All right, we might get started. Just as I destroy the microphone. Good morning, everyone, and welcome to PYC Therapeutics 1st quarter investor webinar. My name is Rohan Hockings, and I'll be your host for this morning. Before we begin, I'd like to start with a couple of notifications. Firstly, to let you know that this call is being recorded, and secondly, to read the following safe harbor statement, reminding you that today's discussion will contain forward-looking statements that involve risks and uncertainties. These risks and uncertainties are outlined in our filings with the Australian Securities Exchange. As such, actual results may differ materially from what we discuss on today's call, and we fully disclaim any obligation or intention to update these statements in the future. The, the objectives for today's discussion are really threefold. Firstly, I would like to walk you through a brief introduction to the company, then we'll get into the substantive agenda items. The first one is to outline the strength of the company's position following on from the recent financing announced to the ASX on the 2nd of February. The second one is to walk you through a status update in relation to each one of the company's four pipeline assets, with a particular focus on the next 24 months as we move those through to human safety and efficacy readouts. Finally, we've had a number of questions from investors in relation to the changes to the timelines, in relation to the time period between last year's financing at the start of the year in Q1 and this year's, and we'll walk through some of the reasons for that before opening up for Q&A. Before we get into the substantive elements, for those of you who are new to the story, PYC is a drug discovery and development company who focus on the creation of life-changing therapies for patients with severe unmet needs, and we do that in a very particular way. We design drugs that address the root cause of genetic errors. Here, what we are looking to do is to increase gene expression in patients who have 1 of the 2 copies of a particular gene in the body affected by a loss-of-function mutation. Where patients are expressing half as much of the gene that they require, the purpose of each one of PYC's drugs is to increase gene expression back to wild type or 100%, of normal levels in the context of the cell type in the body that needs that gene to be expressed. These are what we call disease-modifying drug candidates because they address the root cause of the patient's condition. We do this for patients who have no or very limited treatment options available today. Life-changing drugs in the context of patients who need them the most, and we do it in the context of genetically validated targets, where there is 1 thing and 1 thing only going wrong for these patients, a spelling error in 1 copy of 1 of the 20,000 genes, occurring in the human. Genetically validated drug targets are far more likely to succeed in clinical development. We are the beneficiaries of two tailwinds here. 1, the confidence that restoring gene expression is going to have a meaningful impact in the life of that patient, because we know that it is this genetic deficit that is driving or the underlying cause of the disease. The second one, in the context of the extent of the unmet need that we spoke about, we will typically benefit from a high-velocity pathway through clinical development because there is not a standard of care against which we are required to evaluate our drug in a conventional phase III study. PYC tries to change the risk curve even further by leveraging a recent development in life sciences, where we can create a model of the target disease from a patient who has the disease in the context of the particular cell type affected. Here we will take a tissue sample from the patient, we will send it backwards into an induced pluripotent stem cell, and then we will forward differentiate from that stem cell, which is a cell that can turn into any type of cell in the human body, to the particular target cell affected. We will assess our drug, both quantitatively and functionally, in the context of that patient-derived model before we take that drug into human development. We are effectively the beneficiaries of a human efficacy readout before we assess that drug in patients, which changes the shape of the risk curve in relation to an early de-risking event and even higher propensity for success as we move into clinical studies. As you are probably familiar now, we are reading out, as outlined on the next page, on the critical data point for each one of these four assets through the course of the next 24 months. Each asset is going to provide us human safety and efficacy data within that window, and we'll look in more detail in relation to what that's going to look like when we evaluate the forward view of each one of the programs and the status update of where they've got to today. I think a lot of the attention from this point on is going to be on the Polycystic Kidney Disease program. You will see Urinary PC1, so the gene or the protein that is missing in these patients is ultimately excreted in the urine. We will get a measure from the patients in the clinical study of whether we can see that protein in the urine increasing, which should be a reflection of increased expression within the kidney, which is what the drug is intended to do. You will also see the gross anatomical measure of the volume of the kidneys on the MRI as those patients progress through three, six, nine, and 12 months on drug, and ultimately, we'll be looking at the function of the kidney, what we call the eGFR, a blood test that measures how efficiently the kidneys are performing. Those three milestones are all ahead of us as we move through into repeat dose studies in patients with Polycystic Kidney Disease in the 2nd quarter of this year. We will be pushing our Phelan-McDermid syndrome program into early clinical development around this time next year, and from there, we'll be looking for a biomarker efficacy readout in relation to complementing the human safety data that we're seeking in that phase I/II study. What we're looking for here is the electrical activity in the brain of the children in response to both a visual stimulus and also physical stimulus as well. That is hopefully going to be a lead indicator of the downstream changes in language and cognition that we really want to see in these patients to move the needle on the dimensions of the phenotype that are most important from a patient and a family standpoint. In the two blinding eye disease drugs, we're going to see the long-term follow-up data on visual acuity, so the ability of those patients to see. You are hopefully already familiar, for those who've been following the story, that we have a blinding eye disease that progresses from the outside in, in the context of Retinitis Pigmentosa type 11, and from the inside out in the context of Autosomal Dominant Optic Atrophy. We have near-term upcoming efficacy data points in both of those programs as well. That's what PYC Therapeutics does. In relation to the feedback that the company received on the back of last year's financing, there were really two points that were made to the company in relation to perceived weaknesses of the investment proposition of PYC Therapeutics. The first one was a mismatch between the ambition of the company and the scale of the undertaking required to take four drugs into late-stage development and the company's balance sheet. It was clear that we didn't have sufficient funds to take these drugs all the way through to commercialization, and so there was a sense of why invest now in the if I'm going to be offered an opportunity to invest later with more data in hand. The second piece of feedback that we received was in relation to the validation from industry. The absence of any large pharmaceutical company partnerships, the absence of specialist investors on the register, and the absence of a recognized management team. Many of you who have been following the life sciences will know that through the course of the downturn through the industry over the last five years, we saw a very clear split between what we call the haves and the have-nots in the industry, and PYC was not an A-list player in that context. The absence of that validation meant that we were in the have-not camp, and there was a clear aspiration, a belief that our science was strong enough to move us into the haves. That's exactly what this financing does. It brings on board Tier 1 specialist investors, at the same time as solving the first problem for the company, which is giving it the absolute strength of the balance sheet to have control of its own destiny, to deliver human efficacy data for each one of the four programs in the pipeline, and critically, to do it for not just the phase I/II efficacy data, which is the fundamental driver of the revaluation of the company, but in the event that the company elects to go it alone, to fund those programs into late-stage or registrational development studies ourselves. It puts the company in a very strong position there. We will raise somewhere between AUD 600 million and AUD 650 million in total upon closure of the retail component of the entitlement offer. That will give us a cash runway somewhere north of $750 million gross. We are developing a multi-asset pipeline, and as we've spoken about previously, these assets are largely decorrelated or uncoupled from a risk standpoint. We have the benefit of the portfolio theory going on from a downside protection standpoint, as well as the commonality of the strategy and the underlying mechanism of the drugs leveraging the upside case. A very strong pipeline that is at the point where the rubber meets the roads, what they refer to in the industry as the turning of the cards. What does the risk profile, risk-benefit profile of each one of these drug candidates look like? How much impact can we see in the lives of the patients affected by these different indications? I think critically, we are now supported by an extremely strong shareholder registrar. We have the investors on board, the company's registrar already, who can take us all the way. Not only do we have an incredibly strong balance sheet today, but in the event that we wish to fund ourselves all the way through to commercialization, we could source the capital, relatively small incremental capital required to do so on the back of strong data from those phase I/II readouts to take those products through to commercial launch. We've really given ourselves a lot of optionality in that respect. These investors have been extremely helpful for the company beyond the capital already. The extent and the number of the introductions that we are receiving to key industry figures in relation to scientific advisory board members, potential analysts in the US who can cover the story, investment bankers who can continue to help the company on its journey going forward. We are receiving a lot of assistance from these players in relation to the forward path of the company, and I think it should give investors a lot of comfort that they are now aligned in terms of their incentives with a very substantial shareholding, having been allocated somewhere north of AUD 333.3 million worth of stock at the same price as is being offered to shareholders through the current financing. We see a very clear and strong alignment of the objectives of those shareholders with our existing register. In terms of where we've got to for each of the programs, there are a couple of important, very near-term milestones that I did want to flag for you, just because we are towards the end of the retail entitlement offer, and there are a couple of milestones coming this week that I did want to flag. Before I forget, we are going to the FDA tomorrow in the RP11 program in a Type D meeting to align on the registrational outcomes. We will not be able to communicate to you in relation to the outcome of that meeting for another several weeks following that meeting, because the minutes are not official until they are delivered to the company in writing, and the FDA will take some time to get those back to us. That everybody is aware, that meeting will occur tomorrow, and I think we've got a pretty high degree of conviction and comfort in relation to where we're going to land there. We can touch on that in the Q&A. The other one is we have completed dosing in Cohort B2 in the Polycystic Kidney Disease program. Single dose in patients at 1.2 milligrams per kilogram, and on Thursday evening, we will have the Safety Review Committee to seek permission to escalate dosing to Cohort B3. We should be in a position before market open on Friday, assuming all goes well, to inform the market of the outcome of that SRC. It gives you a very small window. Unfortunately, it just happened to be the overlap with the retail offer there, but flagging so that everybody is aware, we will be communicating the outcome of that SRC on Friday of this week. In terms of the look forward to each of the programs, I wanted to run through what's coming in the next 24 months. I think there is some concern, and linking this to the conversation that follows in relation to the timelines, the changes that we are seeing are primarily in relation to the timing of the start and the duration of the phase III study. They do not relate to the execution of the ongoing phase I/II programs. We are not shifting, or changing the timeline or expectations in relation to execution of those phase I/II studies. Where we have revised some of the thinking in relation to the timing of these milestones, in particular, as you see, milestones 1 and 2 here relating to the Polycystic Kidney Disease program, is that with a refined understanding of how long we are going to need to see drug exposure in the target organs of the patients, we are expecting a meaningful outcome, potentially later than the early insights that we initially spoke about. So it's really the difference between the early insights and the definitive outcomes there. We are not changing the expectations in relation to the timing of those interim outcomes. So everyone should be aware, we are trying to represent a continuous variable as a binary outcome, and that's not quite true, and it's not quite how things are going to turn out in reality. What we are not saying, to be very clear, is that you're not going to get any data in relation to Urinary PC1 and Total Kidney Volume this year. You will, for the patients in the single ascending dose study, you may well also get it for patients at the earlier time points in the multiple dose study, and you will certainly be getting data for those patients in the multiple dose study through the course of 2027. We'll touch on why we have revised the thinking and just given ourselves, a little bit more of a conservative view in relation to the ability to interpret that data as it comes to hand, and it relates to the variability of the outcomes seen in those conditions. Where we have got to in relation to the Polycystic Kidney Disease program, firstly, and going through each of the assets in turn, you will have got a significant clue from the discussion of the timing of the SRC in Cohort B2. We will be looking, assuming a favorable outcome of the SRC, to complete dosing of patients in Cohort B3 in March, and that will put us in a position to roll over and start dosing patients in the Part C study, the repeat dose study in the 2nd quarter of this year. That will start the clock on simulating the outcomes that we'll be looking at in the registrational study that follows that 12-month primary readout on Total Kidney Volume and the 24-month confirmatory endpoint on eGFR. We are moving at speed towards delivery of the urinary biomarker and the anatomical surrogate endpoints that are going to give us the very high degree of conviction in this program. In relation to the Phelan-McDermid syndrome program, you are aware that we have a very elegant preclinical data pack. The objective here is to gear up for an IND submission in the 1st quarter of next year. There has been a delay in this program. This is one that is different. We have got a delay to the timelines expected for progression of the asset into clinical development. The reason for that is because we have set the target patient population for the phase I/II study for patients between the ages of two and 18 years old. The reason for that is we believe those patients are most likely to give us the strongest conviction in that interim efficacy signal. The consequence of that decision is that we now need to run our toxicology studies in monkeys, firstly in adult monkeys and then in juvenile monkeys, both in the dose range finding studies and subsequently in the GLP tox studies. The availability of those juvenile monkeys has restricted the timeline for development there. We have incurred a cost penalty in the order of 12 months in order to realize that outcome. It will be progression towards that IND and delivery of that data, the benchmarking data that we have already outlined to you, compared to other RNA therapeutics via the same route of administration for central nervous system diseases. That's what we want to put on the table, as we progress towards that IND to give us very high conviction that we are going to see the efficacy signal, at a safe and well-tolerated dose that we're looking for in these patients. That comes from a couple of different items that will flesh out that preclinical data pack. The first one you've seen, a lovely quantitative restoration of the missing gene in the brain cells derived from patients with this condition. You've seen some lovely functional data in relation to correction of the activity of those neurons. What we would like to do is to complement that with a further functional assay, measuring the electrical activity of those neurons, as well as getting into the rodent model of Phelan-McDermid syndrome. There are two pieces of the preclinical data from an efficacy standpoint, one piece from a GLP tox, safety tolerability standpoint as well, that will complement that data pack and push us into human development in the first half of next year with very high conviction in the asset. That is what is coming. In Phelan-McDermid syndrome, in RP type 11, it's about alignment with the FDA in relation to the pathway to a registrational outcome for this program, as we spoke about, that will happen tomorrow. The key additional piece of information that we need here is to see the long-term efficacy data in the patients in the Open Label Extension study that is currently ongoing for phase II. We'll have a look at the data and explain how that differs from our initial understanding, as well as the other dynamic variables that are relevant to a consideration of the timing of launch of that phase III study shortly. ADOA, we are moving through a global multi-dose study. We have finished dosing patients in the single-dose 60 microgram cohort, and we are now waiting to roll through into the repeat dose study setting at that dose, and we have initiated the repeat dose study, first dose for patients at the 10 and 30 micrograms. The drive here is towards building out the encouraging early efficacy and very clean safety tolerability data that we have seen to give us conviction that we have clinical proof of concept, and again, much like in RP11, the conviction and the understanding of what the phase III looks like that is required to support registration of that drug candidate. In relation to the questions on the movement in the timelines, I think firstly, the company does accept responsibility that there has been too much movement in relation to these. What I will walk you through in relation to the mitigating circumstances is in no means an attempt to escape or responsibility or to suggest that we haven't taken on board the need to improve here. If all 4 programs are moving, albeit for different reasons, we very clearly understand the need to be better in relation to providing guidance to the market in relation to what's going to happen. I think what we really need to do, the headline feedback, is to think through in the context of a dynamic integration of the phase I/II and the registrational trial in more depth, what that transition looks like, and to build in a little bit of conservatism rather than always defaulting to the best-case scenario in relation to the assumptions that underpin those variables. We will certainly take that on board, and I think this roadmap now does give a much clearer picture in relation to reasonable assumptions in relation to those programs. What we will do is we'll look at, well, why did each one of these programs change? I'll give you the short answer before we move into the detail in relation to each one of them. I think we were overly bullish in the Polycystic Kidney Disease program in assuming that we could scale up the phase 1b study, directly roll that over into a registrational format. As it turns out, I think the better path there is, given the competitive tension between the need to extract full value from the phase 1b study to increase the certainty and the quality of the design of the registrational trial, in particular on the dimensions of dose and dose interval. It's a much better pathway to try and glean as much information as we can from the 1b, but then run a separate registrational study that will follow that program. That's what happened in relation to Polycystic Kidney Disease. We've touched on why we've seen that deferral of the IND in relation to Phelan-McDermid syndrome. If you look at the ophthalmology programs, really the driver of the extension is the start date of the registrational trial as one. That's 12 months behind where it was before, and this is a variable that's entirely within the control of the company. We could have started that registrational trial earlier, but if we were to have gone down that pathway, I think we would have been doing it in the context of suboptimal information. We really need to wait for more data from the phase II studies, how patients are responding to the drug after continuous exposure for 12 months or more, 24 months in total, noting that all of the patients in the dataset to date have had a window of six months or more when they're not on drug, either because we were waiting for the SAD to roll over into the Open Label Extension, or we were waiting for the MAD to roll over into the Open Label Extension. It's very difficult to decipher data when patients on drug, off drug, back on drug again. We have made some changes in relation to the integration of the multiple dose study and the Open Label Extension in the ADOA program and in PKD to learn that lesson. We really need to make sure that we've got high conviction in relation to the understanding of how we get this drug approved. I think there is an underappreciated distinction between the question of, is this drug working, as compared to, can we find a pathway to getting a regulatory approval for this drug? It's the latter question that we're really grappling with there. What does that really mean? We'll look at the VP-001 example here, why can we not give you a very linear clinical development pathway from the start of a p hase I trial? The answer is because there are a lot of moving pieces of the puzzle. We are gleaning information from the early studies, including the natural history studies, as well as dealing with a shifting landscape in relation to the regulator. We are also looking at what's happening with our peer companies in relation to their experiences in similar conditions and trying to learn from those. It's not like we can give you, from day one, the roadmap for exactly what's going to happen in the clinical study. The first dynamic variable is the red line here. This is coming from PYC's ongoing natural history studies. We need to know how quickly these patients are losing their visual acuity, and that is a dynamic variable. You can see this is a very slowly progressive disease, where patients are losing around two letters of visual acuity per annum on the ETDRS. We also need to know how quickly and how far patients' vision is going to improve on the back of treatment with the drug candidate. While it's very encouraging to see all of the blue dots above the red line, this is not a regenerative therapy. It's different to the PKD and PMS programs, where we see partial reversibility of the phenotypes because of the plasticity of the cells or their ability to communicate with cells around them. Once you have lost your photoreceptors or your retinal ganglion cells, they either don't come back at all, or they come back very, very slowly, probably the former. This is not aiming to restore vision in these patients, rather to stop them from losing any further vision. We know that that blue line is going to turn right at a certain point. Whilst very encouraging that we're seeing the improvement in the visual acuity as compared to the natural history and the fellow contralateral eye, the bigger question, and what we're grappling with here, is when is there going to be a 15-letter delta between the blue line and the red line? That is the bar that the FDA are going to hold us to from a clinical meaningfulness standpoint. It's not a question of whether the drug is working, it's a question of how much impact is that drug having in the lives of patients who have taken it. What can the patient do after having taken the drug that they could not do beforehand? We know at the same time that that is an imperfect measure. The European regulator adopts a 10-letter delta. We know from drugs that have been approved, like Luxturna, on the base of different functional endpoints, showing that the patient can, in fact, do something different after the drug. They only saw an eight-letter improvement on visual acuity. We were hopeful early on in the course that the evolution in the FDA's thinking in relation to gene therapies for rare diseases, particularly where you have a very strong, what they call a plausible biological mechanism, that we would see some flexibility from the FDA. We were hopeful that microperimetry might provide that. I think as we have learned more about what others are seeing in the field and the experience in relation to our phase I/II studies and natural history studies, is that microperimetry can only really serve as a secondary endpoint. It's far too difficult in relation to the parameters that have been put on it for a registrational outcome to rely on that as the primary endpoint. I think that is out of the picture. If we look at, even within visual acuity, the way that we use that endpoint is still very important. If we look at the Johnson & Johnson experience with the RPGR asset that they acquired from MeiraGTx, they nominated the Visual Navigation Course as the primary endpoint. They missed on that primary endpoint, but they would have had a registrational outcome had they nominated the proportion of patients achieving 15 letters or more of visual acuity improvement. That's different from the mean change in visual acuity. That's different from the proportion of patients losing 15 letters or more within the study window. Even within the one endpoint, there are different ways that we can use it, and we're trying to learn as much as we can from those phase I/II studies, as well as engage with the regulator in a dynamic conversation around what that endpoint could look like. Is there a way where we can hybridize and not go all in on one particular element of that visual acuity improvement? We saw the FDA making noises in relation to accelerated approval pathways. The Division of Ophthalmology has not been as progressive as other divisions within the FDA. We don't see, within ophthalmology, any pathway for an accelerated approval, today. There have been dynamic elements to the understanding of the regulatory environment that have shifted that mean we don't have the conviction to start that phase III study yet, because we don't know how to fully optimize its design in relation to maximizing the probability of a successful outcome. Once we get patients moving through that 24 months mark, that will start to help build the conviction and the understanding in relation to how we design that study going forward. I think investors need to prepare themselves for a high degree of variability in the Polycystic Kidney Disease study as well. To show you the outcomes on Total Kidney Volume and the spread of the datasets in the tolvaptan study, the one drug that is approved in this indication, albeit serving a minority of patients, only 5% to 7% penetration of the total market. What you're looking at here in the vertical axis is the change in Total Kidney Volume over time in the horizontal plane. The patients on placebo are in orange, and the patients on treatment are in blue, and you can see that there is an enormous amount of variability in the natural history of this disease. You've got orange data points that are well below the horizontal axis, starting point at 0% at the 12-month mark. Those are patients whose kidneys are shrinking, despite the fact that they're not on drug, and you have got some very high growers, including in the treatment arm, patients whose kidneys are growing at 40% plus per annum, even though they're on drug. The drug is ultimately deemed to be effective because of the changing gradient of these two lines over the 36-month window. It's, it's this data we initially were thinking, and I still think we will get some early signals at three and six months, but you can see that the separation in the context of a much smaller dataset, bearing in mind that we have two patient cohorts of 12 patients per cohort for the initial 1.2 and 2.4 milligram per kilogram doses planned in the MAD, it's going to be quite difficult to glean conviction in that data at the earlier time points. When we model how long it's going to take to see meaningful separation, you're really looking at the nine, 12-month plus data points to get conviction in that outcome. To be clear again, what we are not saying is there is any delay in the execution of the clinical trial. I think the clinical operations team have done an exceptional job. That's not what's driving this. It's a revised understanding in the context of our sample size and the variability of the dataset on this endpoint in particular, but knowing that Urinary PC1 is also a highly variable endpoint, we will not get full conviction in the data until later on. I just wanted to ensure that people were aware of that. Hopefully, it's given you some color as to why we see movable timelines in relation to interpretation of the phase I/II data, how that is informing the registrational trial, in terms of its start date and its design. It is not that anything is off track. It's much more a refined understanding of the variability of the data and how we are going to interpret that as we parlay into registrational studies. With that, I'm going to stop and open up for questions. If anyone in the room has one, Garrett will give you the microphone. We have one coming online to start with. I'm not sure if it's the chat function or Q&A. Are they different or just Q&A? Just- Just in the Q&A section. First question, "PYC seemingly has a strong case for the FDA to consider an accelerated approval pathway for RP11 within the parameters of the Type D meeting due shortly. Is such a pathway in the mix of matters pertaining to the Type D meeting? If not, could you please provide some color as to why PYC would not explore this potential pathway?" It's a good point, and I think we've touched on it previously. It's not in the mix, unfortunately, and the reason for that is because we haven't seen any flexibility from the FDA with respect to any endpoint that can act as an accelerated approval endpoint. The FDA are not willing to accept. partial progression towards that clinical meaningfulness bar, a 5-letter delta, a 10-letter delta as a lead indicator, even in the context of a slowly progressive disease, that you are on track for the longer-term outcome of the 15-letter separation. We can't, unfortunately, look at an accelerated approval pathway and then the real-world evidence in the context of a confirmatory study, to maintain the marketing authorization for that drug candidate. Which is disappointing, I think, in the context of where the European regulator is and the broader noises within the organization to show some flexibility in the context of these rare diseases where the disease progression is very slow. We would like to see some more flexibility. We will continue to work with the FDA towards that end. I think the FDA will communicate around abstract concepts in relation to totality of the data, some degree of flexibility here in relation to exactly where that bar is going to land, but I don't think shareholders should expect certainty coming out of that meeting in relation to exactly where that is. I think if we see a 10-plus letter gain on visual acuity and alignment with the key secondary endpoints, like the microperimetry, there could be a pathway, but we would really like to gain conviction in relation to exactly where is the finish line before we launch that study. That's what we're waiting for in relation to seeing the phase II data play out at the later time points, is to get a better understanding of exactly how long does that study need to go for before we can be confident of a registrational outcome. Rohan, just to get clarity, the 15 letters, that given over time, you showed that there's a loss of letters, obviously two after one year and four after two years. It's 15 delta difference between, It's not 15 on top of where you start, it's, you could be 11 letters plus the four, gives you the 15. Secondly, whilst you're doing this for the FDA, if you end up with a number of 12, would that mean you could still seek registration of that drug in Europe? Because Europe has a 10-letter difference. I know you're focusing on the US, but is it possible that you don't meet the US standard, but you can definitely still proceed in Europe based on this study that you're doing? Yeah. The answer to the latter question is yes. It's a different registrational bar, therefore, the outcome may be acceptable to one regulator in the context of not being to the other. That's quite right. In relation to the former question, unfortunately, it's a little bit complicated. That's what I was talking about in relation to the different ways in which you can use that low luminance visual acuity endpoint. There are three distinct endpoints within the one concept. You can either nominate the proportion of patients who are achieving a 15-letter gain, as in compared to that patient's own baseline at enrollment in the study. Are they performing 15 letters or better at the designated time point for evaluation of the trial? If you see a higher proportion of patients achieving that 15-letter gain, and that is statistically significant as compared to the sham control, that's an approvable outcome. You could flip it on its head and look at the proportion of patients losing 15 letters, and that is also a registrational outcome when compared to the sham, this time compared to the treatment arm, assuming that we have higher rates of loss of the 15 letters compared to that patient's own baseline. Or you can choose a bidirectional delta between the improvement in the treated group and the loss in the sham group. So if you look at, that's where the spread between the blue line and the red line becomes relevant. This is no longer comparing to that patient's own baseline. This is comparing between the patient cohorts. This is the mean change in the treatment arm as compared to the mean change in the sham control, which we expect to perform very much like natural history. That's the only one that gives you the bidirectional change. If you don't go for the mean change, you are pegged to a flat line, 15-letter improvement, and you're looking at the number of patients in the treatment group who are above that line or conversely, below that line. The problem with that is, if you get one or two I's in the sham control or the treatment arm, depending on whether you're looking at the gain or the loss, respectively, the ability to gain statistical significance becomes very tricky indeed in the context of a small sample size. You are taking a bit of a risk if you're going all in on those outcomes. Appreciate that we're still waiting to see data, but can you talk to potential dosing considerations for PKD, dose level, and frequency? Can you please talk to PK/PD work related to PYC003 and feedback from the FDA, and how is that baked into the timelines?" Yes. What we've done here is we have built a PK/PD model. This question is from an analyst. Stepping back, the question relates to: how can we be confident that we have enough drug in the kidney in order to see efficacy? How do we link all of the disparate pieces of the preclinical data pack together to gain conviction that we are going to see efficacy in the patient population? The way that we do this is we measure the equilibrium between the plasma concentration and the kidney concentration in the non-human primate, and we build ourselves a model of that distribution to the target tissue. The blood is, the drug is administered intravenously, so it's directly administered into the plasma, and then the plasma delivers the drug into the kidney. We're looking at the ratio or the equilibrium of drug in plasma over time to the peak target tissue concentration within the kidney. Here, we're the beneficiaries of being able to sample the kidneys from the non-human primates. We obviously can't do that in humans. We take that equilibrium, and we superimpose that on the observed human plasma concentration of the drug. We can bleed the patient to take a tissue sample to get a reading on the levels of drug in plasma over time. We infer from the plasma concentration, based on that non-human primate model, the tissue equilibrium, and therefore the target tissue concentration. We then look at the individual cellular level within the kidney. Have we got enough drug in the human kidney based on the efficacy readouts that we're getting in the kidneys that come out of the patients or are created, derived from the patient, in order to achieve that efficacy outcome? Very helpfully, at the minute, what we are seeing is the peak trough concentrations in the target tissue are above the minimum effective concentration from the patient-derived models 100% of the time, at a six weekly dosing interval at 1.2 and 2.4 mgs per kg. That is suggesting to us that if we wanted to, we could extend the dosing interval in the clinical trial, eight weeks or 12 weeks. The issue that we have there, and to further give some insight in relation to the complexity of clinical trial design, in the event that we see a dose response in the repeat dose studies between the 1.2 and 2.4 mg per kg patients, having not seen a dose-limiting tox in the dose escalation studies, we will be inclined to add a dose cohort above 2.4 mg per kg, because it's suggesting that you haven't necessarily maxed out your efficacy signal. In the event that we don't see a dose response, we will be inclined to add a dose cohort below to show reverse titration of the dose response curve to demonstrate that we have, in fact, maxed out the efficacy signal in the context of a safe and well-tolerated dose. The question becomes the relative prioritization of the dose response as compared to the extension of the dosing interval. It's precisely those variables that we're talking about in relation to the need to glean full insight from the phase 1b studies before committing to that registrational trial. We haven't syndicated that conversation with the FDA as yet, because the ongoing clinical trials are in the Asia-Pacific region. We've had a pre-IND meeting with the FDA here, we didn't have any of that information to hand when we engaged them. To the extent that the question relates to syndication with the U.S. regulator specifically, that has not yet occurred. We'll be looking to do that through engagement with the FDA later this year and next year as we move to open the IND. Are there any plans for PYC to seek breakthrough therapy designations across any of the current programs, notably RP-11, given longer-term OLE data later this year? Yes, and it's a lot easier based on compelling human efficacy data. It's a much more efficient process from that standpoint, and so we will be looking to seek that designation in the context of that program, as well as other pipeline programs at some point later this year in the context of RP-11. When you say a good outcome of Type D meeting with FDA would be 10-letter gain for primary endpoint, do you mean gain from baseline or delta versus placebo? Just to be clear, I think the likely outcome from the FDA engagement is going to be a 15-letter delta. I want to be unequivocally clear in relation to that. The extent to which the FDA may provide concessions on that endpoint will be under the guise of totality of the data. That is the expectation on the part of the company. They're not going to give us a commitment to a firm number that aligns to the European regulator or is below that 15-letter threshold. A 10-letter gain there, it can be in any one of the three dimensions that I responded to the previous question. It could be a 10-letter increase from baseline in a higher proportion of patients in the treatment arm as compared to sham. It could be a lower proportion of patients in the treatment arm losing 10 letters as compared to the sham, or it could be a bidirectional change if we're looking at mean change in LLVA in the treatment arm as compared to the sham arm. If you, if you spend a little bit of time thinking about it, you will see that the focus for each one of those study designs is different. In relation to the proportion of patients gaining 15 letters or more, you're looking at your best responders. If you're looking at the bidirectional change, you're looking at your average response across both cohorts, and if you're looking at the proportion of patients losing, you're looking at the worst responders, primarily in the sham arm, and trying to believe or hoping to believe that you're going to stabilize the disease in every single patient in the treatment arm. You can see how nomination of a different endpoint actually shifts the focus to one particular subpopulation of the patients in the study. That's the information that we're seeking to understand more fully through the extension of the phase II data. Will we be reporting Urinary PC1 results for the SAD-treated patients or wait until we have data from the MAD Open Label Extension? The answer is we will try to, where we can. The Urinary PC1 assay is very tricky. It's been difficult to establish. We are only now in the position where we can transfer the method to the CRO in order to process those samples for us. One of the problems that we've got here in relation to the samples that have been stored from both the healthy volunteers and the patients who've been dosed to date, is we've frozen that urine. When you thaw the urine, a protein is crashing out, and it's dragging the urinary exosomes with it as it's undergoing the freeze-thaw cycle. It's making it much harder to gain the fidelity that we want to gain in relation to reading how much urinary PC1 protein is present, because it's embedded within those exosomes that are being pulled out by that freeze-thaw cycle. I think there is going to be some complexity in evaluating the results from cohorts B1 and B2. I think you'll get a much clearer signal in relation to the patients in B3, and really, where we're interested in is the early data points, in patients in the phase 1b study, the MAD, as we move to starting to dose patients in the 2nd quarter of this year. In the RP11 study, why are you doing both the 30 and 75 dose level if you believe, as you stated on previous occasions, that a higher dose is more likely to produce better results? It's to confirm that belief in the context of the P3, because what we wouldn't want to do is expose patients to potential risk, even though we haven't seen any treatment-related serious adverse events in any patients dosed to date. What we wouldn't want is there to be an accumulation of the drug over time that could cause that. If we saw that the 30-microgram dose was performing equivalently in the registrational study to the 75 microgram, we would seek a label that approved patients for treatment at the 30-microgram dose, because we'd be suggesting that we'd maxed out the efficacy there at a lower dose. That's always preferable from a safety tolerability standpoint, even where we haven't seen adverse safety tolerability issues in the context of the clinical trials. Is the start of the ADPKD MAD Open Label Extension on schedule? Yes, it is. We will, as I mentioned before, look to complete dosing of patients in the single ascending dose study Cohort B3 in March, from there, we'll be focused on the transition into the Part C or the 1b study, repeat dose study, kicking off in the 2nd quarter of this year. Very much on track. Based on PK/PD model and PKD, is it correct to assume multi-dosing in low 0.4 mg per kg PYC-003 is below the threshold in which you expect to see impact on TKV PC1? Given variability, could overshadow if a minimal effect, not seeing a difference is not unexpected? Look, I think that's right. The challenge that you've got there is when you lower the PK/PD modeling to the 0.4 mg per kg dose cohort, you do see that the peak concentration predicted in the kidney is above the minimum effective concentration in the patient-derived models. Because you've got a lower peak concentration, you've got a faster metabolism of the drug candidate, and you're moving below that minimum effective concentration much faster than you are at 1.2 or 2.4 mg/kg. It's not that it doesn't reach a therapeutic concentration, and if the efficacy is driven by Cmax rather than area under the curve, it's possible that you could derive a signal there, but it's not going to be as strong as the signal that we're looking at in the context of 1.2 and 2.4 mg/kg if we take a direct read-through from the non-human primate study into humans. There are a number of different unknowns there. We're modeling this based on PK, not PD. There's potential for the protein upregulation to persist for much longer than the drug is present in kidney. There are a number of factors that are relevant there that we are trying to discern. That's very much why we're looking for the PD signal from a dose-response standpoint, either Urinary PC1 or TKV, ideally both, in the phase 1b study, before determining what the final design looks like in relation to that additional patient cohort that we spoke about. We seem to have exhausted our friends online. Oh, no, coming through. Can we assume that PKD 1b will enroll 40-60 patients? I think that's a reasonable assumption. At this stage, what we know is we'll be taking the 1.2 and 2.4 mg/kg doses in at a six-weekly dosing interval to begin with. There'll be 12 patients per cohort, so you'll see your first 24 patients there. We know that we'll look to either add additional cohorts at a different dose, above or below, depending on that dose response that we've spoken about. That would be at least an additional 12 patients there. If we look to enroll at the eight or 12 weekly dosing interval, I think it would be a similar cohort size. I think in total, you're looking somewhere between 30 and 50 patients. That's right. The presentation today seems more about risk mitigation. If we assume some good news, could early kidney news show positive results in the change of size of the kidney? Eye programs are longer, but continue to show the drugs are working. This is a positive in trying to get a BD deal. Yeah, I think that's right on both fronts. It's, it's more in relation to, I, I don't think it's so much about risk as it is about focusing on the longer time points in relation to being able to meaningfully interpret the data sets. Hopefully, if you go back and have a look at the variability in the PKD patient population in the natural history studies, the reference that we've given you there from the tolvaptan trial, you'll see what we're talking about. There's a lot of variability in that patient population on that particular endpoint, and urinary PC1's probably got even more noise in the assay. It's really just trying to shift expectations. You, you will get the early read, and I'm sure there will be people looking to run comparisons with farabursen specifically at the three-month time point. For us internally, it's much more the later time points that are going to give us conviction in relation to the strength of that efficacy signal. In relation to the eye programs, I think having both the registrational certainty from that Type D meeting, irrespective of what the outcome is, coupled with the later time points from the ongoing phase II study, so the data that we're looking at in Q4, very much is the driver of the transactional opportunity in that context. I think the counterpart is just looking at exactly the same thing that we're looking at, which is the propensities to succeed with a New Drug Application of a first-indication drug. That comes down to integration of the data that we've seen, with the registrational expectation of the regulator. The more closely your phase II data recapitulates what you're looking at in the phase III, the better the read you've got on Phase success. Yes, very much, we still think that that is in the transactional window in that context. Is PYC still actively looking to partner on the ophthalmology drugs? Look, we are interested in proposals that come from counterparties continuously, and we are actively engaged in BD all the time at the minute. We are open to a partnership in relation to the ophthalmology drugs, specifically because they target smaller indications. Very much the focus of the incoming US investors is on PKD and PMS programs. We see those as the core assets that we're really looking to push forward, but we are still very interested and enthused by what we're seeing in ophthalmology. We need to grapple with the phase III go criteria, exactly where are we setting the specification to say, "Okay, now we're ready. Now we're ready to go in the phase III because that P success has crossed the critical threshold." We're very much still active on all fronts in relation to business development. It's important, even when you're not looking to partner the drugs, necessarily, to get that perspective from industry of exactly where we stand. How do we need to build out the strength of these data packs? What does the understanding of the counterpart look like with respect to their interpretation of the data generated to date? We have been engaging continuously with the industry, and certainly, the cadence of those conversations is moving up. Although I think you said you would not expect vision improvement in RP11 patients, it looks like you do have an improvement. Does biology dictate that this is possible in early treatment of patients? Yeah, this is an interesting point. Yes, it does, and it's certainly consistent with what has been seen in other trials of disease-modifying drug candidates in the context of blinding eye diseases, genetic causes of blinding eye diseases. If you look at the patient population in the Luxturna trial in particular, but more recently in the other AAV gene therapy trials, Beacon Therapeutics and others, we see this early improvement in visual function, specifically visual acuity. What we think is happening here is that there are traditionally considered to be two types of cells in the retina, dead cells and alive cells, but that is an oversimplification. There are dead cells, there are alive cells, and there are some cells that are so sick that they're not contributing to the processing of the visual signal, but they haven't yet died. The idea is that with the restoration of the missing gene expression, you recover those cells, they then start helping process the visual signal, and you get that initial improvement in the visual function, but that is going to plateau at a certain point in time. That's the driver behind that plateau expectation. There are only so many sick cells, cells left that we can expect to recover. That's not going to go on forever. That's why getting the fidelity of that blue line and working out when it's going to take that right turn and at what level of visual acuity improvement is so important, because if we nominate the mean change in LLVA, it's the delta between the blue line and the red line that is going to dictate those registrational outcomes. Are the US investors looking for positive early data, or are they comfortable in waiting for the full data set? I think both. I think everybody's looking for positive trends early. I think the US investors have got an appetite for going longer, further in the journey. I think they are very comfortable with what they've seen to date, and I think they would be very confident in terms of the transition of these candidates into late-stage development. I don't think they would balk in any way, shape, or form at the organizational build-out required even to launch the drug candidates. For them, it very much comes down to the quality of the data that we're generating, the amount of risk that we're taking out of the proposition of launching first-in-indication drugs with very attractive profiles. There's no doubt they'll be looking for the early efficacy signal. They're very, very skilled in the indications that we're looking at. They're well and truly across what to expect in the context of disease-modifying drugs in these indications. They'll be poring over the data, but I think they're very comfortable in going on the journey for the longer term, and you've seen that based on the magnitude of their commitment to the company. We have the license to conduct the multiple dose studies and receive those through to efficacy readouts. We also have the license to transition into registrational trials, and there'll no doubt be an ongoing conversation in relation to future direction beyond that point. I think the basic synthesis is that the U.S. investors are here for the long term, but they will be very focused on looking for the early indications of efficacy because it's very much what we expect to see. Is there a plan for a U.S. listing? I think it's something that the board are certainly considering. We know that we trade at a substantial discount to our U.S. peers. I think we've corrected one of the fundamental deficiencies in relation to the quality of our shareholder register. There's an expectation on the part of our US investors that we will see the valuation and the liquidity commensurate with the data that we're capable of generating. If that means a transition to the Nasdaq, I don't think the board will think twice about that. Any final questions? Oh, we have one. Go, do you mind? Just congratulations, Rohan, on the raise. I'm just curious about maybe using RA as a proxy for the US, just in terms of how much diligence they've done. Was it all desktop review, did they to formulate their convictions over, I guess, individually over the assets? How much inference individually, I guess, they're seeing four in a row, mechanically all align and achieving goals, how much inference is that to the platform? Any insights into how they view the future waves. Is this any of the funding is gonna be allocated towards that? Yeah, I guess just overall, their, their view of us in terms of where we place- Yeah. Against it, against it. I, I think the answer to the first part of the question is a lot. They are very sophisticated players. If you think about RA specifically, but the US specialist investors more generally, they are receiving briefings from everybody in the ecosystem all of the time. They are looking at confidential data packs each time round, right? They're seeing more data than what is available in the public domain. They have got a very sophisticated understanding of each of these indications. PKD specifically is a focus for them. They've done a lot of work even before they've seen any of the company's data. They immediately know how to orientate our data pack in the competitive landscape. They're very aware on that front. I was pretty impressed with the elements that they turned up through the diligence process, that they've evidently gone very deep in relation to kicking the tires on every different area in relation to this company as a whole and what we're doing. The primary area of focus for those US investors is the PKD and PMS programs, or are the PKD and PMS programs. I don't think there's too much inference in relation to ophthalmology on that front. I think there is an interest in the use of the platform for kidney disease more generally, assuming that we see continuation of the favorable safety tolerability profile that we've seen to date. I think there's an interest to see whether we could potentially change the route of administration from intravenous to subcutaneous at a certain point in time. Not critical for the existing program, but that might open up new opportunities in the context of kidney disease, diseases affecting tubular epithelial cells in particular. If we can harness that same capability in the context of second-generation approaches, and I can't talk too much about it now just for commercial sensitivity reasons, but in relation to the neurodevelopmental disorders, if we can enhance the delivery profile to neurons, and there's a particular type of tox that we want to avoid in the context of the central nervous system, that would then be seen as an enabling platform to go after other neurodevelopmental indications. We know, fortunately, that a lot of those are driven by haploinsufficiency, so our particular mechanism that we specialize in. I think they're longer shots, to be honest. Very much the focus, because of the scale of the opportunity here and the unique nature of the assets, it's on PKD and PMS in the first instance, those clinical readouts that are coming. From there, it'll be a secondary consideration, knowing that you can have some small bets in the discovery realm that are not high cost, but can give you that additional information and conviction that you're looking for to make the larger bets later. No, it didn't really come up in the process at all. I mean, there's a lot of literature emerging on the importance of mitochondrial function in retinal diseases generally, so we haven't necessarily put it to the wayside yet. The focus in the short term is very much on clinical readouts for the existing pipeline, given that these are enormous patient needs. The scope of the opportunity, if they're successful, is massive. The derivative co-commercial benefit in the order of $30 billion per annum. That's the focus for now. Yeah. Is ADOA similar. Sorry, given all the market chat on AI, has the partnership with Google progressed any further? Not really, unfortunately, is the answer there. I think we are seeing progress made by different players in the space, but that is at a scale that we are not currently operating on, and we haven't seen the early signals of efficacy there that we would have wanted to, of success, in order to pursue that further. Albeit, this is quite a dynamic space, and there is an interest on the part of multiple counterparts in going further in that collaboration. It's not our core priority right now. Is ADOA similar to RP11, and you do not expect large recovery of vision, more slowing of vision loss? Yes, it's identical, and that's why you see the flow-through of that more conservative consideration of the timelines going from the RP11 program to ADOA. Okay, I think we have addressed all questions. Thank you very much. A very exciting time for the company. We are looking forward to keeping you abreast of progress as things unfold. Most notably on Friday, on the first occasion in relation to the outcome of the Safety Review Committee, a very rapid progression then through Cohort B3 and the SAD, progression into the MAD, starting the clock on those important PKD readouts, and some significant progress to expect throughout the pipeline and the other assets through the course of this year. Thank you very much for your attendance and interest. We will update you as things unfold.