ECUR-506 shows early response in neonatal-onset OTC deficiency trial

iECURE reported preliminary data from the first completed low-dose cohort of ECUR-506, an investigational in vivo targeted gene insertion therapy, in male infants with genetically confirmed neonatal-onset ornithine transcarbamylase (OTC) deficiency enrolled in the ongoing OTC-HOPE trial. The company said the first treated infant remained off standard-of-care therapies and had no hyperammonemic events (HAEs) through 18 months after dosing, as of February 11, 2026.¹ “In infants with neonatal-onset OTC deficiency, HACs, which are spikes in plasma ammonia >100 umol/L associated with neurological status change, are a primary driver of mortality and morbidity, sometimes resulting in seizures, coma, and rapid neurologic decline,” Gabriel Cohn, MD, chief medical officer of iECURE, said in the release.¹

The data, presented at the Society for Inherited Metabolic Disorders 2026 Annual Meeting, are early and involve a very small cohort. Still, the findings are clinically relevant because neonatal-onset OTC deficiency is associated with recurrent hyperammonemia, neurologic injury, need for intensive medical management, and risk of death despite dietary restriction and nitrogen-scavenging therapy.^2,3

OTC-HOPE is a first-in-human study evaluating single-dose intravenous ECUR-506 in eligible male infants up to 7 months of age at screening with severe neonatal-onset OTC deficiency. The main study includes screening, stabilization, dosing eligibility assessment, study drug administration, and 6 months of follow-up, followed by a 14.5-year long-term follow-up study, ECUR-LTFU.¹

In the completed low-dose cohort, 3 infants received ECUR-506 at 1.3 × 10^1,3 genome copies/kg. According to iECURE, annualized HAE rates declined by 57% after treatment compared with before dosing, and annualized hyperammonemic crisis (HAC) rates declined by 65%; the company reported P values of .018 and .011, respectively.¹ Two of 3 participants had no HAEs or HACs after treatment, whereas the third had reductions in event rates. One participant was removed from the liver transplant waiting list after treatment, and another proceeded to liver transplantation during long-term follow-up.¹

The company emphasized that posttreatment outcomes reflect both ECUR-506 and ongoing standard-of-care management, except for the first participant, who reportedly discontinued ammonia scavenger therapy, liberalized dietary protein intake to age-appropriate levels, and remained free of HAEs through 18 months, including during intercurrent illness.¹

Safety data were reported across 7 treated participants in 3 dose cohorts: 3 in the low-dose cohort, 3 in an intermediate-dose cohort of 2.4 × 10^1,3 genome copies/kg, and 1 in a high-dose cohort of 4.0 × 10^1,3 genome copies/kg. No unexpected ECUR-506–related safety events, infusion-related reactions, or thrombotic microangiopathy were reported. Grade 2 to 3 asymptomatic transaminitis occurred and was managed with reactive immunosuppression without recurrence after taper. One death from hypoxemic respiratory failure was assessed by the company as unrelated to ECUR-506 and attributed to underlying OTC deficiency progression and complications.¹

OTC deficiency is an X-linked urea cycle disorder caused by deficient hepatic ornithine transcarbamylase activity, impairing ammonia detoxification. Neonatal-onset disease can present within days of birth with poor feeding, lethargy, vomiting, respiratory alkalosis, seizures, coma, and rapidly progressive cerebral edema if hyperammonemia is not corrected.^2,3 Current management includes emergency ammonia-lowering interventions during decompensation, chronic protein restriction, nitrogen-scavenging medications, supplementation with urea cycle intermediates when appropriate, and consideration of liver transplantation in severe disease.^2,3 Longitudinal data from patients with urea cycle disorders underscore persistent morbidity, including neurodevelopmental impairment and recurrent metabolic crises, despite available therapies.⁴

ECUR-506 is designed to insert a functional copy of the OTC gene into the PCSK9 locus in hepatocytes using 2 adeno-associated virus vectors with the same capsid. One vector carries an ARCUS nuclease intended to create the insertion site, and the second delivers the functional OTC gene cassette.¹ ECUR-506 remains investigational, and no approved indication was reported in the company announcement.

For clinicians, the main interpretive issue is the gap between biologic plausibility and clinical certainty. The reduction in annualized HAEs and HACs is encouraging, but the cohort size is 3 infants, there is no concurrent control group described in the release, and event rates in neonatal OTC deficiency may be influenced by age, intercurrent illness, transplant decisions, dietary management, and adherence to scavenger therapy. Longer follow-up and additional participants, particularly in intermediate- and high-dose cohorts, will be needed to clarify durability, dose selection, neurodevelopmental outcomes, transplant avoidance, and late safety.

References

1. iECURE Reports Sustained Clinical Response in the First Patient Dosed with ECUR-506 & Reductions in the Annualized Rates of Hyperammonemic Events and Crises in the First Completed Cohort of ECUR-506 in Ongoing OTC-HOPE Trial. Business Wire. Published May 18, 2026. Accessed May 18, 2026. https://www.businesswire.com/news/home/20260518376613/en/iECURE-Reports-Sustained-Clinical-Response-in-the-First-Patient-Dosed-with-ECUR-506-Reductions-in-the-Annualized-Rates-of-Hyperammonemic-Events-and-Crises-in-the-First-Completed-Cohort-of-ECUR-506-in-Ongoing-OTC-HOPE-Trial

2. Häberle J, Burlina A, Chakrapani A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: first revision. J Inherit Metab Dis. 2019;42(6):1192-1230. doi:10.1002/jimd.12100

3. Simpson KL, MacLeod EL, Kakajiwala A, et al. Urea Cycle Disorders Overview. 2003 Apr 29 [Updated 2025 Jul 3]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1217/

4. Batshaw ML, Tuchman M, Summar M, Seminara J; Members of the Urea Cycle Disorders Consortium. A longitudinal study of urea cycle disorders. Mol Genet Metab. 2014;113(1-2):127-130. doi:10.1016/j.ymgme.2014.08.001