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NCT Number: NCT06255782

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

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Key information

Conditions

Ornithine Transcarbamylase Deficiency Amino Acid Metabolism, Inborn Errors Brain Diseases Brain Diseases, Metabolic Brain Diseases, Metabolic, Inborn Central Nervous System Diseases Congenital, Hereditary, and Neonatal Diseases and Abnormalities Digestive System Diseases Genetic Diseases, Inborn Genetic Diseases, X-Linked Hyperammonemia Liver Diseases Metabolic Diseases Metabolism, Inborn Errors Nervous System Diseases Nutritional and Metabolic Diseases Ornithine Carbamoyltransferase Deficiency (Disorder) Ornithine Carbamoyltransferase Deficiency Disease Ornithine Transcarbamylase Deficiency Disease Pathologic Processes Pathological Conditions, Signs and Symptoms Urea Cycle Disorders, Inborn

Age range

24 hour–7 month

Sex eligibility

Male

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

The Children's Hospital at Westmead, Sydney, New South Wales, Australia

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Key Inclusion Criteria:

  • Male sex
  • Gestational or adjusted (corrected) gestational age ≥ 37 weeks
  • Age at screening is 24 hours to 7 months
  • Weight ≥ 3.5 kg and ≤ 13.5 kg at screening
  • Has received age-appropriate vaccinations
  • 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.
  • 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.
  • Current or historical biochemical profile consistent with OTCD
  • Participant's parent(s)/LAR must be able to comprehend and be willing to provide a signed IRB/IEC-approved ICF.

Key Exclusion Criteria:

  • Neonatal diagnosis of severe to profound Hypoxic Ischemic Encephalopathy due to birth injury
  • Requiring urgent liver transplant due to liver failure as assessed by the PI.
  • 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.
  • Known or suspected major organ injury/dysfunction/anomalies.
  • Vital sign and laboratory abnormalities outside of reference ranges.
  • Treatment with any other gene therapy or gene editing therapy
  • Co-enrollment in any other study unless approved by the sponsor.
  • Any condition, that in the opinion of the Investigator, would compromise the safety of the participant or study data
  • Documented vertical transmission of HepA/HepB/HepC
  • 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

Treatment and study plan

ECUR-506

Genetic

ECUR-506 is a gene editing treatment delivering a gene encoding the editing enzyme and an OTC gene.

Primary outcomes

  1. Treatment-emergent adverse events (incidence, severity, seriousness, and relatedness)

    Time frame: Over 24 weeks post infusion

    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.

  2. Physical exam parameters

    Time frame: 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.

    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))

  3. Vital sign parameters

    Time frame: 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.

    Safety- (Includes PI assessment of Systolic Blood Pressure, Diastolic Blood Pressure, Pulse Rate, Respiratory Rate, Temperature)

  4. Pediatric neurologist exam parameters

    Time frame: 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.

    Safety- (Includes Pediatric Neurologist assessment of Neurological status by review of Cranial Nerve Function, Motor System Function, Sensory System Function, Primitive Reflexes.)

  5. Blood safety tests including hematology, serum chemistry, liver function tests, coagulation tests

    Time frame: 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.

    Safety- (Blood Safety tests to be reviewed in relation to established normal ranges for each assessment for the applicable age group)

  6. Urinalysis evaluations

    Time frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.

    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.

  7. 12 lead ECG parameters

    Time frame: 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.

    Safety- (Includes PI review of Heart Rate, PR Interval, RR Interval, QRS Duration, QT Interval, QTcF Interval, Overall Interpretation)

  8. Complete clinical response

    Time frame: Over 24 weeks post infusion

    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.

Secondary outcomes

  1. Number of HAEs/person-year

    Time frame: Day 1 post dose through Week 24

    Key Secondary Endpoint: Pharmacodynamics and Efficacy

  2. qPCR measurement to evaluate the clearance of both vectors in body fluids over time

    Time frame: Over 24 weeks post infusion

    Supportive Secondary Endpoint: Pharmacokinetics

  3. Incidence of hyperammonemic episode (HAE)

    Time frame: Over 24 weeks post infusion

    Supportive Secondary Endpoint: Pharmacodynamics and Efficacy

  4. Incidence and number of hyperammonemic episodes (HAE/HAC) resulting in hospitalization

    Time frame: Over 24 weeks post infusion

    Supportive Secondary Endpoint: Pharmacodynamics and Efficacy

  5. 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)

    Time frame: Will be assessed Day 1 post dose through Wk 24 on all enrolled and dosed participants

    Supportive Secondary Endpoint: Pharmacodynamics and Efficacy.

  6. Duration of hospitalization for each HAE/HAC

    Time frame: Over 24 weeks post infusion

    Supportive Secondary Endpoint: Pharmacodynamics and Efficacy

  7. Requirement for Intensive Care Unit (ICU) care during hospitalization for each HAE/HAC

    Time frame: Over 24 weeks post infusion

    Supportive Secondary Endpoint: Pharmacodynamics and Efficacy

  8. Time to liver transplant from dosing to end of study (EOS)

    Time frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.

    Supportive Secondary Endpoint: Efficacy

  9. Transplant free survival

    Time frame: Time to lever transplant or any-cause death from dosing to EOS

    Supportive Secondary Endpoint: Efficacy

  10. Overall survival

    Time frame: Time to any-cause death from dosing to EOS

    Supportive Secondary Endpoint: Efficacy

  11. Achieving and maintaining complete clinical response through end of study

    Time frame: Over 24 weeks post infusion

    Supportive Secondary Endpoint: Efficacy

  12. Scavenger drug dose

    Time frame: Over 24 weeks post infusion

    Supportive Secondary Endpoint: Efficacy

  13. Dietary protein intake g/kg/day

    Time frame: Supportive Secondary: Over 24 weeks post infusion

    Supportive Secondary Endpoint: Efficacy

  14. Blood urea nitrogen measurements

    Time frame: Over 24 weeks post infusion

    Supportive Secondary Endpoint: Pharmacodynamics

Other outcomes

  1. Clinical Response (CR) defined as reduction in baseline standard of care therapy

    Time frame: Assessed at Week 24

    Efficacy

  2. Serum Neurofilament Light Chain

    Time frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.

    Safety

  3. Number of participants with antibodies to AAVrh79 capsid in blood

    Time frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.

    Pharmacodynamics

  4. Number of participants with antibodies to hOTC transgene in blood

    Time frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.

    Pharmacodynamics

  5. Number of participants with antibodies to M2PCSK9 transgene in blood

    Time frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.

    Pharmacodynamics

  6. Incidence and time to medical management adjustments based on iECURE guidance (protein diet or scavenger medication)

    Time frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.

    Efficacy

  7. Fasting plasma ammonia

    Time frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.

    Pharmacodynamics

  8. Fasting plasma citrulline and fasting plasma glutamine levels

    Time frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.

    Pharmacodynamics

  9. Serum PCSK9

    Time frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.

    Pharmacodynamics

  10. Urinary excretion of phenylacetate metabolites

    Time frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.

    Urinary phenylacetate (mcg/mL), urinary phenylacetylglutamine (mcg/mL), urinary phenylacetate/ phenylglutamine ratio.

  11. Urinary excretion of orotic acid metabolites.

    Time frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.

    Urinary orotic acid (mmol/ mol creatinine), urinary uracil (mmol/mol creatinine).

  12. Urinary nitrogen to urinary creatinine ratio.

    Time frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.

    Urinary nitrogen to urinary creatinine ratio (mg/dL)

  13. Change from baseline at Week 24 post infusion in length.

    Time frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.

    Length measured in centimeters.

  14. Change from baseline at Week 24 post infusion in weight.

    Time frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.

    Weight measured in kilograms.

  15. Percent liver transduction via ISH/IF (in-situ hybridization / Immunofluorescence)"at Wk 24 collected by liver biopsy.

    Time frame: The following will be assessed at Week 24 if liver biopsy tissue sample is sufficient.

    Pharmacodynamics

  16. Assess the potential on and "off" target editing by amplicon-seq in liver tissue samples of participants who received ECUR-506.

    Time frame: The following will be assessed at week 24 if liver biopsy tissue sample is sufficient.

    Pharmacodynamics

  17. Assess potential off-target editing with AAV vector ITR insertion by ITR-seq in liver tissue samples of participants who received ECUR-506

    Time frame: The following will be assessed at Week 24 if liver biopsy tissue sample is sufficient.

    Pharmacodynamics

  18. Assess for potential genetic changes in the liver tissue, collected by liver biopsy, through long read sequencing, in participants who have received ECUR-506

    Time frame: The following will be assessed at Week 24 if liver biopsy tissue sample is sufficient.

    Pharmacodynamics

  19. 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.

    Time frame: Will be assessed Day 1 post dose through Wk 24 on all enrolled and dosed participants.

    Safety

  20. 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

    Time frame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.

    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.

  21. Quality of Life, as measured by the Pediatric QOL inventory Infant Scale (PedsQL-IS)

    Time frame: Will be assessed Day 1 post dose through Wk 24 on all enrolled and dosed participants.

    Quality of Life

Study contacts

Contact information is provided by the study sponsor or research team.

George Diaz, M.D., Ph.D.

CONTACT

[email protected]

1-877-694-3558

Trial Recruitment

CONTACT

[email protected]

Sponsors and collaborators

Lead sponsor

iECURE, Inc.

Industry

Registry information

Official study title

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

Important dates

Study start
2024
Primary completion
2027
Study completion
2027
First posted
Feb 13, 2024
Registry last updated
Apr 15, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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