Decreased rate of hyperammonemic crises in infants with neonatal-onset OTC deficiency post ECUR-506 administration: preliminary update from the OTC-HOPE study

Decreased rate of hyperammonemic crises in infants with neonatal-onset OTC deficiency post ECUR-506 administration: preliminary update from the OTC-HOPE study. Gabriel M Cohn MD, MBA1; Julien Baruteau MD, PhD2; Shawn E. McCandless MD3; Gerald S. Lipshutz MD4; Margo Sheck Breilyn MD5; Ángeles García-Cazorla MD, PhD6; Matthew Hall BS1; Karen Kuhn, BSN, RN1; Thomas White PharmD, BCPS1; George A. Diaz MD, PhD1 1iECURE, Inc., Blue Bell, PA; 2Great Ormond Street Hospital for Children, London, UK; 3Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO; 4David Geffen School of Medicine at UCLA, Los Angeles, CA; 5Icahn School of Medicine at Mount Sinai, New York, NY; 6Hospital Sant Joan de Déu, Barcelona, Spain ASGCT 2026, Boston, MA Disclosures • Gabriel M. Cohn, is an Employee of IECURE, INC. Ornithine Transcarbamylase Deficiency (OTCD): Neonatal & Post-Neonatal-Onset OTCD 3 - Neonatal-Onset OTCD Presents in the First Month of Life - Presentation in the First Week of Life is the Most Severe Form of OTCD 1 Ah Mew N, Simpson KL, Gropman AL, et al. Urea Cycle Disorders Overview. 2003 Apr 29 [Updated 2017 Jun 22]. In: Adam MP, 2 Brassier et al. Orphanet Journal of Rare Diseases. 2015 Ornithine Transcarbamylase Deficiency (OTCD) • XL condition: OTC gene (400+ unique pathogenic variants) • Deficiency in the liver enzyme, ornithine transcarbamylase, responsible for the detoxification of ammonia Outcomes • High ammonia levels can lead to lethargy, seizures, coma, death and neurodevelopmental delays among survivors • Hyperammonemic crisis (HACs): NH3 >100 umol/L & neurological status change Up to 74%2 1:56,5001 Hepatocytes OTCD Incidence Mortality Rates • Neonatal-onset OTCD is the most severe form of OTCD • Onset in the first week of life is the most severe form of neonatal-onset OTCD Management Of Neonatal-Onset OTCD 4 Goals of Treatment3-7 • Improve survival • Promote growth & development • Manage & prevent hyperammonemic Crisis (HACs): - HACs: Associated with mortality, neurocognitive & developmental deficits Acute Management3, 8 • Promotion of anabolism • Protein restriction diet • Ammonia lowering drugs (nitrogen scavengers) • Often extracorporeal detoxification Long-Term Management3, 4 • Low protein diet • Oral nitrogen-scavenging drugs • Essential amino acid supplementation Honeymoon Period4 • Infants are metabolically stable for some months due to rapid growth and high protein tolerance • As growth slows, patients begin experiencing breakthrough hyperammonemia & HACs on standard of care (SOC) management Liver Transplant (LTx)3,4,7,8 • Performed to prevent further HACs & neurodevelopmental deterioration 3Donovan K et al. Ornithine Transcarbamylase Deficiency. StatPearls [Internet]. 2026 4Lichter-Konecki U 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. 5Maestri NE et al.. Long-Term Treatment of Girls with Ornithine Transcarbamylase Deficiency. NEJM 335, (12), 1996: 855-860 6Kent JD and Holt RJ. Hyperammonemic crises in patients with urea cycle disorders on chronic nitrogen scavenger therapy with either sodium phenylbutyrate or glycerol phenylbutyrate. Neuropsychiatry . 2017;7(2):131–136. 7 EIMD: European Registry and network for intoxication type Metabolic Disease: Urea cycle disorders: Quick reference guide 8Garcia Vega M e al. Urea cycle disorders and indications for liver transplantation. Front. Pediatr. 11:1103757. doi: 10.3389/fped.2023.1103757 ECUR-506 Is Being Developed For The Treatment Of OTCD 5 - Safe Harbor, Variant-Agnostic, Gene Insertion Approach - Dual AAV Vectors: ARCUS Nuclease & OTC Donor Gene; Safe Harbor: PCSK9 Locus iECURE has licensed the ARCUS® nuclease from Precision BioSciences for four gene insertion programs including OTC, CTLN1 and PKU. 1 *OTC1 ASS2 * PAH3 The ARCUS® encoding vector targets the exon 7 of PCSK9 and can be combined with any donor vector containing disease relevant therapeutic genes for insertion into the same locus Nuclease Gene Cassette Donor Gene Cassette ECUR-506A ECUR-506D OTC-HOPE Clinical Trial Design (NCT06255782)* 6 - Patients 0 to 9 Months with Severe, Neonatal-Onset OTC Deficiency - Dose Escalation/Dose Finding Phase is Ongoing Trial Design • PH 1/2/3, global, multi-center trial, open label, FIH, adaptive, dose finding and dose confirmation study - Low Dose: 1.3x1013 GC/kg - Intermediate Dose: 2.4x1013 GC/kg - High Dose: 4.0x1013 GC/kg Intervention • One time, single IV infusion of ECUR-506 Study Duration • Pre-dose: (3 weeks - 9 months): Enrollment, Screening, Stabilization • Post-dose follow up: 6-months - 14.5-year long-term follow up study (NCT06805695) Primary Endpoints • Assessment of safety and tolerability of ECUR-506 • Efficacy: - Complete clinical response (CCR) by end of study o 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 Select Secondary & Clinical Endpoints** • Efficacy: - Incidence and number/p-y of HAC resulting in hospitalization (SAEs). o HAC is defined as plasma NH3 >100 μmol/L with associated neurological status changes **For a more complete listing of secondary and exploratory endpoints visit: https://clinicaltrials.gov/study/NCT06255782?cond=Ornithine%20Transcarbamylase%20Deficiency&term=iECURE&rank=2 *As of 20APR2026 OTC-HOPE Clinical Trial Dose Finding Phase* 7 - Dose Cohort Assessments are Ongoing - Preliminary Clinical Outcomes Analysis *As of 20APR2026 Descriptive Outcomes & Descriptive Statistics • Data cut date: 20APR2026 • Data source: Electronic data capture & safety reports • Data QC’d & discrepancies resolved Preliminary Safety Observations To Date • Generally, well tolerated, no thrombotic microangiopathy (TMA) • Asymptomatic, non-dose dependent, transient Grade 2-3 transaminitis, resolved with reactive immunosuppression (in 5 of 7 pts) • One death: Hypoxemic respiratory failure unrelated to ECUR-506 Preliminary Efficacy Observations Evaluated To Date • Incidence & annualized rate of HACs of all dosed participants (n=7): - Pre-ECUR-506 (Enrollment to the day of dosing) - Post-ECUR-506 (Dosing to end of study or to data cut date) • Primary efficacy endpoint evaluation (CCR): - To be performed once dosing in all three dose cohorts has been completed & all participants have completed their 6- month post-treatment evaluations HACs – Preliminary Observations* 8 - 71% (5 of 7) of Participants Have Experienced NO HACs Post ECUR-506 - 60% Risk Reduction in # of Participants Who Experience a HAC Post ECUR-506 *As of 20APR2026 71% HAC-Free Post ECUR-506 Before ECUR-506 SOC After ECUR-506 +/- SOC 0 1 2 3 4 5 6 7 8 Number of Participants with 0 Annualized HACs Preliminary Observations* 9 - 52% Risk Reduction in Annualized HAC Rate Following ECUR-506 *As of 20APR2026 Low 1 1 (87) 4.20 194 0 (165) 0 Low 2 0 (87) 0 140 0 (166) 0 Low 3 2 (86) 8.49 244 2 (169) 4.32 Intermediate 4 1 (126) 2.90 142 2 (164) 4.45 Intermediate 5 0 (120) 0 266 0 (138) 0 Intermediate 6 1 (65) 5.62 191 0 (103) 0 High 7 1 (130) 2.81 275 0 (76) 0 Totals 6 (701) 3.12 4 (981) 1.49 Dose Participant Pre-ECUR-506 (Enrollment to Dosing Day) (SOC) Annualized Rate ECUR-506 Post-ECUR-506 (+/- SOC) # HACs (Days Observed) Age at RX (Days) # HACs (Days Observed) Annualized Rate Summary & Conclusions Preliminary Clinical Observations* 10 *As of 20APR2026 Treatment Goal for Neonatal-Onset OTCD • Manage & prevent HACs which are associated with mortality, neurocognitive deficits, and the need for LTx • Honeymoon period: Initial metabolic control; as infant growth slows → breakthrough hyperammonemia on SOC → LTx OTC-HOPE Trial • Severe, neonatal OTCD • Dose escalation is ongoing • Safety & efficacy assessments are ongoing Preliminary Post-ECUR-506 Safety Observations • Generally, well tolerated • Transient, non-dose related, Grade 2-3 transaminitis managed with reactive immunosuppression • One death unrelated to ECUR-506 Preliminary Post-ECUR-506 Efficacy Observations • Post-ECUR-506 HACs (+/-SOC): - 71% (5 of 7) participants have experienced NO HACs following ECUR-506 administration - 52% risk reduction in annualized HAC rate following ECUR-506 administration The observed safety profile and reduction in HACs support the continued, ongoing evaluation of ECUR-506 Acknowledgements 11 iECURE has licensed the ARCUS® nuclease for ECUR-506 from Precision BioSciences. The technology and science behind iECURE’s genome editing approach was developed from early research done at the University of Pennsylvania’s Gene Therapy Program (GTP) led by Dr. James M. Wilson. Patients & Their Families

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