OTC-HOPE: The first in vivo, liver directed, AAV-mediated, gene insertion clinical trial in infants with Ornithine Transcarbamylase Deficiency

Figure 8: Mean Plasma NH3 Levels Figure 9: Mean BUN Levels 0.6 0.5 0.4 0.3 0.2 0.1 0 W8 W9 Phenylbutyrate (gm/kg) Figure 6: Participant Nitrogen Scavenger Dose BUN (mM/L) [0.7-5 mM/L] 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Treatment Stage Mean & SE 1.3 3.4 Pretreatment (Scavenger Monotherapy, Protein Restriction) (Pretreatment; n=4) Post-Liberalization (ECUR-506 Monotherapy, Protein Liberalized) (Wks 13-Mo 10; n=14) Acetyl-CoA + Glutamate AspartateCitrulline Arginine ArgininosuccinateOrnithine Urea Fumarate NH4 + +HCO3 - +2ATP Carbamyl Phosphate N-acetylglutamate Mitochondria NAGS CPS1 Cytosol OTC ASS1 ASLARG1 Figure 1: The Urea Cycle Figure 3: Participant Clinical Journey Phenylbutyrate (gm/kg) W9.5 W10 W11 W13W12 Figure 2: ECUR-506 Dual AAV Construct Figure 7: Protein Intake Pre and Post ECUR-506 Dosing LLN n = # samples evaluated ULN Reference rec. (g/kg/day)Prot rx (g/kg/day) 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0 Screening D-7 (1) D-7 D7 W4 W8 W12 W16 W20 W24 M7 M8 M9 Protein Intake (g/kg/day) M10 NH3 (uM/L) [0-40 uM/L] Phenylbutyrate Protein Restriction Phenylbutyrate Protein Restriction ECUR-506 ECUR-506 ECUR-506 45.0 40.0 35.0 30.0 25.0 20.0 15.0 10.0 5.0 0.0 Treatment Stage Mean & SE LLN n = # samples evaluated ULN 32.6 16.0 Pretreatment (Scavenger Rx Monotherapy, Protein Restriction) (Pretreatment; n=7) Post-Liberalization (ECUR-506 Monotherapy, Protein Liberalized) (Wks 13-Mo 10; n=15) Figure 4: Three Treatment Stages 15th 3rd 97th 50th 85th Figure 10: Weight-for-age Boys (Birth to 2 Years) Weight (kg) Age (completed months and years) 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 1 2 3 4 5 6 7 8 9 10 11 1 2 3 4 5 6 7 8 9 10 11 Birth 1yr. 2yrs. Figure 11: Length-for-age Boys (Birth to 2 Years) Length (cm) Age (completed months and years) 45 50 55 60 65 70 75 80 85 90 95 45 50 55 60 65 70 75 80 85 90 95 15th 3rd 97th 50th 85th 1 2 3 4 5 6 7 8 9 10 11 1 2 3 4 5 6 7 8 9 10 11 Birth 1yr. 2yrs. Dosed Dosed Screening Stab 1 D-7 (1) D-7(2) D-1 D7 D12/W2 W4 W5 W6 W7 W8 W10 W12 W14 W15 W16 W18 W20 W22 W24 M7 M8 M9 M10 900 800 700 600 500 400 300 Figure 5: Participant Glutamine Levels Plasma Glutamine (480-800 uM/L) Visit (pre-treatment and post-treatment weekly visits) GLN (480-800 uM/L) UL LLN OTC PCSK9 OTC INTRODUCTION Urea cycle disorders (UCDs) are a group of biochemical diseases caused by de/f_iciency of one of six enzymes necessary to convert toxic ammonia into urea. As a result, UCD patients are prone to developing hyperammonemia and progressive encephalopathy leading to lethargy, seizures, coma and/or death. Developmental delay is common among survivors. Ornithine transcarbamylase de/f_iciency (OTCD) is an X-linked disorder and the most common UCD with an incidence rate of 1:56,500./one.numerator Neonatal onset represents the most severe form of the disease with symptoms typically presenting in the /f_irst 48-72 hours of life. Management may include renal replacement therapy acutely, and nitrogen scavengers and protein restriction both acutely and long-term. Orthotopic liver transplantation is the only curative option. ECUR-506 is a liver-directed, investigational targeted gene insertion product being evaluated for the treatment of neonatal onset OTCD. The therapy comprises of two vectors, an ARCUS® (Precision BioSciences, Durham, NC) nuclease vector which encodes a meganuclease responsible for targeted gene editing of the well characterized PCSK9 gene locus and a donor vector that inserts the desired functional OTC gene. ARCUS® is a single component protein containing both a site-speci/f_ic DNA recognition interface and endonuclease activity. The nuclease vector and donor gene vector that comprise ECUR-506 are co-administered intravenously in a 1:3 ratio respectively. ECUR-506 is designed to allow for integration of the OTC transgene into exon 7 of the PCSK9 locus of the hepatocyte genome for long-term expression of OTC in transduced hepatocytes and their progeny. Mean ammonia levels remained within normal limits during the 6-month clinical trial and have remained within normal limits during LTFU (Figure 8). The participant remained off standard of care therapy (nitrogen scavenger + protein restriction) beginning at week 16 through the end of study visit (week 24) and into LTFU. The participant did not experience an HAC following treatment with ECUR-506. The subject has experienced consistent weight gain and remained above the 50th percentile for weight during the 6-month study and into LTFU . A reduction in glutamine levels in weeks 6 & 7 post-ECUR- 506 (Figure 5) prompted the weaning of nitrogen scavenger therapy starting week 8 post-ECUR-506. Discontinuation of nitrogen scavenger therapy was achieved 12 weeks post ECUR-506 administration (Figure 6). Ammonia and glutamine levels remained in normal range post discontinuation of nitrogen scavenger therapy which allowed for complete protein intake liberalization (Figure 7). 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 was the minimally effective dose identi/f_ied in a murine model of OTCD. Subsequent doses will be based on an assessment of the totality of the safety and efficacy data accumulating in the trial. A 14.5-year follow-up study will evaluate the long-term safety and efficacy of OTC-HOPE participants (ECUR-LTFU; NCT06805695). RESUL TS Prior to receiving ECUR-506, the /f_irst participant in the study experienced a hyperammonemic crisis (HAC) shortly after birth with ammonia levels reaching 16X ULN. The infant underwent dialysis and standard of care treatment was initiated. A known OTC pathogenic variant, c.77G>C (p.Arg26Pro), was identi/f_ied. The participant experienced a second HAC at 5.5 months of age. The participant underwent ECUR-506 (1.3 x 10/one.numerator/three.numerator GC/kg) infusion at 6.5 months of age. The infusion was generally well-tolerated. Four weeks post dose, the participant experienced Grade 3 asymptomatic transaminitis which resolved over the ensuing four weeks following the addition of immunosuppressive therapy. CONCLUSION These are data from the /f_irst infant to undergo in vivo, liver directed, AAV-mediated gene insertion and to complete the OTC-HOPE clinical trial. The observed increase in BUN along with normal mean ammonia levels and increased protein intake following ECUR-506 administration in conjunction with scavenger medication discontinuation are suggestive of increased nitrogen /f_lux through the urea cycle and restoration of at least partial functional hepatic OTC enzyme activity. As protocol de/f_ined, complete clinical response was observed, continued evaluation of the low dose of ECUR-506 (1.3 x1013 GC/kg) in the OTC-HOPE study has been supported by the Data Monitoring Committee. REFERENCES 1. Ah Mew N, Simpson KL, Gropman AL, et al. Urea Cycle Disorders Overview. 2003 Apr 29 [Updated 2017 Jun 22]. In: Adam MP , Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm. nih.gov/books/NBK1217/ After birth, developed symptomatic encephalopathy with ammonia levels of 16x ULN (HAC#1). Underwent dialysis to manage hyperammonemia and was transitioned to oral treatment and placed on a protein restricted diet. OTC pathogenic variant c.77G>C (Arg26Pro) identi/f_ied. Experienced HACs at 5.5 months of age Grade 3 transaminitis, ALT 3-5x ULN, prompting Safety Review Team (SRT), voluntary Clinical Halt, and DMC meeting. Treated with oral and IV corticosteroid and tacrolimus, hospitalized for monitoring (Grade 3, SUSAR). Liver biopsy showed acute in/f_lammation with T lymphocyte in/f_iltration. Infusion at 6.5 months of age was generally well tolerated. Normal plasma ammonia concentrations. Increased blood urea nitrogen (BUN). Stable protein intake, and consistent weight gain. Reduced plasma glutamine levels below LLN. Tapering of daily scavenger medicine dose completed. Remained clinically stable. Normal plasma ammonia concentrations. Discontinued corticosteroids and weaning tacrolimus. Normal blood urea nitrogen (BUN). Increased protein intake, and consistent weight gain. Normal plasma glutamine levels. Remained clinically stable. Normal plasma ammonia concentrations Weaning tacrolimus Normal blood urea nitrogen (BUN). Unrestricted protein intake, and consistent weight gain. Normal plasma glutamine levels. Remains clinically stable. Completed Ph1/2 Study. Normal plasma ammonia concentrations. Discontinued tacrolimus. Normal blood urea nitrogen (BUN). Unrestricted protein intake, and consistent weight gain. Normal plasma glutamine levels. Remains clinically stable. Pre Dose Weeks 4-8Day 1 Dosing Weeks 12-16 Weeks 16-24 Months 7-10Weeks 8-12 Julien Baruteau; Gabriel Cohn; Anil Dhawan; Anupam Chakrapani; Stephanie Grunewald; Molly Abbott; Helen Ashton; Sophie Foxall; Ai-Ling Koh; Christos Lazaridis; Havea Navarro-Kennedy; Hamza Patel; Siyaminji Sivananthan; Eleni Tamvaki; Katy Vecchiato; Matthew Hall; Karen Kuhn; Thomas White; Barbara Pinho; George A. Diaz Initial clinical results from OTC-HOPE, the /f_irst in vivo, liver directed, AAV-mediated gene insertion study in neonatal OTC de/f_iciency; complete clinical response observed in /f_irst male infant to receive ECUR-506: 10-month data Despite being administered corticosteroids, which have been known to induce hyperammonemia in UCD participants, ammonia and glutamine levels remained controlled during this time. Serum PCSK9 levels decreased by 37% at 24 weeks compared to baseline, suggesting editing within the PCSK9 gene. Current data and observations are indicative of enhanced urea cycle activity, suggestive of investigational product activity. Participant 1 History: The male infant was born to a family with no prior history of OTCD. Participant received ECUR-506 at 6.5 months of age. ECUR-LTFU

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