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

Phase 2RecruitingNCT06255782

iECURE, Inc.20 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Ornithine Transcarbamylase Deficiency

Eligibility

Sex: MALEMin age: 24 HoursMax age: 7 Months

Medical Language ↔ Plain English

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 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. 7. 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. 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 and laboratory abnormalities outside of reference ranges. 6. Treatment with any other gene therapy or gene editing therapy 7. Co-enrollment in any other study unless approved by the sponsor. 8. Any condition, that in the opinion of the Investigator, would compromise the safety of the participant or study data 9. Documented vertical transmission of HepA/HepB/HepC 10. 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

Locations (12)

UCLA Mattel Children's Hospital

Los Angeles, California, United States

RECRUITING

Children's Hospital of Colorado, Anshutz Medical Campus

Aurora, Colorado, United States

RECRUITING

Emory University School of Medicine

Atlanta, Georgia, United States

RECRUITING

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States

RECRUITING

Icahn School of Medicine at Mount Sinai

New York, New York, United States

RECRUITING

Oregon Health and Science University

Portland, Oregon, United States

RECRUITING

The Children's Hospital at Westmead

Sydney, New South Wales, Australia

ACTIVE_NOT_RECRUITING

The Royal Children's Hospital

Melbourne, Victoria, Australia

ACTIVE_NOT_RECRUITING

Hopsital Sant Joan de Deu

Barcelona, Spain

RECRUITING

Hospital Universitario 12 de Octubre

Madrid, Spain

RECRUITING

...and 2 more locations

Outcomes

Primary Outcomes

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.

Time frame: Over 24 weeks post infusion

Physical exam parameters

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))

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.

Vital sign parameters

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

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.

Pediatric neurologist exam parameters

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

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.

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

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

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.

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.

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

12 lead ECG parameters

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

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.

Complete clinical response

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.

Time frame: Over 24 weeks post infusion

Secondary Outcomes

Number of HAEs/person-year

Key Secondary Endpoint: Pharmacodynamics and Efficacy

Time frame: Day 1 post dose through Week 24

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

Supportive Secondary Endpoint: Pharmacokinetics

Time frame: Over 24 weeks post infusion

Incidence of hyperammonemic episode (HAE)

Supportive Secondary Endpoint: Pharmacodynamics and Efficacy

Time frame: Over 24 weeks post infusion

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

Supportive Secondary Endpoint: Pharmacodynamics and Efficacy

Time frame: Over 24 weeks post infusion

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)

Supportive Secondary Endpoint: Pharmacodynamics and Efficacy.

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

Duration of hospitalization for each HAE/HAC

Supportive Secondary Endpoint: Pharmacodynamics and Efficacy

Time frame: Over 24 weeks post infusion

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

Supportive Secondary Endpoint: Pharmacodynamics and Efficacy

Time frame: Over 24 weeks post infusion

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

Supportive Secondary Endpoint: Efficacy

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

Overview

Conditions

Interventions

Eligibility

Locations (12)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts