All right, we might get started and put an end to the excruciating silence within the room. Welcome, everybody, to PYC Therapeutics' first quarter investor call for 2024. My name is Rohan Hockings. I'm the Managing Director of PYC, and I will be your host for this morning. Before we begin, a couple of housekeeping matters. The first one is to let everybody know that today's call is being recorded, and the second one is to read 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. So with that, the theme for today's presentation, to give you a snapshot headline message for shareholders, is that the company is very much on track and in the window. And we will put a bit of color around that with respect to the company's longer-term ambition of becoming a commercial stage at scale biotechnology company. We'll look at the broader 48-month journey the company is embarking upon to realize that ambition. And then what we'll do, is we will bring our vision back, in particular, to the first quarter of that 48-month journey, 2024, to give you an understanding of where the company hopes to be by the end of this year and how that links into that overarching objective. PYC is very much a patient-focused organization. They are front and center of everything that we do. Today's conversation is going to focus very much on the commercial framework within which we're driving towards that patient impact. So what we wanted to do is to give shareholders an understanding of the overarching ambition for the organization and how near-term milestones feed into that, within that context. In the context of the commercial elements, specifically, given that we are at the start of a new year, it's effectively a framework for you to judge the progress of the company throughout the course of 2024. So that will be very much our focus in this context. It's a reasonably short session, and what we're going to try and do is, after we've given the commentary on the company's objectives, strategy, and the implementation plan for 2024, is to walk you through, in the context of the Q&A, some of the recent industry developments that are playing into the space, 'cause there's a lot going on. So we'll leave that for the Q&A, but we're largely going to put where the conversation goes back into your hands for the second half of the presentation. I'll try and keep my presentation to 20 or 30 minutes. I'm under strict instruction from the chair to keep it simple, keep it concise, and keep it relevant to the company's ambitions. So we'll do that, and then we will let you take the conversation where you want to go, because, we would like to give you as much insight as possible. Today's session is really, for you. For those who are new to the story, PYC is a precision medicine company progressing a pipeline of best-in-class drug candidates towards major unmet patient needs, and each one of those drug candidates represents a significant commercial opportunity. We're going to have a look at that. I think those of you who've been following the story understand that these are multi-billion dollar target markets that we're pursuing, and they don't have, in most cases, any drug available in market, and in one case, there's one drug that has got a very small penetration, and doesn't address the underlying cause of the disease. So there's a huge unmet patient need in these different indications. I think the very exciting thing from PYC's standpoint, and it's nice to come back in 2024 after the Christmas break, because last year we were saying, "Next year, next year, next year." And as we've come back, the focus is very much now on this year, and generation of that human safety and efficacy data that is really the currency of the industry. And so I listened over the course of the break, actually to a podcast on transactions within the industry, and there was an expert who was talking about the three different dimensions that are required to consummate an at-scale commercialization opportunity. The first one is to be on strategy for a pharmaceutical company. The second one is to have a very clear scientific hypothesis in relation to why your drug for your target is going to make an impact in your disease. And the third one is the generation of high quality clinical data in support of that scientific hypothesis. So we have two pieces of the puzzle, and 2024 is very much about generation of the third critical piece of the puzzle. The company has built itself on the back of a platform technology, a pipeline of drug programs that are directed towards these indications that have a very significant impact on patient lives and for which there are no treatments available. And so we have outlined in the subsequent pages what this 48-month journey to get to the point of becoming the commercial stage enterprise looks like. But what we wanted to touch on initially was how is it that a biotechnology company from Perth, Western Australia, has managed to get itself for first-in-class and potentially best-in-class assets? And that largely is a function of the first dimension that we just spoke about. It's very difficult to predict where pharmaceutical company strategy is because they all have a different one. And so what that translates to for a company like PYC is to make sure you have a very clear strategy, and an understanding of where you want to play and why. PYC has communicated to its shareholders over the course of the last five years, since Alan and I became involved in the company, a very clear direction that the organization was heading. We were going to become a drug development organization, very different to the business model that the organization had before. We made a strategic bet that RNA therapeutics were going to become a very significant force within the industry, and we saw that largely play out on a very accelerated timeframe in the context of the COVID vaccinations. We made a bet on the PPMO modality specifically, and that has turned out to be a very well-chosen pathway for us to go down. We'll talk later on about some data that came out of, Sarepta Therapeutics earlier this week, providing the first human clinical validation of that modality in the context of Duchenne muscular dystrophy. We also made a bet that genetic validation in the form of pursuing the very simplest end of the pharmaceutical industry spectrum, or the complexity of biology that drives different disease processes, would stand us in good stead. And we have seen recent understandings that the long-recognized enhanced probability of success has actually risen dramatically with respect to the outperformance of these monogenic drugs. So the single gene disorders, we want to get insights on what's going to happen in the clinic before we get into human studies. So we have used these patient-derived models or the organoids that we've spoken about at length, to give us clinical insights before we enter the clinic. All of that is directed towards ensuring that we have a higher prospect of success when we enter clinical development. So that stands us in very good stead now for this phase, as we start to generate that human data. On the right-hand side of the page here, you are seeing how we differentiated across modalities. So we suggested that subtly turning genes up, not too much, but not turning genes down, was the best place for RNA therapeutics to play. And I think there's an increased recognition that haploinsufficient diseases or diseases that are caused by a loss of one copy of a gene, and therefore the protein, are very well suited to RNA therapeutics specifically, and that has given us a very lovely differentiation within the precision medicine space. On the far right-hand side here, we needed to differentiate within the RNA therapeutics modality, and so the way that we have done that is by linking up to the company's delivery technology. We have chosen to go after those diseases that are occurring inside cells. So we have very carefully thought through how we integrate each one of these dimensions to put ourselves in a position where we're able to go after diseases that other companies haven't been able to date. And if we think about the back ends of the vertical line, the transition between late-stage clinical development and commercial, what we wanted to do, I think we've had a very clear view internally, but we haven't given a lot of guidance externally in terms of when we think these drugs are going to make it through to market. So we've had a particular focus today in trying to give you some guidance as best we can, and subject to all of the usual caveats, which we will go through shortly. We see the RP11 program entering market in 2028. So that should mark the transition, assuming that everything is successful and we have good regulatory outcomes in that regard, should be PYC's first entry into a commercial market, followed in the subsequent year by the polycystic kidney disease program before the optic atrophy asset. We haven't put Phelan-McDermid on here just because that's an earlier stage program. We gave an overarching commitment to shareholders that we would put three first-in-class and potentially disease-modifying drugs into human development before the end of this year. We're very much on track for those. These are those three drugs. So we're going to speak further about those going forward. This is not to say, and I want to be very clear here, that the value creation has to wait until we hit revenue generation. The size of the organization that we are hoping to build in the context of the size of these markets and the lack of an effective therapy within each one of them, is a very, very, very significant ambition. What you have seen last year is if you wind the clock forward to where the company will be in 2027, 2026. In late-stage clinical trials, we have seen companies focused on rare disease like Reata Pharmaceuticals and Iveric Bio, taken out for very significant sums, in those cases, $6.9 billion and $7.2 billion, respectively, for those two organizations. We know that if you wind the clock back even further to where the company is in 2024, 2025, there are also some nice benchmarks that have been emerging very recently. I would encourage all shareholders to have a look at the Johnson & Johnson acquisition of the last remaining shareholding in the MeiraGTx Phase I/II program for a rare blinding eye disease, just because of the proximity of what they are doing to where the RP11 drug is right now. It's a slightly difficult transaction to get your teeth into because it's been completed over multiple different stages, starting back in 2019. But the implied valuation of the residual 20% holding in aggregate, including the buybacks, is in excess of $2 billion for that asset on the takeout provision. So you can see that the industry does recognize the value of these assets early. That is not to say that PYC is necessarily looking for a partner, but it is nice to have options as we go through the course of the journey, and this is very much communicating to shareholders that we're in the window. For the reasons that we spoke about at the outset, generation of that critical human data is the final piece in the puzzle, both for us to have the conviction in relation to preparing for the market launch, but it's also the window in which the big players in the pharmaceutical industry become very interested in licensing the assets. So we're very close, and we're going to look shortly at what sits before that. Before we get into the detail of this page, and it's very exciting because the company has maintained a very broad ambition. We explicitly, as a board, have chosen not to do what the majority of players in the industry have done through the course of the recent downturn, which is to consolidate around the most advanced asset and just nurse that through to more advanced data. We have remained broad. We have pushed all of our assets forward in parallel, knowing that the turnaround in the macro environment would come. And so we now have a very rich pipeline of data that is coming, and we have managed to maintain our position with respect to advancing assets into clinical development, which is the critical stage gate, because if we're into clinical development first, we know that we're out of clinical development first as well, assuming that we've designed the clinical studies correctly. So just before getting into the detail of this page, I want to take you through to this vertical line at the end of the 12-month period. It's a, it's a very significant evolution that your company is going on over the course of the next 12 months. So where should we be at the end of this year? We should be transitioning into a late-stage registrational study in RP11. We're looking to kick that off next year. We should have a second asset that is progressing through a Phase 1 single ascending dose study, that is starting to generate early insights on both safety and efficacy. We should be filing, or having just recently filed, the regulatory submission to enable our third asset, which appears second here in polycystic kidney disease, to enter human development with a view to dosing patients in the first quarter of 2025. So I, I think you can see that that is a, a very broad ambition for an organization of our size. We're going to have to work very hard in order to deliver on that objective, but it's a very exciting pipeline of news flow for shareholders. The interesting thing is that out of those four quarters, the each one of the 12-month windows that set us through to that revenue generation, this quarter now is likely to be the most critical for the organization. This is the window where we're transitioning through validation of the safety profile of our technology. I think at the AGM, I referred shareholders to the Atlas Venture's presentation, suggesting that Phase I is actually the highest attrition phase in clinical development right now. So if you think about the implications for that, on the flip side, if we successfully progress from a Phase I study into later-stage studies, the associated increase in intrinsic valuation as we navigate through that, that part of the journey. Not only that, but shareholders need to be aware that we are not conducting studies in healthy volunteers, that we're straight into patients with these programs, so you are actually starting to draw efficacy insights from the initial clinical studies as well. We know that we have read-through from a safety tolerability standpoint of the modality, from the RP11 programs through to ADOA. And the other thing that we know is that we, as an organization, are on the frontier. We are the first company to take the PPMO modality into a human eye, so we know that the relevance of those safety readouts is primary to us as an organization because we are doing something that nobody else has done. So this data that is being generated now, the ability to escalate doses under the guidance of the Safety Review Committee and the RP11 clinical trial, is very relevant to you as shareholders in this organization for that reason. If you think about what's coming within the course of that 12-month window, we are going to be generating a lot of data in support of the RP11 program. So the plan here, I think most shareholders are aware, at the start of this period, we are into the third cohort of a single ascending dose study. We have the potential to add a fourth patient cohort at a 75 µg dose. In the context of seeing a very clean safety tolerability profile in those earlier patient cohorts, the company is planning on progressing to a multiple ascending dose study in the second quarter of this year. And so as we progress through to the fourth quarter of the year, the design of that registrational study that we'll be looking to kick off, it's a little bit earlier here. We've been a little bit conservative here just to make sure that we have some buffer in terms of the execution of that registrational study. We'll be drawing insights from the ongoing natural history study to have a look at how the disease progresses in the absence of any treatment. It will be looking at the data that we generate from patients in the Phase I single ascending dose study to see, firstly, the safety tolerability profile of the drug. But also whether or not we are the beneficiaries of a trend that has been seen more broadly within the industry, which is that patients who receive these gene therapies actually have an improvement in their vision in the early stages of treatment with the drug. As you're starting to rescue cells in the retina that are dormant but non-functional, they have not yet died. So you can actually see an improvement before you get the inhibition of the progression of the disease process. So we're very much looking out for that signal. What we will be looking to do is to convert some of those patients in the single ascending dose study into a repeat dose format under our expanded access protocols. So we will actually draw on an expanded body of data, patients who've been on the drug for a 12 or 18-month window, as we look to think through how we need to design the registrational study. Critically, we will be much more selective in the patient recruitment in the open label multiple dose study set to kick off in Q2, because what we need to do now is really to refine our focus on recruitment of patients who are likely to show us an efficacy signal sooner rather than later. So we've had an ingoing view in discussion with the KOLs, that we were likely to see faster disease progression on the part of earlier stage patients who are losing their peripheral vision. If the patient is moving rapidly on the endpoint, that gives us a better opportunity to see in a shorter space of time, the disease progression and consequently the impact of the drug, if it is capable of stopping progression of that disease. So that's where we've got to on the RP11 program. That is obviously a very exciting time and is going to be the focus of what we're doing as an organization. I'll drop down just to stick with the ophthalmology assets in the first instance, because I think from the RP11 program, you get a very good understanding of what we're going to do in ADOA as well. We will be pushing that asset through to a regulatory submission in the second quarter of this year, with a view to dosing patients in the third quarter of this year. And so from a shareholder standpoint, you're getting a lot of color now that we're a multiple clinical asset company. You know also that we are going to have read-through benefits from the safety tolerability profile of RP11 into ADOA. So we're actually amplifying the value of the data from the RP11 program in the context of ADOA. The particularly exciting thing here was that we were able to generate that data from a non-human primate or a monkey, late last year, in the context of showing a fully integrated pharmacokinetic, pharmacodynamic, and safety tolerability profile. So after a single dose of the drug, this is a monkey that does not have the disease, it's a wild-type monkey. But we were able to see in the retina an increase in the target gene, OPA1, the deficiency of which is the underlying cause of ADOA. And so that is a really encouraging feature of that program that we were not able to achieve in the context of the RP11 program. We had to rely on drug concentration in retina because the target gene in a non-human primate is different to the human gene in RP11. So the human drug did not work in the context of RP11. That's the difference between those programs, and it's a very exciting feature of ADOA. It also employs a different mechanism of action in the RNA therapeutic itself. So it's... We've spoken before about uncorrelated risk throughout the portfolio. There's read-through benefit from a safety tolerability perspective, but they're actually standalone assets from an efficacy perspective as well. There is a lot of excitement around our polycystic kidney disease program, and we have spoken on the webinar that was directed towards this program last year around why that is. We can dig into that again through the course of the Q&A. It's a much larger indication, and we have seen the tantalizing prospect based on the animal models of this disease indication, that you can actually not just stop progress of the disease, but you can actually reverse it. In the context of an indication that is worth in excess of $10 billion in the US market alone, there is a huge amount of interest on this asset from a pharmaceutical company perspective, but also a PYC shareholder perspective. There's a trend within the pharmaceutical industry to focus on what we call the mega blockbusters or the drugs that are targeted towards markets of $5 billion or more. So, a very elegant non-clinical data pack that is simple to understand because the drug is addressing the underlying cause of the disease, coupled with the animal model, suggesting if you address the underlying cause of disease, you can actually reverse that disease process. This is, an incredibly exciting program for PYC. We have a milestone coming at the end of the, well, start of the second quarter, where we are looking to see the safety tolerability profile of that drug in non-human primates or monkeys. It's a very, very important readout because that non-GLP study will then inform a repeat of those same studies in a GLP format, but you get a very good insight on what's going to happen in those GLP studies. So the critical milestone is actually the one that's coming around April, May, in relation to the maximum tolerated dose of that drug, and specifically, what is the concentration of drug in the non-human primate kidney, at which we're able to see, safety and good tolerability profile of the drug. Because as you all know, for precision therapies, delivery, delivery, and delivery are the challenges. What you want to do in order to get a lot of drug inside a cell, is to start with having a lot of drug outside a cell. So when we inject the drug into the bloodstream, does it traffic primarily to the kidney? We have a beautiful picture from a mouse model. We've showed it, it's in the public domain, showing that drug distributed in a very broad, even in deep fashion, suggesting that we are going to have a very good profile from a biodistribution standpoint in the mouse. What we need to do now is to recapitulate that in a non-human primate. And there will no doubt be a lot of focus and enthusiasm for that asset as it transitions to dosing a human, this time in 12 months. So next year, we'll be looking forward to a program that has got a biomarker for the first time for PYC, an endpoint on which we can measure the impact of the drug in very early stage human studies, because the protein that is missing is actually ultimately excreted in the urine. So you can take a sample of the patient's urine, and what we should be seeing is that the protein that was missing from the kidney is actually increasing in the context of treatment with the drug. There's lots happening in PYC, and that's just scratching the surface, but we are very much focused as an organization. We know that it is now execution of these clinical studies that is going to drive valuation and recognition of the valuation that we consider has already been built within the organization. We know that we're in the transition point. You look at the reports coming out of the US in relation to the valuations of biotech companies in Phase II and Phase III, with what we call very good data, and they're in the multiple billions of dollars. So we've got a significant journey to go on, both as an organization, but also, from a shareholding standpoint with respect to recognition of the value of these drug candidates. 24 minutes in. So we're on for Q&A. That's where we're at. I'm hoping to share some of the energy and enthusiasm. It's very much as we spoke about last year with respect to where we expected to be. That's the on-track dimension to it, and I think everybody understands, you know, typically, conventionally, it's been considered Phase II was the exciting time within the industry for the generation of data. Not only do we have the vastly greater probability of success in clinical development, but we're actually getting some data that would conventionally be constrained until a Phase II environment is coming in Phase I, because we're going directly into patients. If you couple that with some of the features of the different diseases that we've spoken about, we think we're really close, right? And so I'm not sure it's going to be as binary as people consider it. I think information is going to come in in a layered fashion. We're hoping to bring forward some, y ou know, that safety is coming in the very near term, but we're hoping to bring forward into the earlier parts of the year some of those insights on efficacy. So let's see how we go. I will throw open to the audience for questions at this point. If you're online, please feel free to type your question into the Q&A. We have a couple that were submitted early that I will go through, but we might start with those that are in the chat forum. The first one, on the most optimistic of timetables, when could we see readouts, I think that might be results from the kidney drug if human trials succeed? Yes, so as we spoke about, that one's coming next year. So the way that the clinical pathway is designated on the clinical program, firstly, it's very helpful that the FDA have come out and committed to a 2-stage clinical trial process, and that indication, they're not looking at the downstream functional improvement in the kidney. They published guidance that they will accept an anatomical surrogate endpoint in what we call height-adjusted total kidney volume. So basically, how big is the kidney, and whether or not we can see a meaningful change in the trajectory of kidney growth in the context of these cysts. So that's great. It's a rapid path to market because of the unmet need in that context. Even better than that, that's what will happen in the Phase II study, but in the Phase I study, we get the benefit of this biomarker that we've just spoken about. So if we're starting to dose patients in the first half of next year, you're going to start to see some results coming in the second half of next year. So second half of 2025. Oh, that should say revenues, sorry, not results then. If it's revenues, you'll have to look back to the previous page that we've got there. It's a 2029 market entry that we're currently projecting there. "Hi, can you please take us through your thoughts on the benefit of the Google AI agreement? Thank you." Yes, we can. So this is a reference to an announcement that came out over the course of the Christmas window. PYC has partnered with Google Cloud in the domain of enhancing the delivery profile of precision drugs to particular target cells within the body. And so I... Firstly, I'll comment on the macro trend. I don't know, it's not easy when you're outside of the industry to understand just how strong this trend is, but AI is going to completely disrupt drug discovery and drug development. It has already started, and it is going to come for rationally designed therapies, like precision therapies first, because we are a field in which underlying all of the biology, there is reason. And so we are actually an engineering discipline, but it's largely been transitioned to a scientific art because there is so much data that the human brain cannot possibly compute all of it. And that is the ideal domain in which artificial intelligence can revolutionize the practice of the discipline and the transition from the science to engineering. That's the window we're in right now, and in my personal view, if you do not have an AI capability as a drug discovery, drug development company in the precision medicine space, it's gonna be extremely hard to compete within 24 months. This is happening right now. So this is much earlier stage. We understand that this is a small part of the team who are working on this, but if you think about where we've got to as an organization, we have nominated our clinical candidate for all three of those drugs that you have seen there. So one is in the clinic, one is about to enter the clinic, one is going through the non-GLP tox studies, about to repeat in the GLP tox studies. It's largely driven by our translational regulatory clinical development team. So we have other scientists who specialize in the earlier phase of our value creation funnel, who are working in the domain of trying to identify with Google, who are really a pioneer in this space. And if you have a look at how quickly Google are moving, you'll be seriously impressed. So as a starting point, AlphaFold, software that was generated by Google, has mapped the three-dimensional structure of every protein in the human body. So it's a radical step forward in its own right. More recently, Google's DeepMind and Isomorphic have started to do the same thing for smaller molecules. So small molecules, peptides, modeling what they look like from a three-dimensional structural perspective. If you're trying to get a ligand, a key to bind to a protein, a lock, that is an incredibly powerful capability. PYC has got a rich, naturally occurring library of peptides that we're putting to work as a training data set for an artificial intelligence algorithm to predict the optimal key for a particular lock that we're going after. The benefits to the organization, this is dominant strategy for the entire precision medicine field. Every precision drug needs more of the drug in the target cell and less of the drug in cells that are not affected by the disease. It does not matter whether you are an AAV vector, looking for a capsid to a peptide protein to stick into the top of that virus, whether you are a lipid nanoparticle and you're trying to embed a targeting moiety into the surface of the lipid. If you're a direct conjugate, like PYC are, where you've got an RNA drug plug, plugged directly onto a peptide delivery technology, all of those technologies, all precision medicines, will need it to be guided into their target cell. So it's, it's dominant strategy in that respect. PYC is not capable of doing this independently. So yeah, we're, we're in the room with a 200 lbs gorilla. We understand that. It's going to be a question of whether or not we can move as fast and remain competitive in the context of our partner. There is risk there, for sure, but this was something that we couldn't do in the absence of a partner like Google. So it's a, it's, it's very clearly a step in the right direction. What comes of it? Let's see. I think it's a very nice additional string to our bow in the context of where the field is heading. "Can we please share our thoughts on the capital funding requirements after the course of the next six months?" Yes, we can. I think we have got a very good grip on what are the capital requirements for fulfillment of that broader ambition of the organization. I will say that we are very much focused at this point in time on delivery of those milestones, those very near-term milestones that we spoke about in relation to recognition of the value. I don't think there's going to be a fundamental change. There's obviously an increased spend and burn rate in association with pushing multiple assets through clinical development. So we know what our figures are in terms of how far down the pathway we want to get each one of these assets. We are confident that in the context of the capital efficiency of the R&D environment, that we can push significant value for shareholders in our ongoing delivery of those outcomes. I think if you look at some of the peer comparisons for companies at similar stages of development in the U.S., if you were running an ambition of a pipeline of three candidates, you'd be looking at about $250 million a year of spend. So we are gross, we're around half of that. Net, we're around a third of that with the benefit of the R&D rebate environment here. So we know that we are creating a lot of value for shareholders here. No doubt we will have to evolve as an organization as we become that late-stage clinical development company. We are thinking through now what that transition looks like for the organization. If the RP11 safety data has shown efficacy, would that patient be used for the next stage of testing? So that's what we spoke about beforehand, the propensity for enabling patients who have a single dose of the drug in the single ascending dose study to access the drug on an ongoing basis in the context of the expanded access provisions. And what we're looking to do there is exactly what you are suggesting. If the drug is showing a benefit in the patient, we want to give that drug to the patient over the longer term. So we will look to facilitate that expanded access and what that's going to give us, if we're using the patients who had the drug last year or early this year, we're getting a longer duration of exposure to the drug, which is very helpful when we start thinking through the design of the clinical study, the registrational study. What we will look to do is to couple that data with the insights from the multiple dose study that we're kicking off this year. So we're effectively running two multiple dose studies in parallel. Yes. When looking at the three candidates you have in development, how should we think about the differences in the development pathway for each on the basis of the size of each market by patient number? Specifically, in terms of size, of trial size, timelines, and relative R&D investment, i.e., PKD being five to ten times larger than ADOA, RP11 on a patient number basis. Simplistically, does this mean you need to recruit five times the patients and five times the spend? Any color on relatives would be helpful. Thanks. Yes, I think generally it's right. It's going to be a larger pivotal study in the context of ADPKD than it is in the other indications. I don't think it necessarily, from a cost perspective, scales directly with the patient numbers because there's some fixed expenditure and there's some variable expenditure that goes with that. But if we are looking at top-down numbers at this stage, you're looking at roughly 250-300 patients in the pivotal study for ADPKD, and we're thinking that that number is probably more towards 50-100 in the blinding eye disease studies. So this is, that's roughly the guidance. We know, and there's been some comments coming out of the FDA this week, again, demonstrating an increased flexibility on the path to market for rare disease drugs. There's a very good understanding that these patient populations need these therapies, and so they are open to communications with sponsors in relation to what that pathway to market looks like. So there's the goalposts are moving a little bit. It does depend on what we see in the early stage studies. As much color as we can give you, I think, I think we've given you a pretty good sense of where our thinking sat in that regard. Funding question, plan for a capital raise or a partnering deal? The answer is always the same. We run both a dual-track process on across both fronts. We know that we're getting to crunch time with respect to the data generation. We know that pharmaceutical partners have got an increased appetite for assets like ADPKD, that we'll definitely partner early in the process. And the company's got a pretty clear view that we are very confident in those assets, and we're very comfortable taking them into human development ourselves. We know, particularly in the first, in human studies, that we are capable of designing and executing those programs efficiently. Possibly in the later stage development, there will be some strategic benefits of bringing a partner on, but we're not in any hurry. It will always depend on the quality of the terms that come across the table in that context. But we are certainly in active discussions. We're in ongoing dialogue with partners or potential partners around all of the assets in the pipeline. I think more of an issue is a real focus on trying to get the equity capital markets to understand the value of what we've got here as well. And so it's a... Look, it's an industry-wide problem as well. You see the commentary coming out of the U.S. Things are improving very definitely, in the context of what's going on over there. It's been a long, cold winter for biotechnology, but I think there is every reason to believe that we are reverting to a more normal environment. What will determine if you do a Cohort 4 for RP11? Will that delay Phase II? So that will be a safety tolerability readout in the third cohort. So in the current 30 µg cohort, if all three patients show a very clean safety tolerability outcome, we're almost obliged to push the dose up to another level because what we don't want to do is to leave the championship putt short. You want to make sure, knowing that it's getting enough drug to the target tissue, that is likely to be the key, that we are pushing high enough up into the registrational study to see in a repeat dosing format and effect in those patients. So, so that's what will inform it. Will it delay the start of a Phase II study? No, it shouldn't, because it's a multiple ascending dose Phase II study, and so we can go ahead with conversion of the 30 µg patients and start to recruit those patients into the multi-dose format. Do we expect much dilution to share capital as we look to fund the programs over the course of the next 12 months? Look, I think that's a function of what we've already spoken about. Can we get value recognized for what we've already done? Can we deliver these near-term milestones that we know have an impact on the intrinsic value? Can we get shareholders to understand and recognize those? And can we continue to perform the way that we have in terms of cleanliness, of execution on the capital efficiency of what we're doing? So, yeah, I think you guys have got a pretty clear idea of where we're up to there. Where is the PMS program up to? So it's very much in line with the guidance that we gave in the course of the AGM last year. What we are looking to do now is, in the first half of this year, to take that drug candidate through validation in human cells, human neurons. We've got some very nice results in reporter cell lines. What we need to do is to establish that in a human brain cell, that we can recapitulate those results. And so that's the program go, no-go decision from that point in time. We know that the central nervous system has got some additional challenges from a delivery standpoint, and so we, we just want to make sure that we've thought through and given every opportunity for us to get maximum distribution of the drug to the neurons. If you want a very good example of just how subtle the differences can be, I'd encourage you all to have a look at the differences in the data generated by Stoke Therapeutics, one of our peers in the RNA therapeutic space. There's no delivery technology here. They're just using the naked oligo, but seeing significant impact in terms of phenotypic improvement at the highest dose, the 70 mg dose, but unable to recapitulate the full extent of those benefits at the 45 mg dose. So even within a sort of twofold variation, they're not quite getting as much drug to the neurons as they want to in order to see that effect. It's the delivery challenge and knowing that we need to overcome that, that had a very significant impact on their market capitalization because that highest dose is under clinical hold in the U.S., but the data's being generated in Europe. So you can see sometimes just how fine a line the delivery challenge can be. Could we touch on the capital needs to fund the development programs? Yes, I think we have given some high-level, top-down guidance in relation to each stage of development previously, but as a very top-down estimate, it's obviously more in the context of the expanded trial that we're looking at for ADPKD. But if you're thinking in the order of $100 million-$150 million to take a candidate from the start of a Phase I trial through to a New Drug Application in the rare disease space, that's, coupled with the capital efficiency of the environment that we're in, that would be a reasonable top-down estimate of the overall cost to market. And to put that in context for you, the estimated cost in the U.S. of taking a new molecular entity to an IND is $100 million. So it starts to show you the capital efficiency with which this organization is operating. What clinical reg team do we have in place to drive these programs? So that's part of our San Francisco office. We've got a Chief Research and Development Officer who is responsible for overseeing a small team of in-house experts. We have five of them. They have a much bigger support network around them. Obviously, clinicians are very heavily involved in the process. We've got contract research organizations, contract drug manufacturing organizations, and then a broader team of networks who fill in each one of the internal gaps. It's a stage-appropriate development for us as an organization. We will look to bring some additional capability in-house and grow the U.S. organization as we move forward to late-stage studies. Given the significance of 2024 for PYC and the data pipeline across the three assets, is there a need to upscale resourcing, and can these resources be accessed? That's a really good question. Yes, along with a monumental ambition for the organization in terms of what we're looking to deliver, there will be a need to fundamentally change the organizational structure in support of that. We do not underestimate what is required in order to get us through to market. The very helpful thing, I think, to your latter point there on the question, can the resources be accessed? We've got a footprint in America, and we've got a footprint in Perth, and we know that we have a preponderance for translational, regulatory, and clinical capabilities in the U.S., as well as depth of subject matter expertise that we don't have in Australia. So yes, very definitely they can be accessed. It's just a question of whether those people join the U.S. office or join the Perth office. The really nice thing is we have a very close integration across the two offices, so we are one team developing a pipeline of drugs. Has the delivery method been proven, or is this in trials at the moment, too? If proven, are PYC likely to rent out this technology? Okay, this is good because that's a segue to one of the industry developments that occurred earlier this week in the first clinical validation from an efficacy standpoint of the peptide conjugated PMO modality. So Sarepta Therapeutics, who have got a marketed drug that was invented in Western Australia, EXONDYS 51, have published the results for their 2nd generation candidate. So the 1st generation candidate is the naked RNA drug that's already approved in market, with a peptide conjugated version showing an order of magnitude improvement in potency. So a really, really nice readout for the modality. No surprises there. If you improve the delivery profile, you get a 10x outperformance in relation to the drug as a whole from its PD perspective. So yes, it has been proven. It triangulates very nicely with the data that PYC has put out. We have compared directly against the Sarepta cell-penetrating peptide, and we, in turn, are an order of magnitude more potent than Sarepta CPP, and that triangulates very nicely. If you think back to the data that we've put out from rabbits, showing outperformance of our facilitated delivery as compared to the naked oligo, we're about a 100-fold more potent than the naked oligo. So all of these little links are just starting to come together for PYC. The really, really exciting thing from a shareholder standpoint, if you look at the drug concentration in target tissue that Sarepta released, you're looking at about 500 ng of the drug in muscle. If you look at the data that PYC has put out to market for drug concentration in retina, we are in the order of 200,000 ng/g. So if you want to get a lot of drug inside a cell in a target tissue, start with a lot of drug outside a cell in a target tissue. So if you're multiplying that fold-out performance by the efficacy profile of that delivery technology, which is downstream in that process, we are starting to get very confident in our ability to give ourselves a maximum prospect of success in terms of overcoming the fundamental limitation of precision therapy. So we're starting to see some really nice data emerge in support of the hypothesis that we've put forward that we're about to validate ourselves in clinical development. At the last briefing, you were departing on a roadshow with institutions. Please, would you share the results outcome, outcomes? So look, we, we again, a bit like the BD process, we're continually engaging with institutional investors, family offices, high net worth individuals. We're trying to encourage on-market buying, in particular to get that value recognized. We've had very positive feedback in relation to those roadshows, so there's no outcome because we, we were not... It was a non-deal roadshow. We weren't raising capital in that context. I think, though, the headline message is that there's very much an increasing understanding and awareness of the PYC story amongst institutional investors, and I think that bodes very well for us going forward. Interestingly, that's the case in the U.S. as well. So U.S. institutional investors are starting to become interested in the story. Again, this was after very much an internal focus on follow-on investments in their own portfolio throughout the course of the downturn, and that was a function of the macro environment improving across the Pacific. So that's good. Are your registrational trials listed on the slide assumed to be Phase II or Phase III trials? And are you assuming accelerated or traditional approval pathways in your timeline? So it's a different answer for each one of those studies in relation to when we've spoken about it. So for ADPKD in particular, we know that a Phase II study and that surrogate endpoint with respect to total kidney volume is the pathway for us to go, slightly different in the context of the blinding eye disease studies. The company has decided optionally to do an open label, multiple ascending dose study. That's to give us more information in relation to the design of the registrational study that will follow. Can we comment on the potential benefit to PYC of Sarepta's recent PPMO data, please? Yes, I think it, it validates the modality as a whole. I think that's very encouraging. If you look at what's happened to the market capitalization of players in the space, it's really dragged the whole field up in that respect. I saw that PepGen, who have got the Sarepta oligo, coupled to a more potent CPP, have risen, I think, 80% throughout the course of this week on the back of that. So that's very encouraging, and that's in the context of a competitive program to the data in which Sarepta's was generated. So I think it, it really just provides a very nice reference point for the modality, but one which we were very much expecting for a long time. So it's confirmation of exactly what we thought we were going to see. When is the Safety Review Committee due to release the latest cohort results? And secondly, are the PKD primate studies on track to start this month? We'll take the latter half first. The PKD primate studies have already started. So we are deep into those, and we will hopefully get the results from our contract research organization in April, as we spoke about earlier, with a view that they will become available immediately thereafter. So April, May, second quarter, we're looking at for those. In relation to the SRC, we had some issues in dosing Cohort 3 over the Christmas break, just patients being away. We've also had a couple of patients in the screening process opting to volunteer for the multiple dose study, which has been very kind of them, but has actually caused some delays in execution of Cohort 3. So we're looking to dose the first patient in Cohort 3. We have two more patients to go. We are hoping that they will both be dosed within fortnight, and the SRC will convene four weeks thereafter. So you're looking at the back end of March for the SRC there. Patient efficacy RP11 timing. Was this mentioned earlier? Possibly second half indications published on any vision improvement suggest this could be a catalyst for increased interest in PYC being not just data related. So on the timing, yes, we're aligned there. We think by Q4, we're going to have some insights. That's an open label, multiple dose study that we're talking about, so we'll see the data as it comes to hand. And also in relation to looking at some of the data generated over a longer time period for the higher dose patients in the single ascending dose cohort. So yeah, Q4, but with the possibility that maybe we could see something earlier than that, if we're lucky. I've neglected a couple that were submitted previously. Will AlphaFold AI platform store PYC's peptide library with 1.5 billion+ entries? No, no, it, we're not putting anything. AlphaFold is not a platform. It was a platform software, but it doesn't store data. It's a predictive software for protein structures. What we're looking to use here from the Google standpoint is the compute. It's the silicon. So there's no uploading of PYC data. It's all proprietary. PYC own the project IP from this collaboration. We won't be making any of those available. Can other pharmas score a match to one of PYC's peptides, or are the peptides in AlphaFold only accessible by PYC? Yeah, we've answered that it's the latter. When is PYC going for FDA approval for the PKD drug, and how long does it take? So I think we've been over the timeline for that one. When are we starting human trials for PKD? Again, over that one, regulatory submission Q4, start dosing in the first half of next year. RP11, how are the trials going, and when we'll see results from the trials that are currently underway? So I think we've addressed that one as well. Okay, anyone in the room? Do you mind, Carol, there's a question. Do you see an opportunity, but just on the PKD, for an opportunity for Fast Track status? And if so, would that bring those timeframes, reduce those timeframes, do you think? I don't think that we can accelerate those materially from what we've projected up here, given the commitment on the... If you're talking about the American market in particular, with the Fast Track status. Given that the FDA have already committed to the surrogate endpoint, I don't know that we are going to be able to accelerate those any further. Thank you. Any other questions? Okay, so to bring it all back together, an organization with a very lofty ambition to become a commercial stage biotechnology company at scale within 48 months. If we drop the vision to the next 12 months, we are moving through the critical window in terms of the final piece of the puzzle, the critical human data that supports not just the execution of the late-stage studies and conviction that we're getting through to market, but also the prospect of the business development and licensing transaction optionality. So it very much opens up multiple paths to market for the company, with a very near-term focus in terms of what we're generating. We have maintained all programs moving in parallel because of the conviction in the assets. That gives us a very rich pipeline. Each one of these drugs addresses the underlying cause of a disease that is a major unmet need in a multi-billion-dollar market. It has been validated in a patient-derived model, so a human organ outside of a human, and it benefits from a five times greater probability of success on the back of it being a monogenic disease. There is a huge amount of excitement, and we very much look forward to updating all of you throughout the course of development of the data that is coming in 2024. So thanks very much.