an open-label study to investigate ecur-506 in male babies less than 9 months of age with neonatal onset otc deficiency

Conditions: Ornithine Transcarbamylase Deficiency; Ornithine Transcarbamylase Deficiency Disease; Ornithine Carbamoyltransferase Deficiency (Disorder); Urea Cycle Disorders, Inborn

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 1/2/3, open-label, multicenter, safety, efficacy, 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, 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 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, a commonly used virus called adeno-associated virus (aav) is used to enter the cells and deliver the genes.

Eligibility 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 7. severe neonatal otcd defined by hyperammonemic crisis with elevated ammonia level of \>560 μmol/l and clinical symptoms within first week of life 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 abnormalities 6. laboratory abnormalities outside of laboratory normal ranges for urinalysis, complete blood count, and comprehensive metabolic panel that are attributable to comorbidities unrelated to otcd 7. treatment with any other gene therapy or gene editing therapy 8. co-enrollment in any other clinical study unless approved by the sponsor. 9. any condition, that in the opinion of the investigator, would compromise the safety of the participant or study data 10. documented vertical transmission of hepa/hepb/hepc 11. 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

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 liver disease liver transplant metabolism metabolic diseases metabolism, inborn errors neonatal nervous system diseases nh4 ornithine ornithine transcarbamylase deficiency otc otc deficiency otcd transcarbamylase ucd urea cycle disorders x-linked