PYC Therapeutics Limited (PYC) Earnings Call Transcript & Summary

Good morning, everyone, and welcome to the PYC Therapeutics Polycystic Kidney Disease Investor Webinar. My name is Rohan Hockings, and I will be your host for this morning. Before we begin today's call, I'd like to firstly remind you that the call is being recorded. And secondly, 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 format for today's presentation, we are going to go through a brief discussion of the results that we've released in the preclinical data pack yesterday, but that will not be the focus of the conversation. Really what I want to do is turn our minds forward to what we're expecting to see as we move this drug development program into first-in-human studies next year. And there are really 2 important questions that I would like to touch on there that can only really be definitively answered in the clinic. But for which we can generate some substantial insights based on the literature and evidence available to us before we progress into the clinic. And these will largely inform the success of the program as we evaluate the results of those clinical studies, so I'd like to share with you our thoughts on that. We will then move into a Q&A to give you an opportunity to ask questions either in relation to the data pack released yesterday or the content of today's presentation. Before we begin, I would like to just acknowledge the extraordinary efforts of the PYC staff members who have been involved in getting this program to this point, in particular, those leading the program, Paula, Sri, [ Anna, Jes, Ash and Ananya ], as well as the contributions of Aron Chakera, who is a renal physician here in Perth, who has been invaluable to the progression of the program and who continues to support us as we move this program into clinical studies. I think sometimes as shareholders, you don't have the visibility into just how much work is going on inside the company and the extraordinary efforts of those individuals to get us here. So I did want to acknowledge that before we begin. In terms of sharing my thoughts on the preclinical data pack that went out yesterday, I think the synthesis here is this is a very elegant and compelling body of work on which we are basing the progression into clinical studies. There's a lot of data that has been released and hopefully you've been able to have the opportunity to dig into that and understand how the integration of each 1 of those pieces of data informs the key questions that we're facing in the drug development program, but fundamentally break down into 2 important questions: Can we get enough of the drug to the target tissue and the target cell within the target tissue in order to have a meaningful impact in the disease process? And once the drug has got to those target cells, is it going to engender the changes that are required to stop or even reverse disease progression? And so if we think to the integration of that work that requires us to look at both an in vivo component, or what's happening in a living system to look at the complexity of a living organism to answer specifically that drug delivery or distribution question, but then also to look at the cellular level to see what's going on inside the cells when the precision medicine is delivered into those cells. Do we see the gene, PKD1, being restored to its wild-type or unaffected levels from the Haploinsufficiency, so we know this disease is driven by having half as much gene expression from the PKD1 gene as what is required to maintain normal function. So can we see that gene expression moving back towards 100%? And does that, in turn, lead to a downstream rescue of the phenotype or the processes that are going on within that patient's kidney to manifest the polycystic kidney disease phenotype. These cyst that form throughout the kidney that will fill with fluid and increase in size over time. And you can see some answers to each 1 of those questions set out. If we look -- we've got it in rodent species as well as nonhuman primates, but I'm going to focus on nonhuman primate studies here as both the more toxicologically relevant, so the more insightful species with respect to predicting what's going to happen from an adverse effect profile in humans, but also the more pharmacokinetically relevant species as well. The species that gives us the greatest insight in relation to what's going to happen in humans in relation to the distribution of the drug within the body. If we look there, we know that we can administer a dose of the drug by the same route of administration, intravenous that we are planning on taking into clinical development, and that we are able to achieve a very high concentration of the drug in the kidney at a safe and well-tolerated dose. So this is an important piece of information that goes to answering that distribution question. We know that the distribution of the drug is very much on target in terms of the organs that it is delivered to, primarily the kidney, the fundamental organ that is affected in patients with polycystic kidney disease, but with a very nice secondary distribution profile to the liver, that bodes very well for addressing the secondary hepatic cysts or cysts in the liver that a subset of patients with polycystic kidney disease also developed. So the drug is very much going to where we want it to be. If we look downstream, we were very fortunate, both in the mice and in the nonhuman primates that the human drug was able to modulate the target gene control that we are expecting in humans. This doesn't always happen, but we got lucky in this instance. So we can go downstream of the distribution of the drug, and we can actually have a look at what is happening at the gene expression level inside those target cells, inside the target organ in the kidney. So we saw in mice and then in nonhuman primates, the increase in the Polycystin-1 protein, which is the protein that is encoded for by the PKD1 gene. So this is the protein that is missing in patients with polycystic kidney disease or not expressed at levels that are required for normal cellular function. And we can see an increase of 1.4-fold in those wild-type nonhuman primates. So this bodes very well for the same results being seen in humans. We know that, that links across to what we see in the human cells, where we're able to generate 1.5-, 1.6-fold upregulation of PKD1 expression. And that then enables us to make the link across to those ex-vivo studies that you have previously seen where we have looked at the effect of the drug in rescuing the phenotype. So the cysts in 3D models that have been derived from patients with end-stage renal failure due to polycystic kidney disease. So for those who haven't been with us on the entirety of the journey, what we've done here is we have been the beneficiaries of a donated kidney from a patient who is undergoing a renal transplant, because they have end-stage renal failure as a consequence of polycystic kidney disease. So as that kidney has come out of the patient, we have been able to take a sample of that kidney, including the cyst-forming cells and to grow from that a 3-dimensional model of the human kidney, which we can then assess the efficacy profile of our drug. And there are some quite striking images of the reduction in both the number and volume of the cysts associated with -- treatment with PYC-003. So that integrated together makes for a very, very elegant data pack. We have some additional details that we'll be rounding out currently with the clinical trials, but for now, our focus very much turns to these first-in-human studies. So we'll make the regulatory submission within the next fortnight, and we expect to hear back from the regulator in February in relation to the approval to progress into human trials, and we're anticipating a March, April start for the study in humans. What I'd like to look at specifically today then is to evaluate why is it that there has been this unmet need for so long. The PYC has now been able to cut through and potentially make a difference in by taking the first RNA drug conjugate into clinical development for patients with polycystic kidney disease. And there are 2 dimensions here that we're going to dig into. The second question is also an important 1 that comes up in some of the industry conversations that we're having is how much Polycystin-1 upregulation is going to be required in order to have a meaningful impact in the disease? So is that 1.4-fold upregulation that we see in the wild-type nonhuman primate is going to be enough, is the 1.5, 1.6-fold that we see in the human cells, really going to make a difference for these patients because, ultimately, that is what we are directing ourselves towards because we know that this is an area of incredible unmet need. It's a primary driver of chronic kidney disease. It is a very, very common rare disease. It only just fits within the cutoff of a rare disease given just how common it is. Estimates vary between 5 million and 12 million people worldwide affected by polycystic kidney disease. If you couple with that the fact that it has a very severe impact on these patients lives, both from a morbidity standpoint while those patients are alive and also with respect to the accelerated mortality that we see in patients with polycystic kidney disease. And then you couple that with the fact that there are no effective or disease-modifying treatments available for patients, in fact, 95% of the patient population don't have any treatment options available at all today. That together informs the urgency of the need to create a therapy for patients with polycystic kidney disease. And so then we turn our minds to, well, how. How are we going to go about doing that? And I think the quote here that you've seen a couple of times is quite important. What we know is that Polycystin-1 for patients with a PKD1 mutation, and that's very much where PYC is focused, those patients who make up around 75% of the PKD patient population and who manifest the most severe form of the disease. Their disease is regulated by Polycystin-1. We know that, but what we don't fully know or haven't fully elucidated is what's happening downstream of the Polycystin-1 protein that is leading to cyst-formation in these kidneys. We know some of the different pathways involved, but we don't yet know precisely what's going on downstream of PC1. And it is quite likely that the different pathways are involved in terms of producing that phenotype or the cysts in these patients, relies on a complex interplay between different pathways sitting downstream of Polycystin-1, which is leading to the observation that you see in the final sentence here that it is possible that the -- it's highly likely that re-expressing Polycystin-1 is the best way of addressing the disease. It's also quite possible that it is the only way of reverting the disorder. And we're going to touch shortly on what we see in animal models where we do reexpress Polycystin-1, and why we've got the conviction to support this statement. I think the other thing to note here that is very important is that PKD1 in isolation is the primary, if not the sole driver, governing cyst on certain growth. So not only is the best way to intervene in the disease process by increasing PKD1 expression or Polycystin-1 protein but that should resolve the disease in its entirety as well. Again, based on the observations that have been made in preclinical studies, there's quite a body of literature supporting this, but we've left 1 of the references in particular that points out or supports this argument at the bottom here that you can have a look at in some more detail. But those 2 dimensions, those sides of the coin that lead us to believe that this is really the best way of addressing this particular disease indication in patients, and also gives an indication in relation to why it's been such a hard disease to treat because it really has a very specific way in relation to how it needs to be resolved. We also know that if we overexpress dosage sensitive genes, we are going to induce a phenotype as well. And that's been confirmed in the animal models of polycystic kidney disease. We're in that Goldilocks window, where patients are manifesting the disease because they don't have enough of the target protein, PC1. But if we give them too much of the PC1 protein or overexpress that protein, we're going to induce a cystic phenotype as well. So we have to have not too little, but also not too much, which is where the strategic link between the RNA therapeutic modality and the pathogenetic mechanism of haploinsufficient is so uniquely well suited or coupled together. So to help you understand that and to set the groundwork for a conversation that we're going to have in relation to the question of how much upregulation is going to have a meaningful impact in these patients, what we wanted to do is just set out a very basic framework. You're familiar with what we call the central dogma in biology, the DNA makes RNA and RNA makes protein. Protein is the effective molecule but it gives effect to the cellular functions that are coded for by the blueprint that is maintained within the patient's DNA. So in an unaffected individual, you will have 2 copies of each gene in the body and that includes PKD1, each copy of the DNA will be responsible for making 1 unit of the RNA and that will be translated into 1 unit of protein. And that's how we maintain healthy function of the kidneys. Specifically, this is occurring within 1 particular cell type within the kidney called the renal tubular epithelial cells. In patients with polycystic kidney disease, 1 copy of, in this case, the PKD1 gene is going to acquire a mutation, and that mutation is going to lead to either no RNA being generated or transcribed from that defective copy of the gene or a lesser amount than normal being transcribed, and we're going to look at why that's important very shortly. So these patients are expressing somewhere less than 100% of what we call wild-type levels. So if they get a genuine null allele, and they don't get any PC1 being expressed from the mutated copy of the gene, they will be expressing Polycystin-1 at about 50% of the normal levels, unaffected levels. If they happen to have what we call a hypomorphic mutation, or a truncating mutation, there will be some functional Polycystin-1, that is coming from this residual PKD1 transcript. So it could be in the order of 10% to 30%. And what we see here, and it's the first clue to answering the question in relation to how much increased PC1 is going to impact the disease phenotype? Is that these patients have a less severe form of the disease than the patients who have a genuine null allele? So if your PC1 protein level is at 60% to 70% of normal, on average, you will have an additional 12 years between the time that you need -- the age at which you need a renal transplant. So in patients with a null allele, 50% of patients will require a kidney transplant at the age of 55 in patients who have a hypomorphic allele, the 50% mark in terms of the need for renal transplantation occurs in patients who are aged 67. So that's giving you a very nice clue already that even subtle increases in expression of Polycystin-1 are going to have a very material impact in terms of that patient journey. And then just to round that out, PYC-003 is a precision medicine. It is acting specifically on that PKD1 transcript. It's doing the 1 thing that is suggested to be the potential for that functional cure to this disease process. It is using the 1 remaining good copy of the gene to compensate for the loss of the functional PC1 generated from the mutated allele. It's doing that by encouraging and enhanced translational process. So 2 units of the PC1 protein are being made from the good copy of the gene. And the idea here is through restoration of the PC1 level that we have a fundamental impact in relation to that patient's journey. So digging into that a little bit deeper. If we look at the different types of mutations that we see in patients with polycystic kidney disease, we know that if you have 2 null mutations in your PKD1 that the impact of that is embryonic lethal, it's not consistent with life. So you can't have 0% expression of Polycystin-1 protein. And the majority of patients, as we spoke about, will have 50% expression because they have 1 wild-type copy indicated here by the plus sign and 1 null allele, that is not making any functional PC1 protein at all. But as I mentioned before, if we substitute that negative for a hypomorph or a mutation that doesn't completely destroy the presence of the PC1 protein, but rather replaces with a smaller truncated protein that is semi functional, even if we can increase the expression of PC1 by a relatively modest 10%, 15%, 20%, don't worry about the letter coding here, this is just a designation of a specific mutation that does exactly that. Yields and outcome that is within that 10% to 20% of functional PC1. We will have a markedly less severe phenotype, a PKD2 like phenotype. So a much more mild form of the disease in terms of the size of the kidneys and consequently the destruction of the architecture and function of that organ. But where things really get exciting is if we have a mutation that engenders even more than that, somewhere between 75% and 80% of wild-type expression in total, we know that the impact then on the kidneys is very mild. It can be -- just a few isolated cysts forming throughout the kidney, and those are unlikely to cause the patient any downstream consequences in terms of the function of that organ, given the residual capacity that we have in the function of our kidneys. So what we are trying to do here with PYC-003 is move as far to the left-hand side of this curve, and back to 100% of wild-type levels as possible. But we know there is a transition point around this 75% threshold level that is really going to have a fantastic impact based on what we're observing from the human mutations and also the observations that we've made when we have reintroduced similar mutations, hypomorphic mutations back into the animal models. So it gives us a very good bar with respect to what we're aiming for. And very fortunately, if we correlate that back with what we see in the preclinical models, 1 thing is the in vivo results, the 1.4-fold upregulation that we're seeing in the nonhuman primates, but we need to be a little bit careful here because, one, we haven't necessarily optimized win to look for the optimal signal nor the appropriate dose to see that. But the second is because these animals are what we call wild-type animals. They have got 2 functional copies of PKD1. So it's quite likely that they've got negative feedback loops because of the dosage sensitivity of this gene, where they're not allowing PYC-003 to have its full effect as you would see in a patient who has only 1 functional copy of the gene and those negative feedback loops are unlikely to kick in until we get back to physiological or wild-type expression levels. So probably at this point, we'll bias towards the in vitro results that we've seen, where we see this dose-dependent upregulation with the administration of PYC-003, but that we're moving back 1.5-, 1.6-fold in terms of wild-type levels. And so if we correlate that back to where we expect to be, that would get you to a 75% to 80% of wild-type expression levels, and it would bring us squarely back into the domain of this relatively normal looking kidney. So there is some great hope there with respect to the insights that are generated from those observations of human genetics and how they're coupled with the animal models to understand the dosage sensitivity of the gene and exactly where we need to get to in terms of informing patient impact, which is ultimately what we're interested in. But the really great hope here in this indication in relation to disease-modifying drugs or drugs associated with the re-expression of the missing Polycystin-1 protein is based on what we've observed in animal models. So if we have a look here at a noncystic kidney, this is representing the benchmark and what we will compare to. If we reduce the amount of Polycystin-1 in mice kidneys and we allow them to get to 13 weeks of age, you can see that the kidney that is generated is very different to the wild-type or unaffected kidney on the left-hand side here. And in fact, you can see the microcyst forming particularly throughout the cortex of that kidney, leading to an increase in size of the kidney. If we continue to allow this mouse to age in the absence of normal levels of Polycystin-1 for a further 3 weeks to 16 weeks of age, you can now see very frank polycystic kidney disease within the organ of that animal. The remarkable thing here is if we allow the animal to get to 13 weeks and use this kidney as the starting point, but then we switch back on expression of Polycystin-1, and we follow out the age of that animal for a further 3 weeks, not only do you see stopping of the progression of the disease, but you actually see this quite remarkable reversion of the kidney to anatomically and functionally looking kidney that is very different even from the kidney that was representative of the baseline starting point in that animal. So not only are we stopping disease progression here, but we're actually engendering a rescue of the function of that kidney and the anatomy of the kidney. So this is really -- I'm just going to close out that question. We'll deal with the questions at the end. But this is the great hope here that we can reverse the phenotype. It's the insight generated from the animal models. Have we got to a level that is sufficient to do this? We don't know definitively. The only real genuine answer can be provided in the form of clinical development once we get into patients. But you can see here why the FDA has accepted the height adjusted total kidney volume as the anatomical surrogate endpoint on which they will support an approval of this drug. What we're looking to do here in the first instance, stop progression of the growth of the kidney from this to this. But ideally, if we have crossed that threshold in relation to the PC1 expression to allow these cells to regenerate, could we, in fact, see a reversion to this very normal looking kidney. That is the, I think, the great excitement and potential of disease-modifying approaches in organs where there is a regenerative capacity. So that is precisely the question we're directing ourselves towards now. As I mentioned at the outset of the call, we will be filing the regulatory documentation within the next fortnight. We are looking then to commence the first-in-human studies in healthy volunteers in the middle parts of 2025, and it will then be in the second half of the year that we will transition into the patient population and start to get some color in relation to the answers to these questions. Those studies will then continue. And the longer that we have exposure in the patient population at therapeutically relevant doses, the better the quality of answer that we're going to get in this context. And by the end or completion of the Phase I SAD/MAD studies, we should have a very high-quality answer in relation to what we're going to see there. By the time you've got 12 months of patient data in hand. We should be in a very good position with respect to informing the progression into that registrational Phase II study, knowing that the FDA will accept that anatomical surrogate endpoint as the registration endpoint in polycystic kidney disease because of the extent of the unmet need in this indication. So with that, I'm going to stop. That's really all I wanted to cover for today. It builds on that very elegant data pack that we have released yesterday, but it's really turning our minds to now the forward view. We're very close to starting to generate some of the answers to the questions that are front of mind for us, which is how is this going to translate to patient impact as we move the program into clinical development. So a very exciting time for PYC, for the polycystic kidney disease patient community, and we very much look forward to keeping you updated as things unfold in the clinic next year. I'm just going to get Andrew to read out any questions that we have in relation to issues that are of interest to shareholders. So if you wouldn't mind just populating those into the chat function, we'll be able to respond to them. I think Gill, you raised the hand at one point through the presentation there. If you don't mind just typing the question into the chat form, it will be easier for us to facilitate the questions that way.

There's a question. Do you have any kidney data on more than 16 weeks or 4 months?

Following the animals out for longer than that. Yes, there are a whole series of different animal models where they have introduced all of those hypomorphic mutations that we've seen or the mouse equivalent of the human hypomorphic mutations where they can show you the full spectrum of PC1 expression levels carried out for longer periods of time. So there's a wealth of literature, if you search that in relation to the animal models and what that looks like at later time points. But effectively, we don't expect that a normal kidney or normal-looking kidney, normal functional kidney in the context of having reverted from that point would look any different so long as we sustain the PC1 expression out for the longer window of time. So we know with the RNA therapies that we expect patients to be on them for life because RNA is turned over. We're not making a permanent change to the genome. But if we've crossed the threshold to seeing any form of disease reversibility, what we would expect is that, we would continue the longer that we administered the drug there. And the 1 exception there is we know through a conversation with the clinicians, that patient kidneys that have progressed or parts of the kidney that have progressed to fibrotic change or scarring, those are probably beyond reversion. So if you look at some of the other forms of the animal models, if you get very late-stage patients, the hope there is to bring them back to earlier stage patients, kidneys or analogous kidneys, not to bring them back all the way to the wild-type kidneys. If we're getting earlier stage patients, the hope then is to bring those back to the wild-type looking kidneys.

Can you provide some color on the market size for this drug and investor interest as well around the program?

So the drug effects one -- sorry, the condition affects 1 in every 1,000 people. We know that there are approximately 160,000 patients in the U.S. diagnosed with this condition. We also know that the pricing of the 1 approved therapy that does have that 5% market penetration is USD 170,000 per patient per annum. So if you combine those 2 together, you get to some extraordinarily large numbers in the order of $20 billion per annum. But then what we need to look at is the subset of patients who are likely to be treated, we think at any given point in time, it's roughly half the patient population in terms of those who are -- who have the disease or the prevalence who are within the interventional window. So if you half those numbers, we're using for current purposes and market estimate of around $10 billion per annum.

Do you expect to do clinical trial work in Australia? And do you anticipate any issues recruiting healthy volunteers in this study?

So the answer to the first question is yes. The reason for that is that we can achieve a faster critical path through clinical development studies if we initiate the studies in Australia. And so what we've done is we have held the pre-IND meeting with the U.S. FDA to ensure that we have perfect alignment and symmetry between the proposed Phase I studies in Australia and how they connect to a Phase II study that would be a global trial enrolling U.S. patients as well. And so we have alignment there in relation to what we need to do. So we are very much on track now and in a very advanced state of planning for the healthy volunteer and then the transition through to patient studies in the second half of next year. With respect to whether or not we expect to have any issues? No, there hasn't been any suggestion that we are likely to, and I think the GLP toxicology outcomes that you saw yesterday showing a very, very clean safety tolerability profile of the drug in nonhuman primates associated with very high concentrations of drug in kidney bode very well for that. What we need to do, and I would like to point out here, we have only run the pharmacodynamic assessment in the nonhuman primate at a single dose. So we see that occurring at 10 milligrams per kilogram. What we're doing now is going to lower doses and looking to see whether we see the same effect. And in the event that we do, that's going to inform the approach to the dosing, the concentration of drug that's administered in humans, what I'll point out there is we know that after a 3-milligram per kilogram dose in the nonhuman primates, we are achieving concentrations in the kidney of approximately 50 micromolar. These are very, very high concentrations. If you turn your mind back to those in vitro studies that we looked at, you're looking at 1.5-fold upregulation in Polycystin-1 expression at 10 micromolar. So 20% of the levels that are achieved in the nonhuman primate kidney at a dose of 3 mg/kg. So if we take the 3 mg/kg dose in the nonhuman primates, if we apply the threefold allometric scaling factor from nonhuman primates to humans, that's an equivalent dosing of 1 milligram per kilogram. If we then wind back based on the in vitro concentrations, you're looking at doses that could have pharmacodynamic effect as low as 0.2 milligrams per kilogram. And even then the bias might be to the downside. I'll point out here that if we look at the clinical efficacy profile of other PMO or PPMO drugs, we have seen an efficacy signal with SRP-5051 in muscle at concentrations of 500 nanograms of drug per gram of tissue. In the 3 mg/kg dose in nonhuman primates, we have 500,000 nanograms per gram of drug in tissue. So we have 1,000 fold more drug in tissue. So if we take the PK scaling factor, you would end up with a much lower dose of the drug again. So in terms of the therapeutic index, things are looking very promising in that respect. And we see a very clear path into efficient execution of those healthy volunteer studies as a consequence.

How long do you expect it would take to see an effect of the drug on patients once dose?

Look, the conversations with the clinicians are suggesting that you may see something in as little as 3 to 4 months after a single dosing. I think it's better for us to be a little bit conservative there. That's why I referenced the 12 months of data in a repeat dosing format, before we got something that we were really comfortable suggesting had, had enough exposure within the organ to have had an opportunity to exert the effect that we're looking for there. So I think if we look at transition to patients in the second half of 2025, we'll have that body of data in hand in the second half of 2026. Having said that, we know that there are biomarkers in this indication. We will be looking at the urinary PC1 levels, so the protein that is used -- missing in used or missing both in the patient kidneys is ultimately excreted in the urine. And so we'll be measuring for that protein. We will be looking now that we have some high-resolution MRI scanners at the individual cyst volume in cardinal cysts within the patient kidneys. And then we're obviously looking at the height adjusted or total kidney volume for obvious reasons, not only is that the registrational endpoint, but you've seen in those animal studies of the disease, what we're expecting to see if we are able to engender those regenerative changes there. So we'll be getting some earlier insight based on the interim or the biomarker assessments of the downstream anatomical and functional movements that we're looking for.

Would we be looking to expand the initial safety study into further dosing of patients as we have done in the RPM program, if positive?

Look, we'd certainly be looking to make the drug available for patients in a rollover extension study in the event that we saw a favorable risk-benefit profile. I think we are 1 obliged to. Two, there will be very strong demand to do it on the part of the clinicians. And three, as a company, I mean, we are all about patient impact, and it's something that we would like to do as well. So yes, we would very much be looking to do that in the event that we see encouraging early efficacy signals in that Phase Ib study that's due to kick off in the second half of next year.

And 1 around the U.S. regulatory side of things with the recent outcoming changes in the presidency over there. Do you see the potential changes in the FDA impacting PYC's clinical trial programs and the progression of those programs in any way?

I don't think it's likely at this point. I mean, I think there's a little bit of water to flow under the bridge before we see those changes fully take shape. I don't think anyone is quite aware of what the full implications of that are likely to be at this point in time. But I think we are very much orientated by the beacon of high patient impact in the context of severe unmet need. So it would be surprising to us for there to be any material changes to our drug development programs given that these are high morbidity or accelerated mortality or combination, indications where there is a genuine unmet need. There are, in fact, no approved therapies for the vast majority of patients. I think it would be incredibly surprising and disappointing if there are any material changes to our plans with that respect. And I think it's quite unlikely as a consequence.

Can you describe the most/least impacted regions where the cyst change in the mouse kidney and why and how the difference in tissue differences between human and mouse kidneys will affect the drug delivery and penetration?

I don't think there's necessarily any great difference in relation to the allometric scaling from the wild-type mice to the humans. I think the point that was raised by a lot of the interested parties from a business development standpoint was whether or not we saw the same distribution profile in the context of a diseased kidney when we compare that to a wild-type kidney. So that was the much more pressing delineation in relation to the body of work that we had previously released versus what we have now released, and it's the importance of 1 particular part of the data pack yesterday that demonstrates unequivocally distribution of the drug to the cyst lining cells. So we know now that even in the context of a disease kidney, we are getting distribution to the cells that are involved in the propagation of those cysts. And so that bodes very well for us from the standpoint of ensuring that we've got distribution to the right cells not only in a wild-type kidney, but also in a disease kidney to the extent that the drug distribution profile could have been impacted by the disease process itself. So that is a very, very powerful piece of data in that context. With respect to the delineation between the organs, we see something reasonably similar in the mice and the nonhuman primates. There is a slight preference for distribution within the organ to the cortex, over the medulla. And we know that the majority of the cysts occur in the cortex, but there are some anatomically sensitive cysts in the medulla. So we have that nice relatively even distribution profile between the 2 regions of the kidney. I think that's all we have. So thank you very much for your time. It's a very exciting time for PYC. I think there's a real buzz within the organization in relation to the prospect of the scale of the impact and the magnitude that we could have in the event that the hypotheses that are supported by the conversation that we've had today play out. We know that it is a very, very good idea to target Polycystin-1 as the Apex regulator of this disease process. We know that it's possibly the only way to rescue this disease in patients and the PYC's technology with the combination of the delivery profile that you've seen in those nonhuman primates coupled with the precision RNA approach that increases gene expression without the risk of over expression is uniquely suited to patients with polycystic kidney disease. We know that relatively subtle increases in Polycystin-1 protein are likely to have a very material impact in relation to disease progression with the observations in relation to the mutations that lead to semifunctional Polycystin-1 protein. We know from the animal models that if we get across a slightly higher threshold and we give the opportunity for these cells that have the ability to regenerate in the absence of having the protein deficiency, there is really great hope that we can have a very profound impact in the lives of these patients. We are extremely excited to share with you that data as we move into the second half of next year and beyond. So thank you again very much for your interest in the company and support. We will be updating you at regular intervals through the course of 2025 when we're returning the New Year with our third clinical stage asset in first-in-human studies. Thanks very much, everybody.