We are on time, we will get going. Good morning, everyone. My name is Rohan Hockings. I am your Host for this morning's second quarter PYC Therapeutics Investor Update. Before we begin, I'd like 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. The company disclaims any obligation or intention to update these statements in the future. I'd also like to notify you that the call is being recorded. Before we start, I'd also like to say a big thank you to all of the patients and patient families who are involved in the company's ongoing clinical trials. It's a very bold undertaking to volunteer for a clinical trial designed to evaluate the utility of a novel therapeutic, and we are extremely grateful to those patients and their families, all of the support staff involved in the execution of those studies for joining us on that journey. Before we begin today and get into the formal agenda, there are really only three points that I wanted to communicate with you. The first one, I think it's been a very good start to the year for the company. We're very well positioned. We're very happy with the progress that we've made against the operational roadmap, and we're going to go into that in quite a lot more detail. The second one is the focus for the organization now is very much on execution. We will talk about why that is, but fundamentally, the strategy has been set, the assets have been moved into clinical development. We are right on the cusp of the meaningful data readouts, which is the third point. We are very proximate to the evaluation of the safety, but importantly, the early efficacy signs in three of those four programs with a view that the Phelan-McDermid syndrome program enters clinical development early next year. We are close to the events that matter. In terms of the agenda for today, it will be a shorter presentation, around half an hour, so that we leave a lot of time to go into detail in the Q&A at the end and allow me to answer your questions comprehensively. I will introduce the company to those of you who are new or relatively recent to the journey. We will then have a look at the five-year developmental pathway, the pathway through late-stage development to commercialization for PYC, and then we will have a look individually at each one of the programs and the more immediate milestones that sit in front of each of the programs before opening up for a Q&A session and allowing you to take control of the direction of the conversation. PYC as a company exists to serve patients like Sierra, patients who have a mutation in one copy of one gene in one cell type in the body that is causing them to have a very severe impact on their quality of life and who have no treatment options available to manage the impact of the disease on their lives. We do it in a particular domain. We do it in a way where we are trying to design the most impactful type of medicine for those patients, a medicine that addresses the root cause of the problem. Is a quantitative cure for the underlying genetic deficit that is driving the behavior of the cell that is causing that disease. The way that we do that, very simply, is to use the one remaining good copy of the gene. You have two copies of every gene in your body, and in the context of patients who have a disease caused by a haploinsufficiency, that describes a mechanism where the mutation is affecting one copy of the gene and causing what we call a loss-of-function mutation. You now only have one functional copy of the gene, creating half as much protein of that gene that the cell needs in order to function normally. The basic strategic concept behind what PYC does is we design an RNA therapy that will do nothing with the mutated allele. It will go to the good copy of the gene, and it will tell that copy of the gene to make two units of protein where it otherwise would have made one. Conceptually, it's a very simple approach to the correction of what we call a monogenic or single-gene disease. The theory then, if we can restore the gene expression back to what we call wild type or unaffected levels, is that everything that sits downstream of that in the disease cascade will be rescued. It's a very elegant theoretical concept. We have used that concept to create four disease-modifying drug candidates that we have pushed through to clinical development. One of those assets is yet to make it into the clinic, although we'll start very soon on the clinical development pathway for the Phelan-McDermid syndrome as well. We're focused very much at the more prevalent end of the rare disease spectrum so that we can achieve patient impact at scale, and the derivative commercial benefit is consequentially very large. These are highly attractive commercial markets in which we're playing. There is a really nice article that is referenced at the bottom here by Bruce Booth from Atlas Venture, where he is quoting a luminary of the drug development field called Phil Needleman. Phil Needleman has 10 commandments of drug development, I've been attracted to them for quite some time, was rereading them recently and continue to think they're directly on point for PYC's journey. I think really the final commandment is the one that describes best where the company is at today. We are in a position where we are so close to seeing whether these drugs are capable of changing the lives of the patients whom we serve, that we are right at what they call the turning of the cards. The understanding not just of the safety profile, but now an increasing understanding of the efficacy profile of the drug candidates as well. The focus, therefore, for the company is very much within the existing pipeline, pushing through to the milestones that you're going to be looking at very shortly that dictate the transition of those assets into late-stage development and consequently their commercial launch. One of the concepts that I'd like to talk about is the link between the proof of concept or early clinical data and that registrational clinical data. I think a big difference in the approach and the views of the two different markets in which we have shareholders, the domestic market in Australia and the U.S. market, is the relative focus on the different clinical outcomes. In Australia, you tend to see people very focused on the registrational outcomes. I think what that view misses is the sophistication of the U.S. audience in understanding how the clinical proof of concept or the early-stage clinical readouts guides and informs what is going to happen in the registrational study, and then in that later stage pathway as you are making the submission to the regulator to get the commercial validation. It's quite a busy page here. This one comes from a U.S. investment bank. Again, a very nice overview on how to build value in biotechnology companies. I think the point to focus on here is in the bullet point that sits third from the bottom down here. This is very much where PYC is focused. If we can generate compelling evidence of patient impact in the context of a clean safety tolerability profile for each one of these drug candidates, three out of our four programs are already large markets, large numbers of patients involved, with a very broad interventional window. RP11 is probably the one exception there that sits at the ultra-orphan or much rarer end of the spectrum. The other three programs have got that very large target market sitting at the back end of the development pathway, as you've just seen on the pipeline page. The focus for us now is very much on the former point there. If the probability of success in each one of those programs, a successful commercial launch, is high, you are going to see that filter through to the valuation of the company. The scope for creation of value for shareholders is greater in the clinical proof of concept than what we see as we progress through the phase III study through to registration. There is some nuance and sophistication here that you have to be aware of. There are varying degrees to which the clinical proof of concept readout, the strength of the relationship to the registrational outcome. We'll talk about it in the context of each one of the programs. The point that I would like to make is the data that is coming now is really the data that matters. We're going to walk through in relation to each one of the programs. You see here in the red dots that clinical proof of concept data, what are we looking for in each of these programs as we go through the next 24 months in particular? I think the other dimension to be aware of here, it looks like a binary outcome, right? There's a point in time that we have committed to when that clinical proof of concept data is coming. In reality, again, it's more sophisticated than that. You will see progressively data coming through the course of the next six months, 12 months, 18 months, that is guiding where we're likely to land as we hit each one of those milestones. If we take a step back, the ambition here is very bold. The scale of the undertaking is large, and the expectations internally within the company for what these assets do in the context of patient impact is very high. We are pursuing best in indication molecules in each one of the indication, sorry, that we have targeted. The bar is very high, and we accept that we need to put out compelling data in support of each one of the programs. I think that's why it's such an exciting window for the company. That data is going to come to hand over the course of the next 18 to 24 months in particular. In polycystic kidney disease, what are we looking for? As we move through to these two outcomes that you see here at the end of 2027, we are going to progress through single ascending dose study, and we are nearly at the point where we have completed the dosing in those studies, and we have now started the transition through to the multiple dose study. The second half of this year is going to be directed towards publication of the single ascending dose study data. Then as we move through 2027, we'll get periodic updates on those patients who are enrolled in the multiple ascending dose study. What we're looking for here are three things. At the top of the cascade, and before we go into looking at what they are, if we think through what the disease is that's going on here, these are patients who have a mutation in the PKD1 gene. The implication of that is they've got half as much PC1 protein, the protein that's encoded by that gene present in the kidneys. The consequence for those patients is they've got hundreds of small cysts throughout the kidney, which over time the body is secreting fluid into. The cysts are getting larger and larger and larger, and they're progressively destroying the renal architecture and downstream the renal function. The idea here is to restore that missing protein. There's some great excitement from the animal models in polycystic kidney disease, where if you can re-express the missing protein here, PC1, you can not just stop the disease from progressing, but potentially actually reverse it in some patients as well, so long as the kidney has not progressed through to fibrotic change. It's an enormously exciting indication. There is huge scope for patient impact because the disease affects somewhere between 1 in every 600 to 1 in every 1,000 people. We call it a rare disease, but it's one of the most prevalent rare diseases. The impact on those patient lives is very high. High degree of morbidity and an accelerated mortality. For 95% of patients today, they don't have a viable treatment option. The scope for the patient impact, the primary driver of what PYC does is very high. What we are looking then to demonstrate in relation to the progression through early-stage clinical development and that transition through to a registrational study, is a series of three outcomes. The first one is the protein that is missing in the kidneys is shared between cells in the kidneys, and as part of that sharing process, some of the protein that's being shared is filtered into the urine. We have what they call a urinary biomarker, or we can actually measure the level of protein within the urine of patients. What we're hoping to see here as the clinical trial unfolds is that the level of PC1 protein in the urinary samples of patients after treatment is higher than their baseline when they enrolled in the study. That's going to give us a very good indication that the drug is doing the thing that we want the drug to do. It is increasing the expression of PC1 in the kidney. It's a directly on-point biomarker. If we go one level down from that, we want that increased level of protein to translate to an arrest of the growth or stopping the volume of the kidney from increasing. Because ultimately, that's what's destroying the function of the kidneys. These kidneys end up becoming very, very large indeed. An unaffected kidney weighs in the order of 700 grams-800 grams. It's about the size of your fist. A polycystic kidney at the time of transplant can weigh anywhere up to 22 kg-25 kg. These are massive organs at the end of the disease. What we can do is we can monitor the volume of the kidney on an MRI scanner as the disease is progressing. What we're looking for here is for the movement to go in the opposite direction. We want the kidney to stop growing or potentially even decrease in size. That is what we call the registrational endpoint here. The U.S. FDA have acknowledged the really very large extent of the unmet patient need in polycystic kidney disease, and they have given guidance that there is an accelerated approval pathway available for drugs targeting polycystic kidney disease, where we can see movement on that total kidney volume endpoint. There's a direct link now in this indication, as we spoke about before, between what we're looking at in the phase I, II studies and the registrational endpoint at the back end. Ultimately, what we care about in these patients is the function of the kidney. There is a downstream confirmatory endpoint, which is a blood test that gives us a proxy for kidney function called the estimated glomerular filtration rate or the eGFR. That takes a lot longer to move, right? We'll be looking at that, but that will be a 24 month - 36 month endpoint that we're looking at. The early indication is going to be given by those urinary PC1 levels and the total kidney volume MRI. What could we expect to see? It's difficult to say, but if we have to predict, if we think about the time points at which the patients are having the MRI studies done, if we go to the total kidney volume endpoint, they have a baseline MRI, and then they'll receive an MRI at three months post-dosing, four months post-dosing, and six months post-dosing. If we think about the modeling of the PKPD or the relationship between how much drug is in the kidney and the effect that we're intending to have, that is suggesting that we should have a dosing interval of somewhere around once every six weeks, as you see in the multiple dose study. Those patients are getting dosed in an area under the curve of drug exposure that is less than half as much as what we would intend for them to have if they were on the drug continuously in a repeat dose setting. It's hard to know whether that's going to be enough to start seeing changes on those endpoints. I think if we get very lucky, and we do see movement on the urinary PC1 and the TKV, we could see directional trending. It's going to be very difficult to get separation from controls just because of the amount of variability, firstly, in terms of the patient progression on that endpoint, and secondly, the ability to, with high fidelity, capture the changes on the assay itself. It will be tricky to see much more than trending, but if we see trending towards the outcome, then I think we'll be in a very good place. As we move through to the repeat dose studies, some of you will be aware of a comparator molecule, a different approach at the RNA level in polycystic kidney disease by a company called Regulus Therapeutics that was subsequently acquired by Novartis, who did see at that three and four-month endpoint, the four-month endpoint in particular, in a repeat dose setting, directional movement on total kidney volume endpoint and urinary PC1. That is suggesting to us that we could see relatively early on in the multiple dose study movement on those endpoints. When we sit down, though, and do the detailed look at the data analytics and bioinformatic modeling of how long it will take to see statistically meaningful separation of the natural history of the disease from the interventional arm. There, it will be the six, nine, and 12-month data. It's the window beyond six months that is critical. You'll be looking very much at the middle, second quarter, third quarter, fourth quarter of 2027 to see those outcomes. From there, it's about the transition into a registrational trial. That's what we're looking for in polycystic kidney disease. In Phelan-McDermid syndrome, we are at an earlier stage of development. We've got some commentary in relation to how we're going to round out the preclinical data pack before we move into clinical development. What we're looking for here in the second half of this year is to initiate the clinical trials, but to do it in an observational context first. This is in the absence of treatment of the drug. We are going to enroll patients and monitor their progression before we cross them over into the interventional trial. We understand the trajectory of the impact of their disease prior to them starting the drug. Simultaneously, we will be completing our GLP or Good Laboratory Practice toxicology studies that will allow us to progress into the interventional study in the first half of next year. In Phelan-McDermid syndrome, because of the lack of approved treatment in this indication and the relative recency of the understanding of the disease, we are still working with the clinical endpoints to fully understand how to monitor the disease and the correlation to the patient progression. What we're looking for in the early clinical development is to see a little bit like in polycystic kidney disease, a biomarker or some proof of concept that the drug is doing the thing that we intend it to do. Here we'll be focusing on the electrical activity in the brain in the first instance, assessment of the response to physical stimuli of those patients as well. We will also be trying to identify a biomarker in the cerebrospinal fluid that is giving us an indication that the drug is having the desired effect, and also seeing whether or not we can get measurement of SHANK3 protein levels elsewhere in the body. There is some literature suggesting that the gene is expressed peripherally as well, and so that we may be able to see in the blood whether or not we are having that desired impact on gene expression, lifting the levels. Those are not the endpoints that we care about in the longer term in Phelan-McDermid syndrome. If we think about it from a patient standpoint, the dimensions of the phenotype that are most troublesome for patients and their families are language and cognition. Ultimately, that's what we care about, and that's where we would like to see the drug changing the lives of those patients. It's about gaining conviction early that the drug is going to do what we want it to do to push through into the registrational trial, which will take a longer time to see movement on those endpoints. Many of you are aware of a company called Stoke Therapeutics, who we follow very closely because of the similarity between that drug candidate and STK-001 for Dravet syndrome, another neurodevelopmental disorder with a very, very similar RNA therapy via the same route of administration for the same target cells. What we saw with the data pack with Stoke, and I was having a chat with one of the U.S. analysts earlier this week in relation to it, was the company got very excited about the early readouts in clinical development. The market didn't. The stock was trading around the AUD six level. As they monitored patients for a longer period of time and we saw a clearer separation on those language and cognition endpoints, that is when I think the real conviction that they had a disease-modifying drug that was going to change the lives of those patients crystallized, and we saw the stock price move up to back towards AUD 30 per share, where it trades today. You can see how the evolution of the clinical data informs the market's assessment of the value here, and the point that was made earlier that investors by and large follow the understanding that it's the probability of success multiplied by the market opportunity that will drive the valuation of those programs and consequently the company. Ophthalmology is a little bit trickier for the two programs in retinitis pigmentosa and autosomal dominant optic atrophy. Here we are reaching all the way down to the ultimate functional endpoint and looking at the functional vision of those patients on an endpoint called visual acuity. We don't have a good biomarker or a proxy for whether or not the drug is working. We can't detect any levels of the target gene. We obviously can't biopsy the patient's retina. We're forced to go all the way downstream, which comes with some good elements and some bad. The correlation between the phase I/II readout and the phase III readout is strong because they're the same. The time that it takes in a slowly progressive disease to see the full spread and delta that you're looking for is a challenge. It means difficult on the sponsor's part to understand quite how to make that transition well into the phase III study, given that all three elements that dictate when we should pull the trigger and the propensity for the outcome that we're looking for are dynamic. We don't know, and are trying to find out from the interventional study, the extent to which patients can improve in their visual acuity through the rescue of the cells, the line that is going up in terms of performance. We're having also to characterize how quickly patients deteriorate in the absence of treatment. That's the objective of the natural history study. We also don't know how far the spread between those two lines needs to be in order to satisfy the regulator. Many of you are familiar that the traditional bar for an approval in ophthalmology has been 15 letters on ETDRS of visual acuity change, which is an incredibly high bar. I think the FDA generally is showing a willingness to be more flexible on that endpoint, they haven't given us a black-and-white understanding of exactly what that means. The lack of clarity as to where the finish line is makes it very difficult to determine whether you wish to start that race or not. We are waiting to see whether or not we can get an appropriate spread on that visual acuity endpoint to have the very high conviction to start that phase III study. That has taken longer than we initially anticipated because of some of the complexities that go into the dynamism of those three variables. It's very much in the company's control as to when we start that because of the cleanliness of the safety tolerability profile to date. I think that's something that everybody should take out of the clinical experience to date, is the fact that this modality has been very well tolerated in patients. It's always nice for me, given how much patient safety is at the forefront of our and my minds, to be able to come to the investor presentations and let you know that we have not had a treatment-related serious adverse event in any subject in any clinical trial. The safety profile is looking very good. The theory of what's being done there, facilitated delivery in the retina via a more convenient route of administration for patients, is very strong. We're just waiting for the crystallization of that data to give us the green light to go into the phase III for some data. We, I think, are very good at sharing with a high degree of visibility what's going on in that data. You'll see a lot more transparency in the releases from PYC than we see from a lot of our peers, including the raw data, in those studies. We will continue to do that so that everybody can get a fully informed assessment in relation to how the assets are progressing. I think for us, this is the very exciting time of the journey, precisely because you get to see the data that matters. All right. We'll now go through program by program and just focusing on the very near term, what are we going to expect? What should we see through the remainder of 2026 and as we transition into 2027? The clinical development pathway for polycystic kidney disease is high velocity. We have a severe unmet patient need waiting at the back end for us. There is the potential to run an accelerated pathway through clinical development. For us, we have come to an extremely exciting time because it's this Part C MAD study that is going to be the direct mirror of the registrational study that follows. What we intend to do here from a clinical development pathway is to have patients in the MAD for 6 months, but because we will have finished our chronic tox studies in non-human primates before that 6 months elapses, we will roll those patients over into an open label extension study to keep them on drug for 12 months and then ideally through to the 24-month endpoint as well. What that allows us to do is to observe how those patients are performing, exactly as they would if they were enrolled in the registrational study. Again, a very tight correlation as the data unfolds between the clinical proof of concept readout and the registrational readout that follows. Where we've got to here is we have dosed the first 3 patients in cohort C1, 1.2 mg/kg. We will now wait for the second dose of those patients and a subsequent safety review committee that will look at the data from the patients in the MAD, as well as the final cohort of patients in the SAD. 4 of the 6 patients at the 2.4 mg/kg dose have been dosed. We're just looking to round out the last 2 patients there, then the SRC will convene to have a look at the 3 sentinel patients from the multiple ascending dose study, as well as the safety data from the 2.4 milligrams per kilogram B3 SAD patient cohort before giving us the green light to escalate to 2.4 milligrams per kilogram in a repeat dose setting. You will run those 2 doses, 1.2 milligrams per kilogram and 2.4 milligrams per kilogram through the MAD. That is the modeled pharmacodynamic range. That's what we're looking for. From there, we'll be looking to see whether there's any dose dependency between those 2 doses. If we do see a dose dependency, it will be an indication that we have left efficacy on the table, that we haven't pushed high enough in terms of the dosing of the drug candidate. Because we haven't hit a dose-limiting toxicity, what we'll do is we'll add a further cohort above that dose level, probably at 4 milligrams per kilogram. If we can't see any clear dose dependency, we will assume, and this is obviously predicated on the fact that we see a compelling efficacy outcome, we will assume that we have hit the plateau of the efficacy curve, that we have maxed out the efficacy. What we'll do there is we will reverse titrate the dosing. We'll add a dose cohort below. We'll add a 0.4 mg/kg dose cohort to try to show the dynamic pharmacodynamic range of the drug candidate, giving us flexibility from a dosing standpoint as we move through to phase III. There is additional information that we want to extract from that study. We are suggesting that we could further extend the dosing interval, but the primary focus of the MAD is to glean that clinical proof of concept efficacy signal and to understand the dose response. That's very much what we're looking for here. We are targeting early Q4, and in particular, the American Society of Nephrology meeting for releasing the data from Part A and Part B. There's data coming in the second half of this year that will help to inform the pathway through to the registrational study for that asset. As I mentioned before, it will be over to looking at the data from the MAD. We'll be capturing that data. Obviously, there are patients on drug now. For some of them, we will have more than six months of data by the end of this year. We want to get those two cohorts fully enrolled, and then it's the six, nine, and 12-month data for both cohorts that is really important in terms of the clarity of guiding that transition pathway through to the registrational study. That will be, hopefully, the clinical proof of concept that we're looking for in that context. Another one of Phil Needleman's 10 Commandments that I like a lot. The idea behind early drug development is to understand all of the dimensions that go into predicting whether or not you have an asset that is going to change the lives of patients, prioritizing those that give you high-value pieces of the puzzle and getting to your 80/20 read on whether or not you have got a compelling candidate. I think Janya and the team have done a really nice job of doing that in the context of Bardet-Biedl syndrome. What I'll talk to you about next is how that then is going to inform our pathway. I think we've had some images that aren't displaying correctly here, but that's okay. We will finish off the preclinical studies concurrently with the GLP tox studies. What we're looking for here, the critical pathway to dosing in humans now is to get the GLP tox outcomes in the non-human primates. That's what's informing the time that it will take to get through to an IND submission in Q1 of next year, and then initiation first patient in in Q2. In terms of the clinical development pathway, what we want from that is to see as high a tolerated dose in those non-human primates as possible, because that's going to give us an indication that we've got a very broad therapeutic index, and it will allow us to start the patients on a dose that is either in or very close to the pharmacodynamically relevant dosing in the clinical study. What that does is it's bringing forward the efficacy signal on those biomarker readouts that we spoke to. That is the fundamental objective here. What we're trying to do is round out that shortest route to heaven. You've seen some very nice pieces of data at the minute. You know that when we apply the drug candidate to neurons that come from patients who have Phelan-McDermid syndrome, we see the missing protein, SHANK3, restore back to wild type levels. That is super encouraging, right? It's a theoretical quantitative cure for the condition in a neuron in a dish. That is a lovely piece of data in the data pack. We know downstream of that the SHANK3 that is increased will localize where it's supposed to be within the neuron. It will plug into the postsynaptic density, and we know downstream of that from a functional standpoint, that those neurons activate more frequently on the back of the restoration of the missing gene. That's a really nice start to the data pack. There are two other things that we would like to see. We want to go back into the rodent model of Phelan-McDermid syndrome and to see an efficacy signal in that model. That will come in the second half of this year, and there is a more complex, more sophisticated patient-derived model in which we can measure the electrical activity of the neurons. That will be a really nice complement to the data sets to push us into the clinic with very high confidence, high conviction. We had one of the team members present the existing data at a scientific conference recently, and she said the overwhelming piece of feedback was, "Why aren't you guys already in the clinic?" I think it's a very nice piece of peer feedback in relation to giving us the sense that we've got that 80/20 view right, and that's certainly our sentiment as well. There's a huge amount of excitement in relation to the Phelan-McDermid syndrome program. We think there is a great opportunity to change the lives of not just the children with the disease, but potentially also adults as well. Given that in the animal models of Phelan-McDermid syndrome, we see something very similar to polycystic kidney disease. If you re-express the missing protein in a neurocommunicative disorder, not a neurodegenerative disorder where the neurons are ultimately dying, you can actually partially reverse the phenotype even into adulthood. We see a very broad interventional window for these patients. Given what we've seen in Angelman syndrome and Dravet syndrome, the RNA therapies are really showing the power of a disease-modifying approach in neurodevelopmental disorders. There is an enormous groundswell of support on the part of the clinicians and the patients. There is a very deep level of interest in these drugs for the reasons that we spoke about before. They are addressing the underlying cause of Phelan-McDermid syndrome. It will be the first drug candidate to enter clinical development that restores full wild type SHANK3 protein in neurons. The excitement around what that could mean from a developmental standpoint is extremely high. Given the validation of this class of drug and the results that we're seeing in assets that have moved through to later stage development, much like Stoke's Dravet syndrome candidate that we spoke about earlier, that is giving us a very strong degree of conviction based on the preclinical comparative data sets to those molecules that we've generated that we are on the right path here. The expectation is very much one of a profound improvement in the lives of these patients. In ophthalmology, as we spoke about beforehand, it's very much about understanding the relationship between that clinical proof of concept readout and the registrational outcome. In ADOA specifically, this asset is important because it is targeting quite a large market in its own right, but it also has potential to treat diseases that go beyond autosomal dominant optic atrophy. Because the single gene that is involved here is a mitochondrial protein, there is the potential application to improve the mitochondrial function and the bioenergetics of the cell in other indications, which we have spoken about previously. That potential for the pipeline in a program means that we're specifically interested in the VA outcomes in this study. It's a very similar paradigm in a smaller patient population in the context of RP type 11. We had the meeting with the FDA that was the immediate objective in the program, and we had a very constructive conversation with the FDA. It's clear that they are trying to move in the same direction as the broader agency with respect to accommodating greater flexibility in the context of rare diseases specifically, and particularly where the drug candidate has got that plausible biological mechanism. I think the challenge for the company here has been the totality of the evidence. Approach doesn't give us the certainty that we need in relation to exactly what do we need to see from that registrational study before we could expect to see an approval of the first drug candidate in RP type 11. It's clear that there is flexibility on the part of the agency, that we don't necessarily need to meet that 15-letter outcome where we have a substantial impact in visual acuity and alignment of the key secondary endpoints. Precisely what that means, we don't yet know. We just have to wait here for the additional data from the open label extension long-term follow-up before we can understand fully what the path forward is for that program. Okay, with that, we will move through to Q&A. Earlier, you mentioned that three of the four programs are large markets. I read various sources that both the PMS and PKD markets are actually materially larger than you have on your slides. Are you being intentionally conservative or am I reading poor research? Intentionally conservative. It's a dynamic situation. In some instances, there's been a very recent publication from the PMS Foundation suggesting that the prevalence of Phelan-McDermid syndrome is higher than the original estimates. The quotation now is that 1 in every 7,300 people has Phelan-McDermid syndrome. As the genetic testing becomes cheaper and more accessible for patients, we're getting a better grip on exactly what the prevalence looks like. We do think that Phelan-McDermid syndrome is a very, very large market indeed for a disease-modifying drug. We are comfortable being conservative there. We're also adopting the median orphan drug pricing. I think there is the potential for the pricing side to increase materially in the context of a disease-modifying drug that has the impact in these patients that we're looking for. Polycystic kidney disease, similarly, the earlier estimates on prevalence around 1 in 1,000, I think the latest estimate's around 1 in 600. Again, if we have a very high impact in the lives of these patients, if we show the ability of the disease-modifying drug candidate to mirror the outcomes that have been seen in animal models or completely stop disease progression, that is an outcome that has a very strongly positive net benefit for the healthcare system. The potential on both the prevalence and pricing side is to see those markets climb. Appreciating 12-month TKV data in late calendar year 2027 is the proof of concept point. Will you be disclosing interim TKV data at earlier time points? We definitely will, because we have the TKV data coming from the single ascending dose study, which is coming out this year. There will be a continuum of data that helps to guide the pathway to that definitive clinical proof of concept. It is harder to say how the MAD data is going to be released, because it will depend on what we see in the SAD and also how quickly the data unfolds in the context of the MAD. You can see if you saw trending in the SAD, that would lower the materiality threshold for the data that is coming from the MAD. We need to spend some time thinking through the balance between waiting until the data is sufficiently mature that people can make a meaningful interpretation of it. We have got a strong desire to do that. At the same time, being mindful of our continuous disclosure obligations, and the gravity of that interim milestone with respect to the primary driver intrinsic valuation increase in the program. We will talk with the KOLs, and try to form a view internally as the data is unfolding. There is scope for even the MAD data to come materially earlier than that. Are you still expecting initiation of PMS phase I study by mid calendar year 2027? Yes, I think we're very much on track with the operational roadmap that we set out at the beginning of the session. The idea there, as I touched on during the Phelan-McDermid syndrome program deep dive, is to initiate clinical development in the second half of this year in the context of the natural history studies, and then to transition through an IND to first patient in an interventional study in the first half of next year. Are the new institutional investors assisting company strategy, and if so, what areas are they focused on? I wouldn't say they're assisting at the strategic level. They've been incredibly helpful at an operational level, and I think the rationale as to why they're not assisting at the strategy level is that's largely set, right? These drug candidates are made. We have chosen a mechanism to focus on particular indications to target composition of matter IP to file. Translational development has been completed in most cases. It's very much about execution. Where they're being incredibly helpful is in guiding the infrastructure around the company that is required to do that execution part very well, and specifically plugging into the U.S. ecosystem. I think it's increasingly clear that the future for the organization is to gravitate more to the U.S. There is a much, much better understanding of this company and its activities in America, so we will embrace the input of those investors and seek to find a way where we can. I see one of the earlier questions here is to address the gap between enterprise valuation and intrinsic value, I think that's an important part of doing that. It is clear that we need to engage more deeply with the U.S. capital markets. We have seen recent RP11 data updates shifted the control natural history from being 2 letters lost per year to 1 letter lost per year to benchmark the efficacy data too. Why the change on this? Is it just conservatism to test the degree of separation, or has it been informed by some patient data suggesting slower vision loss than previously anticipated? That data's coming directly from the natural history study. As I spoke about before, this is the difficulty. All three sides of the triangle are dynamic. The interventional arm showing the improvement in the visual acuity, the anticipated performance of the sham, which is guided by the natural history of the disease, and the regulator's assessment of the delta between the two lines. A lot of that is driving the changes in the timelines anticipated of the RP11 program, right? If we had an accelerated approval pathway or even flexibility on the part of the regulator to look at a 10-letter improvement in visual acuity, you could cut years out of your clinical development pathway. Unfortunately, we haven't got that, we need to deal with the dynamic variables that are coming out. That's why we want to take the time to look very carefully at that ongoing phase II study data to try and get a better sense of what the probability of success of that phase III study is, and why and how we need to design it in a manner that optimizes the potential to bring that drug to patients sooner. Hang on one second. Can we just get you to take the microphone? Rohan, the 15 letters that you talk about that they're currently looking at, you have base level, and you have a improvement of, say, 10 letters. On the natural history, if it drops 5 letters, is that 15 or is it 15 from the base? It's the mean change in visual acuity in the treated group as compared to the control. If your patients who are on drug increase by 10 letters and the sham decreases by 5 letters, that's a 15-letter spread. Yeah. That's right. As long as it goes. Exactly. Yeah. Are you working with Key Opinion Leaders in designing the PMS clinical pathway? Yes. There has been very strong support from the KOLs in the U.S. in relation to the PMS data pack to date. I think a massive amount of excitement about the transition of that asset into clinical development, and the design of those lead-in natural history studies actually came from a suggestion from one of those KOLs in relation to how are we going to accommodate the highly variable nature of the disease, and in particular in Phelan-McDermid syndrome, because we see this phenomenon of regression where patients at a certain point of their developmental pathway will start to lose skills that they previously acquired. The design of those studies is very much informed by the KOLs. It is part of the reason why we will conduct those studies in the U.S. undercover of an IND. The ecosystem in the U.S. for neurodevelopmental disorders, the presence of the patient advocacy bodies, the number of patients who have been genotyped, and the infrastructure required to support those clinical trials is far more advanced in the U.S. We are actively engaging with all of those centers that have a special interest in Phelan-McDermid syndrome, and they've got a reciprocal special interest in us because, as I mentioned before, it will be the first opportunity to see what the impact of upregulating or restoring fully wild type SHANK3 protein in the neurons of those children and adults will be from a patient impact standpoint. Why did Firetrail sell, and who took up the position? Look, it's difficult for me to comment on the motivations and rationale for individual investors. I have seen media commentary in relation to loss of mandate, fund redemption in that context that has driven some forced selling in the market. I think that does help to explain what's happened in the aftermarket of the capital raising. I think that's greatly unfortunate. I understand that Firetrail continue to be and have been very good supporters of the company. I don't know where the buying is coming from, but I'm very interested to see whether or not we have follow-on support out of the U.S. capital markets, and we're working very hard to raise awareness of the company in the U.S. We are engaged with a number of different banks over there. I'm hopeful that we will start to see research coverage initiated by multiple banks in the U.S. very soon. A lot of effort is being invested in trying to drive the U.S. investor base onto the ASX to start to build a position in the company and market. Got a couple of other questions. Rohan, the company you mentioned that was taken over by Novartis, which with the kidneys had seen those two positive indicators, how did they treat the disease? What was their method? It's biologically very similar to the approach taken by PYC. It doesn't directly target the transcript, the good copy of the gene at the RNA level to make a second unit of protein. They're going after what we call a microRNA. There's a small piece of RNA that's floating around inside the cell that regulates the expression of other genes. It's regulating maybe 200 genes inside the cell. One of those genes is PKD1. By targeting the microRNA and stopping it from binding to PKD1, you are increasing the half-life of that RNA transcript and the ability for it to make protein, basically. It's a very similar outcome in relation to upregulation of PC1 protein. What you've got to be very careful of there, amongst other things, generic safety issues in relation to the backbone chemistry that's being used is what does it mean to target a microRNA that's doing lots of things inside the cell? What are the downstream implications with respect to the other genetic pathways that are going to be modulated there? That's one of the reasons that we haven't seen a microRNA targeting drug approved different to RNA therapies that target specific individual genes. That's the approach that they have taken. From what we understand, Novartis are suggesting that they will initiate the phase III study for that asset in the second half of this year. What did Novartis pay for it? They paid U.S. $800 million in cash up front and a U.S. $800 million contingent value right on approval of the drug candidate, which is typically considered to be extremely conservative in terms of the value of the deals that we've seen. If you look at the difference between assets that have gone where there is a very limited phase I, II clinical proof of concept, as in the case of [uncertain], where there was only a 14-week multiple dose study, so you had to do a lot of work to interpret the data, extrapolate out to the endpoints that will be applied in the context of the registrational study, as compared to assets like Avidity Biosciences, where you've got a much more comprehensive phase I, II data pack, and you've commenced the phase III study. That company sold for $12 billion to Novartis on the strength of the RNA therapeutic platform and the data that they had from the phase I, II there. You can see that spread, and that is precisely the point that we're making here with respect to the strength of the clinical proof of concept outcome is going to dictate this company's future one way or the other. Whether we decide to retain, develop, and go all the way to market or partner at that point, or we're subject of an M&A activity, it all comes down to the quality of the clinical proof of concept data. That phase I, II data is absolutely critical. Rohan, at what stage of the PKD disease do you put people into the trial? We're looking at a classification of the kidney under what they call the Mayo imaging classification criteria. We have a look at the volume of the kidney on MRI. And there is a five subdomain stratification, A and B for the earlier stage patients, C, D, and E as the disease progresses. We are enrolling in the clinical study patients who are Mayo imaging classification C, D, and E. That is counterintuitive, because if we think that the ability to impact the patient lives is predicated on how far the disease has progressed, with the earlier stage patients likely benefiting more from the drug candidate, why are we going for the late stage patients? The answer there is if you look at a two by two of the rate of progression on the two endpoints that we're fundamentally interested in, total kidney volume and eGFR, there is a step change in the annual rate of growth of the kidney and the decline in eGFR for the C, D, and E patients. The theory here is that in the faster progressing patients, it's going to be easier and quicker to pick up the split between the natural history of the disease and the interventional arm, assuming that you can stop kidney growth. You're looking at a rate of growth on TKV of 5%-7% per annum in those patients as compared to 2% in the A and B patients. The difference between a 0% growth rate and a 5%-7% one is much more profound than zero to two. Consequently, fewer patients, shorter time to get that definitive clinical proof of concept. You have discussed U.S. capital markets, how much better they are, that you want to access those capital markets. This implies that U.S. listing is the obvious step. Does this align with your thinking? If so, do you have any thoughts on timeframe? Look, I do think so. Yeah. I think a Nasdaq listing is very much on the cards here, and it's something that we haven't formed a definitive view on at the board level, but it is something that I will be recommending to the board. Once we have got a better elucidated view on the timeframe for that, we'll come back and inform the markets. It's something that I think we should be doing sooner rather than later. We have the luxury of a five-year cash runway now, so we're in a very strong position from a financing standpoint. I think it would be very nice, and for exactly the reason that we've spoken about here, I would like for the U.S. market to value the milestones that are coming up in the next 24 months. I think it's really important that we are listed on an exchange that understands the gravity of the undertaking, and the consequence of those readouts. It's something that at board level we'll be considering sooner rather than later. What has been the FDA's feedback regarding taking PYC-003 straight through to a registrational trial? Are you awaiting the final phase I-A/I-B data before having that meeting? Yeah, that's a very good question. We've had a pre-IND meeting with the FDA, where we have aligned broadly on the clinical development pathway, and they are supportive of the idea of a phase I-A/I-B study being directly enabling of a transition to the phase III. The plan there is to have a Type C meeting again in the second half of this year to further engage with the U.S. regulator on the back of data from the phase I-A study, and whatever data we have generated to date at that point in the phase I-B MAD study, just to confirm that we have got that directly enabling link between the phase I-B and the phase III. Will PYC be affected by the proposed changes to the R&D rebates? Yes, is the answer to that one. We were going to be affected even under the old system because of the amount of capital on the balance sheet. It's a good problem to have. Because of the anticipated yield on that capital, we would have fallen foul of the eligibility criteria being AUD 20 million or less of annual turnover, in order to receive the R&D tax incentive as a cash rebate. It would have become a tax offset, a future credit. We were going to be impacted under the old system. Certainly, if the proposal in its current form is adopted, the company is 10 years old or more. We would be ruled ineligible for a tax incentive in cash if that proposal is accepted. I think under either system, we had a finite time in relation to receipt of the tax incentive. Any update on board additions? Front of mind topic. As we spoke about last year, we do see the optimal size of the board being an expansion on the current three-member board. I think it would be nice to get out to five to six members of the board. There are ongoing conversations with respect to potential candidates. I think you can expect to see some additions in the second half of this year. Good. I think we've exhausted the questions on both fronts. Maybe just to reiterate the key messages before we close. I think it's been a very strong start to the year. I think it's a tremendous credit to the team in relation to what has been achieved across the entirety of the pipeline. The organization has matured a lot, in particular in the last 12 months. I think the sophistication of the key leaders within the organization and the performance of the group as a whole has been incredibly encouraging. We are in a very good place as an organization. We need to build out with respect to late-stage development capability, and, similar to the board, we are actively pursuing that now. A very strong performance window to open the year, but we are now on the doorstep of the critical milestone. This is the exciting point in the journey, the turning of the cards. The company really has to focus very much on execution. There are so many material milestones within that next 24-month window for PYC. It is a company making event in the context of successful execution and the biology going our way. We're at the point where the rubber meets the road. We must now have the discipline to continue to execute well. A very exciting time for the company to see what is the full potential of these disease-modifying drug candidates in patients. We are very much looking forward to reporting back to you as we progress through those milestones, starting in the second half of this year. A phenomenally exciting time. Thank you for your support. We look forward to updating you as those events unfold. Thanks, everybody