The ENERGY 3 Study: Evaluation of Efficacy and Safety of INZ-701 in Children With ENPP1 Deficiency

The ENERGY 3 Study: A Randomized, Controlled, Open-Label, Phase 3 Study to Evaluate the Efficacy and Safety of INZ-701 in Children With Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Deficiency

The primary purpose of Study INZ701-106 (The ENERGY 3 Study) is to assess the efficacy and safety of INZ-701 in children with ENPP1 Deficiency.

Study Overview

• Status: Terminated
• Conditions: Generalized Arterial Calcification of Infancy; Autosomal Recessive Hypophosphatemic Rickets; Ectonucleotide Pyrophosphatase/Phosphodiesterase1 Deficiency
• Intervention / Treatment: Drug: INZ-701; Drug: Control Arm (Conventional Therapy)

Detailed Description

INZ-701 is an ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) enzyme replacement therapy (ERT) in development for the treatment of ENPP1 Deficiency, an ultra-rare genetic disorder with an incidence of 1 in 64,000 pregnancies.

Study INZ701-106 (The ENERGY 3 Study) is a multi-center, randomized in a 2:1 ratio, controlled, open-label Phase 3 study to evaluate the efficacy and safety of INZ-701 in children with ENPP1 Deficiency.

The study will consist of a Screening Period of up to 52 days (including a washout period of up to 7 days for prohibited medications post-Randomization) and a Randomized Treatment Period (INZ-701 or control) of 52 weeks, followed by an Open-label Extension Period during which all study participants may receive INZ-701, and an End of Study (EOS) Safety visit 30 days after the last dose of INZ-701.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • South Brisbane, Australia, 4101
    • Queensland Children's Hospital
• Canada
  • Montreal, Canada, H3T 1C5
    • Centre Hospitalier Universitaire (CHU) Sainte-Justine
• France
  • Le Kremlin-Bicêtre, France, 94270
    • Hôpital Bicêtre, Service d'endocrinologie et diabète de l'enfant (Childhood Endocrinology and Diabetes Department)
• Saudi Arabia
  • Riyadh, Saudi Arabia, 12713
    • King Faisal Specialist Hospital and Research Centre
• Turkey (Türkiye)
  • Istanbul, Turkey (Türkiye), 34764
    • Umraniye Training and Research Hospital
  • Sarıçam, Turkey (Türkiye), 01330
    • Cukurova Universitesi Tip Fakultesi
• United Arab Emirates
  • Dubai, United Arab Emirates, 30726
    • Al Jalila Children's Specialty Hospital
• United Kingdom
  • Manchester, United Kingdom, M13 9WL
    • Royal Manchester Children's Hospital
• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 12 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

Study participants must meet all of the following inclusion criteria:

1. Caregiver's written informed 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)
2. Study participant's assent in accordance with local regulations
3. A confirmed postnatal molecular genetic diagnosis of ENPP1 Deficiency with biallelic mutations (ie, homozygous or compound heterozygous) performed by a College of American Pathologists/Clinical Laboratory Improvement Amendments (CAP/CLIA) certified laboratory or regional equivalent
4. Males and females ≥1 year and <13 years of age at Study Day 1
5. Open growth plates of the distal femur and proximal tibia in both legs
6. Plasma PPi concentration of <1400 nM at Screening
7. 25(OH)D levels of ≥12 ng/mL at Screening
8. Radiographic evidence of skeletal abnormalities based on an RSS ≥2
9. Women of childbearing potential (WOCBP, as defined in Clinical Trials Coordination Group [CTCG 2024]) must have a negative serum pregnancy test at Screening and must not be breastfeeding
10. Males who are sexually active must agree to use condoms from the period following first dose of INZ-701 through 30 days after the last dose of INZ-701
11. WOCBP and partners of fertile males who are WOCBP must be using or must agree to use a highly effective form of (as per CTCG) from at least 1 month before the first dose of INZ-701 through 30 days after the last dose of INZ-701 (greater than 5 half-lives of INZ-701)
12. In the opinion of the Investigator, able to complete all aspects of the study

Exclusion Criteria

Study participants meeting any of the following exclusion criteria will not be eligible to participate in the study:

1. In the opinion of the Investigator, has clinically significant disease or laboratory abnormality not associated with ENPP1 Deficiency that will preclude study participation and/or may confound the interpretation of study results
2. If receiving any of the following prohibited medications as indicated in the protocol: systemic corticosteroids (>5 mg prednisone equivalent per day), anti-FGF23 and oral and/or IV bisphosphonates
3. Unable or unwilling to discontinue calcitriol or other active forms of vitamin D3 (or analogs) within 7 days prior to Study Day 1 and/or oral phosphate supplements within 36 hours prior to Study Day 1 if randomized to the INZ-701 arm
4. Planned orthopedic surgery or other procedures that may confound the interpretation of study results during the 52-week RTP
5. Known intolerance to INZ-701 or any of its excipients
6. A positive COVID-19 test within 5 days prior to Randomization, only if required as per local regulations or institutional policy
7. Previous treatment with INZ-701
8. Concurrent participation in another interventional clinical study and/or has received an investigational drug within 5 half-lives of the last dose or within 4 weeks prior to the first dose of INZ-701, whichever is longer, or use of an investigational device

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: INZ-701; Subjects randomized to the INZ-701 arm will be administered a 2.4 mg/kg once weekly dose by subcutaneous (SC) injection for the duration of the 52-week Randomized Treatment Period (RTP). RTP will be followed by a Low-dose Open-label Extension Period during which all study participants will receive INZ-701 at a dose of 2.4 mg/kg QW while the primary analysis is pending. If dose escalation criteria are met, all participants will transition to the Randomized Extension Period (REP) where participants who were originally randomized to INZ-701 during RTP will transition to a higher dose regimen of INZ-701 at 1.8 mg/kg twice weekly. Participants who were originally randomized to the active control arm during RTP will continue receiving INZ-701 at 2.4 mg/kg QW in the REP.	Drug: INZ-701; Recombinant fusion protein that contains the extracellular domains of human ENPP1 coupled with an Fc fragment from an immunoglobulin gamma-1 (IgG1) antibody.; Other Names: (rhENPP1-Fc).
Active Comparator: Control Arm (Conventional Therapy); Subjects randomized to the control arm will continue taking their conventional therapy as clinically indicated by their treating physician for the duration of the 52-week Randomized Treatment Period.	Drug: Control Arm (Conventional Therapy); Conventional therapy is defined as oral phosphate supplements and calcitriol or other active forms of vitamin D3 (or analogs). No other agents for treatment of ENPP1 Deficiency are allowed in the control arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in Plasma Inorganic Pyrophosphate (PPi) concentration through Week 52	For each subject, plasma PPi will be measured via a series of blood samples obtained throughout the study, comparing the subject's baseline value over time.	52 weeks (Baseline through Week 52)
Change from Baseline in skeletal abnormalities as measured by the Radiographic Global Impression of Change (RGI-C) global score through Week 52	The RGI-C is an overall radiographic score which can be used to monitor response to a therapeutic intervention comparing scores from 2 time points. A determination of healing on a scale of 0 to +3 with 0 being no change or healing and +3 being complete healing; worsening is also measured on a scale of 0 to -3 with 0 being no change and -3 being severe worsening.	52 weeks (Baseline through Week 52)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in rickets as measured by Rickets Severity Score (RSS) total score through Week 52	The RSS assesses rickets severity by utilizing a scoring system that uses a scale from 0 to 4 for the wrists and 0 to 6 for the knees, to generate a total score of 0 to 10, where 0 is normal and 10 is the worst score possible ie, most severe skeletal abnormalities observed radiographically.	Baseline, Week 26, Week 52
Change from Baseline in growth Z-score (height/body length and weight) through Week 52	A Z-score represents the degree to which that particular measurement for that individual differs from the reference value in the general population. (height/body length and weight) through Week 52	Baseline, Day 29, Week 8, Week 13, Week 26, Week 39, Week 52
Area under the Plasma Concentration versus Time Curve (AUC) of INZ-701	For each subject, variation of concentration of INZ-701 in the plasma will be measured via a series of blood samples obtained throughout the study, comparing the subject's baseline value over time.	52 weeks (Randomized Treatment Period)
Maximum Plasma Concentration (Cmax) of INZ-701	For each subject, the maximum concentration of INZ-701 in the plasma will be measured via a series of blood samples obtained throughout the study, comparing the subject's baseline value over time.	52 weeks (Randomized Treatment Period)
Change from Baseline in ENPP1 activity (µM/min) through week 52	For each subject, the activity of INZ-701 (µM/min) in the serum will be assessed through hydrolysis of a substrate to the enzyme, via a series of blood samples obtained throughout the study, comparing the subject's baseline value over time.	52 weeks (Randomized Treatment Period)

Collaborators and Investigators

• Sponsor: Inozyme Pharma
• Collaborators: BioMarin Pharmaceutical

Study record dates

Study Major Dates

• Study Start (Actual): November 5, 2023
• Primary Completion (Actual): January 29, 2026
• Study Completion (Actual): August 19, 2026

Study Registration Dates

• First Submitted: August 28, 2023
• First Submitted That Met QC Criteria: September 18, 2023
• First Posted (Actual): September 21, 2023

Study Record Updates

• Last Update Posted (Actual): October 1, 2026
• Last Update Submitted That Met QC Criteria: September 28, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: Generalized Arterial Calcification of Infancy; ENPP1; GACI; Autosomal Recessive Hypophosphatemic Rickets Type 2; ARHR2; Ectonucleotide Pyrophosphatase/Phosphodiesterase1 Deficiency; Hypopyrophosphatemia
• Additional Relevant MeSH Terms: Arterial calcification of infancy; Hypophosphatemic Rickets, Autosomal Recessive, 1
• Other Study ID Numbers: INZ701-106

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No