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

Primary Purpose

Ectonucleotide Pyrophosphatase/phosphodiesterase1 Deficiency, Autosomal Recessive Hypophosphatemic Rickets, Generalized Arterial Calcification of Infancy

Status

Recruiting

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

INZ-701

About this trial

This is an interventional treatment trial for Ectonucleotide Pyrophosphatase/phosphodiesterase1 Deficiency focused on measuring ectonucleotide pyrophosphatase/phosphodiesterase1 deficiency, hypopyrophosphatemia, ENPP1, Generalized Arterial Calcification of Infancy, GACI, Autosomal Recessive Hypophosphatemic Rickets Type 2, ARHR2

Eligibility Criteria

18 Years - 64 Years (Adult)All SexesDoes not accept healthy volunteers

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

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)
Clinical diagnosis of ENPP1 Deficiency supported by prior identification of biallelic ENPP1 mutations (ie, homozygous or compound heterozygous)
Male or female, 18 to <65 years of age at Screening
PPi <1300 nM at Screening
Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test at Screening
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.
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.
In the opinion of the Investigator, must be willing and able to complete the Dose Evaluation Period.
Agree to provide access to relevant medical records.

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

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
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/1.73m2,
2. 25-hydroxyvitamin D (25[OH]D) levels <12 ng/mL, or
3. parathyroid hormone (PTH) >40% above the upper limit of normal
Known active fungal, bacterial, and/or viral infection including human immunodeficiency virus, hepatitis B virus, hepatitis C virus, or COVID-19 virus.
Malignancy within the last 5 years, except non-melanoma skin cancers or cervical carcinoma in situ
Known intolerance to INZ-701 or any of its excipients
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.
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
Subjects who are pregnant, trying to become pregnant, or breastfeeding
Subjects who are trying to father a child

Sites / Locations

Mayo ClinicRecruiting
Clinilabs Drug Development CorporationRecruiting
University of Saskatchewan
Necker University Hospital-Sick ChildrenRecruiting
Parexel International GmbHRecruiting
University of Hamburg (Universitatklinikum Hamburg-Eppendorf)
Richmond Pharmacology (RPL)Recruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

INZ-701

Arm Description

The study design during the Dose Evaluation Period is a MAD 3 + 3 with 3 dose cohorts. The planned doses will be 0.2 mg/kg, 0.6 mg/kg, and 1.8 mg/kg administered via subcutaneous injection twice weekly. During the Extension Period, subjects will be administered INZ-701 at the dose and dose schedule assigned in the Dose Evaluation Period. However, the administered dose and dose schedule for a subject may change once the selected dosing regimen has been determined upon completion of the Dose Evaluation Period, at which time all subjects will be assigned to the selected dosing regimen.

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

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.

Secondary Outcome Measures

Full Information

NCT ID

NCT04686175

First Posted

December 22, 2020

Last Updated

December 16, 2022

Sponsor

Inozyme Pharma

1. Study Identification

Unique Protocol Identification Number

NCT04686175

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2022

Overall Recruitment Status

Recruiting

Study Start Date

November 21, 2021 (Actual)

Primary Completion Date

November 7, 2023 (Anticipated)

Study Completion Date

December 5, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Inozyme Pharma

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

Detailed Description

INZ-701 is an ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) enzyme replacement therapy in development for the treatment of ENPP1 Deficiency, an ultra rare genetic disorder. Study INZ701-101 is a Phase 1/2, multi-center, first-in-human (FIH), multiple ascending dose (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. 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 a follow up visit 30 days after their last dose of INZ-701.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Ectonucleotide Pyrophosphatase/phosphodiesterase1 Deficiency, Autosomal Recessive Hypophosphatemic Rickets, Generalized Arterial Calcification of Infancy

Keywords

ectonucleotide pyrophosphatase/phosphodiesterase1 deficiency, hypopyrophosphatemia, ENPP1, Generalized Arterial Calcification of Infancy, GACI, Autosomal Recessive Hypophosphatemic Rickets Type 2, ARHR2

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Model Description

Study INZ701-101 is a Phase 1/2, multi-center, open-label, first-in-human (FIH), multiple ascending dose (MAD) study followed by a long-term open-label extension period conducted in adults with ENPP1 Deficiency. The study design during the Dose Evaluation Period is a MAD 3+3 with 3 dose cohorts.

Masking

None (Open Label)

Allocation

N/A

Enrollment

9 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

INZ-701

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

INZ-701

Other Intervention Name(s)

rhENPP1-Fc

Intervention Description

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.

Primary Outcome Measure Information:

Title

Number of Treatment Emergent Adverse Events (TEAEs)

Description

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.

Time Frame

32 days (Dose Evaluation Period)

Title

Number of Treatment Emergent Adverse Events (TEAEs)

Description

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.

Time Frame

52 weeks (Day 1 through Safety Follow-up Visit)

Title

Incidence of Anti-Drug Antibodies (ADA)

Description

For each subject, the presence of ADAs will be assessed and, if present, further evaluation will determine specificity and subtypes.

Time Frame

32 days (Dose Evaluation Period)

Title

Incidence of Anti-Drug Antibodies (ADA)

Description

For each subject, the presence of ADAs will be assessed and, if present, further evaluation will determine specificity and subtypes.

Time Frame

52 weeks (Baseline through Safety Follow-up Visit)

Title

Area under the Plasma Concentration versus Time Curve (AUC) of INZ-701

Description

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.

Time Frame

32 days (Dose Evaluation Period)

Title

Maximum Plasma Concentration (Cmax) of INZ-701

Description

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.

Time Frame

32 days (Dose Evaluation Period)

Title

Systemic Clearance of INZ-701

Description

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.

Time Frame

32 days (Dose Evaluation Period)

Title

Change from Baseline in Plasma Inorganic Pyrophosphate (PPi) Levels

Description

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.

Time Frame

32 days (Dose Evaluation Period)

Title

Change from Baseline in Plasma Inorganic Pyrophosphate (PPi) Levels

Description

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.

Time Frame

52 weeks (Baseline through Safety Follow-up Visit)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

64 Years

Accepts Healthy Volunteers

Eligibility Criteria

Individuals eligible to participate must meet all of the following inclusion criteria: 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) Clinical diagnosis of ENPP1 Deficiency supported by prior identification of biallelic ENPP1 mutations (ie, homozygous or compound heterozygous) Male or female, 18 to <65 years of age at Screening PPi <1300 nM at Screening Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test at Screening 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. 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. In the opinion of the Investigator, must be willing and able to complete the Dose Evaluation Period. Agree to provide access to relevant medical records. Individuals who meet any of the following exclusion criteria will not be eligible to participate: 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 Clinically significant abnormal laboratory result at Screening in the opinion of the Investigator, including but not limited to screening laboratory results demonstrating estimated glomerular filtration rate (eGFR) (Chronic Kidney Disease-Epidemiology Collaboration [CKD-EPI] equation) < 60 mL/min/1.73m2, 25-hydroxyvitamin D (25[OH]D) levels <12 ng/mL, or parathyroid hormone (PTH) >40% above the upper limit of normal Known active fungal, bacterial, and/or viral infection including human immunodeficiency virus, hepatitis B virus, hepatitis C virus, or COVID-19 virus. Malignancy within the last 5 years, except non-melanoma skin cancers or cervical carcinoma in situ Known intolerance to INZ-701 or any of its excipients 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. 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 Subjects who are pregnant, trying to become pregnant, or breastfeeding Subjects who are trying to father a child

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Inozyme Clinical Trial Information

Phone

+1 857 330 4340

clinicaltrials@inozyme.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Borut Cizman, MD

Organizational Affiliation

Inozyme Pharma, Inc.

Official's Role

Study Director

Facility Information:

Facility Name

Mayo Clinic

City

Rochester

State/Province

Minnesota

ZIP/Postal Code

55905

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Melissa Wang

Phone

507-266-6911

wang.melissa@mayo.edu

First Name & Middle Initial & Last Name & Degree

Vishakantha (Vishu) Murthy

Phone

507-255-8112

Murthy.Vishakantha@mayo.edu

Facility Name

Clinilabs Drug Development Corporation

City

Eatontown

State/Province

New Jersey

ZIP/Postal Code

07724

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Dana Tiernan

Phone

212-994-4567

ARHR2-PXEstudies@clinilabs.com

Facility Name

University of Saskatchewan

City

Saskatoon

State/Province

Saskatchewan

ZIP/Postal Code

S7N 0W8

Country

Canada

Individual Site Status

Active, not recruiting

Facility Name

Necker University Hospital-Sick Children

City

Paris

ZIP/Postal Code

75015

Country

France

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Alix Besancon

alix.besancon@aphp.fr

Facility Name

Parexel International GmbH

City

Berlin

ZIP/Postal Code

14050

Country

Germany

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Lena Taghipour

Phone

49 030 30685-2063

lena.taghipourlelabadi@parexel.com

First Name & Middle Initial & Last Name & Degree

Rainard Fuhr

Rainard.Fuhr@parexel.com

Facility Name

University of Hamburg (Universitatklinikum Hamburg-Eppendorf)

City

Hamburg

ZIP/Postal Code

22529

Country

Germany

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Nicole M Muschol, MD

muschol@uke.de

Facility Name

Richmond Pharmacology (RPL)

City

London

State/Province

London Bridge

ZIP/Postal Code

SE1 1YR

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Omari-Jordan Daniel

Phone

+44 (0)20 7042 5800

volunteer@richmondpharmacology.com

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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