GUGGENHEIM 3RD ANNUAL HEALTHCARE INNOVATION CONFERENCE - ARCTURUS THERAPEUTICS HOLDINGS INC

Explicit Guidance:

• Cystic Fibrosis (CF) Program:
  • Complete fourth cohort Phase 2 data presentation scheduled for Q2 2027.
  • Enrollment for the 12-week, 10mg once-daily inhalation study to be completed by end of current calendar year.
  • Top-line data to be released on an "open schedule" between the present and the Q2 2027 full data presentation; no specific date provided to maintain flexibility for the Phase 3 go/no-go decision.
• OTC Deficiency (ARCT 2601) Program:
  • Clinical trial for the reformulated Lunar 2.0 asset (ARCT 2601) anticipated to initiate in early 2027.
  • Top-line data for ARCT 2601 expected in the second half of 2027.
• PKU (Phenylketonuria) Program:
  • Intent to submit an Investigational New Drug (IND) application in the second half of 2027.
• Financial Triggers:
  • A successful Phase 2 go/no-go decision for the CF program will trigger a $40 million milestone contribution from Thermo Fisher, with the total funding for Phase 3 noted to be "cut in half" compared to prior expectations.

Business-Segment Outlook:

• Cystic Fibrosis:
  • Focus on Class 1 CF population (nulls) representing ~15% of the total CF market (potentially up to 35-40% in specific regions like Turkey and Israel).
  • Enrollment criteria updated to target patients with lung function between 45% and 85% predicted FEV1 to optimize clinical signal detection; patients at the lower end expected to see stabilization (preventing 1.5–2.5% annual decline), while those at the higher end may see reversibility.
  • Phase 3 study design is being informed by CF Foundation "REACH" natural history data to ensure efficient powering; management expects the Phase 3 trial to be less expensive and time-consuming than previously anticipated.
• OTC Deficiency (ARCT 2601):
  • Pivot from Gen 1 (0.5 mg/kg every 2 weeks, 3-hour clinic visit) to Gen 2 (Lunar 2.0) targeting less frequent dosing (potentially once a month) with lower doses and shorter administration times (<1 hour), potentially shifting administration to home nursing.
  • Market positioning shifted from "dark horse" to "featured program" with a multi-billion dollar peak potential; management now views the asset as a potential market leader (#1) rather than a 20% share player in the urea cycle disorder space.
• Pipeline Expansion:
  • Lunar 2.0 platform validation opens opportunities for new liver targets, specifically PKU, previously considered untractable due to dosing frequency constraints.

Market and Competitive Outlook:

• Differentiation: Arcturus' inhaled mRNA approach builds a new CFTR protein, distinguishing it from modulators that fix broken transporters; this targets the ~50% of Class 1 patients who are ineligible for existing modulator therapies.
• Competitive Landscape: The CF segment has seen multiple programs suspend, withdraw, or terminate; Arcturus notes increased spotlight and community/regulatory interest in their approach given this attrition.
• Benchmarking: Management compares the potential value creation of the Lunar 2.0 validation to Alnylam's 2012 lipid nanoparticle reformulation, which created ~$5–6 billion in enterprise value within 18 months.
• Standard of Care: Success with ARCT 2601 (normalizing both ammonia and glutamine with improved convenience) could establish a new standard of care, displacing current ammonia scavengers which fail to control glutamine levels.

Macro / Industry Outlook:

• Regulatory Path: Management indicates strong encouragement from the regulatory agency and the Cystic Fibrosis Foundation, which are actively tracking Class 1 patient degradation and "really, really want to see something" from the program.
• Data Utility: Reliance on high-resolution CT scans, lung clearance index, and quality of life measures alongside spirometry to establish efficacy in the presence of chronic lung damage.
• Geography: Targeting specific high-burden geographies (Turkey, Israel) where Class 1 prevalence is higher (35–40%) to improve enrollment efficiency and signal detection.

Strategic Initiatives:

• Technology Advancement (Lunar 2.0): Deployment of a next-generation lipid nanoparticle technology demonstrated to be 38 times more potent than Lunar 1.0 in non-human primates; intended to enable lower doses and increased dosing frequency convenience.
• Platform Expansion: Leveraging Lunar 2.0 to enter new therapeutic areas (PKU) that were previously impossible due to vector limitations.
• Partnership Execution: Accelerating Phase 3 initiation for CF contingent on Phase 2 success; Thermo Fisher has already begun "at-risk steps" to prepare for the milestone trigger.
• Regulatory Strategy: Planning for separate pivotal trial paths for stable adult females and pediatric males in OTC deficiency following a small (n<6) bridge study in early 2027.

Risks and Headwinds to Outlook:

• Enrollment Variability: Prior challenges with patient effort-dependent spirometry (high baseline variability) necessitated protocol changes; failure to secure reproducible data could delay go/no-go decisions.
• Data Interpretation Risk: Phase 3 advancement is contingent on a "collective" data set; failure to show stabilization or improvement will result in termination, as the regulatory bar is high for Class 1 CF.
• Timeline Uncertainty: Specific timing for top-line data and Phase 3 initiation is not locked; management retains flexibility to release data based on internal decision-making rather than external schedules.
• Preclinical Translation: While primate data for Lunar 2.0 is strong (n=6), management acknowledges the risk inherent in translating non-human primate potency gains to human efficacy, though they cite high historical translation rates for this technology.

Management Tone on the Future:

• High Confidence: Management expresses significant excitement and confidence, particularly regarding the OTC asset, stating it is "no longer a dark horse" and "exciting as the CF program, if not more exciting" due to higher likelihood of success.
• Urgency: There is a clear motivation to expedite the CF Phase 3 decision to trigger funding; management emphasizes efficiency in Phase 3 study start-up.
• Strategic Pivot: Tone reflects a strategic shift from "testing" the platform to "commercializing" it, with a focus on convenience and standard-of-care disruption for OTC.
• Value Creation: Explicit comparison to historical value creation events (Alnylam 2012) suggests management anticipates substantial enterprise value appreciation upon successful Lunar 2.0 validation.

Miscellaneous:

• Safety Profile: Lunar 2.0 (ARCT 2601) is expected to maintain the safety and tolerability of Gen 1 while improving potency.
• Data Metrics: OTC efficacy will be measured by plasma OTC levels, ammonia, and glutamine normalization; CF efficacy by FEV1 stability/improvement, CT scans, and lung clearance index.