Decreased rate of hyperammonemiccrises in infants with neonatal-onset OTC deficiency (OTCD) post ECUR-506 administration

Decreased rate of hyperammonemic crises in infants with neonatal-onset OTC deficiency (OTCD) post ECUR-506 administration. Julien Baruteau MD, PhD Great Ormond Street Hospital for Children, London, UK Disclosures Julien Baruteau, MD, PhD iECURE, Inc — Primary Investigator Neonatal-onset OTCD: Unmet Need • Approximately 30% of individuals with OTCD present during the neonatal period1 • hemizygous males typically exhibit the most severe phenotype • mortality rates up to 74%1 • Liver transplantation provides durable metabolic correction but is complicated • donor availability • immunosuppression risks (malignancy, renal dysfunction, infections)2,3 • 5-year graft failure rate of ~15%4 Despite standard of care Neonatal Crisis Hyperammonemic encephalopathy, 48–72h of life Apparent Stability Early metabolic stability during rapid growth Recurrent HAEs/HACs Cumulative Neurologic Injury Irreversible damage over time 1.Brassier A, Gobin S, Arnoux JB, et al. Long-term outcomes in ornithine transcarbamylase deficiency: a series of 90 patients. Orphanet J Rare Dis. 2015;10:58. 2. Blondet NM, Healey PJ, Hsu E. Immunosuppression in the pediatric transplant recipient. Semin Pediatr Surg. 2017;26:193-198. 3. Yanik EL, Smith JM, Shiels MS, et al. Cancer risk after pediatric solid organ transplantation. Pediatrics. 2017;139:e20163893. 4. Ziogas IA, Wu WK, Matsuoka LK, et al. Liver transplantation in children with urea cycle disorders: the importance of minimizing waiting time. Liver Transpl. 2021;27:1799-1810. Targeted Gene Insertion Approach • Gene addition approaches have the potential to restore OTC activity • HOWEVER episomal transgene dilution during rapid hepatocyte proliferation in infancy may limit long-term durability. • Base and prime editing are potentially more durable approaches • HOWEVER >600 OTC pathogenic/likely-pathogenic variants limit the usefulness of this approach Nuclease Cassette Donor Cassette OTC-HOPE Six-month Phase 1/2/3 study with 14.5-year Long-Term Follow-Up Eligibility criteria: • 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 • 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 Why this is different Inverted Development Paradigm OTC-HOPE begins with the youngest and most severely affected populations. Rigorous Durability Test Rapid hepatocyte proliferation and liver growth occur during the first years of life. Disease-Specific Insights May better identify disease-specific factors, including baseline disease severity and immune maturation, that influence safety and therapeutic response which may not be apparent in older or less severely affected populations. 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) Safety Preliminary Safety Observations (n=9) Data as of 28JUL2026 Generally well tolerated across all three dose cohorts (1.3x10¹³, 2.4x10¹³ and 4.0x10¹³ GC/kg), n=3 in each group No unexpected safety events No thrombotic microangiopathy Asymptomatic, non-dose- dependent, transient Grade 2–3 transaminitis resolved with reactive immunosuppression (7 of 8 patients)* *One patient did receive prophylactic corticosteroids post-ECUR-506, per protocol One death: hypoxemic respiratory failure, determined unrelated to ECUR-506 No infusion reactions Editing Efficiency Liver biopsy was performed at 24 weeks in low dose cohort (1 patient's family withdrew consent to biopsy). Liver biopsy results from intermediate and high dose cohorts are pending. Pt-1 Pt-2 In-Situ Hybridization (%) 12.6 14.5 Immunofluorescence (%) 1.5 1.9 Indel (%)* 1.5 0.7 Serum PCSK9 % Reduction Post ECUR-506 + + results are from Week 20 visit *The assay only detects small insertion/deletion events and does not reflect events in which insertion of transgene cassettes have occurred Clinical Response Low-dose cohort; Data as of 28JUL2026 Participant (Pt) Age at Presentation (day) Enrollment (months)Dosing weight (kg) OTC variant Peak NH₃ at presentation (µmol/L) Pre-Rx Breakthrough HAEs (days observed) Post-Rx Breakthrough HAEs (days observed) Pre-Rx Breakthrough HACs (days) observed) Post-Rx Breakthrough HACs (days) observed) Pt-1 7 3.5 6.5 8.4 c.77G.C p.(Arg26Pro) 840 1 (87) 0 (165) 1 (87) 0 (165) Pt-2 5 1.7 4.7 7.3c.403G>C p.(Ala135Pro) 2106 1 (87) 0 (166) 1 (87) 0 (166) Pt-3 3 5.3 8.1 11.5c.533C>T p.(Thr178Met) 1600 4 (86) 5 (169) 2 (86) 2 (169) Annualized HAE and HAC rates, pre- and post-ECUR-506, were reduced by 57% (p = 0.02) and 74% (p = 0.01), respectively. Age at enrollment (month) Age at dosing (month) Weight at dosing (kg) Baseline Disease Severity May Influence Treatment Response • Posset et al. — Natural history establishes a severity– enzyme activity relationship. • Residual OTC activity ≤4.3% of normal was associated with higher initial ammonia and mortality • Cohort 1: Same low dose, heterogeneous clinical response • Participant 1, peak ammonia 840 µmol/L • Complete clinical response (d/c scavenger therapy and protein restriction) • Other participants, peak ammonia ≥ 1600 µmol/L • Less pronounced responses. Consistent with a more severe underlying enzymatic deficiency. The greater the underlying OTC deficiency, the greater the amount of restored enzyme activity that may be required to achieve metabolic stability. Source: Posset R et al.; Urea Cycle Disorders Consortium (UCDC); European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group. Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders. Genet Med. 2024 Apr;26(4):101039. Summary • OTC-HOPE represents the first clinical use of PCSK9 as a safe harbor target, the first clinical use of the AAVrh79 capsid, and the first clinical application of a dual-AAV, variant agnostic, targeted gene therapy approach in infants. • Low-dose ECUR-506 demonstrated an expected and manageable safety profile along with targeted hepatic editing and evidence of improved metabolic control. • Baseline disease severity may influence treatment response. • Safety and efficacy data to date support continued evaluation of higher ECUR-506 dose levels. Acknowledgements Patients and families OTC-HOPE principal investigators • Mark Anderson-Great North Children's Hospital, Newcastle • Josh Baker - Lurie Children's Hospital, Chicago • Marcello Bellusci- Hospital 12 de Octubre, Madrid • Margo Breilyn - Mount Sinai, New York • Angeles Garcia Cazorla-Sant Joan de Deu Hospital, Barcelona • Cary Harding - OHSU, Portland • Gerry Lipshutz - UCLA, Los Angeles • Shawn McCandless - Children's Hospital Colorado, Aurora • Rossana Sanchez Russo - Emory, Atlanta iECURE • Gabriel Cohn • George Diaz • Matthew Hall • Karen Kuhn • Tom White

The release as fetched from its publisher. iecure.com ↗