• 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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