosis in adults, characterized by fractures and low bone mineral density, indicating a gene dose effect on bone health.

The study found that individuals with ENPP1 deficiency had elevated FGF23 levels and hypophosphatemia, similar to findings in mice with ENPP1 deficiency, suggesting a shared mechanism affecting bone mineralization and structural integrity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human Heterozygous ENPP1 Deficiency Is Associated With Early Onset Osteoporosis, a Phenotype Recapitulated in a Mouse Model of Enpp1 Deficiency. Oheim, R., Zimmerman, K., Maulding, ND., et al.[2022]

Conventional therapy for ARHR2 patients improves rickets symptoms but does not increase bone mineral density (BMD), and half of the treated patients developed medullary nephrocalcinosis, indicating potential risks associated with phosphate supplementation.

In contrast, treatment with recombinant Enpp1-Fc protein in ENPP1-deficient mice not only normalized trabecular bone mass and improved bone strength but also prevented nephrocalcinosis, suggesting that enzyme replacement therapy could be a safer and more effective option for increasing bone mass in ARHR2 patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice. Ferreira, CR., Kavanagh, D., Oheim, R., et al.[2022]

In a study using genetically modified mice, the removal of the Nmp4 gene from mesenchymal stem/progenitor cells significantly enhanced the bone-building effects of parathyroid hormone (PTH), indicating that targeting this gene could improve osteoporosis treatments.

The research showed that while Nmp4 deletion in osteocytes increased bone volume, it did not enhance the response to PTH, suggesting that the timing and type of cell targeted are crucial for maximizing the effectiveness of bone anabolic therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conditional Loss of Nmp4 in Mesenchymal Stem Progenitor Cells Enhances PTH-Induced Bone Formation. Atkinson, EG., Adaway, M., Horan, DJ., et al.[2023]

INZ-701, a human ENPP1-Fc protein, shows promise as an enzyme replacement therapy for ENPP1 deficiency, effectively restoring pyrophosphate (PPi) levels and preventing ectopic calcification in a mouse model over an 8-week treatment period.

The treatment not only improved growth and corrected bone defects in ENPP1-deficient mice but also significantly reduced mortality, highlighting its potential efficacy in addressing the severe symptoms associated with conditions like generalized arterial calcification of infancy (GACI) and autosomal-recessive hypophosphatemic rickets type 2 (ARHR2).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

INZ-701 Prevents Ectopic Tissue Calcification and Restores Bone Architecture and Growth in ENPP1-Deficient Mice. Cheng, Z., O'Brien, K., Howe, J., et al.[2021]

The study identified Inpp4bα as a crucial regulator of osteoclast differentiation, with its expression linked to both the early and activation stages of osteoclasts, impacting bone mass.

Mice lacking Inpp4b showed increased osteoclast differentiation and reduced bone mass, indicating that INPP4B is a significant gene associated with osteoporosis risk in both mice and humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inositol polyphosphate 4-phosphatase B as a regulator of bone mass in mice and humans. Ferron, M., Boudiffa, M., Arsenault, M., et al.[2021]

ENPP1 deficiency leads to osteoporosis through mechanisms that suppress Wnt signaling pathways, rather than through reduced bone volume, as shown in studies of Enpp1asj/asj mice compared to wild-type siblings.

The skeletal phenotype in younger ENPP1 deficient mice is driven by non-catalytic functions of ENPP1, while older mice show that low levels of extracellular pyrophosphate (PPi) contribute to bone issues, indicating a complex relationship between ENPP1 function and bone health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic pathways disrupted by ENPP1 deficiency provide insight into mechanisms of osteoporosis, osteomalacia, and paradoxical mineralization. Maulding, ND., Kavanagh, D., Zimmerman, K., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Human Heterozygous ENPP1 Deficiency Is Associated With Early Onset Osteoporosis, a Phenotype Recapitulated in a Mouse Model of Enpp1 Deficiency. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Conditional Loss of Nmp4 in Mesenchymal Stem Progenitor Cells Enhances PTH-Induced Bone Formation. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

INZ-701 Prevents Ectopic Tissue Calcification and Restores Bone Architecture and Growth in ENPP1-Deficient Mice. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Inositol polyphosphate 4-phosphatase B as a regulator of bone mass in mice and humans. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Genetic pathways disrupted by ENPP1 deficiency provide insight into mechanisms of osteoporosis, osteomalacia, and paradoxical mineralization. [2022]