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.
Male sex
Gestational or adjusted (corrected) gestational age ≥ 37 weeks
Age at screening is 24 hours to 7 months
Weight ≥ 3.5 kg and ≤ 13.5 kg at screening
Neonatal diagnosis of severe to profound Hypoxic Ischemic Encephalopathy due to birth injury
Requiring urgent liver transplant due to liver failure as assessed by the PI.
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.
Known or suspected major organ injury/dysfunction/anomalies.
Sequential
ECUR-506
GeneticECUR-506 is a gene editing treatment delivering a gene encoding the editing enzyme and an OTC gene.
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.
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))
Vital sign parameters
Safety- (Includes PI assessment of Systolic Blood Pressure, Diastolic Blood Pressure, Pulse Rate, Respiratory Rate, Temperature)
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.)
Number of HAEs/person-year
Key Secondary Endpoint: Pharmacodynamics and Efficacy
qPCR measurement to evaluate the clearance of both vectors in body fluids over time
Supportive Secondary Endpoint: Pharmacokinetics
Incidence of hyperammonemic episode (HAE)
Supportive Secondary Endpoint: Pharmacodynamics and Efficacy
Incidence and number of hyperammonemic episodes (HAE/HAC) resulting in hospitalization
Supportive Secondary Endpoint: Pharmacodynamics and Efficacy
Clinical Response (CR) defined as reduction in baseline standard of care therapy
Efficacy
Serum Neurofilament Light Chain
Safety
Number of participants with antibodies to AAVrh79 capsid in blood
Pharmacodynamics
Number of participants with antibodies to hOTC transgene in blood
Pharmacodynamics
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