An Open-label Study to Investigate ECUR-506 in Male Babies Less Than 9 Months of Age With Neonatal Onset OTC Deficiency

A Phase 1/2/3 First-in-Human, Open-Label, Dose-Escalation Study to Evaluate the Safety and Efficacy of a Single Intravenous (IV) Administration of ECUR-506 in Males Less Than 9 Months of Age With Genetically Confirmed Neonatal Onset Ornithine Transcarbamylase (OTC) Deficiency

Ornithine Transcarbamylase (OTC) deficiency, the most common urea cycle disorder, is an inherited metabolic disorder caused by a genetic defect in a liver enzyme responsible for detoxifying of ammonia. Individuals with OTC deficiency can develop elevated levels of ammonia in the blood, potentially resulting in severe consequences, including cumulative and irreversible neurological damage, coma, and death. The most severe form presents shortly after birth and occurs more commonly in boys than girls.

This is a Phase 1/2/3, open-label, multicenter study evaluating the safety, efficacy, and dose of ECUR-506 in male babies with neonatal-onset OTC deficiency. The primary objective is to evaluate the safety, tolerability, and efficacy of up to three dose levels of ECUR-506 following intravenous (IV) administration of a single dose.

Study Overview

• Status: Recruiting
• Conditions: Urea Cycle Disorders, Inborn; Ornithine Transcarbamylase Deficiency; Ornithine Transcarbamylase Deficiency Disease; Ornithine Carbamoyltransferase Deficiency (Disorder)
• Intervention / Treatment: Genetic: ECUR-506

Detailed Description

The study drug, ECUR-506, is an investigational gene editing therapy. Gene editing is an approach used to repair, replace, or introduce functional copies of genes that are not working properly. ECUR-506 contains a functional copy of the OTC gene, along with a gene to encode an editing enzyme that enables insertion of the OTC gene into the genome. The study drug is administered as a single IV infusion. Because genes cannot enter cells on their own, ECUR-506 uses a delivery system based on adeno-associated virus (AAV), a commonly used viral vector, to transport the genetic material into cells.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: George Diaz, M.D., Ph.D.; Phone Number: 1-877-694-3558; Email: medinfo@iecure.com
• Study Contact Backup: Name: Trial Recruitment; Email: clinicaltrials@iecure.com

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia
      • Active, not recruiting
      • The Children's Hospital at Westmead
  • Victoria
    • Melbourne, Victoria, Australia, 3052
      • Active, not recruiting
      • The Royal Children's Hospital
• Spain
  • Barcelona, Spain, 08950
    • Recruiting
    • Hopsital Sant Joan de Deu
    • Contact: Angels Garcia-Cazorla, PhD, MD; Email: angeles.garcia@sjd.es
  • Madrid, Spain, 28041
    • Recruiting
    • Hospital Universitario 12 de Octubre
    • Contact: Marcello Bellusci, MD; Email: marcello.bellusci@salud.madrid.org
• United Kingdom
  • London, United Kingdom
    • Recruiting
    • Great Ormond Street Hospital
    • Contact: Christopher Jackson; Email: christopher.jackson@gosh.nhs.uk
  • Newcastle upon Tyne, United Kingdom
    • Recruiting
    • The Newcastle upon Tyne Hospitals NHS Foundation Trust- Great North Children's Hospital
    • Contact: Mark Anderson, MD; Email: m.anderson10@nhs.net
• United States
  • California
    • Los Angeles, California, United States, 90095
      • Recruiting
      • UCLA Mattel Children's Hospital
      • Contact: Monserrath Campos; Email: monserrathcampos@mednet.ucla.edu
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • Children's Hospital of Colorado, Anshutz Medical Campus
      • Contact: Ruth Fisseha; Email: ruth.fisseha@childrenscolorado.org
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Emory University School of Medicine
      • Contact: Eleanor Geller Botha; Email: egeller@emory.edu
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Ann & Robert H. Lurie Children's Hospital of Chicago
      • Contact: Michael Sawin; Email: msawin@luriechildrens.org
  • New York
    • New York, New York, United States, 10029
      • Recruiting
      • ICAHN School of Medicine at Mount Sinai
      • Contact: Silvia Gunderson; Email: silvia.gunderson@mssm.edu
  • Oregon
    • Portland, Oregon, United States, 97239
      • Recruiting
      • Oregon Health and Science University
      • Contact: Hadley Morotti, MS; Email: morotti@ohsu.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Male sex
2. Gestational or adjusted (corrected) gestational age ≥ 37 weeks
3. Age at screening is 24 hours to 7 months
4. Weight ≥ 3.5 kg and ≤ 13.5 kg at screening
5. Has received age-appropriate vaccinations
6. Genetically confirmed OTCD defined by genetic confirmation of an OTC variant (pathogenic or likely pathogenic) associated with severe neonatal OTCD defined below in Inclusion Criteria #7 or has the same OTC variant as a family member who had severe neonatal OTCD within first week of life.
7. Severe neonatal OTCD defined by hyperammonemic crisis with elevated ammonia level of >560 μmol/L and clinical symptoms within first week of life, and currently receiving treatment with both dietary protein restriction and nitrogen scavenger therapy.
8. Current or historical biochemical profile consistent with OTCD
9. Participant's parent(s)/LAR must be able to comprehend and be willing to provide a signed IRB/IEC-approved ICF.

Key Exclusion Criteria:

1. Neonatal diagnosis of severe to profound Hypoxic Ischemic Encephalopathy due to birth injury
2. Requiring urgent liver transplant due to liver failure as assessed by the PI.
3. Contiguous gene deletion involving the OTC gene and including at least the CYBB gene on the telomeric side or the TSPAN7 gene on the centromeric side.
4. Known or suspected major organ injury/dysfunction/anomalies.
5. Vital sign and laboratory abnormalities outside of reference ranges.
6. Treatment with any other gene therapy or gene editing therapy
7. Co-enrollment in any other study unless approved by the sponsor.
8. Any condition, that in the opinion of the Investigator, would compromise the safety of the participant or study data
9. Documented vertical transmission of HepA/HepB/HepC
10. Documented in-utero teratogen, substance, and/or alcohol exposure, which in the opinion of the Investigator may increase the participant's risk of developmental delays, congenital anomalies, and/or significant medical complications

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low Dose Level; Participants will receive the Low Dose of ECUR-506 delivered one time via IV Infusion.	Genetic: ECUR-506; ECUR-506 is a gene editing treatment delivering a gene encoding the editing enzyme and an OTC gene.
Experimental: High Dose Level; Participants will receive a higher dose of ECUR-506 delivered one time via IV infusion.	Genetic: ECUR-506; ECUR-506 is a gene editing treatment delivering a gene encoding the editing enzyme and an OTC gene.
Experimental: Intermediate Dose Level; Participants will receive an intermediate dose of ECUR-506 delivered on time via IV infusion	Genetic: ECUR-506; ECUR-506 is a gene editing treatment delivering a gene encoding the editing enzyme and an OTC gene.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urinalysis evaluations	Toxicity is graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Adverse events (AEs) are reported based on clinical laboratory tests, vital signs, physical examinations, electrocardiograms, and any other medically indicated assessments from the time informed consent is signed through the end of the safety follow-up period. AEs are considered to be treatment emergent (TEAE) if they occur or worsen in severity following the administration of the study treatment. TEAEs are considered treatment-related if relationship to study drug is possibly related, probably related, or definitely related.	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Treatment-emergent adverse events (incidence, severity, seriousness, and relatedness)	Toxicity is graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Adverse events (AEs) are reported based on clinical laboratory tests, vital signs, physical examinations, Pediatric Neurologist exam parameters, electrocardiograms, and any other medically indicated assessments from the time informed consent is signed through the end of the safety follow-up period. AEs are considered to be treatment emergent (TEAE) if they occur or worsen in severity following the administration of the study treatment. TEAEs are considered treatment-related if relationship to study drug is possibly related, probably related, or definitely related.	Over 24 weeks post infusion
Physical exam parameters	Safety- (Includes PI assessment of General Appearance, Dermatological, HEENT, Lymphatic, Respiratory, Cardiovascular, Gastrointestinal, Musculoskeletal, Neurological (Cranial Nerve Function, Motor System Function, Sensory System Function, Primitive Reflexes))	Assessed as change from baseline at pre-specified timepoints as described in the SOE throughout the duration of the study on all enrolled and dosed participants.
Vital sign parameters	Safety- (Includes PI assessment of Systolic Blood Pressure, Diastolic Blood Pressure, Pulse Rate, Respiratory Rate, Temperature)	Assessed as change from baseline at pre-specified timepoints as described in the SOE throughout the duration of the study on all enrolled and dosed participants.
Pediatric neurologist exam parameters	Safety- (Includes Pediatric Neurologist assessment of Neurological status by review of Cranial Nerve Function, Motor System Function, Sensory System Function, Primitive Reflexes.)	Assessed as change from baseline at pre-specified timepoints as described in the SOE throughout the duration of the study on all enrolled and dosed participants.
Blood safety tests including hematology, serum chemistry, liver function tests, coagulation tests	Safety- (Blood Safety tests to be reviewed in relation to established normal ranges for each assessment for the applicable age group)	as change from baseline at pre-specified timepoints as described in the SOE throughout the duration of the study on all enrolled and dosed participants.
12 lead ECG parameters	Safety- (Includes PI review of Heart Rate, PR Interval, RR Interval, QRS Duration, QT Interval, QTcF Interval, Overall Interpretation)	as change from baseline at pre-specified timepoints as described in the SOE throughout the duration of the study on all enrolled and dosed participants.
Complete clinical response	Discontinuation of scavenger medication for a minimum duration of 28 days without reductions in prescribed daily protein intake during this time period by end of study.	Over 24 weeks post infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of HAEs/person-year	Key Secondary Endpoint: Pharmacodynamics and Efficacy	Day 1 post dose through Week 24
qPCR measurement to evaluate the clearance of both vectors in body fluids over time	Supportive Secondary Endpoint: Pharmacokinetics	Over 24 weeks post infusion
Incidence of hyperammonemic episode (HAE)	Supportive Secondary Endpoint: Pharmacodynamics and Efficacy	Over 24 weeks post infusion
Incidence and number of hyperammonemic episodes (HAE/HAC) resulting in hospitalization	Supportive Secondary Endpoint: Pharmacodynamics and Efficacy	Over 24 weeks post infusion
Overall and by hospitalization severity (Mild: adjustment of dietary protein intake and oral scavenger medication / Moderate: cessation of dietary protein intake and initiation of IV scavenger therapy / Severe: requirement for hemodialysis)	Supportive Secondary Endpoint: Pharmacodynamics and Efficacy.	Will be assessed Day 1 post dose through Wk 24 on all enrolled and dosed participants
Duration of hospitalization for each HAE/HAC	Supportive Secondary Endpoint: Pharmacodynamics and Efficacy	Over 24 weeks post infusion
Requirement for Intensive Care Unit (ICU) care during hospitalization for each HAE/HAC	Supportive Secondary Endpoint: Pharmacodynamics and Efficacy	Over 24 weeks post infusion
Time to liver transplant from dosing to end of study (EOS)	Supportive Secondary Endpoint: Efficacy	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Transplant free survival	Supportive Secondary Endpoint: Efficacy	Time to lever transplant or any-cause death from dosing to EOS
Overall survival	Supportive Secondary Endpoint: Efficacy	Time to any-cause death from dosing to EOS
Achieving and maintaining complete clinical response through end of study	Supportive Secondary Endpoint: Efficacy	Over 24 weeks post infusion
Scavenger drug dose	Supportive Secondary Endpoint: Efficacy	Over 24 weeks post infusion
Dietary protein intake g/kg/day	Supportive Secondary Endpoint: Efficacy	Supportive Secondary: Over 24 weeks post infusion
Blood urea nitrogen measurements	Supportive Secondary Endpoint: Pharmacodynamics	Over 24 weeks post infusion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum PCSK9	Pharmacodynamics	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Change from baseline at Week 24 post infusion in Bayley Scales of Infant and Toddler Development 4th Ed (BSID-4) for the Cognitive, Language, and Motor scales	Total Raw Scores, Growth Score Values (GSVs), and Age Equivalent Scores will be analyzed; Raw Scores range 0-162; GSVs range 428-599; Age Equivalent Scores range 1-42 months; a higher score reflects a higher level of skill.	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Urinary excretion of phenylacetate metabolites	Urinary phenylacetate (mcg/mL), urinary phenylacetylglutamine (mcg/mL), urinary phenylacetate/ phenylglutamine ratio.	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Urinary excretion of orotic acid metabolites.	Urinary orotic acid (mmol/ mol creatinine), urinary uracil (mmol/mol creatinine).	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Change from baseline at Week 24 post infusion in length.	Length measured in centimeters.	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Change from baseline at Week 24 post infusion in weight.	Weight measured in kilograms.	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Assess for potential genetic changes in the liver tissue, collected by liver biopsy, through long read sequencing, in participants who have received ECUR-506	Pharmacodynamics	The following will be assessed at Week 24 if liver biopsy tissue sample is sufficient.
Urinary nitrogen to urinary creatinine ratio.	Urinary nitrogen to urinary creatinine ratio (mg/dL)	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Clinical Response (CR) defined as reduction in baseline standard of care therapy	Efficacy	Assessed at Week 24
Serum Neurofilament Light Chain	Safety	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Number of participants with antibodies to AAVrh79 capsid in blood	Pharmacodynamics	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Number of participants with antibodies to hOTC transgene in blood	Pharmacodynamics	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Number of participants with antibodies to M2PCSK9 transgene in blood	Pharmacodynamics	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Incidence and time to medical management adjustments based on iECURE guidance (protein diet or scavenger medication)	Efficacy	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Fasting plasma ammonia	Pharmacodynamics	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Fasting plasma citrulline and fasting plasma glutamine levels	Pharmacodynamics	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Percent liver transduction via ISH/IF (in-situ hybridization / Immunofluorescence)"at Wk 24 collected by liver biopsy.	Pharmacodynamics	The following will be assessed at Week 24 if liver biopsy tissue sample is sufficient.
Assess the potential on and "off" target editing by amplicon-seq in liver tissue samples of participants who received ECUR-506.	Pharmacodynamics	The following will be assessed at week 24 if liver biopsy tissue sample is sufficient.
Assess potential off-target editing with AAV vector ITR insertion by ITR-seq in liver tissue samples of participants who received ECUR-506	Pharmacodynamics	The following will be assessed at Week 24 if liver biopsy tissue sample is sufficient.
With an observed genetic safety signal, genetic analysis of Whole Blood DNA may be performed on samples collected and stored at screening and week 24, in the event of an observed genomic safety signal.	Safety	Will be assessed Day 1 post dose through Wk 24 on all enrolled and dosed participants.
Quality of Life, as measured by the Pediatric QOL inventory Infant Scale (PedsQL-IS)	Quality of Life	Will be assessed Day 1 post dose through Wk 24 on all enrolled and dosed participants.

Collaborators and Investigators

• Sponsor: iECURE, Inc.
• Investigators: Study Director: George Diaz, M.D., Ph.D, iECURE, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2024
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: December 19, 2023
• First Submitted That Met QC Criteria: February 2, 2024
• First Posted (Actual): February 13, 2024

Study Record Updates

• Last Update Posted (Actual): April 15, 2026
• Last Update Submitted That Met QC Criteria: April 10, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Nervous System Diseases; UCD; Central Nervous System Diseases; Liver Disease; Genetic Diseases, Inborn; X-Linked; Ammonia; Neonatal; Brain Diseases; Metabolic Diseases; Metabolism; Metabolism, Inborn Errors; Urea Cycle Disorders; Liver Transplant; Inherited Metabolic Disorders; Brain Diseases, Metabolic, Inborn; Genetic Diseases, X-Linked; Inborn; Inborn Errors; OTC; Brain Diseases, Metabolic; OTC Deficiency; OTCD; Ornithine; Transcarbamylase; Ornithine Transcarbamylase Deficiency; Hyperammonemia; Amino Acid Metabolism, Inborn Errors; High Ammonia; NH4; Neurometabolic disorders
• Additional Relevant MeSH Terms: Pathologic Processes; Digestive System Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Genetic Diseases, Inborn; Liver Diseases; Brain Diseases; Nervous System Diseases; Central Nervous System Diseases; Metabolic Diseases; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Genetic Diseases, X-Linked; Ornithine Carbamoyltransferase Deficiency Disease; Urea Cycle Disorders, Inborn; Amino Acid Metabolism, Inborn Errors; Hyperammonemia; Brain Diseases, Metabolic, Inborn
• Other Study ID Numbers: ECUR-506-OTC-101; OTC-HOPE (Other Identifier: iECURE, Inc.)

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