PYC Therapeutics Limited (PYC.XA) Earnings Call Transcript & Summary

Good morning, everyone, and welcome to the 2025 Annual General Meeting of PYC Therapeutics Limited. My name is Rohan Hockings, and I will be chairing today's meeting on behalf of the Chairman, Mr. Alan Tribe, who is an apology for the meeting. I'd like to introduce you to my fellow Board members. Here with me in the room, I have Professor Ian Constable; and Mr. Kevin Hart, our Company Secretary. I'll deviate from the script momentarily, so that's just quite loud that microphone, take a step back. Just to acknowledge the contribution of Mr. Alan Tribe to the company and to thank him for his efforts over the course of the past 7 or 8 years. When Alan and I set about turning this company around from a cold start back in 2018, Alan was the only one who really had the vision for what PYC could become in that time and the commitment to see that through. We'll talk at the end of today's meeting about the proximity to human efficacy readouts for 4 first-in-class drugs with disease-modifying potential over the course of the next 24 months, and we would not be in a position to have that opportunity today in the absence of Alan's commitment and contribution to PYC. So on behalf of the Board and all of the staff I'd like to acknowledge and thank Mr. Tribe for his contribution. I'd also like to welcome our 2 new directors to PYC. Firstly, Professor Ian Constable. Professor has been helping me over the course of the last several years already in the background, but I'm delighted to bring Prof. Constable on board with his depth of knowledge in our scientific programs and also the journey that sits in front of us, the challenges and opportunities for a company like PYC Therapeutics as we seek to move multiple assets into late-stage development. So I'm personally very grateful, Prof, that you have joined the Board and very much looking forward to working with you. And although not officially part of today's meeting, Mr. Peter Coleman is our incoming Chair from outside of the industry, but with a very deep corporate and commercial capability that is going to be very helpful for the company, particularly in the domains of at scale M&A and overseas listings as we pass through those human efficacy readouts and the associated commercial optionality that those afford for the company. So also very much looking forward to working with you going forward, Peter, and welcome to both of you to the Board of PYC. For the record, I'm advised that a quorum is present, and I declare the meeting open. The format for today's meeting will be as follows: Firstly, I will attend to the formal business of the meeting, which on conclusion will be followed by a presentation on the company's outlook over the coming 12 months. A copy of the notice convening this meeting has previously been made available to all shareholders and sets out in detail the nature and purpose of the resolutions to be considered at today's meeting. I propose to take the notice as read. The company has received valid proxies from 198 shareholders holding a total of 225,119,341 shares, representing 39% of the issued capital of the company. After each resolution is displayed on the screen, I will invite questions from the floor. I'll be limiting questions to the motion being considered. Opportunity will be provided for shareholders to ask questions on the resolutions. I would ask that you state your name for the record when you address the meeting. If a question is asked, which in my opinion, does not relate to the motion, which is before the meeting, I will rule the question is inadmissible. In my capacity as chair, all resolutions today will be decided on by a poll rather than any vote on a show of hands. Accordingly, the resolutions will be for discussion purposes only. The poll will be taken once we have been through all of the resolutions. Ballot papers were given to eligible shareholders at the time of registration, and I will ask you to complete these. The poll will be taken, results of which will be announced to the market later today, I will further explain the procedure for the poll at that time. Note that each shareholder at the meeting can only vote for his or her personal shareholding at this time. Only proxies lodged with the company up to 48 hours before can be counted in the vote. We will now proceed with the business of the meeting. Agenda Item #1 is the annual report. The first item on the agenda is consideration of the financial statements, the director's statement and report and the auditor's report for the financial year ended 30 June 2025, all of which have been made available to shareholders in accordance with the requirements of the Corporations Act. The company's auditors, PricewaterhouseCoopers, are represented here today by Mr. Adam Thompson. In accordance with the requirements of the Corporations Act, and he is available to address appropriate questions or comments from shareholders on this agenda item. Are there any questions or comments in relation to the reports under consideration? There is no requirement for a vote on this item, so we shall proceed with the second item of business. Agenda Item #2 is Resolution #1, the remuneration report. The next item relates to adopting the rem report, further details, including key management personnel, which includes directors, voting prohibitions and the voting of undirected proxies are included in the Notice of Annual General Meeting dated 17 October 2025. The remuneration report is set out in the annual report. In accordance with legislation, the vote on the resolution is advisory only and does not bind the directors of the company. However, the Board will take the outcome of the vote into consideration when reviewing remuneration practices and policies of the company. I now refer shareholders to the screen -- just laying in full and the valid proxy results. We don't have those ones actually. We've got a blank table. Do you want to come in and have the microphone.

Results for proxies for the first resolutions are: For, 224 million; Against, 178,000; Open, 85,000; and Abstained, 109. So that's 99.88% of the votes are in favor of this resolution.

Thanks, Kevin. I now formally move the motion that Resolution 1 be put to the meeting in the form set out in the Notice of Meeting. Is there any discussion on this Resolution? Resolution 2 relates to the reelection of Mr. Alan Tribe. As announced to the market on 13th November, Mr. Tribe will be stepping down from the Board at the conclusion of this meeting and will not be seeking reelection. Accordingly, the resolution has been withdrawn and any votes cast on Resolution 2 will be disregarded. Resolution 3 relates to the reelection of Professor Ian Constable. I now refer shareholders to the screen. Kevin, you might have to jump off again.

Okay. Shares in favor, 224 million; shares against, 372,000; open, 94,000; abstain, 34,000; that's proxies 99.79% in favor of the resolution.

Thank you. I now formally move the motion that Resolution 3 be put to the meeting in the form set out in the Notice of Meeting. Is there any discussion on this resolution? It's now time to take polls for Resolutions 1 to 3 and a representative from Automic Share Registry, Eric Mervin, will act as Returning Officer. Recent changes to the Corporations Act have changed the law in relation to the obligations of proxies to vote where a poll is called on any resolution. If the proxy is the chair of the meeting at which the resolution is voted on, the proxy must vote on a poll and must vote as directed. If the proxy is not the chair of the meeting, the proxy need not vote on the poll, but if the proxy does so, the proxy must vote as directed. If you're a proxy holder with open votes, you may vote as you wish. You have been handed the ballot paper for the poll on registration this morning. The resolutions upon which the poll is being taken is to be set out on the ballot paper by you, that is Resolutions 1 to 3. You should record your vote by placing a cross in either the For or Against square on the paper. You should also print on the ballot paper your name. If you are a shareholder or the name of the shareholder whose proxy representative or attorney you are. If you hold multiple proxies, please state this, and we will complete the information from the proxies. [Voting]

Thanks. Have all persons who intend to vote now voted? It appears as though the voting process has been completed, the results of the poll will be announced to the market later today. That concludes the last item on the agenda. I now open the meeting to all members to ask questions. Does any member have any questions or comments? You just wait for the microphone to come.

Greg Wall. In the press recently, you talked about the company that granted subord and talking about Board renewal. What we've seen is the exit of 2 very senior people who are experienced in bringing pharma to market in America, in particular. And we've seen the exit of the major funder to date of this business, being replaced by highly respected Professor, albeit -- Senior Professor of 82 plus years of age and an oil and gas man doesn't seem like board renewal to me. Could you comment, please?

Yes, I think as I alluded to at the start of the meeting, both Professor Constable and Mr. Coleman bring skill sets that are highly relevant to the company in its journey going forward. So we talked about Prof. Constable's background both as a physician with a very deep understanding of the patient interface, but Prof. Constable's experience is far broader than that. He has a background in research and has founded several companies that have been on the drug development journey and made their way through to the U.S. market. He also has a very deep understanding of the commercialization journey associated with drug development pathways as a whole. And in relation to Mr. Coleman, you're quite right that he comes from without -- outside of industry. And I think that is a good thing to have the diversity on the Board representation as well. I think the domain skill set that Mr. Coleman brings to the company is, as we spoke about before, the at scale M&A and the experience with dual listed entities. And in particular, those that grow up on 1 market and move across to another market, that is potentially closer to their home in the longer run. So I think both of our 2 new appointments bring highly relevant skill sets to the company. I don't think the Board renewal process has ended yet, and we may look to further build out the Board, particularly through the course of next year with additional industry-based skill sets that I think will stand the company in very good stead going forward for its journey. Any other questions?

Stephen Yaxley. How does the Board handle Mr. Tribe's not insignificant holding in the company now, given that he has left under those circumstances when I mean holds 33% of the shares.

Look, Alan has been a long-standing supporter of PYC. And as you point out, retains a very large shareholding in the company. I think Alan has got a very clear understanding of the company's trajectory going forward, the gap between the intrinsic valuation that has already been created and the enterprise valuation in the company. So I think Alan's interests are very much aligned to the broader shareholder base with respect to the company's need to find a pathway for closing that gap as well as continuing to build intrinsic value as we move through these critical upcoming human safety and efficacy readouts. So I don't see any misalignment there between Alan's longer-term objectives and those are the broader shareholder base in PYC. Any other questions?

I suppose I was anticipating an update on how you're progressing with a number of the drugs. Are you still going to do that?

Once we close the formal part of the meeting, we'll have a presentation in relation to where the company has got to through the course of 2025 and the outlook for 2026, '27. Yes.

Because I'm sort of very keen to understand whether progression is on the various products that you're developing, in particular, the kidney, which is the one that really offers the greatest return for shareholders. So I'll be very interested in that.

Hopefully, we satisfy you through the latter parts of the presentation. Any other questions? No. Ladies and gentlemen, that concludes the business of the meeting. Thank you all for your attendance, and I formally declare the meeting closed.

Now to the informal part of the meeting and the presentation of progress on the scientific programs and the company's outlook. I'm going to keep the presentation relatively brief today. We will endeavor to give you a holistic update in relation to each 1 of the 4 programs and specifically what 2026 holds for the company in relation to those -- each of those programs going forward. But given the proximity to our recent investor webinar, what I thought we'd do is open up early for Q&A to give you control over the topics of most interest for you, and we can take a little bit more time to elaborate and give some slightly more fulsome answers in relation to those. So what I propose to do through the course of this presentation is to give those who are new to the story, a very brief introduction to the company, and what we do to look back on the highlights of 2025, a year in which a great amount has been achieved by the company, but spend most of the time looking forward to what's coming in 2026 and extending that vision to include 2027, specifically as it relates to our Phelan-McDermid Syndrome program as our fourth drug development asset moves into clinical development. We'll then open up for Q&A to ensure that everybody is fully comfortable with where we've got to and where we are heading. For those unfamiliar with the company, PYC makes drugs for patients who have severe genetic diseases and who don't have any treatment options available to them today. We do this in a very particular domain. We serve patients who have diseases that are caused by Haploinsufficiency. And what this means is that you have 2 copies of every gene in your body and patients with a Haploinsufficiency have a mutation or a spelling error in 1 of those 2 copies of the gene. And consequently, they are expressing half as much of that gene at the protein level in 1 particular cell type in the body as they need. And this is a very well-suited domain for RNA therapeutics where we can design a drug that goes to the good copy of the gene and tells that gene to make 2 copies of the protein when it otherwise would have made one. So what we are trying to do here is to create what we call quantitative cures for these patients. If you look at a cell that is unaffected by the disease process and you compare that to a cell that is affected by the disease process, but it's been treated with PYC's RNA therapeutic at the protein level, you should not be able to see any difference between those 2 cells. So the quantitative cures, they're very high-impact drugs because they are what we call disease-modifying drugs, they are addressing the root cause of what is driving that patient's phenotype or the disease manifestation. It's a very elegant approach to disease correction, but it brings you head long into the Achilles' heel of the RNA therapeutics, which is that they don't get inside cells very well and they are only active on the inside of cells, meaning that we have a delivery challenge. This is where the other half of PYC's technology comes into play. We use a delivery peptide to take that drug inside the cell where it is active. And we use that delivery differentiation to create a competitive advantage over other RNA therapeutics players in the space. So there is a very carefully considered and proximate link to the way the disease is manifesting and the use of this specific modality to correct it. We have used those 2 platforms to create 4 drug development programs. Three of those drug development programs have entered human testing, and the fourth one is anticipated to do so next year. So we are now in the window where we are going to generate human safety and efficacy data for all 4 programs over the coming 24 months. These are the 4 patient communities whom we serve. And I would like to extend a particular thanks to all of the patients with Retinitis Pigmentosa Type 11, Autosomal Dominant Optic Atrophy, and polycystic kidney disease who have volunteered to participate in one of PYC's clinical trials. It is a very brave thing indeed to do to volunteer to help characterize the risk benefit profile of a drug candidate that has never been evaluated in a human before. On behalf of the entire team at PYC, we extend our gratitude to those patient populations with whom we feel very much part of the journey together. So we are very grateful to each of those individuals as well as the healthy volunteers in the case of polycystic kidney disease who are volunteered for those trials. If the potential of each of these programs is fully realized in the clinic and associated with that disease modifying potential that we spoke about beforehand, there is a very large derivative commercial benefit to changing the lives of those patients. The 4 indications that you see in front of you today have a collective annual market value of $30 billion. So we are playing a very high-stakes game here in relation to genuine innovation, creating therapies for patients who have no treatment options available today with a view that we make a very profound impact in the treatment landscape because of the extent of the impact that those drugs can have in those patient populations. To give you some color, many of you will be familiar with the acquisition of Avidity Biosciences over the course of the past month by Novartis for USD 12 billion. Avidity are going after 2 different rare diseases, 2 forms of muscular dystrophy, both of which have a prevalence that is very similar to Phelan-McDermid Syndrome. And one of the comments, we're going to look at some of the other comments of the Novartis CEO in acquiring that asset. But 1 of the comments that was made by Vas Narasimhan at the time was there are 2 assets within this pipeline that could potentially repay that USD 12 billion purchase price. And I think that's a particularly relevant comparison or transaction for you to be aware of because the acquisition was made on the back of Phase I/II data with a comment -- a further comment from the CEO that we will look at later that suggested had we waited for the Phase III readout, we would have had to have paid double for the asset. So the human efficacy data that is coming over the course of the next 24 months is what moves the needle from a big pharma standpoint. That is what is going to create the commercial optionality for this company and its path going forward. In addition to the patients, I'd also like to extend a very heartfelt thank you to all of the PYC staff for all of the late nights, early mornings, and weekends committed to those patient populations. It is a very long and arduous journey, 1 of drug development. It is referred to in the life sciences as a team sport, and it very much is. PYC has an exceptional team who are working very hard to drive impact in these patient populations. And it's through those efforts that we have been able to already achieve quite remarkable outcomes. If we look back on the top 3 highlights of 2025, for me, those have been the progression of the polycystic kidney disease drug program into human trials. Not only did the asset dosed its first subject in the second quarter of this year, but all 4 cohorts in Part A, the healthy volunteer study have now been successfully dosed. We have also dosed the first cohort in Part B of the study in polycystic kidney disease patients. And we expect through the efforts of our clinical operations team to have dosed the second cohort in B2, in Part B of that study before the end of the year. That will leave us with 1 final cohort B3 in the new year before we move through to the very highly anticipated repeat dose studies, the Phase Ib study in polycystic kidney disease, upon which we all have a very lot riding. The second achievement is in relation to the Phelan-McDermid Syndrome program. You have seen a nonclinical data pack here. And it's interesting that we are getting very excited in relation to preclinical results here due to the elegant and comprehensive nature of the outcomes that we're seeing. Many of you, the familiar faces who were here at the other investor webinars first saw the data that we generated in the patient-derived neurons or brain cells, the brain cells that come from the children with Phelan-McDermid Syndrome. What we were able to show there is the quantitative rescue, the lift from 50% gene expression back to 100% or unaffected levels of the target gene, in this case, SHANK3. We were also able to show that the SHANK3 protein localizes after we have that increased synthesis of the protein, but it localizes to where it needs to be. So it is found in the cell in the postsynaptic density where it is responsible for helping the neurons communicate with 1 another. And then many of you will remember that quite remarkable video showing downstream of that, the restoration of the communication between the neurons post-treatment with the drug. So on the patient-derived model side, we have some very elegant data. More recently, you've seen how that applies at the level of zooming out to the whole organism in the nonhuman primate studies. Here to answer the critical questions of when we administer the drug to a living organism. Can we, at a safe and well-tolerated dose, achieve enough drug in the target regions of the target organ, in this case, the brain. And you've seen those very nice results that have been generated there. Not only that, but we got very fortunate and the nonhuman primate was able to show us an efficacy signal. So we see target gene or SHANK3 movements in the key regions of the brain, but we are then able to link across to the extent of the up-regulation in the patient-derived models and the rescue of the phenotype. So we have a very, very high degree of conviction now as we move that drug into clinical development that we're going to see the full potential of up-regulating wild-type SHANK3 protein in children with Phelan-McDermid Syndrome, and that is something very much to look forward to as that asset moves into clinical development next year. And we see the early safety and exploratory efficacy outcomes in 2027. The third achievement of this year has been the establishment of the clinical proof-of-concept data in Retinitis Pigmentosa Type 11. And you've seen this presented very recently at the RANZCO presentation, you're starting to see the longer-term follow-up of those patients who've been enrolled in not just the single ascending dose study and the open-label extension of that, but also the multiple ascending dose study. We have now progressed those patients through to an open-label extension of the multiple dose study and we'll be seeing the longer-term 12-month-plus follow-up in relation to those patients through the course of next year as well as crossing them over to treat the fellow eye once we have that 12-month safety package in initially treated eye. So extraordinary things by an extraordinary team of people. I do want to call out a couple of the key individuals. Paula, I think your efforts and those of the team, not just in getting the PKD program to where it is today, but all of the thinking in relation to where that program is going have been quite extraordinary. I think it's not well understood what the implications of the high-velocity clinical development pathway are. We have a very narrow window of time within which to optimize our dose and dose interval for the repeat dose studies and we need to start preparing very early for the new drug application submission. There is a lot of work that goes into a comprehensive NDA pack. That when you have a limited time in clinical development for a very good reason, the extent of the unmet need, there are multiple parallel bodies of work that need to be synthesized and it's quite a sophisticated undertaking. I think the team has done an extraordinary job in that indication. I think [ Jane Greenoak ] and the PMS team, the generation of that data pack and the excitement that they have been able to generate amongst the key opinion leaders, the pediatric neurologists who really lead the thinking in Phelan-McDermid Syndrome to get them on board and excited about running this clinical trial, particularly because that team have moved further downstream in the drug development journey than they are typically used to. That is a really exciting asset. And as you, I think, are getting the sense, we are very much looking forward to seeing what that can do in clinical development next year. And then I think Sri has done an outstanding job, again, with multiple concurrent complex bodies of work, running the clinical trials, engaging with the key opinion leaders over in the U.S. and now preparing for the regulatory meeting with the FDA that is scheduled for the first quarter of next year to align on that registration study format. What is it going to take to get that drug across the finish line and create the first treatment for these patients with this blinding eye disease of childhood. I mentioned before some of the commentary in relation to the acquisition of Avidity Biosciences by Novartis. And these were the 2 sentences that really stuck out to me. I think there is a perception amongst the ASX Life Sciences community, in particular, but you can sit back and wait for Phase III outcomes. And I'm here to tell you today that, that is very much not the case because of the different trajectory of precision medicines going after a genetically validated target and the fundamentally altered shape of the risk curve, the Phase I/II data that we generate in these programs is absolutely critical to driving propensity for these assets to be launched as first in indication and potentially best in indication drugs. And that very much changes how the industry looks at these assets, which is where that commercial capability and skill set is really relevant to the organization going forward. It is these efficacy readouts that are coming within the next 24 months that are going to change the game for PYC. So if we look ahead to what's coming, there's a lot here because we are a company that is running multiple programs concurrently. But the ones that I specifically want to call your attention to in the first column, in the polycystic kidney disease program, the efficacy data in the second half of next year, 3 to 6 months' worth of drug exposure in the kidney in patients. And as that leads through into the first half of 2027, it's really that window, the 3-month data plus that is going to be critical in understanding the propensity for that rapid transition into the registrational study. And if we zoom out for a moment and we think about what's the broad objective here, you guys know that there are 2 studies that are required to see an approval in polycystic kidney disease. There is the currently ongoing combined Phase Ia/Ib study, and then there is a single registrational trial, 12-month primary endpoint trial, that is directed towards the volume of the kidney. That's the primary endpoint, an accelerated approval pathway. Those patients are then followed for another 12 months to look at what we're ultimately interested in, which is the function of the kidney, the estimated glomerular filtration rate. But that's what we mean by a high velocity or rapid clinical development pathway. What we're looking to do in that Ib study is to show in a smaller number of patients, probably 30 to 40 patients, what we expect to see in the registrational trial that sits thereafter in approximately 200 patients directed towards the NDA, the same endpoint and the same outcomes. It's the volume of the kidneys in the first instance and then downstream to the function of those kidneys that you're going to be looking at next year. And this is really going to captivate the interest of the pharmaceutical industry as a whole. Polycystic kidney disease is a very, very important indication. The next one that we are extremely excited about, as I spoke about before, is the exploratory efficacy data that's not coming in 2026. You'll see an IND in the second half of next year to transition to first-in-human studies, but it will be the 2027 data in the Phelan-McDermid Syndrome patients, where we see the full potential of a disease-modifying drug at the RNA level in that patient population. So some very exciting material coming there. In Q1 of next year, we will have the meeting with the FDA where we align on that registrational pathway that we spoke about in RP Type 11. You will continue to see data generated in that multiple dose study, the extension study, that will be running ultimately parallel with the mask registrational trial. So you'll be looking at the Phase I/II study to try and glean what is going on in the mask registrational study so that we know when to unmask that study and submit the new drug application. We can go into that in a bit more detail in the Q&A if you'd like to. And then finally, in Autosomal Dominant Optic Atrophy, we basically need to get this program to where the RP-11 program is today. We want to see the impact on the vision of those patients, bearing in mind that it's a very slowly progressive disease with about 12 months or more drug exposure in the retina. So we have now dosed our first patient in the multiple ascending dose study. So you need to wait until very late next year or the early part of 2027 to see the meaningful efficacy data in that context, bearing in mind that that's also an open-label study. And as you've seen already, a very clean safety tolerability profile and some encouraging early efficacy outcomes in that patient population. So with that, I'm going to stop and hand over the floor to you. Did we fulfill your expectations in relation to the update on the program? And are there any questions in relation to where the organization is heading?

Thanks, Rohan. In relation with the RP-11 program, if you worked out which hurdle that you want to overcome because in the results, I think it was early this week, there were 4 that you've kicked goals on. Does that sort of help you determine what your ultimate goal is going to be because presumably, when you set the program with the FDA, you're going to get one shot at goal. So we've got to choose your best shot, if I'm right.

Yes. I think that's right. Maybe in relation, there might be 1 minor qualification to the last part of the statement. There potentially is some flexibility in relation to nomination of more than 1 endpoint on which the FDA will have an interest on the back of the extent of the unmet need in this patient population. And certainly, the conversations that we've had with the regulators today to have that look at the totality of the data. But that being said, we do have to consider a nomination of the primary endpoint in that study. And yes, I think we've got a very good idea in relation to what we are going to propose to the FDA in Q1, and we are trying to give the information to investors very much guided by our thinking in that respect. So you see the first chart or figure 1 in that ASX announcement looks at the mean change in low luminants visual acuity. I think to make that relatable for you, you're probably all familiar with going to the doctor's office and reading the letters on the eye chart, these patients are doing that under a low luminent setting. So they're turning the lights down and getting the patients to read the eye chart, that is the low luminants visual acuity endpoint and that is almost certainly going to be the primary endpoint that we nominate. Within the LLVA endpoint, there are a few different ways you can slice and dice it. I think what we'll be looking at there is the mean change in LLVA as between the treated arms of the study and the sham control group. So if we think about the design of the P3, almost certainly, you'll have 3 arms, 2 treatment arms at the 75 and 30-microgram doses versus the sham control arm. And so what we're going to be looking at there is exactly that data that you're seeing. To what extent can we see an improvement in the visual acuity of the patients who are receiving the drug and how does that compare to what we expect to see in the sham control group, which is very similar to the natural history studies or the rate of progression of the disease in the absence of treatment. And then not only do we need to see a statistically significant spread of the data between those 2 groups, but there is also an absolute clinical meaningfulness threshold that the FDA imposed. So they want to see a 15-letter gap which is quite a substantial gap. It's 3 lines on the eye chart, delta between the treatment arm and the sham control group. So I think you'll see something very similar to that to come out of the Type B meeting with the FDA in Q1. Any other questions?

On previous occasions, you mentioned of the therapy for glaucoma.

Yes, you want an update in relation to it? Yes. So the commentary in relation to the potential for creating a drug for glaucoma patients is in re-purposing the ADOA program, PYC-001. And the rationale here is although glaucoma is not a single gene disease, so it's not the domain in which PYC specializes. There is a substantial advantage once you have established safety tolerability profile in a patient population in a Phase I study of using drugs that have already established that safety profile in other indications. You can go directly into a Phase II study here to look at the efficacy profile of the drug. So the concept that we were floating around was the idea of using the ADOA drug in the context of glaucoma to see whether the enhancement of OPA1, the target gene, or increasing the expression of the OPA1 protein could actually help preserve the retinal ganglion cells in patients with glaucoma to cells that are dying, that are compromising the vision of those patients. And this is based on data from animal models suggesting that if you increase OPA1 expression, you can actually help those retinal ganglion cells survive. So we have an ongoing body of work effectively, the bar for us is to build out internal conviction that we can see meaningful rescue of a sufficient number of retinal ganglion cells in an appropriate model of glaucoma preclinically. And so we're trying to complement those animal models of the disease with patient-derived models. So what we've done is formed a collaboration with an academic group who have taken tissue samples from patients with glaucoma and created those patient-derived models with which you're familiar, retinal ganglion cells. And so we are continuing to evaluate the potential utility of the ADOA drug program in glaucoma. I think for us as an organization, we're very much focused on, in the first instance, the delivery of those 4 efficacy outcomes in the single gene diseases because of the much higher propensity for success in the genetically validated targets. In glaucoma, we're still very interested in pursuing that body of work. But you must remember, it's a more complex disease process. There are multiple things going on concurrently. And so the big question is, do we have the conviction that increasing the OPA1 expression is sufficient to meaningfully change the course of disease in those patients. We'll continue to update you as that data comes to hand.

From a commercial perspective, you've got a runway of cash and you've got the objectives you're trying to get to. Unless one of those does come off, then in the situation where you're short of cash, how does that fit into those programs versus the cash in the runway?

I think firstly, that's the paradigm for all drug development companies that they're facing. I think one thing that is nice about PYC is we're a multi-asset company. And we have uncorrelated risk within the pipeline. So you've got in the 3 different target organs that we're going after, 2 delivery technologies, 4 unique oligos, 2 unique chemistries. So you get a lot of downside protection from a portfolio theory event. And I think that's one of the other areas of excitement in relation to the Phelan-McDermid Syndrome program. Remember here, this is the 2 prime MOE chemistry that's being used by SPINRAZA, nusinersen, the approved drug in spinal muscular atrophy. So we've got a lot of downside protection if something goes wrong within the programs. But very much exactly as you described, we are funded through to fiscal year 2028. So we've got quite a long runway from a biotechnology standpoint. And you can see within that time frame, we have got a lot of technical milestones that can drive potential upside. So we're very much looking at the same paradigm as you, but perhaps with a different lens, looking at what can we achieve from a technical validation standpoint that's going to drive further increases in the valuation of what we're doing before we would look to extend the runway. And as I spoke about before, you get into the realm of commercial optionality very, very quickly as you're moving through the generation of human efficacy data. So we know the transactional window for these assets has been delayed in ophthalmology because it's a relatively niche area, and these are smaller indications. So it's not a therapeutic area of primary interest to big pharmaceutical companies. But when you get into late-stage development, when you've got compelling human safety and a good group on the human efficacy data, that's going to open the window and talking to the transactional bankers, it's very clear that post the Type B meeting with the FDA, you are now in the window where you have the potential to out-license those assets. We've, I think, been very clear that that's our preferred pathway going forward. But I think it's also really important to know that we need to have the wherewithal and the capability to develop these assets ourselves. It's the P3 trial that we spoke about beforehand is very manageable in RP Type 11 for a small company like ours, even the commercial launch is very manageable for a small company like ours. So we have the flexibility there. And I think what you'll find is as we're generating data in the polycystic kidney disease program, you're starting to get yourself into the realm of transactions, very much like the Novartis acquisition of Avidity Biosciences. If you think through the relative prevalence of the indications that I alluded to in the earlier page, polycystic kidney disease is 5x the size of those 2 muscular dystrophies combined. Very, very important indication from an unmet need standpoint. And I think if you're seeing in that multiple dose study, a good indication that we are going to reproduce the registrational outcomes in the P3 sitting behind us, we're going to see a fundamentally different company to what you're looking at today. So you're right. But I think the downside protection is there, and we're very much looking at the upside opportunity of delivering these technical milestones over the existing funding runway.

If the magic moment in the kidney drug is when the kidney starts to reduce in size, in a meaningful way. Does that mean you measure it before we start and then you measure it at 12 months? Is there any point in measuring it in the middle at 6 months to get a clue? Is that the plan?

Yes. Yes, that's right. So the -- in the single ascending dose studies, firstly, you're quite correct, the patients are screened and have an MRI at baseline to assess the volume of the kidney. In the single ascending dose studies, those patients are having an MRI at 3 months and 4 months to look at the follow-up delta. And we also, as we move through to the multiple dose studies have regularly planned MRIs of those patients to give us that continuing feed of data in that respect. That's the very nice thing about a truly objective endpoint, the size of the kidney. There's nothing complicating it there. So we'll have those images processed in multiple different dimensions, not just the size, but looking at individual cyst volume, the amount of residual renal parenchyma that's present within the kidneys, and we'll be having a look at all of those metrics continually through the course of next year, which is why that data gets so exciting because you are looking at it 3, 6, 9 and 12 months as we're seeing patients who are receiving continual exposure to the drug candidate in the repeat dose format in the same manner as what we expect to take forward in the pivotal. So you're looking at identical outcomes in a smaller patient population, still substantial, 30 to 40 patients. Did you have any online?

Online, I think 2 of them you've already addressed effectively, they're about the potential for accelerated approval across the different programs. So I think you've already talked about the trial design for RP11 and the pathway for PKD. There's a third question, which is any positive leads from the AI program into future drugs or diseases?

Sure. The AI program being the Google collaboration here?

Yes.

Okay. So for everybody's background awareness, we entered into a collaboration with Google Cloud to see whether we could use Google's investment in the 3-dimensional modeling of proteins, technology known as AlphaFold to design a ligand or a binder that could specifically engage with that particular protein. And the idea here is that you're trying to concentrate is the drug delivery challenge, you're trying to concentrate your drug in a particular cell type that is expressing that protein. So if we can find a receptor binding domain or a ligand to engage with it, we can append the drug onto the targeting motif and get more drug inside the particular target cell and this has become an enormous area of interest to the field as a whole. The more drug that is in the target cell, the lower the dose at which you need to administer in order to achieve efficacy. Therefore, the lower the propensity for toxicity or side effect profile. We are struggling to put together all of the different elements that are required in order to successfully navigate that challenge. And in particular, it's the fidelity of the in silico -- or in the computer docking simulation between the ligand and the protein that is causing us a challenge. We remain very, very interested in that field. You can clearly see if you're across what's going on in the space, everybody is heading into this domain. So we have got some more work to do there. At the minute, it's a secondary focus for us because we're very much focused on those clinical readouts, but I think as we think through the evolution of the company to programs 5, 6, 7, 8, it remains an area of active exploration for PYC.

On the potential deal parameters for the RP11 drug in 2026?

Look, deal parameters, you guys get the same information that I get. I'd potentially get a little bit more because I'm privileged to the conversations with the bankers. But I don't think there's anything in those conversations that would surprise you. If you look at the recent transaction between Eli Lilly and MeiraGTx, I think for LCA 4, another inherited retinal dystrophy that is very rare. The potential patient population is about 10% to 20% the size of RP11. They got USD 75 million upfront. I believe it was $300 million to $400 million in milestones, and they'll retain a royalty that's typically in the low teens, tiered royalties between 10% and 20%. I think that, I mean, if you scale for the prevalence, possibly in a nonlinear format, that's around the ballpark that you'd be looking at based on the peer transactions somewhere in that USD 100 million to USD 200 million upfront, $300 million to $500 million in milestones, and a 10% to 15% royalty would be what we would consider to be the peer transactional value in that context. Now it always depends because there are factors that influence higher-quality terms. Obviously, the later stage we move, the greater the terms that we would expect in relation to the licensing of that asset. Any additional data that we can generate from those open-label extension studies that is giving us higher conviction that we can reach that [ statsig ] and the 15-letter threshold between the treated arm and the natural history of the disease would give us a greater expectation in relation to what we would want to see back. Now there is potential scope for trading off at risk money from the front end to farm into a larger royalty at the back end, but I think that gives you a decent color in relation to where our expectations would be on an out-licensing of RP11.

The last question that we have here is, I think, seeking some assurance about the tenure of Rohan Hockings into the future.

On the back of the recent events, I have made a commitment to see the organization through 2027, and in relation to the human efficacy data that we have on the screen. I'm Very, very excited about the potential for patient impact here. And I would love to be a part of the journey as we see those results come to hand. I think what goes beyond that is going to be dictated by what we, as an organization, look like on the back end of that process. So no reason why I would want to step out at that point, but I think shareholders do need to understand the magnitude of change that is going to come for PYC over the course of the next 24 months in the event that we're successful. And we have an enormous amount as we sit down as a new Board to grapple with in relation to the longer-term future of our organization. So very much dedicated to PYC to its staff, very enthused about the potential for patient impact. We are at the critical juncture in relation to realization of the outcomes that are going to move the needle. And I am super excited to work with our new Board and chart that course together. Any other questions? No, I don't think so. Look, I think the synthesis is very positive for PYC. We've been through a tumultuous window. I think we've largely put that behind us and are very much focused on the future now. In relation to each of the 4 drug development programs, we are in 1 of those unique windows where they are all going well together. Drug development is usually a process of problem solving and touch wood. We happen to be at a juncture where all of the programs are showing an enormous amount of propensity concurrently. And I'm not sure that any of us thought that all 4 of them would be looking like they are progressing into late-stage studies without a hiccup or a drama. Now I'm sure there will be twists and turns to come, but as we stand here today, I think the excitement amongst the team in relation to those who are driving forward, all 4 of the assets in the pipeline is stronger today than it's ever been. So what we now need to do is to the point before, we need to find a way of having the value recognized within those assets and evolve our organizational future on the back of the certainty that, that will afford us into where are we going in the longer term. And I think we have a lot of thinking to do there, but it's all exciting a great range of options. And I think if we chart that course well, we put ourselves in a very, very strong position going forward. And hopefully, we drive a substantial return for all of our shareholders in the process. Two more?

Two more that we'll [ pick up ] -- and then maybe we'll call it that. So one is asking about your shareholding in PYC. And then the other is asking if there's a chance that the FDA might agree to 10 letters instead of 15.

In relation to a shareholding in PYC, it's a matter of public record that I don't have one today. I'd very much like to acquire one. I'll be working with Peter as he comes on Board to find a window in which I'm not in blackout, so that I can go into market and buy some. So very keen to be part of the journey in that respect and also with Peter to incentivize the broader staff base from an employee share option plan. We have a huge body of work in front of us, and I think it's entirely appropriate that our staff are rewarded for the outcomes that we are looking to generate here. So that's the first one. In relation to the second and the propensity for the regulators to lower the bar. Look, it's a matter for the regulator primarily. Talking to the IRD specialists, I think there is a clear recognition that a 15-letter improvement in the words that one of the IRD physicians requires a monster of a drug to get there. So it is a very high bar on visual acuity, and we see very few drugs realizing that outcome. So we will engage with the FDA in a conversation in relation to what else might we be able to look at in relation to -- and we touched on it before, the other ways that we can use both the LLVA endpoint looking at the proportion of patients who are achieving that outcome. So focus on the best responders rather than the median responders and also to look at exactly what the FDA described they will look at with respect to the totality of the data. So in particular, and this is why we continue to list microperimetry, the assessment of the retinal sensitivity to light. If we see directional alignment of all of the endpoints, which we have done in the Phase I/II study to date, is that sufficient in the context of an unmet need to warrant the approval of the drug even in the context of a requirement to conduct a real world evidence or a Phase IV post-marketing study in that context. So it's an area of active exploration, but I'm cognizant of the fact that the regulator's opinion in this regard carries a lot more weight than mine. So we'll have to wait and see what the outcome of the Type B meeting is. I think the general sentiment within the FDA is favorable, as everybody is aware, there is a push for genetic medicines where we have a very strong mechanistic understanding of what's driving the disease and how a disease-modifying drug is addressing the root cause of it to contemplate alternative pathways for approval, and we're seeing that evolve in real time in the FDA. We'll continue to work with the FDA through the various designations that we've achieved there, fast-track designation, rare pediatric disease and orphan drug designation, hopefully, in the future, breakthrough therapy designation as well to have a conversation in relation to what is required to get this drug to patients with RP11, but I can't give a more concrete answer than that, I'm afraid. One final opportunity for those in the room. Otherwise, we'll consider you all fully abreast of progress in each of the 4 programs. No. Well, thank you very much for your ongoing support of the organization. I do think the team have worked exceptionally hard to put you in a position where you are going to see the outcomes in patients over the course of the next 24 months. We are quite a unique beast in the sense that you have 4 programs that are going to do that concurrently. So it's an incredibly exciting time for us and for the patient communities whom we serve. We are very grateful for the support of all of the clinical staff, but particularly the clinicians who are seeing these patients who I think have understood why these drugs offer something to these patients that no other drugs do. And the momentum that we have been able to build on the back of that has then rolled through to very efficient execution of the clinical trials that puts us in a position where we are extremely proximate to seeing the currency of the realm, human safety and human efficacy data. And if we start to see compelling data in that regard, I think we're going to be in a good position, has been complicated by the variability of the endpoint assessment and the very slowly progressive nature of these blinding eye diseases, which is a good thing for patients and that makes our life a little bit harder. It will become more black and white as we move through to polycystic kidney disease because of the objectivity of those endpoints that we've spoken about and in particular, in Phelan-McDermid Syndrome, language and cognition improvements. If we see similar outcomes to what we've seen with the other RNA drugs for neurodevelopmental disorders, it's going to be a very, very exciting time. Thank you all, and we look forward to updating you on the journey through 2026.