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

A Phase I/II 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 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 up to two 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 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, the carrier is called adeno-associated virus (AAVs) that is able to enter cells and deliver these genes. This is a commonly found virus that has been changed to make it essentially harmless.

• Study Type: Interventional
• Enrollment (Estimated): 13
• 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

• United Kingdom
  • London, United Kingdom
    • Recruiting
    • Great Ormond Street Hospital
    • Contact: Christopher Jackson; Email: Christopher.Jackson@gosh.nhs.uk

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Male sex
2. Gestational age ≥ 37 weeks
3. Age at screening is 24 hours to 7 months*

4. Genetically confirmed OTCD

   • Documented analysis either through prenatal testing or post-birth genetic testing.

   Note: a prenatal testing diagnosis will be confirmed post-birth and prior to dosing.

5. Severe neonatal OTCD defined by the following:

   • Current or past hyperammonemic crisis (which includes but is not limited to: severely elevated [>8 x ULN] ammonia levels, lethargy, poor feeding, coma, seizure) within first week of life OR
   • Family history and genetic confirmation of pathogenic or likely pathogenic variant consistent with severe OTC, or has same genetic mutation as previous family member who had severe disease with neonatal onset within first week of life AND
   • Currently receiving treatment (e.g., dietary and scavenger therapy)
6. In participants not prenatally diagnosed, current or historical (within 2 weeks prior to Screening) biochemical profile consistent with OTC: below LLN of plasma citrulline/arginine and urine orotic aciduria at time of diagnosis
7. Participant's parent(s)/LAR must be able to comprehend and be willing to provide a signed IRB/IEC-approved ICF which will include consent for participation in this 24-week trial with immediate roll-over into the 14.5 year ECUR-LTFU study *Participant's age at screening: Any subsequently enrolled participant must be stabilized and dosed by less than 9 months of age. Participants ≥5 months and ≤ 7 months at screening will therefore have a shortened stabilization window (i.e., <120 days) to achieve dosing prior to turning 9 months of age. No exceptions to dosing age will be granted.

Exclusion Criteria:

1. Neonatal diagnosis of severe to profound Hypoxic Ischemic Encephalopathy (based on standard HIE metrics) 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 (brain, heart, liver, kidneys) other than what is consistent with OTCD, based on routine medical assessments performed as part of standard of care.
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 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: Cohort 1; 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: Cohort 2; Participants will receive the High 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: Expansion Cohort; Participants will receive ECUR-506 at one of the doses evaluated in Cohort 1 or Cohort 2 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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, 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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent liver transduction	Pharmacokinetics	Assessed at Week 24
Number of hyperammonemic crises (HAC)	Pharmacodynamics and Efficacy	Over 24 weeks post infusion
qPCR measurement to evaluate the clearance of both vectors in blood over time	Pharmacokinetics	Over 24 weeks post infusion
qPCR measurement to evaluate the clearance of both vectors in urine over time	Pharmacokinetics	Over 24 weeks post infusion
qPCR measurement to evaluate the clearance of both vectors in feces over time	Pharmacokinetics	Over 24 weeks post infusion
Scavenger drug dose per body surface area (BSA)	Efficacy	Over 24 weeks post infusion
Protein allowance g/kg	Efficacy	Over 24 weeks post infusion
Blood urea nitrogen measurements	Pharmacodynamics	Over 24 weeks post infusion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with antibodies to hOTC in blood	Pharmacodynamics	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Number of participants with antibodies to M2PCSK9 in blood	Pharmacodynamics	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
Number of participants with antibodies to AAVrh79 in blood	Pharmacodynamics	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
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.
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.
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.
Plasma ammonia and plasma glutamine levels	Pharmacodynamics	Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.
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.
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.
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 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.
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.
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.
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.

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 (Estimated): April 1, 2024
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): September 1, 2026

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 10, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: April 1, 2024

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; 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
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Nutrition Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Malnutrition; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Ornithine Carbamoyltransferase Deficiency Disease; Deficiency Diseases; Urea Cycle Disorders, 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