Hello, everyone, and welcome to the PYC Therapeutics Investor Update. My name is Rohan Hockings, and I'm the Managing Director of PYC. I'm gonna be your host for today's call. Before we begin, I'd like to just let you know two things from a legal administrative side. The first one is that today's call is being recorded, and the second one is 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. In terms of the structure of today's presentation, we're going to go through a high-level overview of our Polycystic Kidney Disease program that we announced to the market earlier this week. Hopefully, we'll get through that in 20-30 minutes, and then we'll open up the floor for Q&A. If you'd like to submit a question, please feel free to do so throughout the course of the presentation in the chat function. Before we begin, I would also like to just acknowledge the extraordinary efforts of the PYC team, who've been working on this program and who've done the hard yards to get us into the position that we're in today. I'm very fortunate that I have the privilege to communicate those results to you, but I wanted to acknowledge the efforts of those who are really driving this program forward. By way of brief introduction, for those of you who are new to PYC, PYC is a clinical stage drug discovery and development company. We focus on the modality with the highest prospect of success in clinical development, making facilitated delivery RNA drugs, and we combine those with the targets that have got the highest propensity for success in clinical development, being genetically validated targets, and in our particular case, the highest form of genetic validation. We're going after diseases that are caused by mutations in one gene, and one gene only, where we know precisely what is going wrong with the target cell, and we know exactly what we need to do in order to fix that. So we combine that approach with the identification of areas of major unmet patient need, where we need to create better therapies for patients because they have inadequate treatment options available for them today. We have built ourselves a pipeline of four first-in-class drugs with disease-modifying potential, all of which are progressing through different stages of clinical trials over the coming 24 months. We will see early, mid, and late-stage progress throughout the pipeline towards commercially attractive markets. There are four pillars from a strategy perspective for those of you who are a little bit more familiar with PYC that underpin the company's approach. We've mentioned the monogenic focus that we have on the genetically validated targets and the reasons for that. We are very interested in intracellular problems to leverage the proprietary delivery technology that the company has. We are particularly interested in diseases that are caused by insufficient levels of a particular protein or gene, and what we need to do is to turn up that gene expression to compensate for a mutation in one copy of the two copies of the gene that you have. The reason for that is that we see RNA therapy specifically as being competitively differentiated in this domain. In the haploinsufficiency, not only will not having enough of the protein cause a disease, but so will having too much of it. The RNA therapeutics are uniquely suited to that Goldilocks window of just enough. The final pillar for our strategy is validation in patient-derived models. So we're really big believers in the revolution that has been offered by the ability to generate three-dimensional models of a human organ from cells that are derived from an individual who has the target indication, and therefore will recapitulate the disease process as the highest form of validation that we can get before getting into a human. So what we're doing here is we are taking risks that would not ordinarily be borne in a phase II clinical trial, and we're bringing that forward into the pre-clinical setting due to the utility of these models. So that's what we do. We're going to have a particular focus today on the Polycystic Kidney Disease program. There is an enormous amount of excitement in the team internally in relation to this program, and I think it's fair to say that it will represent genuine fulfillment of a dream if we are able to see this drug candidate realize its potential in clinical development. For many members of the PYC team, that will really be the pinnacle of their scientific career. So, great excitement, and my job is to explain to you today why that is. There are really six reasons for it. We're going to touch on each of those in a high level, and then we're going to go through each one in more detail. But the crux of it comes down to point number one. It's the excitement about what we can do for patients here, and the fact that we have a major unmet patient need is driven by three things. The first of them is that there are a huge number of people who are affected by this disease. So we know that one in every 1,000 autosomal dominant polycystic kidney disease. we know that it has a severe impact on those patient lives, and we're going to touch on that very shortly in relation to the patient experience. The final point is that we know that there are an absence of meaningful treatments available for those patients today. So if we take those three features of the unmet need, and we couple that with the tantalizing potential that we see from the animal models, that if you can address the underlying cause of this disease, you actually allow the kidneys the opportunity to regenerate, and therein holding the potential for reversibility of this disease phenotype, it's a very, very exciting disease indication for us to be pursuing. Having said that, we know that RNA therapies have got an Achilles heel, and so we need to tackle head-on the delivery challenge.... They're beautiful drugs because they are precise and potent once they reach the inside of the cell. The challenge for the RNA therapies is reaching the target cells in the target organ and crossing the cell membrane so that they can achieve their efficacy profile. To round out the backward-looking point of the discussion today, we're going to touch on the killer experiment in this context, the model that gives us the maximum insight into what is likely to happen when this drug enters clinical development late next year. That was the subject of the announcement earlier this week. What we've done here is we have created a three-dimensional model of the kidney from a patient with end-stage polycystic kidney disease, who's undergoing a renal transplant. They're receiving a donor organ, so we are the beneficiaries of some of the tissue from that kidney that has been removed from the patient to give us a very, very nice model for what is happening in this particular disease indication. When you couple that with point number two, data or the animal model data, that shows us that we have got a very nice drug distribution profile to the target cells, and then we can see what happens once we are able to achieve effective delivery in the context of a human target cell, increase the missing gene expression, replace that protein that is the apex therapist, and we see that downstream phenotypic correction. It's a very exciting combination to have. We'll transition then to a forward-looking view. We don't have to wait long, and this asset is in clinical development. It's been announced at a later stage than some of PYC's earlier program. We have designated our clinical candidate, and we are currently conducting the manufacturing run to facilitate the GLP tox studies in non-human primates that will be required to see us into clinical development next year. Not only do we have a rapid path to clinical trials, we have a rapid path through clinical trials as well. So we have got a very nice template set out for us in relation to an accelerated approval pathway for this drug. That would suggest that on completion of a phase II trial, we can submit a new drug application and concurrently commercialize the drug candidate at the same time as running that post-approval confirmatory study, looking at the functional impact. And I think we've got some friends from Regulus Therapeutics on today's call. I think those guys have done a very nice job in setting out the path to market. There's some additional FDA documentation in relation to the recognition of that path to market that is footnoted here, if you want to have a deeper look at it. As we mentioned before, not only do we benefit from a greater than 5 times likelihood of success in clinical development, but when you couple that with the patient-derived models, we're really looking to push that even further north in this context. So we'll, we'll touch on that again. It's very much a cornerstone of the PYC strategy and what we do. All right, so PYC-003, a first-in-class drug candidate for the autosomal dominant polycystic kidney disease. we'll kick off a little bit... I'm not going to read this page. This just gives you a little bit of color the polycystic kidney disease patient perspective. I think for me, I often thought about the window in which the patient had developed the end-stage organ failure, and they were dependent on dialysis and the impact on their life at that point, and in particular, post-transplant with the chronic immunosuppression. Having seen some of these patients, you're not left in any doubt as to the magnitude of the impact on their life then. What I think I had underappreciated was the manifestation of the disease prior to the progression to end-stage impact and organ failure there. If you look at, in particular, these acute, unpredictable onsets of pain for these patients and just how life-altering they are, it's very clear that the impact of the disease is affecting them for a lot longer window than when the kidney is failing. What's happening in these patients to drive that symptomatology? The first issue that is occurring here, the apex problem, is an inadequacy or insufficiency of the Polycystin 1 protein. And what that is causing is cysts to form throughout the kidney and to grow as the disease progresses and become filled with fluid. What is happening there is you are destroying the internal architecture of the kidney, and as you lose that internal architecture, it's no surprise that you're losing the functionality of that organ as well, and that is what is ultimately driving the end-stage renal failure in these patients. We've autosomal dominant polycystic kidney disease affecting one in every 1,000 people. That's culminating between a global prevalence. Estimates vary anywhere between five and 14 million patients worldwide, so, affecting an awful lot of people, and we know that the impact of the disease is profound. So more than half of patients will require a kidney transplant due to the disease by the age of 60. We also know that with the standard of care, we are not addressing the underlying cause of the disease, it is not tolerated by the majority of patients, and it comes with some very serious consequences from a lifestyle perspective that, are certainly suboptimal. We've touched on this page before, and I just want to recognize the importance of the delivery challenge here. It's key for any player in the RNA therapeutic space, not just to acknowledge the fact that, delivery is the fundamental challenge here, but ideally, and in PYC's case, it's a factor that we really try to differentiate on. So it's the situation today, for those who are less familiar with the industry, you can do almost anything that you want when you're inside a cell today. The tools that we have available are so extraordinary that we can affect really any change that we desire. The challenge doesn't lie so much in the precision therapy side, it lies in getting that precision therapy to every single cell that is affected by the disease in the context of the complexity of a living organism. So that's why this data is really beautiful. What it's showing you here, what you're looking at, is a cross-section of a mouse kidney following a single administration of a 10 ml/ kg dose of the mouse version of PYC-003. So, we've changed the letter sequence because the mouse PKD gene is a little bit different from the human. But really what we're interested in here is the drug distribution profile. And what we see when we look at this is a broad, even, and deep distribution profile within the target organ. So, we have very much given ourselves conviction here that we have solved the delivery challenge. If you have a look at these little pink dots that are spread throughout the images, you're seeing an indication or a marker of the drug being present out the entirety of the organ. I think one of the key things, we'll touch on competitive differentiation later, but if you're looking at the outside part of the kidney here, the renal cortex, you're looking at the red image at the top. The critical part here is that we are also seeing an even distribution throughout the renal medulla, where you've got the more sensitive architecture, and the cysts are likely to have a significant impact earlier. A very important point for us, we have got some additional data that has been already in the public domain in relation to the previous systemic studies that PYC has put out, that shows we are getting fantastically high levels of this drug distributing to the kidney. We have chosen for ourselves a peptide that has got a very specific biodistribution profile, that not only reaches the kidney, but has this terrific distribution in the renal tubular epithelial cells affected by the disease. We have got a little bit, we've chosen a, specifically chosen a peptide that has got a little bit of off-target distribution to the liver as well, because we know that for polycystic kidney disease patients, generally, liver cysts are a secondary feature. So we're actually hopeful that some of the secondary elements of the disease will be affected by this as well. But we're extremely fortunate with the diversity of offering of our peptide libraries, to have been able to have chosen a delivery technology that is so well suited to this indication. There'll be a technical data pack that follows this presentation coming out to market, and you will see a drug recovery assay showing 1 million nanograms per gram present within the target organ. And that is staying at very high levels throughout day 28, which is suggesting that we're going to get a very nice, long dosing interval for these patients as well. Just to put that into context for you, in our RP11 program, that's entered clinical development, when we put the drug right next to the non-human primate retina, we're looking at drug recovery within the retina of around 50,000 nanograms per gram. So we have got about a 20-fold outperformance in the context of this particular indication. We really have nailed that delivery challenge. So having overcome the delivery challenge, the next question then is: How do we get the most accurate prediction of what is going to happen in clinical development? And here, we want to direct our attention towards the killer experiment. We want to go straight for the gold standard model that is going to give us that maximum insight on exactly what's going to happen when we get into a human. There's no better model for doing that, as you can see illustrated here, than taking a three-dimensional model directly from a patient autosomal dominant polycystic kidney disease, and having a look at the effect of our drug in that context. I think in that context, you'll have some understanding of why we were so excited to see what we've seen in the release to market on Monday. I'm going to draw your attention down here to the right-hand side of the page, where you're seeing these two pictures. What we've got here is a three-dimensional model of a ADPKD kidney. So what's happened, to give you a little bit of background information, a tissue sample has been taken from the kidney that has come out of the ADPKD patient. It has been grown in a 3D format, to give us some of the complexity of the organ itself, and it has been treated with a bunch of accelerants that are trying to simulate many, many, many years of disease progression in a very short window of time, about a week, the assay runs for. So what we're doing here is we're artificially pushing these cysts to grow, grow, grow, grow, grow very, very quickly, and that's what you're seeing form here in these jellyfish-like structures on the left-hand side. What they are doing is recapitulating what you saw at the macro level, those big cysts that are destroying the architecture of the kidney. So, it's a very accurate recapitulation of what's going on. It is, in fact, the human disease in an ex vivo environment. Simultaneously, with the treatment, with those accelerants, we put a single dose of the drug on the model, and we have a look at the effect on the size and frequency of those cysts. What you're seeing here is a significant reduction. I mean, you can immediately see it. It's visually intuitive. It's quantified on the left-hand side here, and you can see a highly significant, statistical significant test there in relation to the reduction in the cyst size and frequency. We have had some questions in relation to what would we hope to see, and the image on the right-hand side here is exactly what we hope to see. If you have a look at the footnoted link to the Crown Bio overview of the assay, in the bottom right-hand corner of the explanatory memorandum for that assay, it explains why you want to see many small cysts, not no cysts at all. Because we want to know that the effect of the drug is mediating a pharmacologically relevant reduction in the cyst size and volume, not a toxicological, killing cells and reducing the number of cysts for that reason. It's actually the optimum outcome to see the small cysts still present, not fully resolved in that context, and you'll get some more additional detail in that context from the Crown Bio assay overview. So this is exactly what we wanted to see here. Okay, so that rounds out the retrospective look at the data that we have generated to date. As I mentioned before, there's a more technical pack for those who want to dig deeper into the program coming very shortly. And what we're going to do now is transition ourselves to the forward-looking view of what's going to happen from this point. I mentioned before, we're currently conducting the chemistry, manufacturing, and control run in order to make a large volume of the drug to facilitate those GLP tox studies in the non-human primates. Those two activities will take us around 12 months from this point, and then we're looking to submit the investigational new drug or equivalent in the second half of next year to facilitate the transition to human trials. What we're seeing at the macro level is a significant progression in the understanding of the regulators, specifically the U.S. regulator, in relation to the need to get these therapies to patients faster. And this is very important from PYC and other rare disease drug makers' perspective. It's a greater willingness to be flexible in relation to the information that is required to support that new drug application, with a commitment to then conducting post-marketing confirmatory studies to ensure that we are seeing the benefits that we want to see in these patients. What that looks like from an after-market perspective for PYC-003, and I think the key thing to take away from this page, is that we have the potential to submit the new drug application after two clinical trials rather than three. So we have a very rapid path through clinical development, which is great, because it means we can have the impact that we're looking to have in these patients more quickly in the event that we see in these two clinical studies what we are hoping to see. There is an even more attractive dimension to this, and we'll comment here and go into more detail on the next page, but you see down here, we have the potential for a biomarker efficacy readout in phase I study, moving to a surrogate efficacy endpoint in the phase II study, moving to a functional endpoint in the phase III study, page four. And so, what we're looking at here in phase I study from a biomarker perspective, and even better, a non-invasive biomarker, the protein that is missing in the kidneys of patients who have polycystic kidney disease is excreted in the urine of those patients. So we can actually take a urine sample and measure the levels of the missing protein to see them rise, hopefully, in the context of treatment with PYC-003. And that will be enough to give us conviction to move through to the phase II study very early on in the disease course, where we are moving to another non-invasive imaging-based biomarker of total kidney volume. So what we're hoping to see here is the size of the kidney shrinking from the grossly enlarged size that we see polycystic kidney disease patients, the size of an Australian rules football, back down to the physiological size of the organ, which is closer to the size of a human fist. And that will then lead into the New Drug Application, which will enable the commercialization window to occur concurrently with the phase III study, that will then transition towards the functional endpoint. But it's relevant to an assessment of have we actually engendered that reversibility of the phenotype that we're looking for, and to see the kidney restore its function. Critically, the glomerular filtration rate is the marker that we're looking at here. This page has been seen before. I think the important point to take away is the appreciation of the industry, of the propensity for success in clinical development of these genetically validated targets, is far greater than what was initially thought. So we knew that these indications were more likely to facilitate successful clinical trials because of the strength of that understanding of exactly what is going wrong and exactly what is required to fix it. What we didn't know was just how much more likely these indications were to lend themselves to successful clinical trials. I think the industry had understood somewhere between 2-3 times more likely. The more recent evidence is that that's actually somewhere between 5-8 times more likely. And one of our board members, on review of the data pack, pointed out recently that is due not only to the enhanced probability of efficacy, with these precision therapies, but also because of the increased probability of safety due to the specificity of effect, in this particular context. And that will form a second pillar of the competitive differentiation of PYC's drug profile here. We are acting specifically on the gene expression that is missing in the polycystic kidney disease patients. so, a very relevant point there. Okay, that's quite a lot to take in, but hopefully, you have borne with me throughout the course of what have we done and where are we going with this. What I think is also helpful is to walk you through a little bit of the biology, so that you can have that contextual understanding of what are we looking for in the preclinical setting, how does that inform what we're looking for in the clinical setting, and how does that link back to the disease process that's occurring in the patients? And so, I want to walk you through here, firstly, the unaffected cascade of the molecular biology. We have two copies of the PKD1 gene, which means we are getting two copies of the PKD1 RNA. As you remember, DNA makes RNA, makes protein as the effector molecule. We get two copies of the Polycystin 1 or PC1 protein. PC1 has got a complex and as yet not completely identified role within the cell, so we've got a number of different functional assays for the roles that we do know that it has, both in terms of calcium signaling and retention of physiological renal tubule architecture. Critically, we know that it's the absence of PC1 that is driving the absence of copies of PC1 that is driving the cyst formation in these kidneys. Not seen here on the normal side, but seen here across on the right-hand side when we look at the PKD patient, we know that we have a loss-of-function mutation in one copy of the PKD1 gene. What that leads to is an unstable m RNA transcript that is degraded very quickly, and t he cell does not have the ability to use that transcript before it decays to make the PC1 protein. Whereas an unaffected individual has two copies of this PC1 protein, here, we're only seeing one copy. That 50% of the gene expression is not sufficient to stop this disease cascade from kicking off. We lose the balance of that calcium channel regulation, we lose a bunch of other functions within the cell, mitochondrial function, regulation of complex cellular processes like autophagy, and what that manifests in are these cysts forming throughout the kidney that will ultimately destroy the architecture and function of the organ. This gives us an extremely nice template for measuring whether or not we are able to have an impact with our drug. We'll move the patient across to the left-hand side, and now what we're trying to do is to restore physiological condition with the addition of the PYC-003 investigational drug candidate. What's happening here is we have the same situation with respect to the loss-of-function mutation in one copy of the PKD1 gene. We have that same unstable m RNA transcript that is being degraded very quickly. The RNA drug, once it has been trafficked through the target cell and across the target cell membrane, so once we are inside the renal tubular epithelial cells, and the delivery technology has done its job, we'll find the one remaining copy of the PKD1 transcript, and it will stabilize it. It will not only stabilize it at the mRNA level, but it will also enhance the translational process that is responsible for making protein from that mRNA. So a dual function in that context, that means that the good copy of the PKD1 transcript that is left can do twice as much protein, and it can recover that loss of the PKD1 protein that then restores the physiological pathways leading to the absence of cyst formation and the disease pathogenesis in the context of the kidney. So what that does is it enables you to follow us through as we're measuring the efficacy of the drug profile. We know, and we can sequence the genotype of the patient to confirm that they have a loss of function mutation in the target gene. We can then measure the levels of m RNA present in those patient-derived cells, and we will see somewhere in the order of 50% expression of the PKD1 transcript. What we hope to see with treatment with PYC-003 is that m RNA level moving back towards the twofold expression that will recover the loss of the mutation-affected transcript. We can go one step further downstream of that to the actual effector molecule. What we hope to see here is the PKD1 protein levels moving back to normal, and then we've got those functional assays that culminate in the clear experiment, and you see where that patient-derived model fits in now. We've gone all the way downstream to the very bottom of the cascade, and we're linking ourselves across to the pathogenesis and what we're seeing at the macro level in the PKD patient. We're seeing a reduction in the number and the size of the cysts that are ruining the architecture of the kidney and consequently its function. What we wanted to do here was to give you a little bit of in vivo data and a little bit of human data, so that we get both the complexity of a living organism, but also the genetic background of the human, knowing that that's the species that we ultimately want to correct the disease in. This is a very nice illustration that after a single safe and well-tolerated dose of the mouse version of the drug, you are seeing an increase in that mRNA transcript. So, we are able to quantify a 40% increase here. Remember that you have an amplification of the effect moving down to the protein. This is lovely. This is telling us that not only has the drug reached the target organ and the target cells within that organ, but it's also crossed the target cell membrane, and it's been able to modulate the target gene expression. So, we've got a very nice mouse candidate for this disease. If we couple that with what we want to see in the human genetic background, we'll go one step further down the cascade for the practice time around, and what you're seeing here is a dose-dependent upregulation, almost all the way to wild type levels, so more than halfway to wild type levels of the PKD1 protein following a single dose of the drug. So, what we're doing here is we're really explaining how we have been able to achieve the effects that we've seen in that PKD patient-derived model. It doesn't in any way surpass the impact of that. That's the killer experiment, but it's a very nice complementary data set that explains exactly how we've been able to engender that effect. Okay, we'll open up for Q&A shortly, but just to step up back to the very high level here, there is a phenomenal amount of excitement around this drug candidate. The extent of the unmet patient needs that we've just walked through, coupled with that exquisite potential to reverse this disease process in humans. The idea here, and we're obviously very early days, but the ambition is very much to create a functional cure for this disease. That is where we want to be, and we're very hopeful that that is played out in clinical studies that will begin next year. We are doing this in the context of a monogenic target. Not only do we know exactly what's going wrong, but we know that our drug candidate corrects exactly the issue that is causative in this context. So we are focused on human causal biology. We know that we have got a very attractive commercial market in the context of success here. What I think is particularly exciting is the speed with which we can move this through clinical studies, reach those patients, and manifest that impact. So with that, I'm gonna stop and open up for Q&A. Right on the half-hour mark, and we're starting to get the questions coming through. First question is: Would it help to validate the mouse delivery result in other species, or will you just go straight to humans? Yes, we are, we are always interested in the model that most closely recapitulates the human from a biodistribution perspective. So, we will use the safety studies that we will be required to conduct in non-human primates in order to have a look at drug recovery from the non-human primate kidney. We will also evaluate whether or not our drug is capable of modulating the PKD1 gene in the context of the non-human primate genetic background. You don't always get that, but you've seen very recently in the ADOA program, we were fortunate enough to do it, and it's lovely because it gives us a PD readout that complements the PK readout. What we've got here is already extremely high conviction that we're going to see what we want to see, and that's for two reasons. One, because the mouse is predictive of the larger species in this context, but the second is, remember, this modality has been used before. And so, we are the beneficiary of the data packs that have been generated in support of PPMO as a modality in other disease indications. And there's a function of the modality as a whole that sees this biodistribution towards the kidney. We've got a specific example within that modality that's driven by the peptide, that gives us a particularly differentiated example in that profile, but it's nice to be able to draw from that background momentum from a biodistribution perspective. And we've got a question here: How much PKD1 upregulation do you see in liver epithelium? Question is directed towards the secondary feature of the cyst that form in the liver as well. That, have a look at the, both the PK and ideally the PD as well, in the context of those larger animal studies. Next question there: Are there any active partnering licensing discussions you've got a path for PYC-003? Look, we've had limited time, since generating this data to be able to have any conversations with anyone. Remember, we're less than a week old at this point in time, but I've got no doubt that, based on the conversations that we have had around the other indications in our pipeline and the suitability of this particular modality for, diseases that are caused by this pathogenic mechanism, that there will be a huge appetite on the part of, bigger biotech and larger pharma to be, part of the, the process and the journey for PYC-003. The next question. Also, I'm just trying to keep up. The screen's moving. I wondered how you're thinking about the fact that most people are not diagnosed until the cysts are quite large, and hence, impacted kidney function is quite progressed. If you're able to reduce the size of the cysts, is it the case that kidney function can be restored, i.e., the reduction eGFR, et cetera? Yes, that's a really good question, and I, I think that's the cascade that is to be played out in the context of the gene modulation and the biomarker readout. We get a surrogate endpoint in relation to shrinking of the kidney size, which gives you a very good indication that you are able to reverse those cysts, exactly as you point out. And then, ultimately, what is important is that we are restoring the function of that organ. Yes, that's exactly what's been seen in animal models. We don't know whether it's the case in humans or not yet, because we haven't had a disease-modifying drug that has moved far enough through clinical development to give us that answer. But that is exactly what we expect to see based on the non-clinical models that are available to date, and what we are hoping to see as we move our candidate forward into clinical development. Is two times the expression increase in the normal allele required, or are you expecting a graded response scaled by upregulation? Yeah, an interesting question. So the hypothesis for disease causation in this indication is what we call a threshold effect. So these patients don't manifest the disease in the very early years of their life, when they have a 50% expression profile of PKD1. What happens is that as you age, you are getting a decrease in your PKD1 expression over time, and when you drop below a critical threshold, we don't know quite where that is, is it 45%, 40%? That's when you're starting to see a significant acceleration in the disease progression at that point in time. And what that suggests to us is that there is probably quite a subtle disease correction threshold that sits somewhere, possibly somewhere even between that lower level of expression in the older individual and the 50% expression seen at the earlier parts of life. But certainly, that we would hope that the increase back towards, you know, 60% upregulation that we are seeing in the context of PC 1, in the context of the human background, should be sufficient to cross the disease correction threshold, and that's supported by what you're seeing in the patient-derived models. Remember, those are very end-stage patients, and so to see the impact on the disease phenotype in the context of that model was particularly encouraging. Have any measures been taken to protect this technology from being copied? Yes, we have got composition of matter, intellectual property protection over the delivery technology, and we have also filed for provisional patent protection over the RNA sequence itself. We've got the accompanying freedom to operate perspectives from the IP attorneys, and we're progressing through the intellectual property pathway in that regard. Would we consider partnering with another pharma company in the development of the PKD trials to help meet the costs? It's possible. The costs associated with the early stage trials, in particular, are not excessive, and they are currently within budget for PYC. So we're hopeful that we don't need to do that. Sorry, I've just lost that question. Did you just miss it, Andrew? Oh, that's okay. Yeah, so we, we're hopeful that we can take this independently through to a position of additional validation, whereby the terms of the discussion are in favor of PYC. We've got a lot of conviction in relation to the progression of where we're going from this point in time. We have got ongoing conversations, as you're aware, throughout the pipeline, with potential partners. I think we would benefit from the validation that comes with working with them. I think there are groups out there who could add a lot to the program as well, and we're certainly very open-minded with them. What is the likelihood that a gain realized reduction in cyst size will be associated with improved renal function? I think that's what we're seeing from the non-clinical models. As we spoke about beforehand, if we re-express the PC1 protein in mice, we do see an improvement in the renal function, in eGFR, in that context. And so that's very encouraging for us. It's also encouraging to have seen in the context of the patient-derived ex vivo model, a restoration, at least at the micro level in the 3D models of the disease, a reduction in that cyst volume that could afford restoration of renal function. We know that the renal tubular epithelial cells have the ability to regenerate after acute kidney injury in the context of other disease formats. So we have a very high degree of conviction that we will see that improved renal function. But the key there is what we see in humans, and so we can't answer that question until we get into clinical development. But I've got a very strong ingoing hypothesis that that is what we're going to see. What is the relative importance of delivery to the renal medulla in comparison to the renal cortex? This is a good point. This is a feature that is exciting the clinicians in this space, and in particular, we've got a lot of help from clinicians in the U.S. who are very excited to be part of this program. They have looked at the non-clinical data pack here and have called out that drug distribution based on the images that we've seen in the in vivo studies conducted to date as being critical. Because we know that cysts are forming in the renal medulla, and we know that we've got some very sensitive architecture of the kidney as you're moving through to the collecting ducts in that context, that can cause symptoms of the disease very early on in the disease course, as opposed to what we're likely to see in the renal cortex. So it's, it's equally important, both cortex and medulla, and it's that even broad and deep distribution facilitated by this peptide, the delivery technology, that has got us particularly excited in that context. Will all stages of PKD benefit from the drug, and would the drug be directly injected into the kidney? I'll take the first question first. We know that patients who progress to fibrotic change or scarring within the kidney are likely to be too late for the restoration of function, if indeed that plays out in clinical development. So there will certainly be some patients who are so advanced that they are not likely to benefit significantly. The trouble is, you might have scarring in some areas of the kidney and not in others, and the question is, can you restore sufficient renal function even in those patients, within the parenchyma that is left unaffected by the fibrotic change, in order to even defer the need for a renal transplant by several years? So even in those patients, there's the potential that it might be attractive to continue to treat them. So we'll have to wait and see. We are early on in the course of looking at the addressable patient population, but the numbers that we are landing on in discussion with the experts in the space are somewhere in the order of 60%-70% of patients at this point in time. Will the drug need to be directly injected into the kidney? No. This will be an intravenous route of administration. So if you think about a patient who's coming to the hospital three times a week for hemodialysis, or even those in the earlier stage of disease, to have an intravenously administered drug is not a problem at all. In particular, because of the very durable profile that we're seeing in the kidney, it looks at this point like it might be a six-eight-week dosing interval. It's very convenient from a patient perspective and very non-invasive. How are we thinking about the fact there are a lack of trials in this space? What early discussions are you having in regards to the trial designs? How are you thinking about the patient population, knowing the current diagnosis patterns, identifying patients early enough in the disease course? Okay, so there are two sets of conversations, and remember, we're early in the planning for the clinical trials. It's happening in the U.S. If you can just leave that question up, because there's a few elements to it, Andrew. There's discussions that are happening in terms of setting ourselves up for the clinical trials in the U.S. We already know, and again, we benefit from the nice work that has been done by Regulus Therapeutics in this context. There are six drugs that are in clinical development for ADPKD, and speaking to the clinicians, really, the only drug that they're capable of consenting their patients for is the Regulus molecule, because patients understand the prospect of the disease-modifying nature of that candidate. And so we, we expect to benefit from a very similar profile. We've got a lot of the clinicians who are involved in treating these PKD patients at the major centers in the U.S. interested on board, joining the scientific advisory committee for PYC and helping us progress this drug into clinical trials and towards patients. So having those conversations is very helpful. How are we thinking about the patient population, knowing the current diagnosis patterns and identifying patients early enough in the disease? For many patients, and remember, this is an autosomal dominant disease, so they know very early on that they're at risk of it. There is a far greater focus on genotyping these days, and there are no, w ith severe in the context of having severe disease manifestations and not having any available treatments, there are many, many, many patients who are eager and willing to be involved in clinical trials, so we are not anticipating having any issues in that regard. In the context of this program and the others running concurrently, is PYC adequately resourced and equally importantly, funded to execute and expedite on these programs to the point of having them released? I think this is one of the really exciting things about PYC. We're not a single asset company. There is an enormous amount of portfolio theory and effect at play throughout our pipeline. Each one of these candidates is incredibly attractive in its own right. The first two we've spoken about at length, the RP11 candidate and the ADOA. What we get with the PKD1 and the Phelan-McDermid program, is evidence in the non-clinical setting that you've got a dimension of reversibility of the disease process. Larger patient populations, and again, a very engaged clinician base, who are very excited about an RNA technology, and who are willing to scale with us, to move these through to clinical readouts very early on in the course. One of the other factors and features of PYC is the capital efficiency with which we operate. There is no other company who is undertaking the scale of work that PYC is undertaking at the level of cost efficiency that we are. We see our peers in the U.S. spending a multiple of what we are progressing individual drug candidates forward, some of them who have not yet even progressed to clinical development. So we are operating, at the minute, somewhere between 25% and 30% of the operating costs of our peers, in large part due to the capital efficiency of the Australian environment and the R&D rebate, and the lower cost base associated with businesses in Australia and the very lean model that PYC has. So what I can tell you is you're getting extraordinary bang for your buck in that context. I think the idea that we are going to be getting so many human readouts coming across all four programs in the next 24 months is very attractive. So we, we certainly retain the ability to top up the company's cash reserves with upfront components and milestone payments from licensing transactions. It's obviously not a good time in the industry in terms of the recognition of the value of these life sciences companies. That will turn at some point as well. So we'll run a dual track process, where we explain exactly what we're doing and the attraction of what we have going in the pipeline to try and improve the recognition of the value that has already been created in this company, at the same time as running those business development and licensing discussions, to create optionality in relation to where we source that capital going forward. At what age does PKD manifest? It's usually in a patient's 20s or 30s that they first notice that they have disease, and then you get increasing severity of the disease into the 40s and 50s. As we mentioned, half of patients requiring a kidney transplant due to end-stage organ failure at the age of 60. What is the cyst volume reduction, if any, for tolvaptan in the Crown Bio assay? So, the, what we're talking about here is the ex vivo patient-derived model, the results of which were released on Monday for PYC-003. Tolvaptan is the current standard of care for patients with polycystic kidney disease. It is non-disease modifying, so it doesn't address the underlying cause of the disease. It is used by Crown Bioscience as a positive control in that assay, and the answer to the question is that we don't see any meaningful change in the cyst size and frequency in association with treatment with tolvaptan in that context. But if you think about the tolvaptan being a drug that's generating over AUD 1 billion per annum with a very small market penetration in that market, the ADPKD market right now, due to the lack of tolerability of the drug, that's one of the other reasons that we are very excited about what we have seen with the outcome of PYC-003. Is the CPP that we're using for this program distinct from the CPPs in the ophthalmology and neurology programs? Yes, it is. It is different from the CPP, the delivery technology that we're using across some of the other assets in the pipeline, and as I mentioned before, it has been chosen specifically for its biodistribution profile to the renal tubular epithelial cells. What's the overlap with Regulus PKD drug candidate, and what's the scope of collaboration? Regulus Therapeutics is a company who is developing a miRNA-17 targeting drug, and who are currently in phase I-B study in patients with ADPKD. The rationale behind the development of the Regulus Therapeutics drug is that miRNA-17 regulates the PKD1 transcript. What they have been able to show is that if you knock down miRNA-17, you are able to see an increase in the expression of the PKD1 transcript, and consequently, downstream an upregulation in PC1. So I think there's a lot of elegance in that approach, and it does have the potential here to be disease modifying as well. The issues that you have got with the Regulus Therapeutics approach, and I, I think you're seeing from the, investment market's view on the company at the minute, the challenges that they will have is that miRNA-17 has got a very important role in many other cellular processes. So you don't have the same specificity of effect. There are many, many genes that are regulated by miRNA-17. So the, the challenge that you have there in an approach that knocks down miRNA-17 is, can you knock it down sufficiently to see the increase in PKD1 that you're looking for, without having an adverse impact on any of those other cellular pathways? And so that's the, the challenge that sits in front of Regulus. The other issue that the company has at the minute is that there are no drugs targeting miRNAs that have progressed through to a market approval. So there's some challenges for the modality as a whole. Having said that, I think there's a lot of merit to that approach, and we would love to see them succeed, not only from a patient perspective, but what it will do is it will validate the link between the PC1 urinary protein upregulation and the, at least at the anatomical level, the reduction in the kidney size. Ideally, that will be followed through by the link to the functional outcome and the eGFR that we're seeing later. Awesome progress. Congratulations. Thank you. What's the distribution penetration in monkey kidneys? So we don't, we don't know with PYC-003 at this point in time because we haven't yet progressed to the non-human primate studies. Those studies are scheduled to kick off in December, so they're very close. You're not going to have to wait long, for that result. But as I mentioned before, we know that with the PPMO modality already, others who've taken drugs forward for different indications in different target tissues, we're seeing a lot of the PPMO go to the kidney in non-human primates and consequently in humans as well. So we've got extremely high conviction that we're going to see a very similar recapitulation for what we're seeing in the mice models at the minute. And, even more so, we know that we have chosen a particularly potent peptide from a renal distribution perspective, that is likely to substantially outperform whatever we've seen before. So we, we are extremely high conviction with respect to the delivery technology, recapitulating in non-human primates and humans, what we have already seen in the, the mouse models to date. Those two pieces together, and, and you see now how the puzzle fits together, the biodistribution profile in vivo, showing us that not just the PK level, how much drug is getting to the target cells, but also in the mouse, what is the extent of upregulation that we can achieve in PKD1 gene? That is terrific data because we can link that across to what we're seeing in the patient cells. Formation that is ultimately driving the disease in these patients. I think we've touched on everything. It has been a very exciting window to get through to this point. Things are going to accelerate very rapidly forward from this point. I mentioned there before, dose range finding studies in non-human primates coming up in December. We'll be transitioning through to the GLP tox studies early next year, compiling the data from those studies, coupled with what we have already seen into the regulatory submission, to enable that transition to human studies. We know that we've got a very rapid path through those human studies. We're very, very much looking forward to seeing what this drug can do for patients.