Good morning, everyone, and welcome to the PYC Therapeutics Second Quarter Investor Webinar. My name is Rohan Hockings. I'll be your host for today, and you may just have to bear with me through the course of the presentation. I've been unwell over the course of this week and haven't quite recovered as much as I had expected, so I am slow in movement, slow of thought, and perhaps the silver lining, slower in speech than usual. Before we begin today's call, I would like to remind you that today's call is being recorded and also to make the following safe harbor statement, reminding you that today's discussion will contain forward-looking statements that involve risks and uncertainties. These risks and uncertainties are outlined in our filings with the Australian Securities Exchange. As such, actual results may differ materially from what we discuss on today's call. We disclaim any obligation or intention to update these statements in the future. The objectives for today are really threefold. Firstly, I wanted to provide each of you with a detailed overview in relation to where each of the four pipeline assets have got to in terms of both their progress year to date and also the outlook for the remainder of the year. This is an ongoing conversation. We have outlined previously our 48-month path to revenue generation, and we are going to focus very much in on the first half of that, the next 24 months. Where did we expect to get to, and how have we performed against that? I would also like to touch on some of the platform implications of the near-term program milestones. As many of you will be familiar, we had an enabling technology, a drug delivery technology, and we have spoken previously around the need to define the programs that came of that, the product that was born of the enabling technology. We are now getting to the point where we are seeing the clinical validation of the programs themselves give a reverse validation to the platform as well. We are going to touch on some upcoming milestones within the drug development pipeline that are going to have read-through for the platform as a whole, and then through the Q&A in particular, but we'd also like to contextualize the recent progress in the context of the broader commercial landscape. I think to run through each one to give you the headline messages before we begin. If we think about the industry as a whole, like an onion at the minute, the outer layer of the onion remains very much rotten. It is a very difficult time for life sciences generally because of the pervasiveness of the risk-off environment. Many of you will see, have seen from monitoring of our peers and what's going on more generally within the space that it continues to be a very difficult time for biotechnology companies. This is really since the downturn of 2020. Things haven't turned around or recovered in any way, shape, or form. Hopefully, as we see yield curves come down and the cost of capital come down, that will be the trigger for that transition back to more of a risk-on environment because it is important what's going on in the macro. If we think about what's happening within each of the layers of the onion that sit within that, the story is very different. Within the subsector of the RNA therapeutics, this continues to be one of the highest momentum areas within the industry as a whole. If you look at the—sorry, one second. We've just got a hand raised. Alex, did you have something that you wanted to say? If so, could you type it into the chat box? I've lost that. Here we go. Come back to that one. I'm not sure whether you did mean to raise the hand there, Alex, but if you have got something to say, if you can type it into the Q&A or chat box, we'll deal with it there. Just looking at some of the transactions in the last couple of weeks within the space, you will have seen Biogen enter into an agreement with City Therapeutics, looking at the facilitated delivery of RNA therapeutics, and also quite recently, AbbVie entering into a platform deal with ADARx. The continued theme of all of these commercial engagements agreements is using a targeting delivery technology to get more of an RNA drug inside of the cell. RNA therapeutics in particular have remained a very hot space, and many of you who remain abreast of what's going on in the industry will have seen a very significant step back from the virally delivered technologies. We've seen a lot of trouble with the AAV gene therapies. We've had a number of patient deaths, including quite tragically one last week in Rocket Pharmaceuticals, ongoing clinical studies that have really highlighted some of the safety issues that go alongside these viral delivery technologies. I think very much validating the PYC strategy of using the non-viral delivery technology and operating at the RNA rather than the DNA level in that context. In terms of PYC's pipeline itself, we've had a very good year to date. I think firstly, the two programs that have been something of a laggard within the pipeline as a whole in the form of the ADOA and PMS assets have really hit their stride. I think we have righted the ship there, and I think we are going to see some significant momentum come from each of those programs very soon. This complements a very positive industry reaction to the presentation of the most recent cut of the RP11 data at the Foundation Fighting Blindness and ARVO presentations earlier this month in the U.S. Where things get really exciting and I think are going to accelerate a lot more quickly than many of you are expecting is in the kidney program. We are going to touch on that in some detail as we go through the program updates. Very broadly, the objectives for the remainder of 2025 will continue to be to take all three of the clinical stage assets through to mid or late stage clinical studies by the end of this year. It is going to be a very significant step change as we look to take three programs to repeat those studies in a multi-geography format across each one of those indications by Q4 of this year. There's certainly a lot going on there. From a platform standpoint, we are starting to see the interest move beyond individual programs from a co-development, business development, and licensing standpoint, and we will talk through why we are seeing that occur and how that is likely to continue for the remainder of the year. Before we get into the deep pipeline update, I wanted to just do a quick revision for those of you who are unfamiliar with the company to make sure that we have introduced ourselves for those who are new to PYC. PYC is a drug discovery and development company who makes precision therapies for patients who have a genetic disease in the context of a very severe unmet need. We make drugs for patients who do not have any treatment options available today, and we make it for patients who have a severe illness. We do it in the context of creating the type of drug that we would like to take if we were a patient with these diseases. These are what we call disease-modifying drug candidates that address the root cause of what is going wrong in the disease, and we validate those in a 3D mini organ as a quantitative cure. We are looking at restoring gene expression back to unaffected or wild-type levels before we take that drug candidate into clinical development. We do it in areas of major unmet need, so we are operating at scale. We want many patients to benefit from the impact of these therapies, so we focus on those rare diseases that are at the more prevalent end of the spectrum. These are markets worth between $1 billion and $10 billion per annum. Because we are going after the very simplest type of disease, a type of disease that is caused by a mutation in a single gene and a single gene only, these drugs are associated with a five times greater propensity for success in clinical development than the industry average. When we start a phase I clinical trial, we have a roughly 10% probability of a successful market entry for the industry as a whole. These drugs are around five times more likely to be successful than that. I think the very exciting part, excuse me, as we've spoken about previously, is that PYC has got multiple human efficacy readouts coming within the course of the next 12 months. As all of you know, human efficacy data is really the currency of the realm. This is what moves the needle for the industry more than anything else. We've managed to use our strategy of creating RNA therapeutics for diseases caused by what we call haploinsufficiency or having a mutation in one of two copies of a gene that results in there being about half as much gene expression from the one remaining good copy as there should be to build ourselves a pipeline of first-in-class drugs with disease-modifying potential. Those assets have progressed through to different stages of clinical development, and we'll go through exactly where each one of them have got to and exactly what the road ahead looks like for each one of these programs as we move forward. Okay, for the program level updates, I'm also very happy to take questions as we go, so please feel free either in the room or online. Let's see if we can monitor the chat forum at the same time. Yeah, I wanted to let you know exactly where we've got to in relation to each one of the programs. For RP11, many of you will know that we have recently presented the clinical proof of concept data at those two international conferences that I mentioned. What we are going to do from here is the first thing we're going to do that I wanted to advise you of today is we are going to roll over this phase one two study into an open label extension trial. We're going to continue to dose those patients who've had their 6, 12-month exposure to the drug candidate for a further 12 months. We have in aggregate 24 months' worth of data for those patients. We can see how the data that you are seeing coming to the public domain continues to evolve through the course of that 24-month window. There will be a couple of changes that we make as we move through to that open label extension in June. One of those will be that we are going to increase the dose. This is not because we are not satisfied with the results that we've seen, but it is because we want to make sure we have maximized the benefit of the drug in the context of the very clean safety tolerability profile that we've observed to date. The 30 microgram patients will be pushed up to a 120 microgram dose, and we'll continue to monitor those patients. If we don't see any safety tolerability signals, it'll be the 120 and the 75 microgram doses that we take into the pivotal study, the registrational trial that will kick off later. We will also start to play around with some of the other elements to make sure we fully optimize things like the dose interval to see whether, if nothing else, if we don't get an enhancement of the efficacy signal, perhaps what that increase or escalation in the dose could do is further extend the dosing intervals to make it more convenient for patients, see whether we can push that out to three or four months between doses for the patients. That is the first body of work. Really there, what we're looking for is to understand when we cross the threshold of registrational approval for the FDA and the other regulators globally as we look at monitoring the signal through the second 12 months of exposure in those patients. As many of you will have seen, we're getting very close to reaching those thresholds, even within the first 12 months of monitoring the patients after enrollment in the study. The particularly important dimension is to understand how does that manifest over the additional 12 months to give us that insight as to when we might be able to unmask the registrational trial that's going on concurrently. The other important dimension of understanding what exactly that registrational study is going to look like is to be to understand from the regulator where their current thinking is in relation to the bar across those two endpoints that you have seen us speak about, the two endpoints upon which the patients are moving, that either of which could serve as the primary endpoint in the study, visual acuity, the low luminance visual acuity that we're looking at, or microperimetry. We are going off, and I think everybody is now aware on the 6th of June to have the conversation with the FDA to gain an understanding from the regulator as to where their current thinking is at. In particular, it will have been of great interest to many of you that the recently appointed head of the FDA has come out and said that there is potentially an adjunct or an additional accelerated approval pathway where we have a plausible biological mechanism supporting the mechanism of action of the drug itself. You do not get a more plausible biological mechanism than a disease-modifying drug in the context of a monogenic indication. Things have moved a little bit at the FDA, and we need to understand what are the implications of that movement for our registrational trial. It is really marrying those two dimensions. Where the regulator's thinking is at in relation to the approval pathway or the bar for approval and how patients continue to evolve in terms of the improvement across those two registrational endpoints throughout the second 12 months of exposure to the drug. As we combine those two pieces of information, we'll go back to the FDA later this year to have the pre-phase III meeting and confirm the design of that registrational trial. Any questions on the RP11 program? Just one second, I'll get you to. Would you be able to inform the investors of the outcome of that meeting with the FDA? Yes. Yes. We'll wait for the 30 days for the meeting minutes to come back, but we will give a synthesis of the outcome of the meeting at some point in July. When will you be able to release to the market the next set of results for the 30 or the 7,530? The open label extension data. I guess it's a judgment question on our part because what we don't want to do is drip feed every time a patient comes in for a follow-up, put the data release out. We'll confirm that later on this year, but I was thinking that at some point in Q4 would be a nice time to do that when we've seen basically all of those patients that you've seen in the data release to date reach the 12-month milestone or more, and the most advanced patients move out to the 18-month mark. It'll come in the study as a whole. There are 12 patients who we're following on through the extension studies. Yeah. Just one second. If you don't mind, just speaking into the microphone so the people online can hear the questions as well. I just didn't think there was a last outcome that would be true. Just mean the. From From the patients. With one patient there who said they were a little concerned about their other one. Yeah. Because they were really excited about it. Now that you're going to be pushing this out for another 12-plus months, what's going to happen to those patients with their eye visit getting the dose? Yeah, that's a very good question. What we need is to have 12 months of continuous dosing safety data in the treated eye before we're allowed to cross over to the untreated eye as well. We will provide access to those patients for the contralateral or the fellow eye, and then we'll have data for both of those eyes after we've reached the 12 months of exposure. Yeah. I think I'll just check online to see whether we don't have any questions here as well. On the previous call, we mentioned the possibility of administering a dose higher than 75. Is that option still under consideration? Yeah. We've answered that question. Yes, we'll be moving the 30 microgram cohort up to 120 micrograms, persisting with the 75 microgram cohort. In the event that we see a safety tolerability signal, we'll drop back down to 30 micrograms and take 30 and 75 into the registrational study. In the event that we don't see a signal, we'll stick with the 75 and 120. Can we clarify whether the FDA has provided any preliminary guidance on the design or endpoints of the planned registrational study? Are there any recent informal interactions you can speak to? No, we haven't had any interaction with the FDA on that to date other than us having submitted the briefing book for the meeting that's coming on the 6th of June. The FDA will get back to us with about a week to go. We are getting very close to the window where we do expect the guidance from the FDA, but we haven't received that yet. We'll give you an update on that after we've had the meeting and we've had the 30 days passing to get the minutes of that meeting. Oh, another one coming through. Is the biological mechanism approval route limited to life-threatening disease or other? That's not clear at the minute. I think the difficulty here is because the commentary is coming largely in the form of media interviews between key personnel at the FDA. We're not seeing the full color or don't have a great understanding in relation to exactly what does it mean. That's part of the reason of going to the in-person meeting to have the conversation in relation to where does the rubber meet the road. What does it specifically mean for sponsors in this context? Okay. In the ADOA study—oh, sorry, I got one more question. Do you want to just—okay. I'll repeat the questions. Yeah. Look, we certainly hope so. It's possible that we've got two better responders who just happen to be the two most advanced patients. If that's the case, then it's nice to have those patients, but what you'll see is a flattening of the line in relation to the intersection of that approvability bar. You can see very much even with the earlier stage patients that we're on track for realizing that outcome. The other possibility is because it's taking longer to get the better response in those patients. We're certainly hopeful that we'll see something akin to the current trajectory. If that happens to be a little bit flatter, all it will mean is that it will take slightly longer to cross the conviction of approvability threshold to unmask that data in the registrational trial. Yeah. Okay, so RP11 is going very well. I think just to give you all a very brief update, there was one patient who had not been dosed in the MAD. That patient has now been dosed and has been through their four-week follow-up period. We have completed the dosing of all of the patients in the initial protocol. We are now looking, as I mentioned before, to move into that open label extension study in June. In ADOA, we ran into a number of operational issues that were quite unfortunate. We had a single site that was involved in the execution of the clinical study. Our principal investigator went on medical leave for a period of time. There was a broken piece of equipment at the Sydney Eye Hospital that we had to replace. That took a while to get shipped to the hospital and then installed within their IT systems. We've been slower from a patient recruitment standpoint than what we had hoped. Things were not as efficient as we had hoped they would be in the early parts of this study. I can confirm now that we have completed dosing in cohort two, and we are within a fortnight of the safety review committee meeting for cohort two in the ADOA study. We've brought a second clinical trial site online, and I think we have addressed the issues that were causing that to be slower. We're expecting to complete the dosing of cohort three before the end of June, and we'll then get four-week follow-up data for those patients in July and three-month follow-up in September. What I'm expecting there, we've put the clinical proof concept into next year, but I expect this to unfold very much like what you saw in the RP11 trial, which is that you started to see anecdotal reports, individual patient outcomes, and some early efficacy signals at a sooner point in time than we could declare the clinical proof concept. Yes. Yeah. I believe that there, again, in early Q4, there is a planned presentation of that data at a scientific conference. We'll be seeing that one come out. In polycystic kidney disease, I can also confirm that we've completed dosing of cohort two in the healthy volunteer study. We're now within six weeks of dosing patients within this trial. For those of you who have been following the Regulus Therapeutics data, I think the very exciting thing around what's happened with Regulus lately is more on the biological side than the commercial side. What they were able to show there was that within a three-month window in the repeat dose studies, they were able to see movement on that registrational endpoint, the anatomical surrogate or the total kidney volume, because the miR-17 that Regulus are targeting is acting on the three-prime untranslated region of the PKD1 transcript. And so is PYC's drug. There is a real proximity of the biological mechanism there for disease-modifying drugs. We are very much expecting that is going to inform an accelerated timeline to see movement on that endpoint in the PYC clinical study. Remember that we'll be moving through patients in Q3, and then we will be getting into a repeat dosing format in Q4. Very much expecting to see the data that we're all very interested in here, either in Q4 or moving through into Q1 for some of those higher dose cohorts there as well. Yes. Yeah. We're targeting the same patient population. We are competitors in that sense. Yes. Look, it's a very interesting situation. I think with Regulus generally, you see the upfront component that Novartis parted with there in the order of $1.25 billion, which is a relatively small acquisition in the context of our industry. That's what they refer to as a tuck-in acquisition, less than $2 billion in value. What we are hoping to see is the preclinical differentiation of our molecule manifesting clinical differentiation. We have touched on this previously, but to recapitulate the points around where we see outperformance and quite a unique profile of PYC's molecule, firstly on biodistribution, it is more drug in the kidney, and secondly on the evenness of the distribution within the kidney. Critically, PYC-003 is distributing to the renal medulla. It is getting to the inside part of the kidney where you have some anatomically sensitive cysts. The next part is on the integration of the PKPD safety tolerability readouts in the non-human primates. If you remember, PYC was able to see the wild-type monkeys that do not have a mutation in the PKD1 gene, but we are able to see the human drug work in the context of the monkey at a safe and well-tolerated dose. That was very encouraging. Next, we have the Ex Vivo 3D Cyst model where at like-for-like dosing, we are outperforming in terms of the reversal of that phenotype, stopping the propagation of those cysts in that context. Finally, from a safety tolerability standpoint, the direct nature, the fact that our drug is acting specifically on the PKD1 transcript lowers the possibility for the off-target safety tolerability or toxicity issues that could be seen in that context. It is a beautiful set of differentiators in the preclinical setting. Very exciting time to see that wind through to clinical translation. I think the other thing that everybody should be aware of here is a relatively narrow data set in the context of what Regulus were able to put in the public domain. They had a three-month multiple ascending dose study, data from a three-month trial that they were able to put out in the public domain because they had done three-month repeat dose tox studies in non-human primates. They were only able to mirror the duration of the dosing and the repeat dosing format in the humans as to what they've done in the non-clinical setting in the monkeys. What that has meant is that it's terrific that we see this movement on the registrational endpoint within a three-month window, but what we don't know is how does that unfold over a 12-month window against that endpoint, and also how does that unfold over a 24-month window to the ultimate registration endpoint, which is the estimated glomerular filtration rate. There was no movement on that secondary endpoint in the context of that study, which we may expect because that will take longer to see that movement, but we do not know fully either how that data is going to manifest over that longer time period or actually what it means for the patient either. Because if we think about tolvaptan, the drug that is approved in this setting, that was able to confer about half of the benefit in terms of reducing the size of the kidneys as we see with the Regulus molecule, but it only ended up deferring the need for a renal transplant by less than 18 months. It did not make a major impact in terms of the efficacy profile from a patient standpoint. There is a lot of unanswered questions, and as we move through to answer those questions through the course of next year, we will be building a much more mature data pack in that sense by taking more and more risk out of that program. We have got a couple of questions coming in online. Many webinars ago, you mentioned 100% of clinical trials that went to phase III made it to market. Do I still hold that confidence? That is referring to a retrospective study. I think it was [cametal who looked at the precision medicines in phase III development, I think in the early 2000s, and showed that very high success rate. I will point out that that was 100% of the drugs having the intended biological impact on the target. I think it yielded a slightly lower rate of approvals in the order of 80% in that context. Yes, fundamentally, we do still hold that conviction. We have been very comfortable, and we're going to touch on it shortly from a partnering standpoint in holding the risk of these assets precisely because they are high-propensity programs. It all comes down to the validation of that target, knowing that this gene is causing this disease. If we can couple that with an understanding in the preclinical setting, in the human organoid model, that if we can fully restore gene expression and we can get enough drug in the non-human primate to the target cell in the target tissue to achieve that effect, yes, we have very high conviction in relation to each of these programs. With the success of competitors in the ADPKD space, how will that impact possible approval? I only approve if improvement and/or impact the portion of the addressable market. What you'll see here is that we'll be starting our registrational trial in ADPKD before the Novartis or Regulus molecule has finished their registrational trial. It won't have any outcome on us on that case. Can we elaborate on outperformance in the cyst model and why is that so important? Yes, if you think about the fact that PYC's drug has got the delivery technology built into it, it's part of the molecule. You've got the peptide that is responsible for delivery of the RNA therapeutic across the cell membrane to where it needs to be. Regulus is what we call a naked technology. It doesn't have a facilitated delivery technology in it. If we look at like-for-like performance in the same model at the same concentration, we'll see a greater reduction in the cyst volume associated with treatment with PYC-003 than what we'll see with the miR-17 targeting molecule. When do we expect to see differentiation versus Regulus? SAD, MAD, NHVs, PC1 protein increasing, or SAD, MAD in patients? What could be the differentiator? We've spoken there. I mean, the differentiator is going to come on one of those two endpoints that we've spoken about, either on the durability or the magnitude of the response from a total kidney volume standpoint, or on the movement on eGFR, the two endpoints that we are most interested in in that context. Will it come in the SAD or the MAD? It's difficult to say. I think we would be very lucky to see it in the SAD, but the one reason that we have got a very different profile again to Regulus is that our molecule has got a much longer half-life in tissue. A single dose of the drug, particularly because the PC1 protein is a transmembrane protein and has quite a long half-life in its own right, it is possible that you could start to see movement there. I think to be safe, we would take the like-for-like comparison with three months' worth of data in the repeat dose setting. There is not long to wait in that context. That will start in Q4 of this year. For higher dose cohorts, that will come through in Q1 next year. It is coming sooner rather than later. Whether or not it's in the urinary PC1, look, it's possible, but I think now, given that Regulus have shown the movement in the TKV, that's where most of the interest will be anyway. Biopsies from the healthy patients at the moment or later since you just urine sample? I'm interested to know how you're seeing more of the drug in that outer layer of the kidney that you mentioned. Yeah, we can't take a biopsy for ethical reasons from the patient. A renal biopsy is a very significant procedure to undergo in that context. This is based on the animal models, looking in both the mouse kidney and the non-human primate kidney, where we're able to harvest the entirety of the kidney and use some much more sophisticated technologies to look at the distribution of the drug within the tissue in that context. It's inferred from that. What we're taking from the patients is the plasma reading, so blood sample, and then also the urinary sample as well. We'll triangulate through those from the data that we see in the preclinical setting in those species. We'll use, if you think of it as two triangles, urinary PC1 plasma concentration of the drug to the target tissue concentration that we saw from the animals. Then we'll use the two variables that we have got in humans to reverse, infer the concentration in the human kidney, given that we can't take the biopsy in that setting. Given the three-month repeat dose NHP tox studies and the start of the DINGO extension, has the FDA indicated whether the DINGO human repeat dose data will contribute to the registrational NDA filing, or is a standalone pivotal trial still required? Look, it's very much our expectation that there will be another registrational trial required in that context. Taysha is now allowed to run their phase III using a natural history control in Rett. Is this something you think you could do in RP11 or any of the other assets? Yes, we think we can compare to the natural history study in terms of the comparative benchmark for the phase III. It will be combined. We will need an in-study control, and then there will be a hybridization of the in-study control with the natural history studies to form that benchmark of comparison. Okay. In the Phelan-McDermid syndrome program, as I mentioned before, this one has really started to hit its stride recently. We have a program go/no-go decision for this molecule coming in the third quarter of this year. What we're looking to do here is really trying to change the shape of that risk curve, the probability of success curve that we've spoken to you about before. The first thing that we do, as you know, is choose the monogenic indications to go after. That gives us a much more aggressive ramp-up in the propensity for success. The second thing that we do is we create the human neurons, the brain cells from the patients with Phelan-McDermid syndrome. We take a tissue sample, a skin sample from those patients, reverse differentiate it into an induced pluripotent stem cell, which is a cell type that can turn into any other cell type in the human body. We turn those stem cells into brain cells, neurons, and then we measure the impact of the drug on the SHANK3 gene. We're looking to see whether or not we can compensate for the one lost copy of the SHANK3 gene by getting the oligo to bind to the remaining good copy and create two units of the protein to fully compensate for that rescue. That's a critical part of the data pack. You've seen that being released previously. Many of you will be aware that we have actually changed our backbone chemistry here. This program has got a different backbone chemistry to any of the other assets in the pipeline. What that's enabling us to do, and the area of greatest interest for us right now, is taking an antisense oligonucleotide for a different neurodevelopmental disorder called Dravet syndrome that shares the same backbone chemistry as the PYC-002 molecule here. One that has been clinically validated in the context of Dravet syndrome. This is by a company called Stoke Therapeutics, who are just about to start their phase III study. They have some very nice phase one two data in Dravet syndrome, particularly across language and cognition. Language and cognition happen to be the two elements of the phenotype that are most important to the Phelan-McDermid syndrome population as well. What we are going to look to do here is show you all of the key preclinical metrics of the PYC molecule and compare them to what we saw for SDK-001, the Stoke molecule. That will give us even more read-through to the clinical validation, given that this is the same chemistry of backbone, same length of oligonucleotide, same route of administration, same target cell in the same target tissue, manifesting in the same phenotype in patients. You can see why that's going to build out further conviction in relation to that program's path forward. That will come in the third quarter of this year. We'll be able to share that data with you. Hopefully that gives you a pretty good understanding. We're very happy with how the pipeline milestones have unfolded in relation to each one of the programs. We're very much on track with respect to where we thought we'd be. I think we have righted the ship in the domains of the pipeline that we were having some difficulties. I think you'll see a very efficient translation through the second half of this year, getting each one of those assets into the mid or late-stage clinical studies that we set out to achieve. The other dimension that I wanted to touch on is the platform validation that is going to be conferred by upcoming program milestones. In particular, here, I mentioned before that we're not going to have to wait for the clinical proof of concept. It's not a binary thing. This comes in an open-label format, so it's going to evolve over time. We're hoping to see some of that in the fourth quarter of this year in relation to the ADOA efficacy signal. This is going to put the company into a very strong position. If you think about having two completely separate molecular entities for two different types of blinding eye disease, both of which are showing improved visual function in the event that that's the outcome that we see in the ADOA patients, this is telling us that we have got a platform for the control of gene expression in the retina via an intravitreal route of administration with a very clean safety tolerability profile. That is actually a unique offering in the world of blinding eye disease drugs. We are not aware of any other modality that has got a similar profile there. We have spoken previously, and I touched on in the last webinar, there's some additional work that we're doing in relation to use of the PYC-001 molecule in the context of other blinding eye disease where we've got a bioenergetic deficit. Remembering that PYC-001 targets a gene called OPA1, which is a mitochondrial protein. This is responsible for helping the cells to produce energy. If we think about other indications where mitochondrial health is compromised, conditions like glaucoma and geographic atrophy, two of the biggest unmet needs within ophthalmology, non-orphan indications, there is potential application of PYC-001 in that setting. What we are running through a collaboration with the University of Melbourne is evaluating the impact of the PYC-001 molecule in patient-derived models from patients with glaucoma and geographic atrophy. We will see that data starting to roll through as well. It obviously opens up a lot of additional indications that we could then turn our minds to with respect to blinding eye diseases caused by mis-expression of different genes within the context of the retina itself. In the context of PKD, we have seen already an incredibly strong biodistribution profile to the kidney. If we can see movement on that registrational endpoint coming in, as we spoke about, either late this year or early next year, that will also give us a very strong conviction to moving into other renal diseases where we have got prominent gene expression involvement. It is that incredible biodistribution and the evenness of the drug within the non-human primate kidney that we spoke about earlier. It really is a unique profile with respect to delivery of a precision medicine outside of the liver. Very interestingly, in the context of the CNS, we have done some work here that we have spoken to you about in relation to identification of receptor-targeting ligands. Not cell-penetrating peptides, a different form of peptides that can confer greater delivery to the target cell. In the context of the Phelan-McDermid syndrome program, the reason that we moved away from the cell-penetrating peptides was because when we administered the drug at the base of the spine, we were seeing the peptide, the cell-penetrating peptide, confer far too much uptake in the spinal cord. It was diluting the amount of drug that was getting to the brain because the peptide was, in a sense, too potent in that context. That was behind the shift to the two-prime MOE, the different chemistry that we spoke about earlier. What we've tried to do here is to replace that with a peptide that is not a cell-penetrating peptide, but is directed towards a receptor that sits on the surface of neurons and can enhance the uptake within the neurons. We've seen some very encouraging results in rats that we're going to recapitulate in the context of the third quarter of this year in non-human primates. If we see that validated, that also becomes an enabling technology for going after other diseases of neurons, an ultra-high-value target in the CNS. I put this one mainly for you to read at home. I wasn't planning on reading it out, but I wanted to give you some insight as to the way that the PYC board thinks about dealmaking. It comes back to the point, the question that was made online in relation to, do we still have the conviction in the assets? The company has always been comfortable with holding the risk of the early mid-stage clinical development, even late-stage clinical development, because of the very special, unique nature of these programs with respect to their propensity for success. What that's really enabled the company to do is to hold on to the assets until a sufficient amount of value has been built that we can extract appreciable deal terms for those assets if we decide to out-license them, but still leave enough value on the table for the counterparty to make them attractive to them too. This page just talks through why companies in the U.S. on U.S. exchanges trade at a premium when their assets are unencumbered or unpartnered in the expectation of that deal premium. I think the really exciting thing for PYC, and acknowledging that it's been a frustrating time from a market recognition of value standpoint, we have a lot of optionality now in relation to each of the assets in the pipeline coming into a window where they are transactable. We can deal with these assets in the event that we want to raise non-dilutive capital. We can out-license one of the assets and reinvest the proceeds in taking the rest of the pipeline deeper into clinical development through to commercial launch. We are getting ourselves into a window where hopefully we see the turnaround in the macro scenario. That would be important. I would love to see it in the equity capital markets as well. If we have strong delivery through the next six and twelve months into that tailwind, it's going to be a very interesting time for the company as a whole. In the event that we don't see that, we've still got the optionality of talking at the asset level from an out-licensing standpoint to access the non-dilutive capital to see the company continue on its journey. With that, I will open up for Q&A. Any other questions in the room? Yeah. Do you have to talk about micro- and micro-integrity conditions? Could you take RP11 through to the endpoint without any other investment? The question is whether we could take RP11 all the way through to commercial launch. When you say without any other investment, do you mean on existing cash reserves, or do you mean do we have the technical capability to do it? Yeah, yeah, we do. The current estimates for the cost of the registrational study for the RP11 asset is in the order of $60 million. We do not think that is going to change too much based on the input that we get back from the FDA. If we wanted to go, and this has been the situation for a while now for the company, if we wanted to go all in on one asset, we could very much take that asset all the way through. If you think about across the spectrum of commercial product launches, RP11 would have to be just about the easiest molecule there is to launch because these patients are all tied to one of a handful of specialist disease registries in the U.S. in particular. Your sales and distribution channel would be incredibly concentrated in that context. Not only do we have the capital reserves to do it, but we also have the wherewithal to do it. It would not be a big undertaking from an organizational development standpoint to be able to do that. I think you know that the appetite is to invest throughout the pipeline and go after those indications that are larger and going to have an impact in more patients at scale, much more commercially attractive indications as well. Each one of the assets in the pipeline right now is looking very attractive. Are the drugs threats to the mutual value of some of these drugs as a real threat to your business? Not at this point in time. I think we have always been very careful to ensure that the drugs were valuating in their own right and not dependent on the orphan drug pricing. If you think about the cost of servicing patients with any one of these indications in the pipeline, Phelan-McDermid syndrome, those children are non-verbal. They require a full-time carer. The cost to society of looking after those individuals in the context of polycystic kidney disease, if you think about the hemodialysis burden, the renal transplant burden, the immunosuppression, the cost of the healthcare system of looking after chronic kidney disease patients. In the context of the blinding eye diseases, not only do you lose that individual's contribution to the workforce, but they also, on average, require 30 hours of a carer per week for patients with retinitis pigmentosa. They all independently will justify reimbursement at that pricing. We have not seen a lot of noise coming from the Trump administration generally, but the rare disease space has actually been relatively shielded from the discussions at this point in time. We are not seeing anything that would cause us particular concern. The forums for RP11 that were presented, did you see any increase in interest? Yeah. Pharma or anybody else? Yeah, yes. The foundation, sorry, the question for those online was, did we see any additional interest on the back of the presentations at the Foundation Fighting Blindness meeting and at ARVO? I think the answer is yes. The first thing that was really lovely was a lot of the principal investigators on the study were present in person at the meeting. What was really nice was I was not there. Sri was attending, so I heard this secondhand from him. A lot of the principal investigators, when they saw the patient-reported outcomes, came and reported very similar outcomes in the context of their patients. They were not involved in giving the testimonials. There is a huge amount of enthusiasm from the KOLs, the principal investigators in the study, firstly. Yes, there are a lot of commercial entities present at the ARVO conference in particular as well. There have been a number of conversations that have, I think, materially moved forwards on the back of the data release there. That was an important body of data that came out there. In relation to the recognition of value, that is publicly determined by the ASX price, but volume there is low and it is hard to buy up for instos. How can you get volume up and/or how do instos come on board? Yeah, look, that is a good point. The liquidity in the stock has been very weak lately. Even for PYC, relative to pre the entitlement issue, we've seen a significant drop-off in the volumes. Look, I mean, I guess very difficult for me to say it's a meeting of the minds in relation to people who wish to sell the stock and people who wish to buy it. I don't know what we can do in relation to increasing the liquidity. We've got a lot of long-only, long-term investors on our books at the minute. I think it's a matter of offering a price that is attractive to try and wash out some of the holders who are looking to exit the story for one reason or another. I'm not sure if I asked any change in view on key personnel changes at the FDA and how that may impact thoughts around trial design and approval. We haven't seen any impact on our engagements with the FDA to this point. We'll give you an update in relation to that question. I think we'll have more insight post the 6th of June meeting there. We saw there was a bidding war for Regulus won by Novartis. Have the other parties been in touch with PYC? I think we've told you all along that we've been in continuous dialogue with key industry participants in relation to a number of the assets in the pipeline. We continue to have those conversations, but generally, I think the best time to talk about a BD deal is when they're done. Given that we flagged the potential for out-licensing one asset to fund the rest of the pipeline, which program is currently seen internally as the most likely candidate for that, and how close are you to initiating those discussions? Look, I think the asset that would probably lend itself to an out-licensing agreement that would meet the needs of the company investors the best is the RP11 program. Increasingly, we're finding in the discussions around the RP11 program that for most counterparties who are interested in the RP11 program, they're also interested in ADOA. The two of them, two rare blinding eye diseases genetically defined, are going together in that context. How close are we to initiating those discussions? Much like the PKD asset, we've been in continuous discussions with a number of industry participants for several years. The reason that we brought forward this investor webinar is because we'll be on the road in the U.S. in June, attending BIO and having a number of meetings around the BIO partnering conference where we will continue those discussions. To your knowledge, is Novartis aware of your ADPKD program? Look, we don't comment in relation to specific counterparties that we are in discussion with other than to say that we are having discussions with a number of large industry participants in relation to the PKD program. Any other questions? No. Okay. Look, a very exciting time for PYC. What we really need now is a very solid 12 months of execution. I think we are going to be in a very different place this time next year when we have three mid to late-stage assets in clinical development. If we have very strong data in support of each one of those assets, as we're expecting to do, we're going to be in a very, very nice situation for the organization. I think that will make all of you very happy. It's also an incredibly exciting time now to see right on the cusp of what are the patient outcomes that we're going to be able to generate across each of these indications. First cab off the ramp was RP11, and we're certainly very pleased with the outcomes that we've observed there. All we need there is more of the same, but now time to bring online the ADOA efficacy signal and the ADPKD efficacy signal. If you think about the maturity of that data pack moving beyond what Regulus were able to put in the public domain through the first quarter of next year, answering those later-stage questions around what does the 12-month data, what does the 24-month data on eGFR look like, it's a particularly exciting time for patients and also for the staff at PYC. Thank you very much for your interest, and we look forward to updating you through the course of the journey.