Good morning, everyone, and welcome to the PYC Therapeutics third quarter investor webinar. My name is Rohan Hockings, and I am the managing director at PYC. I will be your host for this morning's call. Before we begin, I would like to read the following safe harbor statement reminding you that today's discussion will contain forward-looking statements that involve risks and uncertainties. These risks and uncertainties are outlined in our filings with the Australian Securities Exchange. As such, actual results may differ materially from what we will discuss on today's call. We disclaim any obligation or intention to update these statements in the future. I also like to remind you that today's call is being recorded. Before we begin, I would like to also thank the PYC team. There are many people within the team who are putting in an exceptional effort to maintain the organizational cadence that allows me to stand up and have the opportunity to present to you meaningful progress across all four of the company's pipeline programs. I am very grateful to those who are leaning in to maintain that organizational momentum. There is really only one objective for today, and that is to give you as much transparency as possible into upcoming human data readouts. I have split out a particular deep dive on the polycystic kidney disease program because that program is in a particularly interesting 18-month window as we look to transition that drug candidate into registrational studies. There are a series of milestones that are coming over the next 18 months that I would really like to engage with you on today to try and give you the benefit of the thinking that we have done in relation to what is coming, what to expect, and why. Prior to doing that, I will give a brief introduction to the company for those who are new to the story. I will also describe the changes that are being made at the organizational level to prepare the company for this transition that sits in front of us to multiple assets into late-stage clinical development. At the end, we will open up for Q&A and give you a chance to go deeper on topics of particular interest to you. PYC designs and develops precision medicines for patients who have severe unmet needs. That is our raison d'etre. We exist for patients like Sierra who have a mutation in one copy of one gene in the body. The particular approach that we have taken to these diseases is to design an RNA therapy that does nothing to the affected allele. You are made up of 20,000 genes and have two copies of each of those genes. Rather engages with the one remaining good copy of the gene at the RNA level in a regulatory region to stabilize that transcript and tell that copy of the gene to make two units of protein where it otherwise would have made one. These are what we call disease-modifying drugs that address a disease at its root cause and therefore hold the greatest potential for impacting the phenotype or the way that that disease is manifesting in patients. These are the types of drugs that if we or any of our family members had any one of the four indications that we are looking at, we would want to have available. We have used that strategy coupled with the platform to facilitate delivery of the RNA therapies, acknowledging that delivery is the primary challenge for this modality, to create a pipeline of four investigational drug candidates. We have taken four of those drug candidates into clinical development at different stages, as you see on the screen in front of you, and we will bring the fourth candidate into the clinic next year. You can see here that we are now at what they call the turning of the cards. For those who have been on the journey, we have described it previously. We are going to go into a lot of depth at the human efficacy data that constitutes clinical proof of concept, accompanied by the all-important safety data that marks the transition between the phase I/II studies and the registrational trials that follow. The ambition of the organization in the near term is now to prepare ourselves to become a late clinical stage development company. In the second quarter of this year, we made two appointments to the executive team in the form of the Chief Financial Officer and the General Counsel or Co-Company Secretary. Those two individuals have been onboarded and have made a very positive start. We are now looking to build out the team in the U.S., and in particular, at the back end of the value chain, focusing here on the clinical development strategy, clinical operations, regulatory engagement, and turning our minds forward to commercialization. I am delighted to welcome Candice Junge as our Chief Clinical Development Officer. Candice joins us from Ionis Pharmaceuticals, where most recently she has been running their phase III Angelman syndrome study. Towards the end of September, we will also welcome Marcy Fowler. Marcy is currently working at Novartis following the acquisition of Avidity Biosciences, where she is leading their Myotonic Dystrophy Type 1 program. We are delighted that those two have decided to join us. They bring a wealth of clinical development, and in particular, late-stage clinical development experience, and in particular, they are astute in the rare pediatric neuro space. Very helpful for the company's Phelan-McDermid syndrome program, and we will speak further about why that is important going forward. We are going to continue to grow, and the near-term focus here will be on a Head of Regulatory Affairs. As we move into late-stage development, that skill set becomes particularly important for the organization, and we will also bring on board a lead for our two ophthalmology programs. That is the near-term recruitment effort that you should be looking for the further expansion there. You will all be familiar with the company's five-year forward view from an operational roadmap standpoint. I am only going to touch very briefly on the PYC-003 program because we are going to go into that in a lot of detail at the back end of this presentation. What I will point out, I would like to do it repeatedly so that everybody is comfortable and hears the message. There are multiple human safety and efficacy readouts coming within that 18-month window that you see in front of you there through to the end of 2027. Before we hit that mirror of the primary registrational readout, the 12-month outcomes on the total kidney volume that will shape the design of that registrational study that follows. These basically split into the outcome of the single-dose studies, which will be presented at the American Society of Nephrology meeting in Denver on the 22nd of October, as an adjunct to the data that you saw released into the public domain earlier this week by Aron Chakera at the Australian and New Zealand Society of Nephrology meeting, covering the safety dimension of that data pack. There is single-dose data coming in Q4 of this year, then throughout the course of 2027, we will start to read out the results of the ongoing phase I-B multiple-dose studies. It is those studies that are really critical to the forward view for this program. We are at present 13 of 24 patients through recruitment in the phase I-B MAD study. The focus here is to recruit the final 11 patients to constitute the initial two cohorts, C1 and C2, 12 patients per cohort. The objective is to have that initial two cohorts fully recruited by November of this year. That will then start the clock on the three, six, nine, and 12-month data, on the TKV endpoint and the urinary PC1. Later in year two, on the open- label extension, we start to track the eGFR there. That data will mature through the course of 2027 to that primary readout at the end of the year. We will come back and have a deeper chat in relation to exactly what we are expecting as that data pack evolves. In the PYC-002 study, the focus as the operational roadmap gives away is on the GLP toxicology studies, another way of describing the investigational new drug-enabling studies. There are multiple studies here, and important for everybody to understand. There is a single-dose study, which we have now completed the dosing of. There is a repeat-dose study, which we are partway through, then there are chronic studies. All three of those studies going on in two species, the rodent and the non-human primate. We will bring that data together in the early parts of next year and complement it with some work that Janya is doing in the in vivo therapeutic model, the rodent model of Phelan-McDermid syndrome, where we will be looking in Q4 at the extent of SHANK3 upregulation in that model, then in the early parts of next year at the functional rescue that we are able to see in the context of the PMS in vivo therapeutic model. That data pack will then enable the transition to first-in-human studies. We have held a pre-IND with the FDA, and we are involved in an interesting conversation around the design of those first-in-human studies. PYC proposed to the regulator that we would conduct a single-dose study followed by a multiple-dose study, having reviewed the safety data package there. The regulator has come back and asked us to go directly into a multiple-dose study. The idea here is that the regulator would like the children enrolled in that study to have the prospective benefit of the drug candidate if they are going to engage in having the risk of an intrathecal drug administration. We now have an evolution of the conversation in relation to the design of those studies, which may be different to what we had first envisaged. You may see the IND move slightly backwards into the middle parts of 2027 if we end up going down the pathway of proceeding directly into a repeat-dose study. That should not impact the overall development timelines for the program as a whole because it is really taking out the single-dose study from the front end. We are also looking at whether or not we need to run an ex-U.S. study to complement the planned study within the United States as well, and leverage a parallel development path for those early-stage studies. There is a little bit of flex there, and you can see it is important that we have that industrial experience that comes on board to guide the development of these rare pediatric neuro programs. Very much looking forward to, Candice has already started, and getting Marcy on board to benefit from their experience in this domain. The two ophthalmology studies are progressing through the phase I/ II trials. I think everybody is familiar with what is going on here. In ADOA, you are very much up to speed in the same capacity as me because you saw yesterday that Clare Fraser has presented the latest data from this program at the Neuro-Ophthalmology Society meeting, showing a very favorable safety tolerability profile and some encouraging early efficacy signals on both the biomarker, the marker of retinal stress, flavoprotein fluorescence, but most importantly on the visual acuity of those patients as well. The opportunity for PYC now is to run those studies, both of them, until we feel confident that we have got a handle on the effect size on each of the relevant endpoints that could serve as the primary endpoint in the registrational trials. Once we have a handle on the understanding of can we create or design a high-propensity registrational trial, that is the point that we are willing to commit to that phase III go criteria. We will continue to develop both of those programs, and you will see the data come out continuously as we move forward. For those of you with a keener eye, you will see that the ADOA program has got a potentially clearer path forward at this time because of the absolute magnitude of the visual acuity improvements that we are seeing in the patients there. Many of you will be familiar that the division of ophthalmology within the FDA, particularly, a lower bar over in the EMA, but holds ophthalmology drugs to a very high standard from a visual acuity improvement. The expectation here, black and white expectation for a slam dunk approval, is that patients will be able to read three lines better than the control group in that registrational study, 15 letters. It is an incredibly high bar. Many of you who followed the story will know that there is some scope for flexibility from the regulator there based on the totality of the data, but defining exactly what that means in the context of multiple endpoints is a nontrivial undertaking. That is the pipeline as a whole. I would now like to go into the PKD program in more detail because, as we spoke about before, there are a series of milestones now coming over the next 18 months as we transition into registrational studies. So I want to make sure firstly that everybody is on board with the overarching clinical development pathway here to understand how the ongoing phase I-A/I-B study enables the transition directly into an integrated phase II/ III trial, and what the endpoints for each of those trials look like. We came across a very interesting video recently, a renal physician from Yale University who is engaged in a very similar undertaking to PYC. Their group have designed an RNA therapy to bind in the regulatory region of the wild-type copy of the PKD1 gene with a view to stabilizing the transcript and enhance the translational process. So a very familiar mechanism to many of you, and it provides a very interesting outside in or external reference point for the company's program when the physician surveys the development pipeline for PKD as a whole. It is very interesting to hear her thoughts, and then we will comment on those, how we develop the molecule, and in particular, what we are seeing in the data that has transpired since that presentation was made late last year. So I think you will find all of that very interesting. The whole video, we are only going to play a 45-second snapshot of it. It is only an eight or 10-minute video, but is available online. If you search the footnote, you will find that video, and it is worthwhile listening to. I think it is a very interesting overview of the PKD space as a whole. We will dig a little bit deeper into the expected timeline for those exploratory efficacy data that I think everybody is keenly anticipating. Then we will have a conversation in relation to what should we expect at each of those time points, the single-dose outcomes, the early multiple-dose outcomes, and then the later multiple-dose outcomes as we move through towards the 12-month readouts on TKV. We are going to effectively outline why it is the six, nine, and 12-month data points in the MAD study that are critical here. That is what we are really going to focus on, and we will explain to you why that is. Then we will open up for that Q&A that we spoke about beforehand. In terms of the overarching development pathway, again, not a new slide for those of you who have been following the journey, other than the fact that we continue to make nice progress through Part C and Part D. We are into the exciting part now, recruiting those patients who are going to have a sustained exposure to the drug candidate and having a look at what the safety and efficacy profile is in that context. But it is actually helpful to understand the PKD landscape from the right-hand side of this page back. The single most important thing here is that there are tens of millions of people worldwide who suffer from polycystic kidney disease caused by a mutation in the PKD1 gene, who do not have any treatment options available to them today. As you know, about 50% of those patients will require an organ transplantation in their 50s. There is an urgent need for new therapies for this indication. The FDA has recognized that, and they have designated PKD an indication that is open to an accelerated approval pathway. The development path in the registrational study, whilst commercialization is based on a confirmatory endpoint, the function of the kidney, a biomarker known as the estimated glomerular filtration or eGFR rate. The approval milestone for that accelerated outcome is an anatomical surrogate outcome based on the volume of the kidneys. If you have a look at the MRI of this patient who is enrolled in the PYC study, you can see those grossly distorted kidneys because of the cysts that we see all throughout the kidney, which are pressuring and ultimately destroying the adjacent residual renal parenchyma, the normal functional tissue that sits next to them. As the cysts get bigger and bigger and bigger over time, they squash the tissue that is next to them. There is a correlation between the volume of the kidney as they get larger and the function of the kidney. Because of that correlation, the FDA are comfortable accepting the TKV anatomical surrogate as the approvable endpoint in the context of polycystic kidney disease. That readout comes 12 months after full enrollment of the study. What we want to do in our phase I-B study is give ourselves the maximum insight into what is going to happen in that registrational study on those endpoints. So you want to get as close to designing the full mirror of that registrational study as possible, albeit obviously in the context of a smaller patient population than what is going to be required to power a registrational outcome. That is exactly what we have done. We have set ourselves up so that we have the Part C or the six-month repeat dose study rolling directly over into a Part D, where those patients will continue to receive the drug for a further 18 months. So you will see the totality of that 24-month data in the context of the extended phase I-B study. You are going to get the full mirror of that registrational trial over the course of the next 24 months, but you can see why the focus is very much going to be on the next 18 months as we move through to that 12-month primary readout for full enrollment of those first two cohorts. What we are looking to do here, and you will see repeatedly the concept of clinical proof of concept or initial efficacy data supporting the efficacy profile of the drug candidate before moving through into those late-stage studies. There is another endpoint that we are interested in here that does not feature on the page. Again, for those of you who have been on the journey, you will know that the drug is intended to modulate a gene primarily in the kidneys, but to a lesser extent in the liver as well, called PKD1, which encodes for the polycystin-1 protein. The polycystin-1 protein is ultimately excreted by the kidneys into the urine. So we can measure the urinary levels of the PC1 protein in the hope that we see an increase in the expression of urinary PC1 after treatment as compared to the baseline. So we want to see the UPC1 going up and ideally the TKV flatlining or in a perfect world, even perhaps going backwards, depending on the stage of progression of the patient. That is the development pathway as a whole. Let us have a listen now to the renal physician from Yale University surveying the landscape and their approach. Then we will have a chat afterwards about some of the insights that come out of that presentation. The disease we are treating is Autosomal Dominant Polycystic Kidney Disease, the cause of 5%-10% of all kidney failure. It is characterized by the gradual accumulation of cysts throughout the kidney, leading to kidney failure by middle age. Majority of patients also have liver cysts, and in a subset, these can become quite symptomatic and require intervention as well. The only approved therapy for ADPKD is tolvaptan. It decreases fluid secretion into the cysts to delay kidney failure by a handful of years by blocking vasopressin 2 receptor. However, it has black box warning for liver toxicity and is poorly tolerated. A better-tolerated therapy could expand the market significantly to all of ADPKD as well as ADPLD, which has a shared genetic mechanism. Imaging and genetic diagnosis can allow us to make diagnosis early, to start treatment early in the disease course. Fortunately, total kidney volume is now an approved biomarker to allow for efficient clinical trials. The disease mechanism, simply put, is insufficient PKD1 or PKD2 dosage, and thus a therapy to increase functional PKD1 dosage should address all of ADPKD as well as ADPLD, with the thought being to increase the function or the levels of the remaining wild type allele or a partially functional missense allele. Our therapy would be a weekly subcutaneous injection with the goal of halting kidney and liver cyst growth. The pipeline is early currently, led by Regulus Therapeutics, who just finished a phase I-B trial, which showed short-term safety of their naked ASO, as well as actually some efficacy, which is a nice proof of concept for this approach of increasing PKD1 across all of ADPKD patients. However, miR-17, their target, affects hundreds of genes, so long-term safety in a disease that requires decades of treatment is of concern. Therefore, Australian company PYC has started a phase I-A trial, trying to block the miR-17 binding site on PKD1 specifically. However, it seems that they need to do this with a PMO with cell-penetrating peptide, and many experts I have talked to are concerned about the toxicity of that compound. Very interesting point there at the end, right? Really piqued our interest in relation to the toxicity of the compound, the safety concern being the primary driver, and a few of you in the audience looking puzzled there in the context of the cleanliness of the safety tolerability data that you have seen. So why is this presenter talking about the safety profile of the molecule? The reason for this is nothing to do with the molecule at all. It is driven by the class to which the molecule belongs. Cell-penetrating peptide conjugated morpholinos have been used by Sarepta Therapeutics, PepGen, and others in clinical trials that are directed towards different disease indications, muscular indication, Duchenne muscular dystrophy, myotonic dystrophy. The issues that have been seen with those molecules in the clinical trials are manifesting in the kidney. There is a disturbance of the electrolytes in the kidney, which is driving a concern on the part of the clinician community that we are seeing an underlying tox event that is happening in the kidneys. That is what really drove the concerns around the safety profile of the PPMO modality, and it is just very interesting to hear the feedback outside in relation to what do people think of our approach here. There are a couple of issues that arise that were front of mind for us as we transitioned into clinical studies with the same modality that had seen these tox issues, because we were aware of these at the time that we put 003 into clinical development. The first one is the Sarepta and PepGen molecules are trying to achieve a PD effect or an efficacy profile in muscle, but their drug biodistributes to the kidney. This class of drug has a natural affiliation to go to the kidney. So we are not fighting that headwind of the fact that we have orders of magnitude more drug in the kidney than we have in muscle, but we need to get an efficacy outcome, high concentration of the drug in a different target tissue. So that alignment of the target tissues massively brings down the dose that we are required to administer at. So we see 10 mg, 15 mg, 20 mg, 40 mg /kg dose of the PPMO modality in the Sarepta and PepGen studies, as compared to the 1 mg- 2 mg /kg that you are looking at in the context of PYC-003. But the differences do not stop there. We spent a long time as a company ensuring that we had a safer class of PPMO, or a safer example of the class of PPMO than what we have seen with the Sarepta and PepGen molecules. Particularly helpfully, we were able to benchmark to those molecules preclinically to evaluate the safety tolerability profile before we moved into clinical development. There is a fundamental distinction between the physicochemical properties of our PPMO as compared to those that were taken into clinical development by Sarepta and PepGen. That is why we are particularly pleased to see the incredibly clean safety tolerability profile as we moved into clinical development that you saw presented earlier this week at ANZSN. Oh, don't want to see that again. Having said that, the company retains the risk that that single dose safety profile translates to a multiple dose safety profile, because we have not yet put out into the public domain the data because we haven't captured it from enough patients. Why, in addition to the generic decrease in dose, extension of the dose interval, change in the physicochemical properties of the peptide, why are we confident that that is going to translate to those repeat dose studies? I want to show you here some data that's going to be relevant for two conversations that we're going to have, first on the safety side, then expectations on the efficacy side as well. What you're looking at here is the inferred human kidney concentration at the three different doses that we took through the single ascending dose study in patients. You see in the purple line, 0.4 mg /kg, I don't quite know how to describe that color, light orange, 1.2 mg /kg, and green, 2.4 mg /kg. The way that this model has been created, it's pulling data from three different sources. It's looking at the steady state distribution between the plasma and the kidney in the non-human primate, the monkey, because in the monkey we are able to take a biopsy or even take the whole kidney at the end of life phase and have a look at the drug concentration in kidney. We cannot do that in a human. What we're looking to do is see the relationship between the plasma and the kidney in a species that directly adjacent to the human species, then we can link that to the observed plasma concentration in the humans to model an inferred kidney concentration. That's what you're seeing here. What we then do is we superimpose this horizontal dotted line, which is the minimum effective concentration of drug that we need to apply in order to see target gene modulation in the context of a patient-derived model. Here, we've taken cells from the patient, reverse differentiated them into a stem cell, then forward differentiated them into a renal tubular epithelial cell, proximal tubule-like cell, because that's the cell type that we're interested in here. We are looking at what is the minimum required dose of the drug in order to see our target gene, PKD1 PC1 protein going up. The true MEC is actually lower than that line. It is down here in the 300 nanomolar range. There is a spectrum or a continuum of the extent of upregulation that you are going to see that increases with an increase in concentration on the vertical line here. So keep that in mind. The first point to note in relation to the video, the peak concentration of the drug, and in fact the area under the curve, is largely simulating in the single dose study what you are going to see in steady state in the MAD based on the predictions of the model. The key here is the peak concentration of drug in kidney is not materially different after the second or third doses to what we are seeing in the first dose. We gave not just an assessment of the biomarkers, the electrolytes that were disturbed in the Sarepta and PepGen studies, magnesium and potassium, but we also published, if you look in the bottom right-hand side of the poster that was presented earlier this week, two very sensitive markers of renal tubular injury. KIM-1, or the kidney injury marker one, and NGAL, and they look incredibly clean. So clean, in fact, that we are not yet committed, but considering the prospect of not waiting for the dose dependency in the MAD before we continue to escalate the dosing in the patient population to 4 mg /kg. Not because we think we need to get there from a PD standpoint, but because we have a completely clean safety tolerability profile. The question then is spending more time at higher parts in this curve going to yield a better outcome from an efficacy standpoint for patients? Given the cleanliness of that safety profile, it is encouraging us, in consultation with the toxicologists and the clinicians, to look at accelerating the evaluation of that higher dose cohort. That is a very important point to take out of it. The other one is to frame your expectations in relation to what to see in October when we present the efficacy data from ANZSN. You can see here your Cmax, you will see no Ctrough here, but you can see Ctrough here when you have got repeat dose introduced, and then the area under the curve in relation to the time spent at the dose above the minimum effective concentration in those patient-derived models. We do not know, nobody knows, what the primary driver of efficacy is in the clinic, which one of those three variables could be driving that outcome, right? That is part of the reason why we are evaluating the different doses in clinical development. But what you can see here is you get a much better profile on all three dimensions in the context of repeat dosing. Right. The presence of the drug above the minimum effective concentration is very short in the 0.4 mg /kg dose cohort. It's longer in 1.2 mg/kg and longer again in the 2.4 mg/kg cohort. We're going to have a chat with you afterwards in relation to the spread of natural history versus assumed interventional outcomes and why it's going to take until the MAD to get really meaningful data in relation to the efficacy signal here. This is just to repeat the timelines, single ascending dose study outcomes in October of Q4, and then we will also aim to complete enrollment of the first two cohorts in the phase I-B study. You will then get a continuum of data generation through the course of 2027 until we get to that mirror of the primary registrational readout on the anatomical surrogate or TKV. Just to be clear on which patient population is in this clinical study, because there are some counterintuitive elements to this as well, and this will inform your expectations for how the control group and the registrational study is going to perform, and therefore what we're going to be comparing to from an effect sizing standpoint. The severity of polycystic kidney disease is graded by effectively the size of the kidneys on MRI, with the later stage letters being the more advanced disease. Patients will progress from 1A through 1B, 1C, 1D, 1E. It is the 1C, 1D, and 1E patients who are the fastest progressers on the two endpoints that we're interested in from a registrational standpoint. Both the growth of the kidney volume per year and also the decline in the estimated glomerular filtration rate. We want to choose those patients who unusually are actually less likely to benefit from the drug because these patients will have the larger kidneys with the larger cysts and the most fibrosis in the kidney. We think ultimately the stage 1A, 1B on Mayo Imaging Classification 1A, 1B patients will respond best to the drug, the greatest potential for arrested progression or even reversibility. Because the gradient of progression is steeper in the later stage patients, it's easier to detect that deflection in the interventional arm. I just wanted to outline who's here, and remember that 5%-8% band of the annual growth rate for these patients, because that now is directly mirrored in this blue line, which is the natural history or disease course of polycystic kidney disease patients in the absence of treatment, what we call the natural history studies. This is how we expect the control in the registrational trial to perform. You can see here, they're very small letters, but in the vertical plane you've got total kidney volume, percentage change year- on- year. You can see the zero line is here. If we take a snapshot at time zero on the horizontal axis, time in weeks out through to 52, you can see 2%, 4%, 6%, and 8% growth year- on- year. So that's that 5%-8% spread that we spoke about with the shaded area representing the 95% confidence interval. So that's what to expect from a comparison standpoint of the control group in the registrational trial. Now, if we assume that our drug is able to completely stop disease progression, as in prevent any growth of the kidney at all, 0% growth over a 52-week window, you will see the green line here. To be clear, this is model data, right? It is not based on real data at all. We have added the 95% confidence interval to that assumption. You can see that with an n= 24, the n=12 patients per cohort, assuming both doses are effective in the phase I-B study, you will not get separation of the 95% confidence intervals until the six-month time point, 27 weeks. Right? It is that longitudinal opportunity to evaluate the six, nine, and 12-month data. That is really what the industry are waiting for from an expectation standpoint to read deeply into the data, to gain that conviction that you have the ability to properly design the sizing of your phase III study in order to reach statistical significance on the two designated endpoints. You can see then by direct inference that if we go out to 12 weeks, we go a little bit further on to the 16-week point, the variability, the 95% confidence interval, it effectively spans the zero line. There is a very limited weight that you are going to be able to put on either the SAD data or the early readouts from the MAD data. This is not something to be afraid of, it is something to celebrate, because if we look comparatively at where Regulus were able to get the molecule to, they were limited to 16 weeks of data in the MAD. They had to stop the study at that point in time because they had not done the chronic tox work in the NHPs at that stage. Novartis, when they bought that asset, were left with 16 weeks of actual data and the rest of the year to extrapolate, to try and work out what should the phase III design look like. You see that challenge took even an organization of the scale and resource of Novartis quite a long time to get their heads around in relation to, well, how do we design the phase III study? If you look, we are not privy to the biostats conversation, but if you look at that trial design, they seem to be pegging themselves to an outcome that sits between these two. Right? No conviction that they can get down to the zero line, rather that you are looking at tolvaptan-like efficacy from an effect sizing standpoint. The consequence of that is that they have a very large phase III study, 900 patients projected to be enrolled in that study, which will take three years, possibly longer, on our estimates to enroll. There is a big opportunity now for PYC, given we have the ability to follow through to the 12-month time point to get a firmer grip on what our phase III design should look like. But it is going to take the patience on the part of the investors and the organization to ensure that we're basing that off the data that is going to matter, and that is the six, nine, 12-month data from the repeat dose studies. So just keep that in mind. What you're going to see then is in the SAD, you're going to see patients get out to this time point here in the context of having less than half of the dose exposure that we want them to have in the MAD. You saw that from the peak to trough, irrespective of what's driving at Cmax, area under the curve, Ctrough, it's much better profile in the repeat dose study than it is in the SAD. So pretty much what people are looking for here, the bar from the industry feedback that we've been given is anything. A trend will be very encouraging in the context of the SAD. But it's important not to put too high, an unreasonably high expectation on the data that is coming later this year. The data that will be most relevant will come from the middle of next year, six, nine, into the second half, 12 at the very end of next year. So I just wanted to have that transparent conversation. We can open up for questions at the end. But that is how we are looking at that data set. Having completed the SAD out to 16 weeks, you'll then see the data coming continuously through the course of 2027 for the MAD. And we will over-recruit that study. So we'll start with the initial n= 24, but the end will get stronger as well. We will continue to push up, so in total, you'll see 48 patients through the course of the MAD. I just went back to my Q2 webinar as I was preparing the Q3 one, and I couldn't resist one Phil Needleman quote. There've been a lot of hard graft on the part of the organization to get to this point. We've spent, since I joined the company, nearly 10 years now. 10 years will be next year's anniversary in relation to the groundwork to get these four drugs, fourth one yet to come next year, but into clinical development. And we have arrived at the point where we are generating that clinical proof of concept data, and so we are now very much in the thick of the interesting window. We can test whether the hypothesis that we had in relation to the safety data, all of the thinking that went into why do we think we can crack delivery to the kidney when the modality has seen these adverse safety signals, why do we think we can engender better outcomes for patients than any other molecule out there? All of this is going to be tested over the course of the next 24 months in each one of those indications, and we will share that journey with you and the data that is generated on the back of it. But we are going to do the hard graft, not get distracted by the bright, shiny things, but focus on execution of the clinical studies. We know exactly what we've got to do now. We have the balance sheet strength to do it. We have the support of the Board. We have organizational and operational clarity in terms of what's required to realize that execution. We have a big undertaking to prepare the organization for success and ensure that we are actually structured for the transition that comes afterwards, because nothing happens in sequence in drug development. Everything is happening in parallel. Just when you think you've done your forward-facing tox studies, you've now got your NDA backwards-facing tox studies to do as well, the additional detail that sits in underneath there. A very significant undertaking for the organization, but a very exciting time for both us inside the company and also for our investor base. With that, we'll stop and open up for Q&A. We have one question coming through online. [Mel Benson's] asked, regarding the Yale pitch, your views on their comments regarding the uORF-targeting naked ASO is driving higher PKD1 protein restoration, inferred higher levels versus those in development, including PYC-003. Do you have any sense for their data or no disclosure to compare to? We have a sense for the data, but it's not an apples for apples comparison. If you go back and watch the video, you'll see that comment is based on a luciferase assay. Very much a reporter where they have spliced in the regulatory region of PKD1 to a reporter protein coding region. We are not confident that that gives you reproducibility or fidelity that you're going to see in a patient-derived line. Until that group migrate downstream and show us what they can do in a patient-derived model, we don't really have the ability to compare to that. Remembering, though, that if you are restoring PC1 protein to 85% of wild-type levels, as seen by PYC-003 in the patient-derived models, you don't have polycystic kidney disease. You have an incidental finding of a cyst in the kidney. It's nearly back to wild-type levels. It's unclear, even in the event that there was additional benefit over and above the two-fold upregulation, whether or not that actually manifests in clinical benefit. One other question. Is there any further development on a potential listing on the U.S. Stock Exchange? Yes. I do not want to preempt a Board decision here, and there has been no formal commitment at this stage, but what I can share is that we are doing the groundwork from an accounting standpoint now. We are ensuring that we are Sarbanes-Oxley compliant, so that we can trigger a three to four month legal process with disclosures next year in the event that the board decide to go to a U.S. listing, such that we are ready to pull the trigger. Rohan, could you go back to slide 12? I think slide 12 is the one slide that does not have a number on it. Yes. Yeah. That is right. So on my right, it seems that when you do the multiple ascending dose, it is ascending. Are you seeing the fact that the kidney obviously is improving, so therefore it does not drop as far? Is that what you were expecting to see? Or is it just the way it is? When you say it is ascending, this is the concentration. It does not drop as far. The green line is higher, and the orange line is higher as you are progressing to the right. So almost like it is not falling as far as what it did the first time. So it is almost like the kidney must be retaining some of the drug, therefore when you add additional drug, it performs? It is just the higher starting burden of the drug. You can see it on the far left-hand side of the image. If you dose at 2.4 mg/ kg, your peak concentration in the organ is higher, and it has got a constant rate of decay halfway. It doesn't fall as far as you do the multiple ascending dose. It doesn't decline as far? Yes, because you haven't completely cleared the drug by the time the second dose is given. So you're getting what they call a plateau, which you're reaching effectively after three doses of the drug candidate. It's a very subtle increase there, but that's the point I was making about if it's the Ctrough that's driving the efficacy, again, you should also expect to see a better outcome in the clinic. The next question is this a drug that if it does work, you would give it over a long period of time or for the rest of your life, or would it be for a two-year period to get your kidney back to a level where it's satisfactory? No, the intention will be that the patients, once they start the drug, are on it forever. With the idea being there that the RNA is turned over. So the RNA therapeutic is binding to the mRNA, and for the life of that mRNA, it's encouraging it to produce more protein. But as that mRNA transcript is degraded, you'll need another unit of the drug to come in and bind the next copy of the mRNA that is created by the cell. Rohan, another NASDAQ related question. Would the consideration regarding the NASDAQ be including an ASX delisting or assumes remaining dual listed given relevant CUV news this month? Yeah, no, we've always planned to retain the dual listing. I think we've been pretty clear on that from the start. We would not, in the event that we sought a NASDAQ listing, seek to be doing anything in relation to the ASX listing, for the foreseeable future. There may come a point in time where more than 50% of your shareholder base is in the U.S., where the SEC will view you as a U.S.-based company, and at that point in time, there may be a question as to whether the ASX listing is relevant, but that is a long way down the track. I think it'd be a very different approach there. I've got off very lightly. Oh, no. There's another one there. Hi. You said you were going to try a higher dose with the MAD. Would that mean that you could then extend out the dosing periods? Yeah. You would still, looking from that graph, look like you would still be well within your efficacy dose? Yeah, that is exactly right. What you are first looking to do is, because of the lack of clarity as to exactly what is driving the efficacy signal, you want to determine the optimal dose before you even turn your mind to the interval. But once you have got the optimal dose clarified, you can then look to extend the interval and exactly as you say, particularly at the 2.4 m/ kg dose already. As I said, I am not sure that we need a higher dose at this point in time. If it turns out that 2.4 mg/ kg is maximizing the efficacy, you could look to extend that dosing interval to eight or even 12 weeks, and you would be remaining above that minimum effective concentration for the entirety of the time. Once we have locked down on the preferred dose, we will then seek to evaluate the dose interval. The question now is how much information can we glean for the optimal design of the registrational study before we want to commit to that transition? Because that is coming very soon, right? You just saw before, you need more than six months worth of data for it to be meaningful. So we are on the clock. How many variables can we answer before we lock down that phase III design? Then you have got the whole biostats exercise in terms of the sizing of the study. Then I do also want to flag there is one additional important consideration. We have talked about the TKV endpoint and powering for that. But we also have to power for the eGFR endpoint as well. There will be a conversation with the regulator as to whether we can start the study based on powering for the TKV outcome, but continue to recruit past the critical mass of patients required to power for that outcome, so we can have the eGFR outcome coming later. That is an open dialogue that we will have with the FDA. Another question. There is one more from [Melissa]. So, there seems to be many new PKD trials popping up, getting busy. What novel approaches are you seeing that are interesting, non-RNA based? Yes. Referring back to the presentation that you saw from the Yale clinician, she has really outlined there for you the disease-modifying approaches in PKD. You saw Regulus, now Novartis with the Farabursen molecule, PYC, Vertex, and a company called Renaissance Pharma. The reason there is because the field is deeply interested in disease-modifying drug candidates for this indication. Specifically because many of you are aware, there was, out of Yale University, a mouse model that was run that shows if you can re-express PC1 protein, even after the disease has established in the mouse kidney, you can actually reverse the disease in the context of early disease progression microcysts. That has helped people to understand. Also, when you just look at the raw biology, the polycysts are apex regulators of multiple downstream cellular processes that are temporally integrated with one another. There is a huge fascination with the disease-modifying approaches that we have outlined there. The reason that you saw Vertex and Renaissance Pharma as small circles is because there are a smaller number of patients who have the specific mutation required in order for that PC1 stabilization approach to work. That is the field of the disease modifiers. At this point, you have obviously got a lot of people in earlier development, like the Yale University crew, also interested in this approach. Then you have got the non-disease-modifying approaches, and here AbbVie and GSK with the PAPP-A approaches that are going to start reading out shortly in the phase II studies. I think the limitation that we see there is if you look at the preclinical data, they have tolvaptan-like efficacy. That is an important point to understand. PKD is a hugely attractive indication for the field as a whole, but the bar is also quite low because, again, as you heard the renal physician articulate, tolvaptan is not a great drug. In terms of the percentage of the patient population who are amenable to treatment, that is between 5% and 10%, carries a black box warning for liver failure. It has got a very difficult safety tolerability profile for patients to tolerate, and it does not have a big impact in terms of the deferral of time of that endogenous renal function before the organ transplantation is still needed. That is pretty much the landscape in clinical development at this point and what we are seeing from an earlier stage as well. Just as a follow-on from that, you mentioned Regulus obviously wanting to conduct their phase III trial and would need something like 900 patients with PKSD. Does that mean you are competing with them when you want to conduct your trial, so patients sort of are choosing between their technology or yours? Would that make it more difficult to actually recruit and therefore complete your trial? Yeah, absolutely. It is going head-to-head with the might of Novartis, so not a small undertaking. That is why the data that you are seeing from the early study is so key, because it is going to be a recruitment effort on the part of patients in consultation with their physicians. If we can establish differentiation on safety tolerability, knowing that Regulus had multiple patients dropping out, even of the MAD, 16-week MAD, because of the injection site reactions from the particular chemistry they are using. Knowing that we have liver function disturbance with Farabursen, that is front of mind for the clinicians. Knowing the point that the Yale physician raised in relation to the lack of specificity of what else is that microRNA doing inside the cell, because there are another 200 genes that sit downstream of miR-17. Those are the questions from a safety tolerability standpoint. That is why translating that very clean safety profile into the repeat dose study is going to give you competitive differentiation. If you happen to be able to demonstrate from an efficacy standpoint, you are differentiated as well. Remembering back to our presentations on the preclinical data, we have 10 x as much drug in kidney at like-for-like dosing as Farabursen. We have a lower minimum effective concentration than Farabursen. Those two dimensions will inform the distribution of patients at sites that are recruiting for both studies, and critically important that we are able to define that data set and communicate it effectively to those investigators who are involved in the studies. To that point, and the video you showed us where the woman referred to your particular drug and the safety I noticed on the lectern it was 2025. We are in 2026. We have got safety data. Clearly, you have data now that would not have been present at the time she would have made those comments. Is that correct? That is the key. Yeah. Exactly. That is the key. That is why we are giving you individual patient-level data, and we are giving you the most sensitive markers of kidney injury. We are trying to give as much transparency as possible in relation to the underlying data because we see a very favorable profile to date. Yeah. At what point in time does a partner become relevant in ADPKD, or useful, if you like? Well, it is largely up to the partner, isn't it? In many respects, it could be a question for those guys. I think the idea here and the concept that we put forward to you was through the capital raising that we undertook in February, we are going to fund the company, to have the ability to independently progress this asset. We can see a very clearly defined pathway through clinical development. Whilst we recognize the challenges of going up against a top 10 pharmaceutical company in the context of a competitive recruitment process, we are firm believers that with a differentiated profile, the phase III execution is well within the capacity of PYC. Now, we will have to change as an organization in order to be able to compete successfully, but that is why you see us building the groundwork right now in order to do that. From our standpoint, you are now starting the clock on the data that really matters, precisely because that phase I-B study is the direct mirror of the registrational study that follows. Safety and the data out there in the single dose study is one tick. We now have to move through to ensuring that that is replicated in the repeat dose study setting. We need to get the early efficacy data into the public domain, and then we need to put the six, nine, 12-month data out there as well. At that point in time, do we wish to hold on further because we are very comfortable with the risk profile? Are we going to wait for the eGFR confirmatory endpoint as well, in which case we will need to stand up the phase III and start the recruitment of that process. We are very happy if we are going to do that, we are going to have the capacity to completely execute that phase III. There are many twists and turns to come. Remember, the effect size, where we land that green line, the precise gradient of that green line is going to inform the statistical powering, the number of patients that we need to recruit in order to ensure that we hit our outcomes from a registrational standpoint. We will be using this data to inform our view. I think at the minute, the answer is we are very comfortable progressing independently. Another one online, this one on the ADOA program. Does management currently see the most likely value creation pathway as taking PYC-001 all the way through development itself, partnering, licensing it, or some combination of the two? As we look back at the pipeline, there is a fundamental distinction in the level of interest in PYC's programs. You will see a lot of industry commentary around mega blockbusters, drug candidates that have got the potential to yield AUD 5 billion + in total annual sales, right? The focus of the big players in the industry is in that domain. The top two programs that you see on that pipeline fit squarely within that bucket. There is scope to bring ADOA, which is a smaller indication in the order of AUD 1 billion- AUD 2 billion per annum estimated total addressable market, into the threshold of the mega blockbusters, unusually for a disease-modifying agent, because it is directed towards a single gene disease, by demonstrating pipeline-in-a-program potential, expansion potential into other indications that have mitochondrial dysfunction as their root cause. We are doing the work now in the preclinical setting to establish both that we can maintain the length of dosing interval, six months or longer, that would be really required to move into glaucoma and other indications, as well as looking at models of glaucoma to demonstrate the efficacy profile of our drug candidate in that setting. Once that work is done, once we have the clarity from the ongoing phase I/II studies that we can design a phase III with a very high propensity for success, you are, I think, aligning the views of both sides of the table from a licensing or acquisition standpoint as to the value of that asset. We would want to hold the asset until that data has fully manifest. From that point, we would probably have more flexibility in relation to whether we choose to out-license or sell that asset, as compared to the other larger indications. Going once. Any general insights you can share into the large pickup in the volume of shares turning over? We are working hard to raise the awareness of what the company is doing. I am getting some feedback from our U.S. investors that they keep talking to their U.S. peers who have never heard of PYC, so we have obviously got some more work to do on that front. I think we are seeing a lot more interest on the part of sophisticated investors, life science specialist investors, on the back of the understanding of PKD in particular, and the emerging safety profile of the drug candidate. So I think that is probably the primary reason. It is the proximity to those efficacy readouts, the fact that we are now very much in the thick of multiple human safety and efficacy readouts over the course of the next 18 months- 24 months. Hopefully also some increased awareness on the part of the Australian Exchange. There will be an index rebalance occurring later today. There seems to be a confluence of factors that are driving it in a very acute window of time. But for those of you who've been on the journey for a long time, you will have seen that there has been very steady progress towards realization of these outcomes. It feels like a 10-year overnight success in that sense. I think the other important thing to keep in mind is the scoreboard for us is number of lives changed. We've got the balance sheet strength to be able to answer these questions. We need to drop our vision to focus on the execution of the clinical studies that dictates the outcomes that really matter. In trying to get a drug to market, is the safety profile the biggest half of the problem? Once you get that right, the other bits fall into place, or there's still a lot of big hurdles to overcome? The two big questions are safety and efficacy, obviously. I think the initial focus, given the principles of first do no harm, is very much on the safety dimension. I think we have the big advantage in this context of these being precision medicines, and the wealth of preclinical data that goes into understanding a quantitative solution to a quantitative problem. We've avoided the most complex question in biology. Will modulation of this target restore this disease phenotype? When you've got multiple things going on inside a structure that is as complicated as a cell, that is a very hard question to answer. That's the primary driver of failure in clinical development, the selection of the target. We've chosen the genetically validated targets here, and that I think does mean that within the industry, there is an expectation if you can establish safety, and if you have done your preclinical modeling showing that you are getting enough of the RNA therapy to the target cell, that there is, perhaps an expectation is too strong a word, but certainly a stronger view that efficacy will be forthcoming in that context. But I wouldn't say it's exclusive. You need to answer both very difficult questions. Have we got a safe molecule in the context of real-world usage profile? Is the drug candidate effective in rescuing the phenotype and having a significant impact in the life of that patient? They are the two big questions that we need to answer through clinical development. One more online, I think. What are the key risks facing the clinical and operational development programs, particularly for ADPKD? Any setbacks or unexpected findings? Not today, touch wood, which is very nice. It is the scale of the undertaking, and we have touched on it here. This is not a trivial undertaking. The one other thing I did want to mention to you as well, actually, with that very much in mind, on the urinary PC1 assay, I think there is a perception outside in that you just get the assay and you run the urinary samples through it, and it is not that easy. Regulus kept the assay as proprietary knowledge. You need to develop from scratch a process for taking a medium as variable as urine, extracting little miniature invisible particles from within it, purifying them, measuring a protein that is embedded within their surface, and comparing that to a benchmark, either at an absolute level or a relative expression level. This has been an incredibly difficult body of work. This has been years and many millions, if not tens of millions of dollars of investment to get to this point. So the urinary PC1 assay is tricky. All of you do not know it, but in Colette, we trust. We think we have got to the point where we have comfortably got a reproducible assay, but it has been a long and arduous process to get to this point, and we do not as yet have any data from the urinary PC1 assay read because of the difficulties in getting that assay up and running. We are working with challenges, technical challenges like that all of the time, working to overcome those. We have a litany of organizational issues in relation to the extent of the build-out required in the U.S., working across two geographies, finding the right people who are willing to push as hard as this organization requires of our employees. There are many challenges, far too many to list in one sitting, but there is nothing specific that we see as rate-limiting for the development pathway for any of our candidates, possibly with the exception of the absolute magnitude of the VA increase in RP11. That is the one challenge that I think is front of mind for me at the minute. What happens if RP just lends itself to six to eight letters of improvement in VA, and the decline in the disease is too slow to run a study that would give you a 15-letter spread within a meaningful time window? That is a big challenge. When we look at the peers in RP, like GenSight, we see six to eight letters of improvement, very much what we are seeing with RP11 as well. But can we find a way on an alternative endpoint or to negotiate with the regulator that the 15-letter bar is too high? That is definitely a challenge that occupies my mind. In relation to the other programs, it's very much about execution at this stage. A lot goes into good execution, though. It's not an easy thing to do. Is there any likelihood that ADPKD patients will remark that they simply feel better if the treatment is working, perhaps sooner than TKV changes show? It's possible. When I spoke to Jay Hagan of Regulus, he did remark that some of the patients in the Regulus study reported decreased frequency of abdominal pain. That was a feature. I think it's also important for everybody to understand, we are not proximate to the patients as the sponsor of the clinical studies. We are a long way removed from the patients. So for us to obtain that feedback, it has to happen serendipitously. So yes, we saw it in RP11, because that's a smaller patient community and a clinician community as well. In ADPKD, harder to glean those insights, I think. So maybe, but I think it's really the objective endpoints that we're most interested in anyway. Obviously, we want to improve patients' lives, but just because of all of the different factors that can go into reports of subjective feelings at that time, we'll be very much focused on the registrational endpoints for now. Any insights to share regarding preclinical discovery pipeline expansion, i.e., CNS as per ADOA asset branching out to touch additional targets? Yes. That is another point that I wanted to raise with everyone as well. We, as a company, we were very well-served by our strategy seven or eight years ago when we set out to increase gene expression with an RNA therapeutic that was designed to bind in the regulatory region of the wild type copy of a gene. It really gave us a monumental platform advantage to move ahead and capture the IP space in relation to some high-value targets. I think it was a beautiful decision. That advantage is gone. This has been commoditized. The beauty of this approach has been well recognized, and this is becoming a fiercely competitive space. RNA therapies generally are taking off, RNA conjugates are a particularly hot area, and second generation RNA therapies to increase gene expression are also very, very attractive to the industry right now. We need to be careful that we are moving quickly enough in terms of programs five, six, seven, and eight. But you see here a very important competitive tension. On the one hand, we want regulatory strategy, clinical development strategy, execution, commercialization skills. We have got to be a risk-off organization that is very much focused on execution of these large, complex clinical trials. Then we need, in the pipeline breadth, abstract thinking, risk-on tolerance, in silico capabilities, discovery chemistry to create second-generation products of our existing pipeline, but also to help us move into other indications. There is a lot going on in PYC right now. We are trying to hedge and straddle to give the organization the scalability of the upside potential beyond the four pipeline programs. But recognizing there are tens of millions of people with these indications spanning AUD 30 billion per annum of addressable market opportunity that we must execute on and deliver within the next 24 months. We are working there in the background. We have nothing to share at this point in time. Unfortunately, increasingly, our industry is not sharing what is going on because of the speed with which things are moving as well. We would be limited in terms of what we could tell you anyway. But yes, we are doing the work now to see whether or not we can create future opportunities for the organization. What data milestone could materially change the commercial valuation of PYC? Human safety, human efficacy data for the full pipeline programs that you see up there. It is very much the point of today, is to give you an overarching understanding of that clinical proof of concept for each one of those assets that sits within the near-term reach of the organization. If you think about all of that data is shaping probability of success, likelihood of approval, the value of the target markets, the value of changing patient lives in these indications is well understood. Spoke too soon with the got off lightly mark. You just mentioned that what you are doing is becoming more competitive, more people. Where would you put yourself in the pack? Front? The middle? Because of that, does that mean it is opportunistic for pharma or somebody to look at where you are and not for them to start from zero, but to come and partner or whatever with you? You have got to go to the top 10 pharmaceutical companies AGM and start asking them these questions as to what is on their shopping list, because I think it is more appropriate for them to be responding to those questions. In terms of where we sit, look, I do think it is emerging because we do not yet have really firm data from a clinical proof of concept standpoint that gives us the conviction to shape a phase III today. Right, so we have got work to do in front of us to define the safety and efficacy profile of these drug candidates. It is coming in the near term, but it is not there today. Front runner, hard to say. Emerging front runner, yes, I think so. I think we have chosen the right indications, and I think we have got far enough ahead with competitively differentiated assets. I do. But we will not get any recognition for that until we show the data that really matters, and we are on the cusp of that, but we have not yet delivered it today. I think there are other companies like Stoke Therapeutics who have done a really elegant job in Dravet syndrome, who are further ahead of us, who have that clinical proof of concept. We see Avidity, Dyne, and others in the oligonucleotide conjugate space who are further through. They are in the phase III study or reading out on efficacy now with the phase I/ II data in hand. Praxis, these are the companies that you see with the very robust data sets, demonstrating what is likely to happen in the phase III. That is something to be celebrated, right? We have laid out the theory as to why we think that is going to happen at PYC over the next 24 months, and that is the risk that we are here to take. We need to define that and show what we can do for patients within that timeframe. Whether that is attractive to a big pharma, we will wait and see. I think I am going to shut it off there. Well, thank you very much for your attendance. We look forward to seeing you again at the Annual General Meeting in November.