Ornithine Carbamoyltransferase Deficiency (Disorder), Ornithine Transcarbamylase Deficiency, Ornithine Transcarbamylase Deficiency Disease, Urea Cycle Disorders, Inborn
Conditions
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, Inherited Metabolic Disorders, Liver Disease, Liver Transplant, Metabolism, Metabolic Diseases, Metabolism, Inborn Errors, Neonatal, Nervous System Diseases, Neurometabolic disorders, NH4, Ornithine, Ornithine Transcarbamylase Deficiency, OTC, OTC Deficiency, OTCD, Transcarbamylase, UCD, Urea Cycle Disorders, X-Linked
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 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.
Detailed description
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.
Interventions
GENETICECUR-506
ECUR-506 is a gene editing treatment delivering a gene encoding the editing enzyme and an OTC gene.
Sponsors
iECURE, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Dose escalation with dose staggering. Dose selection will be based on an assessment of the totality of the safety and efficacy.
Eligibility
Sex/Gender
MALE
Age
24 Years to 7 Months
Healthy volunteers
No
Inclusion 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 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-emergent adverse events (incidence, severity, seriousness, and relatedness) | Over 24 weeks post infusion | 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. |
| Physical exam parameters | 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. | 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)) |
| Vital sign parameters | 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. | Safety- (Includes PI assessment of Systolic Blood Pressure, Diastolic Blood Pressure, Pulse Rate, Respiratory Rate, Temperature) |
| Pediatric neurologist exam parameters | 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. | Safety- (Includes Pediatric Neurologist assessment of Neurological status by review of Cranial Nerve Function, Motor System Function, Sensory System Function, Primitive Reflexes.) |
| Blood safety tests including hematology, serum chemistry, liver function tests, coagulation tests | 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. | Safety- (Blood Safety tests to be reviewed in relation to established normal ranges for each assessment for the applicable age group) |
| Urinalysis evaluations | Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion. | 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. |
| 12 lead ECG parameters | 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. | Safety- (Includes PI review of Heart Rate, PR Interval, RR Interval, QRS Duration, QT Interval, QTcF Interval, Overall Interpretation) |
| Complete clinical response | Over 24 weeks post infusion | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of HAEs/person-year | Day 1 post dose through Week 24 | Key Secondary Endpoint: Pharmacodynamics and Efficacy |
| qPCR measurement to evaluate the clearance of both vectors in body fluids over time | Over 24 weeks post infusion | Supportive Secondary Endpoint: Pharmacokinetics |
| Incidence of hyperammonemic episode (HAE) | Over 24 weeks post infusion | Supportive Secondary Endpoint: Pharmacodynamics and Efficacy |
| Incidence and number of hyperammonemic episodes (HAE/HAC) resulting in hospitalization | Over 24 weeks post infusion | Supportive Secondary Endpoint: Pharmacodynamics and Efficacy |
| 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) | Will be assessed Day 1 post dose through Wk 24 on all enrolled and dosed participants | Supportive Secondary Endpoint: Pharmacodynamics and Efficacy. |
| Duration of hospitalization for each HAE/HAC | Over 24 weeks post infusion | Supportive Secondary Endpoint: Pharmacodynamics and Efficacy |
| Requirement for Intensive Care Unit (ICU) care during hospitalization for each HAE/HAC | Over 24 weeks post infusion | Supportive Secondary Endpoint: Pharmacodynamics and Efficacy |
| Time to liver transplant from dosing to end of study (EOS) | Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion. | Supportive Secondary Endpoint: Efficacy |
| Transplant free survival | Time to lever transplant or any-cause death from dosing to EOS | Supportive Secondary Endpoint: Efficacy |
| Overall survival | Time to any-cause death from dosing to EOS | Supportive Secondary Endpoint: Efficacy |
| Achieving and maintaining complete clinical response through end of study | Over 24 weeks post infusion | Supportive Secondary Endpoint: Efficacy |
| Scavenger drug dose | Over 24 weeks post infusion | Supportive Secondary Endpoint: Efficacy |
| Dietary protein intake g/kg/day | Supportive Secondary: Over 24 weeks post infusion | Supportive Secondary Endpoint: Efficacy |
| Blood urea nitrogen measurements | Over 24 weeks post infusion | Supportive Secondary Endpoint: Pharmacodynamics |
Countries
Australia, Spain, United Kingdom, United States
Contacts
CONTACTGeorge Diaz, M.D., Ph.D.
CONTACTTrial Recruitment
STUDY_DIRECTORGeorge Diaz, M.D., Ph.D
iECURE, Inc.
Outcome results
None listed