Evaluation of Safety, Tolerability, and Efficacy of INZ-701 in Adults With ENPP1 Deficiency

A Phase 1/2, Open-Label, Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of INZ-701 Followed by an Open-Label Long-Term Extension Period in Adults With ENPP1 Deficiency

The purpose of this study is to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple ascending doses of INZ-701, an ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) enzyme replacement therapy, for the treatment of ENPP1 Deficiency. The goal of the study is to identify a dose regimen for further clinical development in the treatment of ENPP1 Deficiency.

Study Overview

• Status: Completed
• Conditions: Generalized Arterial Calcification of Infancy; Autosomal Recessive Hypophosphatemic Rickets; Ectonucleotide Pyrophosphatase/phosphodiesterase1 Deficiency
• Intervention / Treatment: Drug: INZ-701

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 INZ701-101 is a Phase 1/2, multicenter, open-label, FIH, MAD, dose-finding study followed by a long-term open-label Extension Period conducted in adults with ENPP1 Deficiency. This study is designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple ascending doses of INZ-701. The goal of the study is to identify a dose and dose schedule (number of doses per week) for further clinical development. No placebo will be used in the study. Subjects will be 18 to <65 years of age, with a confirmed genetic diagnosis of ENPP1 Deficiency and biochemical evidence of hypopyrophosphatemia (ie, PPi <1300 nM). Exploratory endpoints for the Extension Period of the study include evaluations of skeletal assessment (X-ray and DEXA), arterial and organ calcification (either Na18F-PET/CT or low dose CT [full body] without contrast, echocardiogram, and renal ultrasound), and cardiovascular function (echocardiogram) as well as patient reported outcomes.

Subject participation consists of a Screening Period of up to 30 days, a 32-day Dose Evaluation Period, and an Extension Period during which subjects may continue to receive INZ-701 (with options for self-, caregiver-, or healthcare provider administration) until INZ-701 is approved and available in the country where the subject resides or until an alternative study for subjects to continue receiving study drug is available. During the Extension Period, follow-up visits will be conducted every 4 weeks until Week 48, followed by every 12 weeks until the subject leaves the study.

Subjects will complete an End of Study (EOS) Visit (Safety Follow-Up Visit) 30 days after their last dose of INZ-701.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 0W8
      • University of Saskatchewan
• France
  • Paris, France, 75015
    • Necker University Hospital-Sick Children
• Germany
  • Berlin, Germany, 14050
    • Parexel International GmbH
  • Hamburg, Germany, 22529
    • University of Hamburg (Universitatklinikum Hamburg-Eppendorf)
• United Kingdom
  • London Bridge
    • London, London Bridge, United Kingdom, SE1 1YR
      • Richmond Pharmacology (RPL)
• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New Jersey
    • Eatontown, New Jersey, United States, 07724
      • Clinilabs Drug Development Corporation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

Individuals eligible to participate must meet all of the following inclusion criteria:

1. 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)
2. Clinical diagnosis of ENPP1 Deficiency supported by prior identification of biallelic ENPP1 mutations (ie, homozygous or compound heterozygous)
3. Male or female, 18 to <65 years of age at Screening
4. PPi <1300 nM at Screening
5. Women of child-bearing potential (WOCBP as defined in Clinical Trials Facilitation and Coordination Group [CTFG 2020]) must have a negative serum pregnancy test at Screening
6. WOCBP and partners of fertile males who are WOCBP must be using or agree to use 1 highly effective form of contraception (per CTFG 2020) and a barrier method 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). WOCBP and partners of fertile males who are WOCBP must also agree to not donate ova from the period following the first dose of INZ-701 through 30 days after last dose of INZ-701.
7. 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. Males must also agree to not donate sperm from the period following the first dose of INZ-701 through 30 days after last dose of INZ-701.
8. In the opinion of the Investigator, must be willing and able to complete the Dose Evaluation Period.
9. Agree to provide access to relevant medical records.

Individuals who meet any of the following exclusion criteria will not be eligible to participate:

1. In the opinion of the Investigator, presence of any clinically significant disease (outside of those considered associated with the diagnosis of ENPP1 Deficiency) that precludes study participation or may confound interpretation of study results, including known uncontrolled cardiovascular, thyroid disease, or unrelated connective tissue, bone, mineral, lipid, or muscle disease

2. Clinically significant abnormal laboratory result at Screening in the opinion of the Investigator, including but not limited to screening laboratory results demonstrating

   1. estimated glomerular filtration rate (eGFR) (Chronic Kidney Disease-Epidemiology Collaboration [CKD-EPI] equation) < 60 mL/min/1.73m^2,
   2. 25-hydroxyvitamin D (25[OH]D) levels <12 ng/mL, or
   3. Intact parathyroid hormone (PTH) >40% above the upper limit of normal
3. Known active fungal, bacterial, and/or viral infection including human immunodeficiency virus, hepatitis B virus, hepatitis C virus, or COVID-19 virus. In Germany and France, a negative COVID-19 test result is required within 5 days prior to the first dose of INZ-701.
4. Malignancy within the last 5 years, except non-melanoma skin cancers or cervical carcinoma in situ
5. Known intolerance to INZ-701 or any of its excipients
6. Unable or unwilling to discontinue the use of any prohibited medication (examples include 1,25-dihydroxy vitamin D, phosphate, anti-FGF23 [eg, burosumab], calcimimetics, calcium-containing antacids, systemic corticosteroids, PTH suppressors). Discontinuation should be undertaken only if considered not detrimental and indicated by the subject's treating physician.
7. Concurrent participation in another non-Inozyme interventional clinical study and/or receipt of any other investigational new drug within 5 half-lives of the last dose of the other investigational product or from 4 weeks prior to the first dose of INZ-701, whichever is longer, or use of an investigational device, through completion of participation in the study
8. Subjects who are pregnant, trying to become pregnant, or breastfeeding
9. Subjects who are trying to father a child

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: INZ-701; The study design of the Dose Evaluation Period is a MAD 3 + 3 with 3 dose cohorts. Additional cohorts may be added to evaluate an intermediate dose and/or an alternative dosing regimen of an existing dose level. Based on nonclinical findings and nonclinical pharmacology modeling, the initial planned doses will be 0.2 mg/kg, 0.6 mg/kg, and 1.8 mg/kg all twice weekly, not to exceed 3.6 mg/kg weekly. During the Extension Period, visits will be every 4 weeks until Week 48 and then every 12 weeks until the subject leaves the study. Subjects will complete an End of Study (EOS) Visit (Safety Follow-up Visit) 30 days after their last dose of INZ-701 (greater than 5 half-lives of INZ-701) for all subjects.

Drug: INZ-701; INZ701-101 is a 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Treatment Emergent Adverse Events (TEAEs)	Treatment-emergent AEs are defined as any AE occurring from the first dose of INZ-701 through 30 days after the last dose of INZ-701.	32 days (Dose Evaluation Period)
Number of Treatment Emergent Adverse Events (TEAEs)	Treatment-emergent AEs are defined as any AE occurring from the first dose of INZ-701 through 30 days after the last dose of INZ-701.	52 weeks (Day 1 through Safety Follow-up Visit)
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.	32 days (Dose Evaluation 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.	32 days (Dose Evaluation Period)
Systemic Clearance of INZ-701	For each subject, clearance of INZ-701 from the body will be measured via a series of blood samples obtained throughout the study, comparing the subject's baseline value over time.	32 days (Dose Evaluation Period)
Change from Baseline in Plasma Inorganic Pyrophosphate (PPi) Levels	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.	32 days (Dose Evaluation Period)
Change from Baseline in Plasma Inorganic Pyrophosphate (PPi) Levels	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 Safety Follow-up Visit)
Incidence of Anti-Drug Antibodies (ADA)	For each subject, the presence of ADAs will be assessed and, if present, further evaluation will determine specificity and subtypes.	32 days (Dose Evaluation Period)
Incidence of Anti-Drug Antibodies (ADA)	For each subject, the presence of ADAs will be assessed and, if present, further evaluation will determine specificity and subtypes.	52 weeks (Baseline through Safety Follow-up Visit)

Collaborators and Investigators

• Sponsor: Inozyme Pharma
• Investigators: Study Director: Kurt Gunter, MD, Inozyme Pharma, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2021
• Primary Completion (Actual): October 29, 2024
• Study Completion (Actual): December 13, 2024

Study Registration Dates

• First Submitted: December 22, 2020
• First Submitted That Met QC Criteria: December 22, 2020
• First Posted (Actual): December 28, 2020

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 4, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Generalized Arterial Calcification of Infancy; ENPP1; GACI; Autosomal Recessive Hypophosphatemic Rickets Type 2; ARHR2; hypopyrophosphatemia; ectonucleotide pyrophosphatase/phosphodiesterase1 deficiency
• Additional Relevant MeSH Terms: Urogenital Diseases; Bone Diseases; Musculoskeletal Diseases; Nutrition Disorders; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Bone Diseases, Metabolic; Phosphorus Metabolism Disorders; Avitaminosis; Deficiency Diseases; Malnutrition; Metal Metabolism, Inborn Errors; Hypophosphatemia, Familial; Renal Tubular Transport, Inborn Errors; Calcium Metabolism Disorders; Vitamin D Deficiency; Hypophosphatemia; Familial Hypophosphatemic Rickets; Calcinosis; Rickets; Rickets, Hypophosphatemic; Vascular Calcification
• Other Study ID Numbers: INZ701-101; 2020-003716-27 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No