Clinical trial NCT06255782: An Open-label Study to Investigate ECUR-506 in Male Babies Less Than 9 Months of Age With Neonatal Onset OTC Deficiency
Official 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Ornithine Transcarbamylase Deficiency
Ornithine Transcarbamylase Deficiency Disease
Ornithine Carbamoyltransferase Deficiency (Disorder)
Urea Cycle Disorders, Inborn
Keywords: Amino Acid Metabolism, Inborn Errors
Ammonia
Brain Diseases
Brain Diseases, Metabolic
Brain Diseases, Metabolic, Inborn
Central Nervous System Diseases
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
High Ammonia
Hyperammonemia
Inborn
Inborn Errors
Liver Disease
Liver Transplant
Metabolism
Metabolic Diseases
Metabolism, Inborn Errors
Neonatal
Nervous System Diseases
NH4
Ornithine
Ornithine Transcarbamylase Deficiency
OTC
OTC Deficiency
OTCD
Transcarbamylase
UCD
Urea Cycle Disorders
X-Linked
Lead sponsor: iECURE, Inc.
Sponsor class: INDUSTRY
First posted: 2024-02-13
Enrollment: 8
Sex: MALE
Minimum age (years): 24
Maximum age (years): 7
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Dose escalation with dose staggering. Dose selection will be based on an assessment of the totality of the safety and efficacy.
Primary purpose: TREATMENT

Brief summary: 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 detoxification of ammonia. Individuals with OTC deficiency can build-up excess levels of ammonia in their blood, potentially resulting in devastating consequences, including cumulative and irreversible neurological damage, coma and death. The severe form of the condition emerges shortly after birth and is more common in boys than girls.

This is a Phase 1/2/3, open-label, multicenter, safety, efficacy, and dose finding study of ECUR-506 in male babies with neonatal onset OTC deficiency. The primary objective of this study 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.

Detailed description: The study drug, ECUR-506, is an investigational gene editing therapy. Gene editing is a way to repair, replace, or introduce new copies of genes that don't work. The study drug contains a working copy of the OTC gene that will be delivered by an IV infusion. It also contains a gene to encode the editing enzyme which is the part of the study drug that can cut DNA so that the OTC gene can be inserted. The study drug was designed to introduce a working copy of the OTC gene and a gene to encode the editing enzyme. A gene cannot enter cells by itself, it needs a delivery mechanism to move the gene into the cells. In this study, a commonly used virus called adeno-associated virus (AAV) is used to enter the cells and deliver the genes.

Eligibility criteria: 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
7. Severe neonatal OTCD defined by hyperammonemic crisis with elevated ammonia level of \>560 μmol/L and clinical symptoms within first week of life
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 abnormalities
6. Laboratory abnormalities outside of laboratory normal ranges for urinalysis, complete blood count, and comprehensive metabolic panel that are attributable to comorbidities unrelated to OTCD
7. Treatment with any other gene therapy or gene editing therapy
8. Co-enrollment in any other clinical study unless approved by the sponsor.
9. Any condition, that in the opinion of the Investigator, would compromise the safety of the participant or study data
10. Documented vertical transmission of HepA/HepB/HepC
11. 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

Primary outcomes:
measure: Treatment-emergent adverse events (incidence, severity, seriousness, and relatedness)
timeFrame: Over 24 weeks post infusion
measure: Urinalysis evaluations
timeFrame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
measure: Achieving normal fasting plasma ammonia levels by EOS
timeFrame: Over 24 weeks post infusion
measure: Complete clinical response
timeFrame: Over 24 weeks post infusion
Secondary outcomes:
measure: Percent liver transduction
timeFrame: Assessed at Week 24
measure: Number of hyperammonemic crises (HAC)
timeFrame: Over 24 weeks post infusion
measure: qPCR measurement to evaluate the clearance of both vectors in body fluids over time
timeFrame: Over 24 weeks post infusion
measure: Scavenger drug dose per body surface area (BSA)
timeFrame: Over 24 weeks post infusion
measure: Protein allowance g/kg/day
timeFrame: Over 24 weeks post infusion
measure: Blood urea nitrogen measurements
timeFrame: Over 24 weeks post infusion
measure: Fasting plasma ammonia
timeFrame: Over 24 weeks post infusion
Other outcomes:
measure: Serum Neurofilament Light Chain evaluation
timeFrame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
measure: Number of participants with antibodies to hOTC in blood
timeFrame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
measure: Number of participants with antibodies to M2PCSK9 in blood
timeFrame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
measure: Number of participants with antibodies to AAVrh79 in blood
timeFrame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
measure: Daily ammonia levels during hospitalization requiring ICU care for HAC event
timeFrame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
measure: Time to liver transplant from dosing to end of study (EOS)
timeFrame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
measure: Transplant free survival
timeFrame: Time to liver transplant or any-cause death from dosing to EOS
measure: Overall survival
timeFrame: Time to any-cause death from dosing to EOS
measure: Number of instances the participant is eligible for medical management adjustments based on iECURE guidance (protein diet or scavenger medication)
timeFrame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
measure: Fasting plasma ammonia, fasting plasma citrulline and fasting plasma glutamine levels
timeFrame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
measure: Serum PCSK9
timeFrame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
measure: 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
timeFrame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
measure: Quality of Life, as measured by the Pediatric QOL inventory Infant Scale (PedsQL-IS)
timeFrame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
measure: Urinary excretion of phenylacetate metabolites
timeFrame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
measure: Urinary excretion of orotic acid metabolites.
timeFrame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
measure: Urinary nitrogen to urinary creatinine ratio.
timeFrame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
measure: Change from baseline at Week 24 post infusion in length.
timeFrame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
measure: Change from baseline at Week 24 post infusion in weight.
timeFrame: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
measure: Assess the potential on target editing by amplicon-seq in liver tissue samples of participants who received ECUR-506.
timeFrame: The following will be assessed at week 24 if liver biopsy tissue sample is sufficient.
measure: Assess potential off-target editing with AAV vector ITR insertion by ITR-seq in liver tissue samples of participants who recieved ECUR-506
timeFrame: The following will be assessed at Week 24 if liver biopsy tissue sample is sufficient.
measure: Assess for potential genetic changes in the liver tissue, collected by liver biopsy, through long read sequencing, in participants who have received ECUR-506
timeFrame: The following will be assessed at Week 24 if liver biopsy tissue sample is sufficient.
measure: 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.
timeFrame: Assessed as any difference between screening and week 24 genetic markers, if a genetic safety signal is observed.
Locations:
city: Los Angeles
country: United States
facility: UCLA Mattel Children's Hospital
state: California
city: Aurora
country: United States
facility: Children's Hospital of Colorado, Anshutz Medical Campus
state: Colorado
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Sydney
country: Australia
facility: The Children's Hospital at Westmead
state: New South Wales
city: Melbourne
country: Australia
facility: The Royal Children's Hospital
state: Victoria
city: Barcelona
country: Spain
facility: Hopsital Sant Joan de Deu
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
city: Newcastle Upon Tyne
country: United Kingdom
facility: The Newcastle upon Tyne Hospitals NHS Foundation Trust- Great North Children's Hospital
Study officials:
affiliation: iECURE, Inc.
name: George Diaz, M.D., Ph.D
role: STUDY_DIRECTOR
References: