Arcturus Therapeutics Holdings Inc. · NASDAQ:ARCT

Arcturus Therapeutics — Technical Presentation (June 2025)

42 slides from Arcturus Therapeutics's technical presentation, Jun 30, 2025

  1. Slide 1: KOL Presentation ARCT-810

    KOL PRESENTATION ARCT-810 June 30, 2025

  2. Slide 2: Forward Looking Statements

    Forward Looking Statements This presentation contains forward-looking statements. These statements relate to future events and In some cases, you can identify forward-looking statements by terms such involve known and unknown risks, uncertainties and other factors which may cause our actual results,

  3. Slide 3: Arcturus Therapeutics

    Arcturus Therapeutics Global mRNA Medicines Company Nasdaq: ARCT mRNA Medicine Candidates KOSTAIVE® Approved in Japan & EU Headquarters: San Diego, CA ARCT-810 Ornithine Transcarbamylase Deficiency Founded: 2013 ARCT-032 Cystic Fibrosis Arcturus is a commercial mRNA medicines company with a pipeline

  4. Slide 4: Ornithine Transcarbamylase (OTC) Deficiency

    Ornithine Transcarbamylase (OTC) Deficiency The most common ARCT-810 Aims to Restore Unmet Medical Need urea cycle disorder OTC Enzyme Function 10,000 prevalence in U.S./Europe Present standard of care Establishing expression of OTC involves a strict diet (low protein, enzyme in liver has potential

  5. Slide 5: ARCT-810: mRNA Rx to treat OTC Deficiency

    ARCT-810: mRNA Rx to treat OTC Deficiency ARCT-810 utilizes Arcturus’ proprietary LUNAR® delivery technology and has potential to be the first and best-in-class mRNA therapeutic to treat OTC Deficiency © 2025 Arcturus Therapeutics, Inc. 5

  6. Slide 6: ARCT-810: Regulatory Achievements

    ARCT-810: Regulatory Achievements Orphan Drug Designation (FDA) • 26 June 2019 Orphan Medicinal Product Designation (EMA) • 18 Jul 2022 Fast Track Designation (FDA) • 30 May 2023 Rare Pediatric Disease Designation (FDA) • 01 June 2023 • Potential for Priority Review Voucher (PRV) Pediatric Investiga

  7. Slide 7: ARCT-810: European and U.S. Phase 2 Trials

    ARCT-810: European and U.S. Phase 2 Trials Objectives • Establish safety and tolerability in OTC deficient adolescents and adults • Evaluate biomarker responses – glutamine, ureagenesis, ammonia European Phase 2 Study – Completed (N = 8; 6 ARCT-810 / 2 placebo) • Randomized, placebo-controlled • 0.3

  8. Slide 8: Glutamine Normalization Following ARCT-810 Administration

    Glutamine Normalization Following ARCT-810 Administration Glutamine normal values range from ~400 to 800 umol/L Phase 2 (EU - 6 dose) Phase 2 (US - 5 dose) (Interim) 1000 1300 1200 900 Mean Glutamine (umol/L) Glutamine Normal Range 1100 Glutamine (umol/L) 800 1000 Final Dose Day 71 900 Final Dose Da

  9. Slide 9: ARCT-810 Significantly Reduces Glutamine Levels

    ARCT-810 Significantly Reduces Glutamine Levels Combined Analysis of Both Phase 2 Studies • Mean glutamine levels decreased significantly (N = 8, p-value = 0.0055) Phase 2 Randomized European Study • Mean glutamine levels decreased significantly (N = 5a, p-value = 0.016) Phase 2 Open-label U.S. Stud

  10. Slide 10: 15N-Ureagenesis Assay: Background

    15N-Ureagenesis Assay: Background New 15N-Ureagenesis Assay published in 2025 (Allegri, et al.) - Measures relative ureagenesis function (RUF) - Less variable than the 13C-Ureagenesis Assay - Low intra-subject variability - Not impacted by ammonia scavengers - Asymptomatic patients have RUF > 50% Ar

  11. Slide 11: ARCT-810 Significantly Increases 15N-Ureagenesis

    ARCT-810 Significantly Increases 15N-Ureagenesis Interim Phase 2 Data U.S. Open Label Study (N = 3): Mean RUF increased +14.7% from baseline to 28 days post-fifth dose -- from 29.0% (SD 9.1%) to 43.7% (SD 21.7%) Mean RUF increase is statistically significant -- p-value = 0.026, LMM analysis Two of t

  12. Slide 12: ARCT-810: Ammonia Stable and Within Normal Range

    ARCT-810: Ammonia Stable and Within Normal Range Phase 2 (Europe) Interim Phase 2 (U.S.) 120 120 Mean Ammonia (umol/L) Mean Ammonia (umol/L) Hyperammonemia ≥100 μmol/L Hyperammonemia ≥100 μmol/L 100 100 80 REF ≤72 μmol/L 80 REF ≤72 μmol/L 60 60 40 40 20 20 0 0 1 15 29 43 57 71 85 1 15 29 43 57 71 85

  13. Slide 13: ARCT-810: Safety and Tolerability

    ARCT-810: Safety and Tolerability • ARCT-810 was generally safe and well-tolerated in single dose Phase 1/1b and multi-dose Phase 2 studies, comprising 40 participants to date, including 20 OTC deficient participants • 9 OTCD subjects received multiple doses of ARCT-810 (up to 6 administrations) • P

  14. Slide 14: Introduction of KOLs

    Introduction of KOLs Dr. Marshall Summar Dr. Johannes Häberle © 2025 Arcturus Therapeutics, Inc. 14

  15. Slide 15: Glutamine Trends and Ureagenesis in Urea Cycle Patients with OTC Deficiency

    Glutamine Trends and Ureagenesis in Urea Cycle Patients with OTC Deficiency Treated with mRNA Therapy Biochemical Findings from European Phase 2 Randomized Study (Study 03) and U.S. Phase 2 Open-Label Study (Study 04) Prepared by Marshall Summar, MD 15

  16. Slide 16: Marshall L. Summar, MD

    Marshall L. Summar, MD Urea Cycle Disorder Experience • Internationally recognized expert in urea cycle disorders (UCDs) with over four decades of clinical, research, and policy leadership • Founding member and Executive Committee member of the NIH UCD Consortium; led national UCD diagnostic and tre

  17. Slide 17: Urea Cycle & OTC Overview

    Urea Cycle & OTC Overview • Urea Cycle is human pathway for clearing nitrogen as well as producing some essential biomolecules. Defects are referred to as Urea Cycle Disorders (UCDs) • Ornithine Transcarbamylase Deficiency (OTCD) is the most common defect as it is located on the X chromosome. • Rest

  18. Slide 18: Why Focus on Glutamine

    WHY FOCUS ON GLUTAMINE In addition to the toxicity from the spillover into ammonia, glutamine has its own toxicity resulting in: • Astrocytic Swelling and Edema • Mitochondrial Dysfunction • Microglial Apoptosis • NO/cGMP Pathway Interference 18

  19. Slide 19: Rationale for Using Glutamine and Ureagenesis for Efficacy

    Rationale for Using Glutamine and Ureagenesis for Efficacy in OTC mRNA Therapy • Glutamine rises earlier than ammonia in OTC deficiency, reflecting nitrogen load before crisis onset • Serves as a nitrogen buffer, offering a more stable indicator of urea cycle stress than ammonia. Used as routine cli

  20. Slide 20: Goal of this study

    Goal of this study • Hypothesis: infusion of a lipid nanoparticle containing OTC mRNA targeted at the liver will restore sufficient function to the urea cycle to affect the glutamine plasma levels and ureagenesis function that are relevant to patient health and cycle function. • Our hypothesis teste

  21. Slide 21: Methods

    Methods • Patients with molecular or enzymatic test proven OTC deficiency stable on some form of standard therapy. • Patients on stable diet and therapy for the month preceding onset of study. • 03 Study glutamine measured at Days: Base, d2, d3, d71, d72, d73. Values past 21 days last dose not used

  22. Slide 22: Statistical Methods for Glutamine

    Statistical Methods for Glutamine: Glutamine Analysis (measured by standard laboratory amino acid analysis) Chi-Square Test (Slope Direction): For each patient, we computed the trend of glutamine over time (linear slope from baseline). We then categorized each patient’s slope as negative (downward)

  23. Slide 23: Slope Calculation

    Slope Calculation: For each patient, we performed a simple linear regression of glutamine (µmol/L) vs. Visit Day to estimate the time trend (slope). A negative slope indicates a downward trend in glutamine over time. Study 03: European Phase 2 Study 04: U.S. Phase 2 23

  24. Slide 24: Chi Square Analysis: Was the slope of glutamine randomly negative or not

    Chi Square Analysis: Was the slope of glutamine randomly negative or not Observed Expected Chi-Square One-Tailed p- Analysis (Decreasing, (Decreasing, Statistic value Non-Decreasing) Non-Decreasing) Study 3 (4, 1) (2.5, 2.5) 1.8 0.090 Study 4 (3, 0) (1.5, 1.5) 3.0 0.042 Combined (7, 1) (4, 4) 4.5 0.

  25. Slide 25: Linear Mixed Model (LMM) Analysis

    Linear Mixed Model (LMM) Analysis Model Specification: We fitted a linear mixed-effects model to glutamine vs. visit day, with Visit Day as a fixed effect and Patient as a random intercept. This accounts for repeated measures per patient. Multiple sensitivity tests did not change the outcome. Number

  26. Slide 26: 15N-Ureagenesis Data

    15N-Ureagenesis Data Participant/Dose Day Base Day 36 Day 60 Day 71 Day 85 101-002 21.4 11.0 28.6 8.7 19.7 (0.5 mg/kg) 101-003 26.7 39.6 36.8 55.4 49.4 (0.3 mg/kg) 101-004 39.0 50.2 40.0 57.7 61.9 (0.5 mg/kg) Mean (SD) 29.0 (9.1) 33.6 (20.3) 35.1 (5.9) 40.6 (27.6) 43.7 (21.7) • The positive coeffici

  27. Slide 27: Urea Cycle Function Improvement Supported by Reduction in Glutamine and Increased 15N-Ureagenesis

    Urea Cycle Function Improvement Supported by Robust Reduction in Glutamine Levels and Increased 15N-Ureagenesis Both European Phase 2 randomized study (Study 03) and U.S. Phase 2 open-label study (Study 04) demonstrate a robust reduction in plasma glutamine levels during the treatment window with in

  28. Slide 28: Johannes Häberle Biosketch

    Johannes Häberle Division of Metabolism and Children’s Research Center University Children‘s Hospital Zurich, Switzerland BIOSKETCH 2002 Board Certification in Pediatrics 2004 Certification in Neonatology 2008 Certification in Intensive Care 2008 – present Consultant in Pediatric Metabolic Medicine,

  29. Slide 29: The urea cycle: pathway for ammonia removal

    The urea cycle: pathway for ammonia removal Produced with biorender.com 29 OTC: ornithine transcarbamylase

  30. Slide 30: The usual diagnostic toolbox for OTC deficiency

    The usual diagnostic toolbox for OTC deficiency … • Ammonia in blood • Glutamine in blood Produced with biorender.com X 30 OTC: ornithine transcarbamylase

  31. Slide 31: The usual diagnostic toolbox for OTC deficiency

    The usual diagnostic toolbox for OTC deficiency … • Ammonia in blood • Glutamine in blood Produced with biorender.com X … benefits from functional studies measuring the total urea cycle flux Ureagenesis assay 31 OTC: ornithine transcarbamylase

  32. Slide 32: Ureagenesis – factsheet published methods & tracers

    Ureagenesis – factsheet published methods & tracers [15N]H4Cl [1-13C] or [1,2-13C] acetate (Yudkoff M, J Clin Invest, 1996; (Tuchman M, Pediatr Res, 2008; Allegri G, Metab Health Dis, 2025) Opladen T, Mol Genet Med, 2016) Safety concerns Patients prone to  NH3 Safe Taste Unpleasant (but little amou

  33. Slide 33: The principle of ureagenesis quantification

    The principle of ureagenesis quantification Glutamine NATURAL 15NH Cl HCO-3 + 15NH SOURCE 4 3 TRACER LC-HRMS Carbamoyl Citrulline Phosphate Ornithine Urea UREA Argininosuccinate CYCLE 61 g/mol 60 g/mol Arginine Allegri G et al, Clin Chim Acta, 2017 Allegri G et al, J Inher Metab Dis, 2019 33 Allegri

  34. Slide 34: Characterization and treatment monitoring of ureagenesis disorders using stable isotopes

    npj | metabolic health and disease Article 8 https://doi.org/10.1038/s44324-025-00051-8 Characterization and treatment monitoring of ureagenesis disorders using stable isotopes ® Check for updates Gabriella Allegri", Martin Poms”, Nadia Ziircher', Véronique Riifenacht’, Nicole Rimann’, Déborah Mathi

  35. Slide 35: RUF according to severity and presence or absence of symptoms

    RUF according to severity and presence or absence of symptoms RUF: relative ureagenesis function Sympt: symptomatic patients Asympt: asymptomatic patients diagnosed through family screening CTRL: controls Allegri et al, Metab Health Dis, 2025 35

  36. Slide 36: [15N]urea enrichment for OTCD females ± symptoms and controls

    [15N]urea enrichment for OTCD females ± symptoms and controls CTRL: 39 investigations in 23 healthy subjects OTCD_F_SYMPT: 10 symptomatic females OTCD_F_ASYMPT: 8 asymptomatic females 36 Allegri et al, Metab Health Dis, 2025

  37. Slide 37: [15N]urea enrichment in patients from ARCT-810 U.S. Phase 2 study

    [15N]urea enrichment in 3 patients from ARCT-810 U.S. Phase 2 study Patient 002 Patient 003 Patient 004 RUF RUF RUF controls 78.0 – 122.0% 78.0 – 122.0% 78.0 – 122.0% baseline 21.4% 26.7% 39.0% day 36; 7 days post 3rd dose 11.0% 39.6% 50.2% day 60; 3 days post 5th dose 28.6% 36.8% 40.0% day 71; 14 d

  38. Slide 38: [15N]urea enrichment in patients from ARCT-810 U.S. Phase 2 study

    [15N]urea enrichment in 3 patients from ARCT-810 U.S. Phase 2 study Patient 002 Patient 003 Patient 004 RUF RUF RUF controls 78.0 – 122.0% 78.0 – 122.0% 78.0 – 122.0% baseline 21.4% 26.7% 39.0% day 36; 7 days post 3rd dose 11.0% 39.6% 50.2% day 60; 3 days post 5th dose 28.6% 36.8% 40.0% day 71; 14 d

  39. Slide 39: Closing Comments

    Closing Comments © 2025 Arcturus Therapeutics, Inc. 39

  40. Slide 40: ARCT-810: Summary of Phase 2 Interim Data

    ARCT-810: Summary of Phase 2 Interim Data • Significant and consistent reduction in glutamine levels in both Phase 2 studies – from abnormal to normal levels • Significant increase in 15N-ureagenesis in the U.S. Phase 2 study – additional evidence of urea cycle improvement • Ammonia – stable and wit

  41. Slide 41: Q & A

    Q&A © 2025 Arcturus Therapeutics, Inc. 41

  42. Slide 42: KOL Presentation ARCT-810

    KOL PRESENTATION ARCT-810 June 30, 2025

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