PYC Therapeutics Limited (PYC) Earnings Call Transcript & Summary

Good morning, everyone, and welcome to the PYC Therapeutics Third Quarter Investor Webinar. My name is Rohan Hockings, and I'm 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'd 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 4 of the company's pipeline programs. And I am very grateful to those who are leaning in to maintain that organizational momentum. There's really only one objective for today, and that's 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. And 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've done in relation to what is coming, what to expect, and why. Prior to doing that, I'll give a brief introduction to the company for those who are new to the story, and 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. [Operator Instructions]. 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. And 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 2 copies of each of those genes, but 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 gene, that copy of the gene, to make 2 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. So these are the types of drugs that if we or any of our family members had any 1 of the 4 indications that we're 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 4 investigational drug candidates. We have taken 4 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've described it previously. We're 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 2 appointments to the executive team in the form of the Chief Financial Officer and the General Counsel or Co-Company Secretary. Those 2 individuals have been onboarded and have made a very positive start. We are now looking to build out the team in the United States 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'm delighted to welcome Candice Junge as our Chief Clinical Development Officer. Candace joins us from Ionis Pharmaceuticals, where most recently she has been running their Phase III Angelman syndrome study. And towards the end of September, we will also welcome Marcie Fowler. Marcie 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 2 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'll speak further about why that's important going forward. We're going to continue to grow, and the near-term focus here will be on our 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 2 ophthalmology programs. So that's the near-term recruitment effort that you should be looking for, for the further expansion there. You will all be familiar with the company's 5-year forward view from an operational road map standpoint. I'm only going to touch very briefly on the PYC-003 program because we're going to go into that in a lot of detail at the back end of this presentation. But what I will point out, I'd 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. And 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 Australia and New Zealand Society of Nephrology meeting covering the safety dimension of that data pack. So there's single-dose data coming in Q4 of this year. And then throughout the course of 2027, we'll start to read out the results of the ongoing Phase Ib multiple dose studies. And it's 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 Ib MAD study. So the focus here is to recruit the final 11 patients to constitute the initial 2 cohorts, C1 and C2, 12 patients per cohort. The objective is to have that initial 2 cohorts fully recruited by November of this year. And that will then start the clock on the 3-, 6-, 9- and 12-month data on the TKV endpoint and the urinary PC1 later in year 2, and the open-label extension, we start to track the eGFR there. And that data will mature through the course of 2027 to that primary readout at the end of the year. We'll come back and have a deeper chat in relation to exactly what we're expecting as that data pack evolves. In the PYC-002 study, the focus as the operational road map 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, and then there are chronic studies. All 3 of those studies going on in 2 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 and then in the early parts of next year at the functional rescue that we're 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're 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. And the regulator has come back and asked us to go directly into a multiple-dose study. And 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. And so 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 time lines for the program as a whole because it's 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. So there's a little bit of flex there. And you can see it's 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 Marcie on board to benefit from their experience in this domain. The 2 ophthalmology studies are progressing through the Phase I/II trials. I think everybody is familiar with what's 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, flavor protein fluorescence, but most importantly, on the visual acuity of those patients as well. So 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. And once we have a handle on the understanding of can we create or design a high-propensity registrational trial, that's the point that we are willing to commit to that P3 go criteria. So 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'll see that the ADOA program has got a potentially clearer path forward at this minute -- at this time because of the absolute magnitude of the visual acuity improvements that we're 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 3 lines better than the control group in that registrational study, 15 letters. It's an incredibly high bar. Many of you who follow 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 non-trivial undertaking. So that's the pipeline as a whole. I'd 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 Ia/Ib 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, 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. And it's very interesting to hear her thoughts, and then we will comment on those, how we develop the molecule and in particular, what we're seeing in the data that has transpired since that presentation was made late last year. So, yes, I think you'll find all of that very interesting. The whole video, we're only going to play a 45-second snapshot of it. It's only an 8- or 10-minute video, but it is available online at the -- if you search the footnote, you'll find that video. And it's worthwhile listening to. I think it's a very interesting overview of the PKD space as a whole. We'll dig a little bit deeper into the expected time line for those exploratory efficacy data that I think everybody is keenly anticipating. And 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. And we are going to effectively outline why it is the 6-, 9-, and 12-month data points in the MAD study that are critical here. That's what we're really going to focus on, and we'll explain to you why that is. And then we'll 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. And we're 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's 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. And as you know, about 50% of those patients will require an organ transplantation in their 50s. But 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. And if you have a look at the MRI of this patient who's 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's next to them. And so there is a correlation between the volume of the kidney as they get larger and the function of the kidney. And 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. And so what we want to do in our Phase Ib study is give ourselves the maximum insight into what's 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. And that is exactly what we have done. We have set ourselves up so that we have the Part C or the 6-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 Ib study. So you're 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 2 cohorts. So what we're looking to do here, and you'll 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 doesn't feature on the page. Again, for those of you who've been on the journey, you'll 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's the development pathway as a whole. Let's have a listen now to the renal physician from Yale surveying the landscape and their approach. And then we'll have a chat afterwards about some of the insights that come out of that presentation. [Presentation]

The disease we're treating is autosomal dominant polycystic kidney disease, the cause of 5% to 10% of all kidney failure 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 cyst to delay kidney failure by a handful of years by blocking vasopressin 2 receptor. However, 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. And 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 that remaining wild-type allele or a partially functional missense allele. Our therapy will be a weekly subcu injection with the goal of halting kidney and liver cyst growth. The pipeline is early currently, led by Regulus, who just finished a Phase Ib trial, which showed safety, 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 blocks affects hundreds of genes. And so long-term safety in a disease that requires decades of treatment is a concern. Therefore, an Australian company, PYC has started a Phase Ia 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 have talked to are concerned about the toxicity of that compound. Very interesting point there at the end, right, really picked 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've seen. So why is this presenter talking about the safety profile of the molecule? And the reason for this is nothing to do with the molecule at all. It's 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. And 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's happening in the kidneys. And that is what really drove the concerns around the safety profile of the PPMO modality. And it's just very interesting to hear the feedback outside in, 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 bio distributes 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, 15, 20, 40 milligrams per kilogram dose of the PPMO modality in the Sarepta and PepGen studies as compared to the 1 to 2 milligrams per kilogram that you're looking at in the context of PYC-003. But the differences don't 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. And particularly, helpfully, we were able to benchmark those molecules pre-clinically to evaluate the safety tolerability profile before we moved into clinical development. And 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. And 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 ANZSM. I 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 in the public domain the data because we haven't captured it from enough patients. So 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? And I want to show you here some data that's going to be relevant for 2 conversations that we're going to have, first, on the safety side and then expectations on the efficacy side as well. What you're looking at here is the inferred human kidney concentration at the 3 different doses that we took through the single ascending dose study in patients. So you see in the purple line, 0.4 milligrams per kilogram. I don't quite know how to describe that color, light orange, 1.2 milligrams per kilogram, and green 2.4 milligrams per kilogram. And the way that this model has been created, it is pulling data from 3 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. So what we're looking to do is see the relationship between the plasma and the kidney in the species that directly adjacent to the human species. And then we can link that to the observed plasma concentration in the humans to model an inferred kidney concentration. And 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, and then forward differentiated them into a renal tubular epithelial cell, proximal tubular-like cell because that's the cell type that we're interested in here. And we're 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's down here in the 300 nanomolar range, but there is a spectrum or a continuum of the extent of upregulation that you're 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're going to see in steady state in the MAD based on the predictions of the model. So the key here is the peak concentration of drug in kidney is not materially different after the second or third doses to what we're seeing in the first dose. And 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, 2 very sensitive markers of renal tubular injury, KIM-1 or the Kidney Injury Marker 1, 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 milligrams per kilogram, not because we think we need to get there from a PD standpoint, but because we have a completely clean safety tolerability profile. And so the question then is, is spending more time at higher parts in this curve going to yield a better outcome from an efficacy standpoint for patients? And 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. So that's 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 ASN. You can see here you'll Cmax, you'll see no Ctrough here, but you can see Ctrough here when you've got a 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 don't know, nobody knows, what the primary driver of efficacy is in the clinic, which one of those 3 variables could be driving that outcome, right? So that's 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 3 dimensions in the context of repeat dosing. Right. The presence of the drug above the minimum effective concentration is very, very short. in the 0.4 mg per kg dose cohort. It's longer in 1.2 and longer again in the 2.4 milligram per kilogram cohort. But 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. So this is just to repeat the time lines, single ascending dose study outcomes in October of Q4, and then we will also aim to complete enrollment of the first 2 cohorts in the Phase Ib study. So 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 in 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. So patients will progress from 1A through 1B, 1C, 1D, 1E. It is the 1C, 1D, and 1E patients who are the fastest progressors on the 2 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. So 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 largest cyst and the most fibrosis in the kidney. We think ultimately, the Stage 1a/1b, Mayo classification 1a/1b, patients will respond best to the drug, the greatest potential for arrest of progression or even reversibility. But because the gradient of progression is steeper in the later-stage patients, it's easier to detect that deflection in the interventional arm. So I just wanted to outline who's here. And remember that 5% to 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. So this is how we expect the control in the registrational trial to perform. So 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. And you can see the 0 line is here. If we take a snapshot at time 0 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% to 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 20 -- sorry, a 52-week window, you'll see the green line here. And to be clear, this is modeled data, right? It's not based on real data at all. And we've added the 95% confidence interval to that assumption. You can see that with an end of '24, the 12 patients per cohort, and assuming both doses are effective in the Phase Ib study, you will not get separation of the 95% confidence intervals until the 6-month time point, 27 weeks, right? So it's that longitudinal opportunity to evaluate the 6, 9 -- where's my cursor, 6-, 9- ,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 P3 study in order to reach statistical significance on the 2 designated endpoints. You can see then by direct inference that if we go out to 12 weeks and we go a little bit further on to the 16-week point, the variability, the 95% confidence interval, it effectively spans the 0 line. there's a very limited weight that you're 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's 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, had to stop the study at that point in time because they hadn't done the chronic tox work in the NHPs at that stage. So Novartis, when they bought that asset, we were left with 16 weeks of actual data and the rest of the year to extrapolate to try and work out what should the P3 design look like. And 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 P3 study? And if you look -- we're 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 2. No conviction that they can get down to the 0 line rather that you're looking at tolvaptan-like efficacy from an effect sizing standpoint. And 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 3 years, possibly longer on our estimates to enroll. So 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 P3 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 6-, 9-, 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 a 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. 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, 6, 9 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 end of '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 have 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 4 drugs, fourth one yet to come next year, but into clinical development, right? 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. 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. And 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. So 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.

One question coming through online. So Mel Benson has asked, regarding the Yale pitch, your views on their comments regarding the uORF1 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. And so if you go back and watch the video, you'll see that, that comment is based on a luciferase assay. So 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. So 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. So it's unclear even in the event that there was additional benefit over and above the two-fold up regulation, 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 don't want to preempt the Board decision here, and there's been no formal commitment at this stage. But what I can share is that we are doing the groundwork from an accounting standpoint now. So we are ensuring that we are Sarbanes-Oxley compliant so that we can trigger a 3- to 4-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.

Sorry, Rohan, can you go back to Slide 12?

I think Slide 12 is the one slide that doesn't have a number on it.

Yes. So on the right, it seems that when you're doing the multiple ascending dose, it's ascending. So are you sort of seeing the fact that the kidney, obviously, is improving. So therefore, it doesn't drop as far. Is that what you were expecting to see? Or is it just the weight?

When you say it's ascending, this is the concentration.

It doesn't 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's not falling as far as what it did the first time. So it's almost like kidney must be retaining some of the drug. Therefore, we get additional drug performance.

It's 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 per kg, your peak concentration in the organ is higher, and it's got a constant rate of decay.

It doesn't fall -- as far as you do the multiple ascending dose, it doesn't decline as far.

Yes, because there is -- you haven't completely cleared the drug by the time the second dose is given. So you're getting as what they call a plateau, which you're reaching effectively after 3 doses of the drug candidate. It's a very subtle increase there, but that's what 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, is this a drug that if it does work, you would give it over a prolonged period of time for the rest of your life? Or would it be sort of for a 2-year period to get your kidney back to a level where it's satisfactory?

No, 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 to 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?

Yes. No, 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. So I think it will be a very different approach there.

I've got off very lightly.

There's another one there.

Hi. You said you were going to try a higher dose with the MAD. So would that mean that you could then extend out the dosing periods? So you would still -- looking from that graph, looks like you would still be well within your efficacy dose.

Yes. Yes, that's exactly right. So what you're 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've got the optimal dose clarified, you can then look to extend the interval. And exactly as you say, particularly at the 2.4 mg per kg dose already, and as I said, I'm not sure that we need a higher dose at this point in time. If it turns out that 2.4 mg per kg is maximizing the efficacy, you could look to extend that dosing interval to 8 or even 12 weeks and you'd be remaining above that minimum effective concentration for the entirety of the time. So once we've locked down on the preferred dose, we will then seek to evaluate the dose interval. And 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's coming very soon, right? And you don't want -- you just saw before, you need more than 6 months' worth of data for it to be meaningful. So we're on the clock, how many variables can we answer before we lock down that P3 design. And then you've got the whole biostats exercise in terms of the sizing of the study. And then I do also want to flag there's one additional important consideration. We've talked about the TKV endpoint and powering for that, but we also have to power for the eGFR endpoint as well. And so there'll 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, and that's an open dialogue that we'll have with the FDA. Another question.