Ann: Investor Webinar Presentation, page-3

PYC Investor Update Presentation on 30 May 2025

The Presentation Slides Pack is available athttps://app.sharelinktechnologies.com/announcement/asx/60ccc721d9324a1267b4d94b730c1ecc

Below is a summary of the 47 minute presentation:

Objectives of the Webinar

1. Pipeline Update: Review the status and outlook for all four pipeline assets.
2. Platform Validation: Discuss how clinical success of specific programs reinforces the value of PYC’s RNA delivery platform.
3. Commercial Context: Position PYC's progress within the broader biotech and RNA therapeutics industry.

Pipeline Highlights

• RP11 Program: Positive reception from the scientific community following recent presentations in the U.S. (ARVO and Foundation Fighting Blindness).
• ADOA & PMS Programs: Previously slower-moving assets have now gained significant momentum and are expected to advance steadily.
• Kidney Program: Described as the most exciting and fast-moving part of the pipeline, with anticipated accelerated development.

Clinical Goals for 2025

• Advance three clinical-stage programs into mid- to late-stage studies by Q4 2025 across multiple geographic regions.
• Expect multiple human efficacy readouts within 12 months, which are key value inflection points in biotech.

Strategic and Platform Insights

• The non-viral RNA delivery platform is being validated not only through internal results but also by growing external interest.
• The success of individual programs is expected to "reverse-validate" the platform and attract further co-development and licensing deals.
• The company is seeing a shift in business development conversations from program-specific to platform-wide interest.

Market Commentary

• The biotech sector remains under pressure due to a prolonged “risk-off” macro environment post-2020.
• However, RNA therapeutics is one of the few subsectors experiencing strong momentum, evidenced by deals such as:
  • Biogen x City Therapeutics
  • AbbVie x ADARx
• Safety concerns and recent adverse events with viral gene therapies (e.g. AAV gene therapies had a number of patient deaths including quite tragically one last week in Rocket Pharmaceuticals) further validate PYC’s non-viral RNA approach.

Key Takeaways

• PYC is progressing toward its 48-month revenue generation goal, now focusing on the next critical 24-month phase.
• The company operates in rare but relatively prevalent genetic diseases (USD $1–10B markets).
• Their therapies are five times more likely to succeed in clinical trials compared to industry averages, due to clear, single-gene targets.
• PYC is approaching a pivotal year with multiple human efficacy data readouts, a major catalyst for investor and industry interest.

RP11 Program (Retinitis Pigmentosa Type 11)

• PYC presented strong clinical proof-of-concept data at two major conferences.
• The current Phase 1/2 study will roll into an open-label extension trial starting in June, extending patient follow-up to 24 months.
• Dosing update:
o 30 µg cohort to be increased to 120 µg to enhance efficacy while maintaining safety.
o Dosing intervals may be extended to 3–4 months for patient convenience.
• Objective: Regulatory registration with FDA and global bodies.
• Two primary efficacy endpoints under discussion with FDA:
o Low-luminance visual acuity.o Microperimetry.
• Meeting with the FDA is scheduled for 6th June, with follow-up meeting minutes and guidance expected by July.
• Next data release expected in Q4, once patients reach 12–18 month milestones.

ADOA Program (Autosomal Dominant Optic Atrophy)
• Faced early operational challenges:
o Investigator medical leave.
o Equipment issues at the clinical site.
• Now back on track:
o Dosing for Cohort 2 is complete.
o Safety Review Committee meeting imminent.
o Cohort 3 dosing expected to complete by end of June.
• Proof-of-concept data targeted for early 2025, but early efficacy signals may emerge by Q4 2024.
• A second clinical site has been brought online to speed up recruitment.

Polycystic Kidney Disease (ADPKD) Program
• Cohort 2 of the healthy volunteer (HV) study is complete.
• Patient dosing to begin within 6 weeks.
• Focus on mirroring Regulus Therapeutics' success in reducing total kidney volume (TKV) within three months.
• PYC aims to outperform Regulus through:
o Better drug distribution within the kidney (especially renal medulla).
o Strong preclinical PK/PD data and safety in non-human primates.
o Superior performance in 3D cyst reversal models.
• Potential for repeat-dose study data in Q4 2024 – Q1 2025.
• Expectation of needing a registrational trial, despite positive early signals.
• Regulatory interactions ongoing to define pathway, including how surrogate endpoints like TKV and estimated glomerular filtration rate (eGFR) might support approval.

Phelan McDermid Syndrome (PMS) Program
• Significant progress noted—program has “hit its stride.”
• A go/no-go decision is expected in Q3 2025.
• Preclinical approach Patient skin cells are reprogrammed into neurons.
o Effect of drug on SHANK3 gene expression is measured.
• New backbone chemistry used for this program (PYC002), which is shared with Stoke Therapeutics’ compound for Dravet syndrome—offering real-world validation.
• Target outcomes include improvements in language and cognition, core issues for PMS patients.
• Comparative preclinical data with Stoke’s compound to be presented in Q3.

Regulatory & Strategic Considerations
• FDA’s evolving stance on accelerated approval for biologically plausible mechanisms is seen as promising, especially for monogenic diseases like PYC’s targets.
• PYC is exploring hybrid registration trials, combining in-study controls with natural history data—potentially lowering trial burden and cost.
• RP11 and ADPKD registration trial designs to be finalized after Q3/Q4 FDA meetings.

Market Position & Confidence
• Management remains confident in the high probability of success for PYC’s pipeline due to:
o Clear gene-to-disease causality.
o Strong organoid (3D mini-organ) data.
o Safety and efficacy observed in non-human primates.
• Response to a question on phase 3 success: Cited a historic analysis showing high success rates (up to 80%) in precision medicines with a validated mechanism of action.

Overall Pipeline Status
• All programs are on track or ahead of expectations.
• Earlier difficulties (e.g., ADOA delays) have been resolved, and the company is now poised to transition multiple programs to mid- and late-stage clinical trials in the second half of 2024.

Platform Validation Through Upcoming Milestones
• PYC anticipates multiple efficacy readouts in 2024–25 that will not only validate individual programs but also confirm the strength of PYC’s drug delivery platform:
o For instance, PYC001 shows potential beyond ADOA for broader retinal diseases such as glaucoma and geographic atrophy, due to its mitochondrial gene target (OPA1).
o Early collaboration with the University of Melbourne is exploring these indications using patient-derived disease models.

CNS (Central Nervous System) Program Delivery Breakthrough
• Shift from cell-penetrating peptides (which caused excessive spinal uptake) to receptor-targeting peptides has improved brain delivery in preclinical models.
• Promising results in rats are being followed up in non-human primates in Q3 2024.
• If validated, this approach could unlock a suite of neuron-targeted therapeutics, creating significant platform value.

Commercial Strategy & Deal-Making Philosophy
• PYC has intentionally retained ownership of its assets to maximize licensing value once clinical data supports strong efficacy.
• Their strategy allows for non-dilutive capital raising through selective out-licensing, while retaining resources to push other programs toward commercial launch.

RP11: Commercialization Potential
• PYC has the resources and capability to bring RP11 to market without additional funding.
• Estimated cost of the registrational trial is ~US$60 million.
• Due to the narrow patient population (centralized in U.S. disease registries), commercial launch would be operationally efficient.
• However, PYC prefers to invest across multiple high-impact programs, rather than focus on a single asset.

Pricing and Reimbursement Outlook
• Each indication in PYC's pipeline—RP11, ADOA, PMS, and ADPKD—has strong health economic justification for pricing and reimbursement, independent of orphan drug pricing models.
• The rare disease space remains relatively insulated from political pricing pressures.

Business Development & Industry Interest
• Strong interest following presentations at the Foundation Fighting Blindness and ARVO conferences.
• Investigators at those meetings validated patient-reported outcomes and expressed strong enthusiasm.
• Commercial interest has increased, and discussions with potential partners are ongoing across multiple assets.
o Notably, RP11 and ADOA are frequently considered as a pair in licensing discussions.
• PYC will attend the BIO Partnering Conference in June to advance these negotiations.

ASX Liquidity Challenges
• Acknowledged reduced trading volume post-entitlement offer.
• Attributed to long-term holders and low seller availability.
• Liquidity issues may limit institutional buying unless price incentives emerge.

ADPKD Program vs Regulus Therapeutics
• PYC believes it can outperform Regulus based on:
o Better kidney biodistribution (including to the renal medulla).
o Superior 3D cyst model results.
o Cleaner safety profile due to targeted RNA mechanism.
• Key differentiators include:
o Longer half-life of the PYC drug in tissue.
o Expectation of early movement in total kidney volume (TKV), with eGFR data likely to emerge over 12–24 months.
• PYC expects to build a stronger and longer-term data pack than Regulus, extending beyond their short-term published data.

Most Likely Asset for Out-Licensing
• Internally, RP11 is seen as the leading candidate for out-licensing, with ADOA often bundled in partner discussions.
• PYC remains in ongoing dialogue with multiple large biopharma companies.

Regulatory Engagement & FDA Outlook
• PYC has not seen any change in FDA responsiveness due to recent leadership transitions.
• More clarity expected after 6th June FDA meeting.
• Open to hybrid trial designs, combining in-study controls with natural history data.

Outlook
• The next 12 months are critical: with strong execution and positive data, PYC expects to have three assets in mid- or late-stage clinical trials.
• This would significantly increase company valuation and open doors for strategic deals or commercialization.
• Management remains confident that continued execution will position PYC as a leader in RNA-based therapeutics for monogenic diseases.

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