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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT06255782
Other study ID # ECUR-506-OTC-101
Secondary ID OTC HOPE
Status Recruiting
Phase Phase 1/Phase 2
First received
Last updated
Start date April 8, 2024
Est. completion date September 2026

Study information

Verified date May 2024
Source iECURE, Inc.
Contact George Diaz, M.D., Ph.D.
Phone 1-877-694-3558
Email medinfo@iecure.com
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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, open-label, multicenter, safety 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 and tolerability of multiple dose levels of ECUR-506 following intravenous (IV) administration of a single dose.


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.


Recruitment information / eligibility

Status Recruiting
Enrollment 13
Est. completion date September 2026
Est. primary completion date September 2026
Accepts healthy volunteers No
Gender Male
Age group 24 Hours to 7 Months
Eligibility Key Inclusion Criteria: 1. Male sex 2. Gestational age = 37 weeks 3. Age at screening is 24 hours to 7 months* 4. Weight = 3.5 kg and = 10.0 at screening 5. Has received all age-appropriate vaccinations 6. Genetically confirmed OTCD 7. Severe neonatal OTCD defined by hyperammonemic crisis 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 4. Known or suspected major organ injury/dysfunction/anomalies. 5. Treatment with any other gene therapy or gene editing therapy 6. Co-enrollment in any other clinical study with an investigational product prior to or during the duration of this trial would require the participant to be withdrawn from this study 7. Any condition, that in the opinion of the Investigator, would compromise the safety of the participant or study data 8. Documented vertical transmission of HSV, HIV, or HepA/HepB/HepC 9. 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 Design


Related Conditions & MeSH terms


Intervention

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

Locations

Country Name City State
United Kingdom Great Ormond Street Hospital London

Sponsors (1)

Lead Sponsor Collaborator
iECURE, Inc.

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Other Number of participants with antibodies to hOTC in blood Pharmacodynamics Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Other Number of participants with antibodies to M2PCSK9 in blood Pharmacodynamics Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Other Number of participants with antibodies to AAVrh79 in blood Pharmacodynamics Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Other Daily ammonia levels during hospitalization requiring ICU care for HAC event Pharmacodynamics and Safety Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Other Time to liver transplant from dosing to end of study (EOS) Efficacy Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Other Transplant free survival Efficacy Time to liver transplant or any-cause death from dosing to EOS
Other Overall survival Efficacy Time to any-cause death from dosing to EOS
Other Number of instances the participant is eligible for 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.
Other Plasma ammonia, plasma citrulline and plasma glutamine levels Pharmacodynamics Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Other Serum PCSK9 Pharmacodynamics Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Other 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.
Other Quality of Life, as measured by the Pediatric QOL inventory Infant Scale (PedsQL-IS) Quality of Life Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Other 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.
Other 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.
Other 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.
Other 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.
Other 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.
Other Assess the potential on 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.
Other Assess potential off-target editing with AAV vector ITR insertion by ITR-seq in liver tissue samples of participants who recieved ECUR-506 Pharmacodynamics The following will be assessed at Week 24 if liver biopsy tissue sample is sufficient.
Other 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.
Other 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 Assessed as any difference between screening and week 24 genetic markers, if a genetic safety signal is observed.
Primary 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
Primary 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.
Secondary Percent liver transduction Pharmacokinetics Assessed at Week 24
Secondary Number of hyperammonemic crises (HAC) Pharmacodynamics and Efficacy Over 24 weeks post infusion
Secondary qPCR measurement to evaluate the clearance of both vectors in body fluids over time Pharmacokinetics Over 24 weeks post infusion
Secondary Scavenger drug dose per body surface area (BSA) Efficacy Over 24 weeks post infusion
Secondary Protein allowance g/kg Efficacy Over 24 weeks post infusion
Secondary Blood urea nitrogen measurements Pharmacodynamics Over 24 weeks post infusion
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