Summary of Arcturus Therapeutics KOL Presentation on ARCT-810 Phase II Interim Data for OTC Deficiency Company Overview - **Company**: Arcturus Therapeutics - **Headquarters**: San Diego - **Focus**: mRNA medicines, specifically targeting rare liver diseases like ornithine transcarbamylase (OTC) deficiency [5][6] Industry Context - **Industry**: Biotechnology, specifically in the development of mRNA therapeutics for rare diseases - **Condition**: OTC deficiency is the most common urea cycle disorder with significant unmet medical needs [6][7] Key Points from the Presentation 1. **ARCT-810 Overview**: - ARCT-810 is an mRNA therapeutic designed to replace dysfunctional OTC enzymes, improving urea cycle activity, detoxifying ammonia, and potentially eliminating the need for liver transplants [6][7][8] - It utilizes Arcturus' proprietary lunar delivery platform for effective delivery to hepatocytes [7] 2. **Regulatory Designations**: - ARCT-810 has received multiple designations: orphan drug designation, orphan medicinal product designation, fast track designation, and rare pediatric disease designation [8] 3. **Phase II Study Design**: - Two Phase II studies were conducted: one in the US and one in Europe, focusing on safety, tolerability, and biomarker assessments [11][12] - The US study enrolled patients with more severe disease, while the European study included patients with stable disease [12] 4. **Biomarker Results**: - **Plasma Glutamine**: - In the European study, mean glutamine levels decreased from high to normal during treatment and began to rise again after four weeks post-treatment [13][14] - In the US study, glutamine levels normalized after three doses and remained normal for approximately twenty days [14] - **Ureagenesis Function**: - The new N15 assay showed significant increases in relative ureagenesis function (RUF) post-treatment, with a mean increase of 14.7% [16][17] - Two subjects achieved RUF levels above 50%, indicating clinically meaningful improvements [17] - **Ammonia Levels**: - Ammonia levels remained stable and within normal ranges after treatment, supporting the favorable glutamine and ureagenesis data [18] 5. **Safety Profile**: - The safety database included 40 participants, indicating that ARCT-810 was generally safe and well-tolerated [19] - No serious infusion-related reactions were reported, and adverse events were manageable [19][20] 6. **Next Steps**: - Arcturus plans to complete the ongoing Phase II US study and engage with regulatory agencies for a multi-biomarker driven pivotal trial [68][69] Additional Insights - **Clinical Implications**: - The KOLs emphasized the importance of normalizing diet and reducing the need for ammonia scavengers as key success metrics for OTC therapies [78][80] - mRNA therapies are viewed as a potential alternative to liver transplants, especially for severe cases [100][101] - **Comparison with Other Therapies**: - ARCT-810 is positioned as a more effective solution compared to existing ammonia scavengers, which do not restore urea cycle function [87][88] Conclusion - The interim data for ARCT-810 demonstrates promising results in reducing glutamine levels and improving urea cycle function, with a favorable safety profile. The company is poised to advance its clinical development and regulatory strategy to address the significant unmet needs in OTC deficiency treatment [67][68]

Financial Data and Key Metrics Changes - For Q1 2025, revenues were $29.4 million, down from $38 million in Q1 2024, primarily due to lower development milestone revenues from the CSL collaboration as the COVID vaccine transitions to commercialization [19][20] - Research and development expenses decreased to $34.9 million from $53.6 million year-over-year, driven by lower manufacturing costs, with expectations for further declines in the second half of fiscal year 2025 [20][21] - General and administrative expenses were $11.3 million, down from $14.9 million in the same period last year, attributed to reduced share-based compensation costs [21] - The net loss for Q1 2025 was approximately $14.1 million, or $0.52 per diluted share, compared to a net loss of $3 million, or $1 per diluted share, in Q1 2024 [21] Business Line Data and Key Metrics Changes - The mRNA therapeutics pipeline is being prioritized, with significant focus on the CF and OTC programs, while the COVID vaccine program is transitioning to commercialization [11][18] - The ARCT032 program for cystic fibrosis is in Phase II, with enrollment expected to complete by the end of 2025, and interim data anticipated in mid-2025 [7][10] - The ARCT810 program for OTC deficiency is also in Phase II, with interim data expected in Q2 2025 [8][10] Market Data and Key Metrics Changes - The company received an initial milestone payment from CSL related to the EU approval of the COVID vaccine, with further payments anticipated as the program progresses [11][19] - The company is preparing for a Marketing Authorization Application in the UK in Q2 2025 and a BLA filing in the US in Q3 2025 [12] Company Strategy and Development Direction - The company has made a strategic decision to focus resources on mRNA therapeutics, particularly CF and OTC programs, due to current market conditions and regulatory uncertainties [18][19] - The STAR self-amplifying mRNA platform continues to receive positive feedback from publications, enhancing the company's position in the market [12][14] Management's Comments on Operating Environment and Future Outlook - Management expressed optimism about the upcoming clinical data from the CF and OTC programs, highlighting the potential for significant advancements in treatment options [22][23] - The company remains committed to maintaining a strong financial position, with a cash runway extended into 2028, allowing for the achievement of near-term milestones [21][22] Other Important Information - The company is utilizing a newly developed 15N ureogenesis assay to monitor the effects of ARCT810 in clinical development, which is expected to provide valuable data [10][18] - Long-term data from the COVID vaccine trial suggests a favorable safety profile, with no reports of myocarditis or pericarditis [14] Q&A Session Summary Question: Can you provide more details on the changes made to extend the cash runway and potential incoming cash flows? - Management indicated that tough decisions were made regarding cost reductions and focusing on critical programs, which contributed to extending the cash runway [27][28] Question: What milestones should we expect related to the UK and US approvals for the COVID vaccine? - There are no milestones associated with the UK or US approvals; however, a milestone is anticipated with the first US revenues from the COVID vaccine, expected in 2028 [30][31] Question: What is the expected size of the initial interim cohort for ARCT032 and the bar for success? - The interim data set is expected to include 6 to 9 subjects, with a bar for success set at a 3% improvement in lung function [35][36] Question: How does ARCT032 differ from competitor programs in terms of tolerability? - The company highlighted its exclusive LUNAR lipid nanoparticle delivery technology and the high purity of its mRNA constructs as key differentiators [42][43] Question: What are the expected biomarkers for the OTC program? - Management confirmed that glutamine, orotic acid, and other biomarkers will be measured to assess the effectiveness of the treatment [86][87]

Financial Data and Key Metrics Changes - For Q1 2025, revenues were $29.4 million, down from $38 million in Q1 2024, primarily due to lower development milestone revenues from the CSL collaboration as the COVID vaccine transitions to commercialization [17][18] - Research and development expenses decreased to $34.9 million from $53.6 million year-over-year, driven by lower manufacturing costs, partially offset by increased costs for CF and OTC programs [18][19] - General and administrative expenses were $11.3 million, down from $14.9 million in the same period last year, mainly due to reduced share-based compensation costs [19][20] - The net loss for Q1 2025 was approximately $14.1 million, or $0.52 per diluted share, compared to a net loss of $3 million, or $1 per diluted share, in Q1 2024 [20] Business Line Data and Key Metrics Changes - The mRNA therapeutics pipeline is being prioritized, with significant focus on CF and OTC programs, while the COVID vaccine program is transitioning to commercialization [10][16] - The company expects to complete Phase II enrollment for ARCT032 by the end of 2025 and provide interim data for the first two cohorts in mid-2025 [6][9] - The ARCT-810 program for OTC deficiency is also progressing, with interim data expected in Q2 2025 [7][9] Market Data and Key Metrics Changes - The company received an initial milestone payment from CSL related to the EU approval of the COVID vaccine, Costave, and anticipates further milestone payments as the program progresses [10][17] - The company is preparing for a Marketing Authorization Application (MAA) filing in the UK in Q2 2025 and a U.S. BLA filing in Q3 2025 [11] Company Strategy and Development Direction - The company has made a strategic decision to focus resources on mRNA therapeutics, particularly CF and OTC programs, due to current market conditions and regulatory uncertainties [10][16] - The STAR self-amplifying mRNA platform continues to receive positive feedback from publications, enhancing the company's position in the market [11][13] Management's Comments on Operating Environment and Future Outlook - Management expressed optimism about the upcoming clinical data from CF and OTC programs, indicating a strong cash runway extending into 2028 [21] - The company remains committed to advancing its therapeutic programs and believes that the science will support its regulatory interactions [100] Other Important Information - The company has received FDA Fast Track designation for ARCT2304, its mRNA vaccine candidate for pandemic influenza A [14] - The 15N Ureogenesis Assay is expected to provide important data for monitoring the effect of ARCT-810 in clinical development [9][108] Q&A Session Summary Question: Can you provide more details on extending the cash runway and potential cash flows? - Management indicated that focusing on critical programs and making cost reductions contributed to extending the cash runway, with a conservative approach to cash burn forecasts [26][27] Question: What milestones should we expect related to UK and U.S. approvals for the COVID vaccine? - There are no milestones associated with UK or U.S. approvals; however, a milestone is anticipated with the first U.S. revenues from Costave, expected in 2028 [31][60] Question: What is the expected size of the interim cohort for ARCT032? - The interim data set is expected to include 6 to 9 subjects, with a bar for success set at a 3% improvement in lung function [36][37] Question: How does ARCT032 differ from competitor programs? - The key differentiators include the exclusive LUNAR lipid nanoparticle delivery technology and the high purity of the mRNA construct, which may enhance safety and tolerability [44][45] Question: What are the thresholds for FEV1 improvement in the CF program? - A 3% improvement in FEV1 is considered a significant threshold, with higher improvements potentially allowing for smaller Phase III trial sizes [86][87] Question: Will other biomarkers be measured in the OTC program? - In addition to glutamine, orotic acid and other amino acids will also be measured as part of the biomarker strategy [88][89]