Eighteen-Month Clinical Update from the First Patient Dosed in OTC-HOPE

Eighteen-Month Clinical Update from the First Patient Dosed in OTC-HOPE An In Vivo Liver-Directed AAV Gene Insertion Trial for Neonatal-Onset Ornithine Transcarbamylase Deficiency UREAGENESIS MEETING 2026 NON-CONFIDENTIAL Julien Baruteau MD, PhD Great Ormond Street Hospital for Children, London, UK Disclosures Julien Baruteau, MD, PhD iECURE, Inc — Primary Investigator Neonatal-Onset OTC Deficiency Ornithine transcarbamylase deficiency (OTCD) is neurometabolic disorder arising from a genetic defect in a liver urea cycle enzyme responsible for ammonia detoxification. Neonatal-onset OTCD is a severe, early form that appears in the first days of life. Incidence 1 : 56,500 live births1 Neonatal Mortality Mortality rates as high as 74% when onset occurs within the first month of life2 Clinical Presentation Hyperammonemic crises (HACs) causing lethargy, vomiting, tachypnea, seizures, coma and neuropsychological sequelae Standard of Care Protein restriction, nitrogen scavenger therapy; orthotopic liver transplantation is the only curative option 1 Summar ML et al, European R, Network for Intoxication Type Metabolic Diseases. The incidence of urea cycle disorders. Mol Genet Metab. 2013;110:179-80. 2 Brassier et al. Orphanet Journal of Rare Diseases. 2015 Gene Therapy Approaches Dual AAV / ARCUS Nuclease / Donor Gene ARCUS: A Well-Differentiated Genome Editing Platform 01 The ARCUS nuclease scans DNA for the target site 02 The ARCUS nuclease binds to the target site 03 The target DNA sequence is cut, creating a 'sticky' 4-base 3' overhang 04 The cut target site is repaired via homology-directed repair (HDR) or non- homologous end joining (NHEJ) Compared with some other gene-editing technologies, an ARCUS nuclease is relatively small (~1.1 kilobases and ~360 amino acids), making it possible to deliver via adeno-associated virus (AAV), which has a packaging capacity of ~4.4 kb. OTC-HOPE A first-in-human clinical trial evaluating ECUR-506 in newborn males with neonatal- onset OTC deficiency — the most severe and life-threatening form of the disease OTC-HOPE: Clinical Trial Design Trial Design* • PH 1/2/3, global multi-center trial, open label, FIH, adaptive, dose finding and dose confirmation study • First participant dose: 1.3×10¹³ GC/kg • Dose escalation up to 4.0×10¹³ GC/kg Vector • IV delivery of dual AAV with ARCUS Nuclease and donor OTC gene Study Duration • 6-month post dose follow up • 14.5-year long-term follow up study Primary Endpoint** • Assessment of safety and tolerability of ECUR-506 • Efficacy: ◦ Complete clinical response (CCR) by EOS, defined as the discontinuation of scavenger medication for a minimum duration of 28 days without reductions in prescribed daily protein intake during this time period, compared to systematic literature review (SLR) Key Secondary Endpoint** • Efficacy: ◦ Rate of hyperammonemic events (HAE)/person-year where HAE is defined as fasting plasma ammonia levels > 100 μmol/L, Day 1 post dose through Week 24, compared to peer-reviewed published literature *Initial dosing cohorts require an 8-week safety stagger between participants **For a more complete listing of secondary and exploratory endpoints visit: https://clinicaltrials.gov/study/NCT05251782?cond=Ornithine%20transcarbamylase%20deficiency&term=iECURE&rank=2 Dose Confirmation Scenario All remaining participants to be dosed in 2026. Adaptive design with DMC oversight at each cohort transition. Up to 11 patients may be dosed in expansion cohort to meet or evaluate primary endpoint Inclusion Criteria Patient Demographics • Male sex • 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 all age-appropriate vaccinations Disease Confirmation & Treatment • Genetically confirmed OTCD • Current or past hyperammonemic crisis (including ammonia levels >560 µmol/L, lethargy, poor feeding, coma, or seizure) within first week of life OR • Genetic confirmation of an OTC variant (pathogenic or likely pathogenic) associated with severe neonatal OTCD or the same OTC variant as a family member who had severe neonatal OTCD within first week of life AND • Currently receiving treatment with both dietary protein restriction and 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 Exclusion Criteria Neurological / Hepatic 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. Genetic / Structural Contiguous gene deletion involving the OTC gene; Known or suspected major organ injury/dysfunction/anomalies. Prior / Concurrent Therapy Treatment with any other gene therapy or gene editing therapy; Co-enrollment in any other clinical study with an investigational product. Investigator Discretion Any condition that, in the opinion of the Investigator, would compromise participant safety or study data. Infectious / Teratogenic Exposure Documented vertical transmission of HepA/HepB/HepC; Documented in-utero teratogen, substance, and/or alcohol exposure. Global Clinical Program IND/CTA Clearances • United States • United Kingdom • Spain • Australia Harmonized global protocol; international referral network with patient transport programs for families outside approved geographies. Regulatory Designations • FDA: Orphan Drug; Rare Pediatric Disease; Chemistry, Manufacturing, and Controls Development and Readiness Pilot (CDRP); Fast Track and Regenerative Medicine Advanced Therapy (RMAT) designations • European Commission: Orphan Designation, Pediatric Investigational Plan (PIP) agreement • MHRA: Innovative Licensing and Access Pathway (ILAP) First Infant Dosed: Clinical Data Eighteen months of follow-up from the first participant dosed with ECUR-506 in the OTC-HOPE trial Patient 1: Clinical Timeline 6 Days Old NH₃ 823 μmol/L Managed with hemodialysis and started on scavenger therapy/protein restriction OTC variant c.77G>C (Arg26Pro) confirmed 4 Months Enrolled in OTC-HOPE 5.5 Months 2nd HAC 6.5 Months ECUR-506 1.3×10¹³ GC/kg 12.5 Months Entered LTFU 24.5 Months Age at data cut The patient presented with severe neonatal-onset OTCD requiring urgent metabolic stabilization. A second hyperammonemic crisis at 5.5 months preceded dosing at 6.5 months of age. The patient successfully transitioned to long-term follow-up at 12.5 months. Grade 3 Transaminitis Episode: Management Timeline Week 4 — ALT 3× ULN Admitted; IV methylprednisolone initiated at 5 mg/kg Week 6 — Steroid Dose Escalation IV methylprednisolone increased to 10 mg/kg and liver biopsy Week 7 — Transition Converted to oral prednisone (10 mg/kg); tacrolimus initiated at 0.5 mg/kg/day Weeks 8–14 — Steroid Wean Corticosteroid taper completed successfully Weeks 12–23 — Tacrolimus Wean Tacrolimus taper completed; immunosuppression discontinued Data as of 11FEB2026 Liver Biopsy Histopathology Results Mild portal and minor interface inflammation Widespread glycogen accumulation within hepatocytes Focal mild fibrosis Infiltrating population of lymphocytes were predominantly T-cells (CD3+), with only very scanty scattered B-cells (CD20+) consistent with a typical inflammatory profile. Mild portal lymphocytic inflammation with mild interface reaction with occasional associated acidophil bodies / single necrotic hepatocytes identified. For-cause liver biopsy taken at 6 weeks post ECUR-506 dosing to help determine underlying cause of inflammation and guide immunosuppressant choice. OTC-HOPE: Clinical Endpoints — Patient 1 Plasma Glutamine Decline Glutamine declined below the lower limit of normal between weeks 6–8 post-dosing, even during high-dose corticosteroid administration. Scavenger Discontinuation Prompted complete weaning of nitrogen scavenger therapy from weeks 8–13 post-ECUR-506 — meeting the protocol-defined CCR criterion. Sustained Response Normal plasma glutamine maintained at 12 months post-discontinuation of standard of care. No biochemical relapse observed. CCR defined as discontinuation of scavenger medication for ≥28 days without reduction in prescribed daily protein intake. Data as of 11FEB2026 Protein Intake Liberalization Diet Liberalized Liberalized after scavenger wean post ECUR-506 dosing. Full Intake Age-appropriate intake achieved without hyperammonemia. Sustained 18 Months Liberalization maintained through 18 months post-dose. BUN Increased Consistent with restored ureagenesis. Data as of 11FEB2026 Plasma Ammonia: LTFU Data Ammonia Control Plasma ammonia levels remain within the normal reference range throughout long-term follow-up. No HAE Events Zero hyperammonemic crises recorded since ECUR-506 administration, despite viral illness. A contrast to the natural history of neonatal-onset OTCD1. Transplant De-listed Patient has been removed from the liver transplant waiting list. Data as of 11FEB2026 1.Lichter-Konecki et al. Ornithine Transcarbamylase Deficiency. 2013 Aug 29 [Updated 2022 May 26]. 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/NBK154378/ Dose-Finding Cohorts: Summary Low— 1.3×10¹³ GC/kg • n=3 dosed • Generally well tolerated • Transient transaminitis (Grade 3) resolved with reactive immunosuppression • Patient 1: CCR achieved • Biomarker response in Patients 2 & 3* Intermediate— 2.4×10¹³ GC/kg • n=3 dosed • Generally well tolerated • Biomarker response observed across cohort* • Potential scavenger medication reductions pending efficacy evaluations High— 4.0×10¹³ GC/kg • n=1 dosed • Generally well tolerated • Biomarker response observed* • Potential scavenger medication reductions pending efficacy evaluations Pre and post ECUR-506 HAC data across all dose cohorts to be presented at ASGCT 2026. * *Biomarker response defined as reductions in plasma glutamine and plasma ammonia levels and elevation in BUN level Summary Disease Severity Neonatal-onset OTCD is the most severe form of urea cycle disorders, with mortality rates up to 74% and no durable non-surgical treatment. ECUR-506 Platform A dual-AAV, ARCUS nuclease–mediated gene insertion therapy offering variant-agnostic, potentially durable correction via PCSK9 safe-harbor integration. OTC-HOPE Trial Phase 1/2/3, open-label, global trial currently enrolling. Seven participants dosed across three dose cohorts; all remaining participants to be dosed in 2026. Patient 1 Outcomes • Grade 3 transaminitis at week 4 resolved with immunosuppression by week 8. • Complete clinical response beginning at 13 weeks. • Ammonia control, zero HAE events, and transplant de- listing maintained through 18 months, post-ECUR-506 treatment, without the need for scavenger medications or protein restriction.

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