Long-Term Safety Follow-Up of AAV‑RH79‑OTC Gene Therapy (ECUR‑506D) in Patients with Ornithine Transcarbamylase Deficiency

The primary objective is to evaluate the long-term safety of the investigational product in individuals with Ornithine Transcarbamylase Deficiency who have received the product and in those who have not, irrespective of causality. Secondary objectives include:

• assessment of pharmacokinetics of the investigational product and associated clinical outcomes in participants treated with the product compared with those managed with standard of care alone;
• evaluation of potential effects on disease‑specific biological markers, developmental milestones, and quality of life.

Ten male participants, identified as a vulnerable pediatric population, were enrolled in the study; all were approximately 2 years of age and had a diagnosis of Ornithine Transcarbamylase Deficiency. Subjects were selected from individuals who had previously been enrolled in the iECURE parent protocol and had either completed or discontinued that study, with enrollment contingent upon consent from a parent or legal authorized representative. Inclusion required willingness of the parent/representative to adhere to protocol requirements and appropriate assent when applicable. The cohort comprised patients with the specified metabolic disorder, reflecting a generally compromised health status related to the disease; no additional lifestyle restrictions such as diet or physical activity were specified in the provided information.

The Long‑term Follow‑up (LTFU) Study enrolls individuals who have completed or discontinued any iECURE parent protocol and evaluates the long‑term safety of the investigational products ECUR‑506A and ECUR‑506D, both administered intravenously as viral vector infusions, in participants with Ornithine Transcarbamylase Deficiency (OTC). The study period extends from 20 May 2026 through 30 June 2041, with each participant remaining under observation until the end‑of‑study visit or earlier discontinuation. The schedule of visits includes: a screening visit to confirm eligibility and obtain consent; periodic follow‑up visits (approximately every six months for the first two years, then annually) during which physical examinations, vital signs, neurologic assessments, 12‑lead ECG, comprehensive laboratory panels (hematology, chemistry, liver function, coagulation, serum PCSK9, urinalysis), vector pharmacokinetic sampling, and developmental assessments are performed; and a final end‑of‑study visit that repeats all safety evaluations. The primary data collection focuses on the primary endpoint of adverse events (AE and SAE) and related clinical assessments, while the secondary endpoints encompass vector pharmacokinetics, liver transduction, hyperammonemic crises metrics, transplant‑free survival, overall survival, immunogenicity, metabolic parameters, and developmental outcomes. Expected participant involvement may span up to 15 years, reflecting the study’s longitudinal design. Early termination may occur if a participant withdraws consent, is lost to follow‑up, experiences a safety issue that mandates discontinuation, or if the sponsor determines that continuation is no longer feasible.

The investigational product ECUR-506D is supplied as an intravenous infusion containing an adeno‑associated virus serotype rh79 vector that carries the human OTC gene. The formulation is administered by intravenous route as a single infusion; specific dose amounts are defined by the protocol and are not disclosed in this summary. Administration is performed under controlled clinical conditions with monitoring for infusion‑related events.

The investigational product ECUR-506A is provided as an intravenous infusion of an adeno‑associated virus serotype rh79 vector encoding a meganuclease designed for targeted editing of the human PCSK9 gene. Similar to ECUR-506D, the product is delivered by intravenous infusion in a single administration, with dosage parameters outlined in the study protocol. Infusion procedures include observation for immediate adverse reactions.

No additional comparator or placebo agents are specified for this long‑term follow‑up study; participants receive standard clinical care as required for their underlying condition, without a designated non‑experimental therapeutic arm. Compliance with the investigational product administration is confirmed by documented infusion records and verification of protocol‑specified timing. Ongoing safety monitoring includes scheduled assessments to capture any delayed events related to the gene‑therapy vectors.

Efficacy will be evaluated using a set of disease‑related secondary endpoints. These include the incidence and severity of hyperammonemic crises (HAC), classified as mild, moderate, or severe based on required interventions; daily plasma ammonia concentrations recorded during hospitalization for each HAC event; duration of hospital stay and intensive‑care unit (ICU) utilization; quantitative assessment of vector pharmacokinetics in blood and shedding in plasma, saliva, urine, and feces; measurement of percent liver transduction; plasma concentrations of PCSK9, ammonia, citrulline, and glutamine; urinary nitrogen to creatinine ratio; and time‑to‑event outcomes such as transplant‑free survival, overall survival, and time to liver transplantation. Developmental progress will be assessed with age‑appropriate neurocognitive instruments, specifically the Bayley Scale of Infant Development IV and the Kaufman Assessment Battery for Children‑II Normative Update.

All laboratory parameters will be obtained using validated analytical assays performed on samples collected at scheduled study visits throughout the long‑term follow‑up period. Vector PK and shedding will be quantified by polymerase chain reaction–based methods, while liver transduction will be assessed by appropriate molecular techniques. Plasma and urine biomarkers will be measured by standard clinical chemistry platforms. Neurodevelopmental assessments will be administered by trained evaluators using the specified standardized scales. Event‑based data such as HAC frequency, hospitalization metrics, and survival outcomes will be captured prospectively in the study database and analyzed using time‑to‑event and descriptive statistical methods.