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.

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

Males present with the highest unmet medical need, and in order to reduce the variability of the study population, participants are restricted to the male sex. OTC is primarily inherited in an X-linked recessive pattern, meaning that it mostly affects males, who only have one copy of the X chromosome. Females, who have two X chromosomes, can be carriers of the condition. Some females may experience milder OTC symptoms, or they may have no symptoms.