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

1- iECURE, Inc., Blue Bell, PA; 2- Great Ormond Street Hospital for Children, London, UK; 3- Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO; 4- David Geffen School of Medicine at UCLA, Los Angeles, CA; 5- Icahn School of Medicine at Mount Sinai, New York, NY; 6- Hospital Sant Joan de Déu, Barcelona, Spain Gabriel M Cohn 1; Julien Baruteau 2; Shawn E. McCandless 3; Gerald S. Lipshutz 4; Margo Sheck Breilyn 5; Ángeles García-Cazorla 6; Matthew Hall 1; Karen Kuhn 1; Thomas White 1; George A. Diaz 1 DECREASED RATE OF HYPERAMMONEMIC CRISES IN INFANTS WITH NEONATAL-ONSET OTC DEFICIENCY POST ECUR-506 ADMINISTRATION: PRELIMINARY UPDATE FROM THE OTC-HOPE STUDY . Preliminary safety observations are provided for all dose cohorts, even as they continue to undergo safety and efficacy evaluations. ECUR-506 was generally well tolerated across all dose cohorts. • No unexpected safety events • No infusion reactions • No cases of thrombotic microangiopathy (TMA) • Asymptomatic transaminitis (Grade 2-3) in 5/7 participants • Effectively managed with reactive immunosuppression (IS) • No recurrence following IS taper • One death (intermediate dose cohort) deemed unrelated to study drug PRELIMINARY SAFETY OBSERVATIONS Seven infants with neonatal-onset OTCD have been dosed across three dose levels (low, intermediate, and high). The low-dose cohort (n=3) has completed the 6-month study, while intermediate (n=3) and high-dose (n=1) cohort assessments are ongoing. Enrollment and dosing for the high-dose cohort is ongoing (Table 1). ADDITIONAL PARTICIPANT DOSING Plasma ammonia levels have generally remained within the normal reference range (0–40 /uni03BCmol/L) throughout the entirety of post-ECUR-506 dosing (Fig. 7), including during a febrile viral illness, which is historically associated with metabolic decompensation and risk for hyperammonemic crisis in neonatal-onset OTCD. The described sustained clinical response in absence of SoC in the /f_irst participant has not been previously reported in patients with neonatal-onset OTCD. Table 1: Participant Baseline Characteristics Low Dose 840 c.77G>C p.(Arg26Pro) Low Dose 2106 ChrX(GRCh38):g.38401291G>C Low Dose 1600 c.533C>T p.(Thr178Met) Intermediate Dose 1238 c.890A>C p.(Asp297Ala) Intermediate Dose 2750 c.986A>G p.(Asn329Ser) Intermediate Dose 1542 c.274C>T p.(Arg92Ter) High Dose 2800 c.299-2A>G Cohort Peak Plasma NH3 OTC Variant (µmol/L) Figure 7: Plasma NH 3 Timeline ULN LLN NH3 (0-40 um/L) NH3 Visit 0 20 40 60 80 100 (umol/L) 120 ScreenStabStabSAEStabD-7D-2D-1 D1 D7 W2 W3 W4 W5 W6 W7 W8W10W12W13W14W15W16W18W19W19.5W20W22W24Unsch M7 M8 M9M10M11M12M15M18 Plasma NH 3(0-40 um/L) Across all dose cohorts, ECUR-506 treatment was associated with a 52% reduction in the annualized HAC rate compared with the pre-treatment period on standard of care. The overall annualized HAC rate decreased from 3.12 events/year pre-treatment to 1.49 events/year post-treatment, supporting the potential of ECUR-506 to reduce disease burden in neonatal-onset OTCD (Table 2). A statistical analysis was conducted on the clinically relevant measures of HAEs and HACs in the low dose cohort which has completed the OTC-HOPE study (Table 3). Breakthrough HAEs and HACs that may have occurred prior to enrollment were not captured. The presenting hyperammonemia was excluded from analysis as SoC was not initiated. Post OTC-HOPE enrollment and prior to dosing, 6 breakthrough HAEs and 3 HACs occurred, corresponding to an annualized rate of 8.43 and 4.21 breakthrough HAEs and HACs per year, respectively. ECUR-506 treatment was associated with a reduction in HAE and HAC events to 5 and 2, respectively, yielding annualized HAE and HAC rates of 3.65 and 1.46, respectively, corresponding to a risk reduction of 57% and 65%. The observed rate changes were statistically signi/f_icant (p=0.0181 and 0.0111 respectively). Two of 3 participants in the low dose cohorts experienced no HAEs or HACs post treatment. The participant with post-dose events had a reduction in annualized rates of HAC (8.49 to 4.32) and HAEs (16.98 to 10.80). Participant 1 was removed from the transplant waiting list and participant 3 went on to liver transplant during ECUR-LTFU. Preliminary data from the OTC-HOPE study demonstrated a clinically meaningful reduction in HACs following ECUR-506 administration. Post-treatment, 71% (5/7) of participants remained HAC-free, compared with 29% (2/7) prior to treatment on standard of care alone, representing a 60% reduction in the number of participants experiencing HACs (Fig. 8). Breakthrough HACs that may have occurred prior to enrollment were not captured. The presenting hyperammonemia was excluded from analysis as SoC was not initiated. PRELIMINARY EFFICACY OBSERVATIONS CONCLUSION: Neonatal-onset OTCD is a life-threatening condition in which breakthrough HAEs and HACs occur despite standard of care, contributing to signi/f_icant morbidity and mortality. In this highly vulnerable population, ECUR-506 demonstrated an encouraging safety pro/f_ile and preliminary evidence of clinical efficacy. We report here the observations of a durable clinical response in the /f_irst participant dosed at the low dose level and statistically signi/f_icant reductions in HAEs and HACs in the low dose cohort that has completed the OTC-HOPE study. While a limitation of these /f_indings include a small sample size, they support early proof of concept and continued evaluation in the ongoing study. HAC/HAE events were captured from electronic data capture and adverse event reports to generate HAC rates. Rate ratios, CIs, and p-values were calculated using generalized estimating equations with correlated count data. For groups with 0 events in the post-dose period, a conditional exact test was used. P-values are for one-sided tests (signi/f_icance levels = 0.025). Table 3: Pre- and Post-Dose HAE and HAC Analysis in Low Dose Cohort Endpoint Period Statistic Low Dose Level Pre Dose Number of Events 6 Number of Person-Years 0.712 Rate 8.43 Post Dose Number of Events 5 Number of Person-Years 1.369 Rate 3.65 Rate Ratio vs Pre Dose 0.43 95% CI 0.20, 0.95 p-value 0.0181 Pre Dose Number of Events 3 Number of Person-Years 0.712 Rate 4.21 Post Dose Number of Events 2 Number of Person-Years 1.369 Rate 1.46 Rate Ratio vs Pre Dose 0.35 95% CI 0.14, 0.86 p-value 0.0111 CI, con/f_idence interval; HAC, hyperammonemic crisis; HAE, hyperammonemic episode (N=3) HAE HAC INTRODUCTION Neonatal-onset ornithine transcarbamylase de/f_iciency (OTCD) is an X-linked urea cycle disorder characterized by hyperammonemia due to impaired OTC activity. Recurrent hyperammonemic events (HAEs; NH3 >100 umol/L) and hyperammonemic crises (HACs; NH3 >100 umol/L with neurologic status change) may occur despite standard-of-care (SoC) management with protein restriction and nitrogen scavengers. HACs are associated with irreversible neurologic injury and can progress to coma and/or death. Metabolic instability, as indicated by recurrent HACs, is a key driver for liver transplantation. Traditional gene addition approaches using adeno-associated virus (AAV) to treat murine OTCD models in infancy have shown limited success due to hepatocyte proliferation-associated episomal dilution. Genome editing (Fig. 1), speci/f_ically targeted gene insertion, offers a promising alternative with the potential for durable clinical response. RESUL TS The /f_irst participant presented at six days of age with plasma ammonia of 840 /uni03BCmol/L, consistent with severe neonatal-onset OTCD. Acute metabolic stabilization required hemodialysis alongside initiation of nitrogen scavenger therapy and dietary protein restriction. A second HAC occurred at /f_ive and a half months of age. The participant received ECUR-506 at 6.5 months of age and the infusion was generally, well tolerated. A grade 3 elevation in alanine aminotransferase (ALT) occurred at week 4 post-dose (ALT 3× ULN) and resolved with a reactive immunosuppression protocol without subsequent elevations (Fig. 3). ECUR-506 (Fig. 2) is an in vivo, liver-directed, investigational genome editing product being developed for the treatment of neonatal-onset OTCD. ECUR-506 is a one-time intravenous therapy comprised of two populations of AAVrh79 delivering either a meganuclease, M2PCSK9, targeting the PCSK9 gene, or a codon-optimized OTC donor gene. Co-expression of these cassettes permits OTC transgene integration into the hepatocyte genome. METHODS OTC-HOPE (NCT06255782) is a 24-week, /f_irst in human, single arm, open-label, global, multi-center trial designed to assess the safety and efficacy of ECUR-506 in male participants with genetically con/f_irmed neonatal-onset OTCD who are <9 months of age and 3.5 kg to 13.5 kg at the time of dosing. Dose levels were informed by nonclinical studies. The initial dose in the OTC-HOPE trial (1.3 x 1013 gc/kg) was the minimally effective dose in a murine model of OTCD. Subsequent dose escalations to intermediate (2.4 x 1013 gc/kg) and high dose (4.0 x 1013 gc/kg) levels were based on an assessment of the totality of the accumulated safety and efficacy data. A 14.5-year follow-up study will evaluate the long-term safety and efficacy of OTC-HOPE participants (ECUR-LTFU; NCT06805695). LTFU data from the /f_irst participant dosed (data cut 11FEB2026) and from the /f_irst cohort to complete dosing and end of study visits (data cut 20APR2026) are shared herein. • Designed to address the underlying genetic cause of disease • Potential for durable gene integration • Variant-agnostic Figure 2: ECUR-506 Mechanism of Action Functional Protein Gene Insertion Safe Harbor Functional Gene Durable gene integration Variant-agnostic T T G A A C Functional Protein Durable More versatile, but still limited to select variants Prime Editing Prime Editor Complex VariantC C A A A C Durability issues in tissue with high cellular turnover Variant-agnostic Gene Addition Functional Gene Functional Protein Variant Functional Protein Base Editor Enzyme A Variant C Durable Limited to single nucleotide variant Base Editing G C Nuclease Figure 1: Gene Addition and Genome Editing Approaches Serum urea increased by Day 10 post-dose and has been maintained within the normal reference range throughout follow-up, consistent with increased ureagenesis (Fig. 6). Figure 6: Serum Urea Timeline ULN LLN Urea (0.7-5 mM/L) Blood Urea Nitrogen Visit 0 1 2 3 4 5 7 (mmol/L) 6 Screen Stab 1 Stab 2 D-7 (1) SAE D-7 (2) D-2 D-1 D-1 D-2 D-3 D-4 D-5 D-6 D-7 D-10 W2 W3 W4 Unsch 1 HospD1 Hosp1’ HospD2 HospD3 HospD4 HospD5 W4+6 W5 W5+1 W5+2 W5+4 W5+5 W5+6 W6 HospD6 W6+2 W6+3 W6+4 W6+6 W7 W7+1 W7+4 W7+5 W7+6 W8 W8+3 W8+6 W9+2 W9+6 W10 W12 W13 W14 W15 W16 W18 W19 W20 W22 W24 M6+2W M7 M8 M9 M10 M11 M12 M15 M18 M21 PT301-001 Serum Urea (0.7-5 mmol/L) Following scavenger discontinuation, dietary protein intake was progressively liberalized. Sustained age-appropriate protein intake was achieved with no biochemical or clinical evidence of hyperammonemia (Fig. 5). At 18 months post-dose, no episodes of hyperammonemia have been triggered by dietary challenge or intercurrent illness. Plasma glutamine declined below the lower limit of normal between Weeks 6–8 post-dosing, despite ongoing high-dose corticosteroid administration for the transaminitis episode. Weaning of nitrogen scavenger was initiated and completed at Week 13 post-dose (Fig. 4). Figure 5: Dietary Protein Intake Timeline Reference Rec. (g/kg/day) Protein (g/kg/day) Protein Intake Visit 0.0 0.5 1.0 1.5 2.0 2.5 3.5 4.0 3.0 (g/kg/day) Screen Stab D-7 W4 W9 W9.5 W8 W12 W16 W20 W24 M7 M8 M9 M10 M11 M12 M15 M18 PT301-001 Protein Intake (g/kg/day) Week 6 Steroid Dose Escalation IV methylprednisolone increased to 10mg/kg and liver biopsy Week 4 ALT 3x ULN Admitted; IV methylprednisolone initiated at 5mg/kg Weeks 12-23 Tacrolimus Wean Tacrolimus taper completed; immunosuppression discontinue Weeks 8-14 Steroid Wean Corticosteroid taper completed successfully Week 7 Transition Converted to oral prednisone (10 mg/kg); tacrolimus initiated at 0.5 mg/kg/day Weeks WeeksWeek WeekWeek 4 6 12-23 7 8-14 a. b. 1.5X ULN A L TA S T xULN D-1 W3 W5 W7 W10 W13 W15 W18 W22 M7 M9 M11 M15Screen D7 W4D-7 W6 W8 W12 W14 W16 W20 W24 M8 M10 M12 W18 PT301-001 Transaminase Levels (x ULN) 0 1 2 3 4 5 6 Visit Figure 3: Timelines for: b. Immunomodulation a. Transaminase a. b. PB High PB Low Phenylbutyrate Scavenger Dose Visit 0 100 200 300 400 500 700 (mg/kg/day) 600 D-1 W3 W5 W7 W10 W13 W15 W18 W22 M7 M9 M11 M15Screen D7 W4D-7 W6 W8 W12 W14 W16 W20 W24 M8 M10 M12 W18 PT301-001 Scavenger Dose U L N L L N G L N (umol/L) Plasma GLN Visit 300 400 500 600 700 800 900 (umol/L) D-1 W3 W5 W7 W10 W13 W15 W18 W22 M7 M9 M11 M15Screen D7 W4D-7 W6 W8 W12 W14 W16 W20 W24 M8 M10 M12 W18 PT301-001 Plasma Glutamine (480-800 umol/L) Figure 4: Timelines for: b. Glycerol phenylbutyrate a. Plasma Glutamine Table 2: HAC Preliminary Observations Low Dose 1 1 (87) 4.20 194 0 (165) 0 Low Dose 2 0 (87) 0 140 0 (166) 0 Low Dose 3 2 (86) 8.49 244 2 (169) 4.32 Intermediate Dose 4 1 (126) 2.90 142 2 (164) 4.45 Intermediate Dose 5 0 (120) 0 266 0 (138) 0 Intermediate Dose 6 1 (65) 5.62 191 0 (103) 0 High Dose 7 1 (130) 2.81 275 0 (76) 0 TOTALS 6 (701) 3.12 4 (981) 1.49 Dose Participant (Enrolled to Dosing Day)(SOC) Pre-ECUR-506 (±SOC) Post-ECUR-506ECUR-506 #HACs (Days Observed) Age at RX (Days) #HACs (Days Observed) Annualized Rate Annualized Rate 52% Risk Reduction in Annualized HAC Rate Following ECUR-506 Figure 8: HAC Preliminary Observations 0 1 2 3 4 5 7 6 Number of Participants with 0 Annualized HACs 71% HAC-Free Post ECUR-506 After ECURE-506 ± SOC Before ECUR-506 SOC 60% Risk Reduction in # of Participants Who Experienced a HAC Post ECUR-506

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