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

Ornithine Transcarbamylase Deficiency Clinical Trial

Official title:

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

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
• Start date: April 2024
• Est. completion date: September 2026

Study information

• Verified date: April 2024
• Source: iECURE, Inc.
• Contact: George Diaz, M.D., Ph.D.
• Phone: 1-877-694-3558
• Email: medinfo[@]iecure.com
• Is FDA regulated: No
• 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 up to two 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, 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.

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

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

Related Conditions & MeSH terms

• Deficiency Diseases
• Ornithine Transcarbamylase Deficiency
• Ornithine Transcarbamylase Deficiency Disease
• Urea Cycle Disorders, Inborn

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	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 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	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, 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 blood over time	Pharmacokinetics	Over 24 weeks post infusion
Secondary	qPCR measurement to evaluate the clearance of both vectors in urine over time	Pharmacokinetics	Over 24 weeks post infusion
Secondary	qPCR measurement to evaluate the clearance of both vectors in feces 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