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

Официальное название

A Phase 1/2/3 First-in-Human, Open-Label, Dose-Escalation Study to Evaluate the Safety and Efficacy of a Single Intravenous (IV) Administration of ECUR-506 in Males Less Than 9 Months of Age With Genetically Confirmed Neonatal Onset Ornithine Transcarbamylase (OTC) Deficiency

Обзор

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.

Подробное описание

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.

Вмешательства

• Генная терапия ECUR-506
  ECUR-506 is a gene editing treatment delivering a gene encoding the editing enzyme and an OTC gene.

Первичные конечные точки

• Treatment-emergent adverse events (incidence, severity, seriousness, and relatedness) [Срок оценки: Over 24 weeks post infusion]
• Physical exam parameters [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.]
• 12 lead ECG parameters [Срок оценки: 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 [Срок оценки: Over 24 weeks post infusion]

Вторичные конечные точки (12)

• Number of HAEs/person-year [Срок оценки: Day 1 post dose through Week 24]
• qPCR measurement to evaluate the clearance of both vectors in body fluids over time [Срок оценки: Over 24 weeks post infusion]
• Incidence of hyperammonemic episode (HAE) [Срок оценки: Over 24 weeks post infusion]
• Incidence and number of hyperammonemic episodes (HAE/HAC) resulting in hospitalization [Срок оценки: 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) [Срок оценки: Will be assessed Day 1 post dose through Wk 24 on all enrolled and dosed participants]
• Duration of hospitalization for each HAE/HAC [Срок оценки: Over 24 weeks post infusion]
• Requirement for Intensive Care Unit (ICU) care during hospitalization for each HAE/HAC [Срок оценки: Over 24 weeks post infusion]
• Time to liver transplant from dosing to end of study (EOS) [Срок оценки: Assessed as change from baseline at pre-specified timepoints through Week 24 post infusion.]
• Transplant free survival [Срок оценки: Time to lever transplant or any-cause death from dosing to EOS]
• Overall survival [Срок оценки: Time to any-cause death from dosing to EOS]
• Achieving and maintaining complete clinical response through end of study [Срок оценки: Over 24 weeks post infusion]
• Scavenger drug dose [Срок оценки: Over 24 weeks post infusion]

Критерии участия

Критерии включения

• 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
• Has received age-appropriate vaccinations
• 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.
• 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.
• Current or historical biochemical profile consistent with OTCD
• Participant's parent(s)/LAR must be able to comprehend and be willing to provide a signed IRB/IEC-approved ICF.

Критерии исключения

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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 6 центров

• UCLA Mattel Children's Hospital — Los Angeles
• Children's Hospital of Colorado, Anshutz Medical Campus — Aurora
• Emory University School of Medicine — Atlanta
• Ann & Robert H. Lurie Children's Hospital of Chicago — Chicago
• Icahn School of Medicine at Mount Sinai — New York
• Oregon Health and Science University — Portland

Австралия · 2 центра

• The Children's Hospital at Westmead — Sydney
• The Royal Children's Hospital — Melbourne

Испания · 2 центра

• Hopsital Sant Joan de Deu — Barcelona
• Hospital Universitario 12 de Octubre — Madrid

Великобритания · 2 центра

• Great Ormond Street Hospital — London
• The Newcastle upon Tyne Hospitals NHS Foundation Trust- Great North Children's Hospital — Newcastle upon Tyne

Идентификаторы

NCT: NCT06255782 · ECUR-506-OTC-101 · OTC-HOPE

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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