PYC Therapeutics Ltd

ASX:PYC

Earnings Call Transcript 2024-Q2

[Rohan Hockings, executive]

Hello, everyone, and welcome to the PYC Therapeutics Second Quarter Investor Update. My name is Rohan Hockings, I'm the Managing Director of PYC and I will be your host for this morning's call.

Before we begin the call, I would like to make the following safe harbor statement reminding you that today's discussion will contain forward-looking statements that involve risks and uncertainties. These risks and uncertainties are outlined in our filings with the Australian Securities Exchange. As such, actual results may differ materially from what we discuss on today's call.

We disclaim any obligation or intention to update these statements in the future.

I'll also let you know that the call is being recorded.

So the main message that I wanted to communicate to all of our shareholders today is that it's been a very strong start to 2024 for PYC. And associated with that, the company has made progress from its near-term ambition of putting 3 first-in-class drugs with potential for disease modification into human studies by the end of this year and is really now starting to focus on the next phase of the company's development, which looks to establishing the human safety and efficacy profile from a proof-of-concept standpoint or a Phase I/II study outcome context for each one of those 3 assets between now and the end of next year.

If we think about the broader organizational journey on the path to market, that forward view of the next 18 months represents one phase of the company's development, what we call clinical proof of concept. And this is the penultimate phase on the transition to a commercial stage company with one further 24-month window, which will focus very much on the design and execution of a registrational clinical trial in each one of those programs as well as the contemporaneous preparation for commercial launch of a product. And at that point, we intend on starting a series of new drug applications, assuming that each of these programs continues to see the success that it has seen to date and then to launch those products into markets starting in 2028.

So it really is this window at the front end here now that represents the pointy end from a biotech standpoint. We know that genetic medicines that enter late-stage clinical studies have a very high propensity for success. In fact, I think we have previously referred investors to an article by [indiscernible] that did a retrospective evaluation of all genetic medicines that underwent our Phase III clinical trial in the period between 2000 and 2008 and 100% of those drugs had the intended effect on the genetic target.

So very similar to the concept of early derisking in the context of monogenic diseases that translates all the way through to late-stage studies. What that means is the critical outcomes from PYC standpoint are represented by the donut human safety and the star here in terms of the clinical proof of concept. These initial efficacy signals are very powerful in each one of these programs. If we design those programs -- sorry, those early-stage Phase I/II clinical studies correctly, we can glean a very significant insight into what is likely to happen as we move these assets through to late-stage development. And we're going to touch on that very shortly as well.

So you can see here the formal readouts that come in relation to each one of these assets. What you're seeing at the [ minute ] is getting an early insight in relation to each one of these. And in particular, on the safety dimension, we have some considerable data that has been released on Monday of this week along with the initial insights on efficacy in the RP11 program. And so what you're looking at here are the formal readouts associated with the studies that are currently occurring.

But it's very important that investors understand this is not going to be a binary event. You don't have to wait until these milestones in order to see data that will inform the outcomes in relation to these. It will be very much layered as we go through the process of executing what are largely open-label studies, where we have visibility and access to the data as events are unfolding.

Very similar to RP11 in both the polycystic kidney disease program, where you see those 2 milestones down here and also the autosomal dominant optic atrophy program, you will start to get insights on these dimensions in the lead up to the formal milestones. And so you can see then that if we take the delineation of the end of next year, it's very much an effort to try and bring forward these insights to within this 18-month window that we have from today prior to the end of next year that the company is focused on right now.

Just a quick comment on the commercial environment and an important macro trends that investors should be aware of. Plan A is obviously to deliver on those milestones that we just spoke about, communicate well in relation to the outcomes and have the value associated with those events recognized in our market capitalization.

But it is also very nice that we have got the benefit of optionality with respect to accessing capital, the transactional window, not just for these specific assets, but generally is shifting from the $5 billion to $10 billion late-stage deals. The industry is moving towards earlier Phase I/II $1 billion to $2 billion deals at this point in time. So that creates a nice ability for PYC to consider not just funding itself through access to capital markets ideally at a fair valuation, but also to have the opportunity to out-license assets to receive upfronts in the event that we decide to partner one of these programs.

And just on that front, we've spoken before about the size of the indications and the target markets that we're going after. This was just a lovely quote from an article recently, but is not in relation to one of PYC's candidates. This relates to a candidate from a different company. But the striking feature is in relation to the prevalence of the indication. So this is a market opportunity that is being described as significant despite having a low prevalence of less than 1 in 100,000 people. So this is a lower prevalence indication than RP11. RP11 affects just slightly higher than 1 in 100,000 people.

And if you look at the peak sales prediction in this indication based on the orphan drug pricing, you can see that there is a very significant commercial opportunity associated with the RP11 drug itself. And if you think from there, we're moving from 1 in 100,000 prevalence in RP11 to 1 in 35,000 prevalence in ADOA and then 1 in 1,000 prevalence in the context of ADPKD. You can see the size of the commercial opportunities that PYC is pursuing increases as we move down the development pathway.

What we're going to do now is to do a deep dive in relation to each one of the programs to give you an overview of progress that has been made and specifically what to expect as we look towards the end of this year and into next year. And at the end, having done that, it's very much about giving you an understanding of where we've got to, to date and what we plan on doing through the course of this next critical 18 months. We'll open up the conversation for Q&A.

Everybody will be aware now of the data that was released earlier this week and presented at the ARVO conference in Seattle by Fred Chen. From all accounts, it was an excellent presentation and it is a very significant milestone for PYC in the context of this being the first insight that we have seen in relation to the efficacy of one of our drug candidates in the context of a human.

What I wanted to touch on, though, is the central access that is emerging that integrates the preclinical pharmacodynamics or efficacy results that we have generated to date through what we call pharmacokinetic/pharmacodynamic relationship. So the link between where the drug is in the body and the concentration at which it's present to the efficacy signal as that informs both human safety outcomes, early insights on efficacy, and ultimately, as we generate more data in support of this program, human efficacy.

And I wanted to take you back to a concept that we've discussed previously in relation to this being a single-gene disease. RP11 is caused by an insufficiency of one protein and one protein only in the photoreceptors and retinal pigment epithelial cells within the human retina. This is an image of photoreceptors in what we call a retina in a dish model. This has been grown from a patient with RP11, and therefore, it is manifesting the deficiency of this particular protein.

And what you're seeing in this image is that protein is being stained in green. So in the top image of an untreated RP11 patient, the amount of green that you see here is not sufficient to maintain normal cellular function in those photoreceptors. Those photoreceptors are unable to continue to convert the light that is hitting the retina into the visual signal for processing through the brain.

What you see after a single dose of treatment with VP-001 is a very significant increase in the expression of this missing protein. This is the root cause of RP11 in a human cell that is the cell type that is most affected by this missing protein. This provides a very, very strong paradigm for progression of this drug candidate into human development. You already know that single-gene diseases are 5x more likely to succeed in clinical trials.

The ability to model this disease process in a human target cell outside of a human before we enter clinical development adds even further conviction to what we expect to see as we get into clinical development. That's why it is so meaningful with respect to the safety outcomes that we're seeing because the fundamental question for the company now is can we deliver enough of the drug to the human retina in order to see this effect recapitulated not in the retina or in a dish, but in the retina in a human.

And what you're seeing now as we move to what we call microperimetry data or an assessment of the human retina after treatment with VP-001 is the same cells, an assessment of the photoreceptors in the retina and their functionality as a consequence of whether or not we are restoring the amount of these missing protein in those cells. So you can see a very powerful link emerging in relation to what we've seen in the nonclinical setting, how that is modeled through the animal studies that we've done in terms of determining the concentration of the drug in the retina, establishing that those concentrations are safe and well tolerated in patients and now starting to inform the early efficacy signals that we're seeing.

We are hesitant to provide an interpretation of data. We prefer just to put the data into the public domain and allow investors to interpret it, but we understand that these are complex endpoints to assess and to get your head around.

To give a personal perspective, noncompany perspective, in relation to what this data means and what we need to see going forward, what we would ideally like to see is these same results occurring in another 4 or 5 patients between now and the end of the year in the SAD and the MAD study, and that will give us very, very high conviction that the drug is having the desired effect and is going to have an impact on the visual function of those patients.

If we design those studies correctly, and we're going to talk about the evolution and thinking behind that study design, we should have a very high degree of insight into what is going to happen in the Phase III study. And you can see the investment bank quote here in relation to the ideal time to run the Phase III studies. If we have been able to glean maximum insight in relation to the risk-benefit profile of this drug in the I/II, we will enter those pivotal studies in the middle of next year with a very high conviction that we are going to convert to a new drug application.

For those of you who've been on the journey for a while now, if you cast your mind back to the conversations that we've had around the RP11 program over the course of the past 18, 24 months, you will know that we anticipated that we would see our signal in the earlier-stage patient population because the clinical studies on those patients to date, what we call natural history studies or observations of the patients in the absence of treatment, were suggesting that there is effectively an S curve of disease progression where patients are progressing fastest in relation to the loss of their peripheral vision. They were losing about 8% or 9% per annum of the perimetry or the peripheral visual field in the context of patients who are at an earlier stage of disease progression.

If you think through the course of RP11, first, you lose your night vision, then you lose your peripheral vision. Ultimately, you lose your central vision very slowly and are declared legally blind.

So we had hypothesized that we might see the signal in the context of earlier-stage patients. And that's very much the observation that has come out of the cohort 3 from the single ascending dose study. We had 2 patients in that cohort who were very significantly progressed in terms of the disease and really only had central visual function left. That was always going to make it hard for us to see the signal because of the very slow nature of the progression of loss of central vision.

And I think the striking feature was in the third patient in that cohort who was younger and at a much earlier stage of disease progression, that is the one in which we saw the most significant signal with respect to the potential response to the investigational drug candidate there.

So what we've done now is we have refined the inclusion criteria, both for the execution of the SAD and the transition to the multiple dose study that is coming later this month. What we are looking to do now is to focus on those early-stage patients. So we are giving ourselves a stratified patient population who are going to enable us to see that signal most clearly to glean most conviction from the Phase I/II studies.

And I want to be clear here, we're not saying that these are the only patients who are responding to the drug. The drug should be, in theory, addressing the root cause of RP11 in every patient. What we are saying is these are the patients who are moving fastest on a dimension that we can measure, and therefore, they are affording us an opportunity to see our signal fastest.

And that's very important now. What we need to do through the completion of the Phase I/II is understand the impact of the drug candidate on the patient's visual function and try to correlate that to an endpoint that is going to serve ideally as our primary endpoint as we transition through to that pivotal study. From there, we need to have a conversation with the regulator to agree that if we see a recapitulation of what we expect to see in the context of that registrational study that, that will support the new drug application. And if we get that right, we'll be progressing very nicely through that second 24-month final horizon before we become a commercial stage company.

Very, very exciting time in the context of RP11. We are very close here, and I think we're going to have a lot more insight between now and Christmas in relation to the data that will be gleaned from this refined patient population, a larger number of earlier-stage patients assessed on the same endpoints that we are focusing on here that relate very much to visual fields.

We'll open up for Q&A on that at the end of the session, but I want to move through the rest of the pipeline as well. In terms of the ADOA drug, you can see that the near-term milestone that we have here is for a regulatory submission to enable first-in-human studies. We're at a very advanced stage of preparing for that regulatory submission, and we expect to be dosing humans in the third quarter of this year.

So what you'll see from the company in the near term is the outcome of what we call the good laboratory practice toxicology studies that will enable that regulatory submission to be made and then the outcome of the regulatory submission. Preparations are very much underway for patient enrollment and preparation for patient recruitment so that we can move seamlessly through dosing in a single ascending dose study later this year.

The very, very nice thing that I do want to draw your attention to, now that we have got the safety, tolerability signal or a large part of that in the RP11 trial and we're seeing a very, very clean safety profile, there is a significant inference that can be made to the extent that this is the first time that this modality has ever been used in a human eye before in relation to the safety profile of a PPMO, a peptide conjugated RNA drug, via an intravitreal route of administration or application to the eye for the treatment of a retinal disease.

And so this is very, very nice read-through data that is being informed from one program to the next. We are using a different delivery technology and a different oligo. So we still need to fully characterize what this specific drug candidate looks like, but there is a lot of read-through at the modality level from the safety signal in RP11.

There are some questions on the ADOA program with respect to the ability to fan out into other indications that we have touched on briefly previously, but we will go into in some more detail through the course of the Q&A.

And then to the big one, polycystic kidney disease. You have seen some data come out earlier this quarter in relation to the safety, tolerability profile of this candidate in nonhuman primates. These are non-GLP, what we call exploratory or dose range-finding studies. The data here is really lovely. It's showing that the drug candidate is safe and well tolerated at doses of 3, 10 and 30 milligrams per kilogram. And not only that, but we are able to achieve very high levels of target tissue concentration. So there is a lot of drug in the kidney at those doses that have been administered.

And the nice thing here is to link the data that we've generated in those studies back to other PPMOs that have proven to be clinically successful that have demonstrated efficacy in humans.

If you look at the target tissue concentration of Sarepta's SRP-5051 in nonhuman primate muscle, that's their target organ in that indication because it's a disease of muscle, they're looking at around 500 nanograms of drug per gram of tissue.

If you look at the concentration of PYC-003 in the kidney of nonhuman primates, we are looking in the tens of thousands of nanograms per gram at a much later time point. So it's inferring, and we'll wait till we get the definitive data here, but it's suggesting that we will likely be at a concentration in the region of 100,000 milligrams per gram plus. This is many orders of magnitude more concentrated than a similar class of drug. It's an identical class of drug, similar drug in a different target tissue. So that bodes very well with respect to that PK/PD insights that we just reviewed in the context of RP11.

The very exciting thing about this program, not only is this a disease-modifying approach and it appears due to the complexity of the target gene in this instance that this may, in fact, be the only way of rescuing this disease indication, but when we go into animal studies of this disease, this is an indication or a disease process where the regenerative capacity of the organ means that we are not just aiming to stop disease progression, but we are actually hoping to reverse the disease process itself. Allow the tissue time to regenerate and restore both anatomically and ultimately functionally the role of the kidney in the human body such that, that patient doesn't need an organ transplantation. That is really the objective of this program.

We are going to see next year whether or not we are on the path of delivering that outcome. So this is something that investors should be aware of. The path to the efficacy signal in the context of the kidney program is going to be a lot shorter than it will in the context of the retinal disease programs by virtue of a couple of different things: one is the rate of progression of the disease; two, the potential for reversibility; three, the existence of a biomarker that is going to give us a really nice early insight on whether that drug is working.

Administer the drug. The protein that we are looking to increase the expression of is ultimately excreted in the urine. So we can measure that in patients and get a very early insight on whether we're on the right path here or not.

Okay. With that, that concludes the formal part of the presentation. I'll leave that page up because it is the critical one. [Operator Instructions] And we have a couple that were submitted here prior to the session that I'll address now and then maybe we'll open up to the room to start with whilst people put their comments into the Q&A function.

[Rohan Hockings, executive]

So the first question that we have here, what was the reasoning for lodging a patent for glaucoma? And this relates to the questions that we've had in relation to the ADOA drug.

The rationale behind lodging the patent for glaucoma is that there is a body of evidence that supports the notion that an increased expression of the OPA1 protein is protective of retinal ganglion cells in the context of glaucoma. And so the idea here is that we can repurpose the ADOA molecule in the context of other blinding eye diseases. And in particular, the benefit that we can glean here is that if we have characterized the safety, tolerability profile of that drug in an ADOA patient population, it enables us to progress directly into a mid-stage clinical study in the context of other indications that share the same dosing, the same route of administration, and by implication, the same preclinical safety, tolerability and ultimately clinical safety, tolerability that will generate in the Phase I SAD in ADOA and get ourselves a read as to whether or not that drug is beneficial for patients in those other indications.

Now what people should be aware of here. Firstly, look, you can look at it as quite a nice body of literature suggesting that increasing OPA1 expression in the context of different animal models of glaucoma is protective of the retinal ganglion cells.

The body of work that PYC is currently doing is we are looking at these patient-derived models. So we're generating ourselves the retina-in-a-dish models from patients with glaucoma to give us the conviction that it is worthwhile progressing into one of these Phase II studies in the context of glaucoma.

It looks very promising at this point in time. We'll come out to the market when we have definitive results in that context and are looking to initiate that process in the context of that indication.

There is a lot of interest amongst the retinal physicians around the use of this drug molecule in the context of that indication specifically. Not just that, but there are other ocular indications in which improving the bioenergetics of the cell could potentially have an impact on the phenotype.

What you are trading off there, and we should be very clear about this, too, glaucoma is not a monogenic disease. So it does not benefit from the same extraordinarily high propensity for success in clinical development that the monogenic drug candidates that you see on the page in front of you do.

That's why it's -- look, it's a terrific starting point that you can get straight into a Phase II study, massively shortens the path to market. So there are some offsets there and it's obviously a much larger patient population that we're going after, albeit that is partially offset by significantly reduced drug pricing in the context of nonorphan indications.

But you can see the key decision from the company standpoint to launch that clinical trial, what is the conviction that we have that this drug is going to have a meaningful impact in those patients. And so the more evidence that we can get in the nonclinical setting around having the conviction that this is going to make a meaningful difference, the better positioned we are to progress into that clinical trial.

Next question, the last announcement said initial encouraging microperimetry data showing improvement in retinal sensitivity for 1 patient in cohort 3 [ 30 micrograms ] of the investigational drug candidate. Does this indicate an improvement in their vision as opposed to not getting any worse? So we'll have a look -- quick look at that microperimetry data.

Look, yes, that's exactly what it means. This patient has improved from a microperimetry standpoint in the context of the treated eye. And notably, they have also got slightly worse in the context of the fellow untreated eye. So there is a delta emerging here.

You can clearly see from the microperimetry imaging here and very helpful Sri has highlighted the different foci that we are looking at here, those that have seen a statistically significant improvement in the sensitivity to the threshold here. So this is an improvement that is occurring in the context of this patient.

This is really helpful for us. We had hoped, but we're not sure that we may be able to see this. You need to keep this in the context of endpoints that can fluctuate. There is a range of outcomes at any given point in time. So hence, my comment earlier in relation to what I personally would like to see going forward.

The potential here is because of that improvement is you can get conviction in a smaller sample size. If we stratify correctly and choose the patients that have the potential to show us this response, if we see this occurring in another 4 or 5 patients, we're going to have very, very high conviction moving through to that registrational study that not only we are seeing an effect of the drug, but we're going to be able to measure and quantify in a statistically significant manner what that delta looks like as we move through to a new drug application.

PYC has filed another patent, advanced compositions and methods for treatment of kidney disease 2, on 6th of May 2024. And this is another advanced composition of methods patent after an earlier one on 4th of April 2024. Would you please shed some light on this subject? Is it related to ADPKD?

Look, that -- the company has a lot of focus on our clinical stage programs right now. We are continuing to work in the discovery realm, leverage the insights and the knowledge that we have gleaned in the context of progressing each one of these assets through to clinical development in the context of different applications of precision therapies and also expansion of our interest to other disease indications.

We are not ready to make any commentary here. This represents a new modality that PYC is contemplating moving into in the future. It's not a focus for the organization right now. We want to keep everybody's attention very much on the assets that are in or near clinical development. We will come back to market at an appropriate juncture and talk further in relation to what we have done there.

And that goes generally for conceptually what is occurring beyond just those patent filings. We continue to be very active in the discovery domain. There is just so much excitement at this point in time around what is happening as these first-in-class assets with disease-modifying potential are moving through to human readouts, where the rubber meets the road in our industry, and so much going on in that domain that we want to make sure we are adequately communicating in relation to what is really going to move the needle in the short term. We'll come back and have other conversations in relation to discovery work at a future point in time.

I'm interested in the comment that if Phase I ADOA is successful, it could lead on to multiple Phase II trials. I note from Google that OPA1 mutation is associated with other conditions such as OPA1 plus conditions, which I assume are rare, but maybe some of the Phase II trials you are referring to.

And I think there's a related question. I also note there seems to be an association with glaucoma, which you mentioned in the presentation. My fairly superficial search was less clear about glaucoma. I would like to know if it's just the normotensive group who tend to have OPA1 mutations? Or is it also in high-pressure group? What proportion of glaucoma carry OPA1 mutations? I'm aware that glaucoma treatment, particularly on the normotensive group, can be challenging and would be great if a significant portion could potentially be treated with our ADOA 1 drug.

So firstly, to be clear here, these glaucoma patients and the indication that we are interested in is not driven by a genetic mutation in OPA1. That's not why we are interested in this indication.

What is happening here is there is a hypothesis, a view, as to the pathogenic cause of glaucoma, which is unknown at this point in time, that relates to what we call a 2-hit model. So firstly, that there is some underlying bioenergetic deficit in the retinal ganglion cells. These are the cells that are affected in glaucoma.

And then there is a lot known about the secondary insult, which is often driven by raised intraocular pressure, raised pressure in the eye that is causing those retinal ganglion cells to become stressed.

And so the theory that we are exploring here is that if we are able to improve the bioenergetics or the energy production of the retinal ganglion cells, we will make those cells stronger, and therefore, more able to resist the secondary insult of the raised intraocular pressure or whatever that may be that is causing them to undergo cell death and for those patients to lose their vision.

And so it's really an exploration in the preclinical setting of getting an understanding of exactly what is going on there and how can that be translated clinically to the 1/3 of patients who have glaucoma who are progressing despite maximal therapy. That's really what we're looking to do in that context. So hopefully, that addresses the question there.

When you say concurrent Phase II trials, is this as soon as the drug passes the Phase I trial for ADOA? Are we then able to progress to Phase II trials for all the conditions with OPA1 mutations assuming we have the resources?

Yes, that's correct with the caveat being that the patients don't have the OPA1 mutation. It's a different hypothesis. It's an ingoing assertion that increasing OPA1 expression in patients with glaucoma or Leber hereditary optic neuropathy, acute ischemic optic neuritis, possibly geographic atrophy, these other conditions could benefit those patients because we are improving the mitochondrial dynamics and kinetics of the cells that are affected and causing that patient to go blind. It's not driven by a mutation in that context. But generally, the concept is correct there.

Okay. We will move across now to the Q&A. At what dosing level is the image of the retina treated with VP-001?

So this is the microperimetry data that you're seeing on screen here is from a patient in cohort 3 who received 30 micrograms of the investigational drug candidate.

What's the profile of the other 2 patients in cohort 3? Were they also early stage? Did you have an expectation on when the drug would have an effect after dosing.

So hopefully, we covered that through the course of the presentation. The other 2 patients in cohort 3 were at far more advanced stage of disease progression.

By focusing RP11 on early-stage patients, does that limit application to other patients without future studies, and therefore, reduce the market opportunity?

No. That was the point I was trying to make before. We're not saying that there are patients with RP11 who won't benefit from the drug. As you've seen from the patient-derived model on the left-hand side, this drug is addressing the underlying cause of all patients with RP11, confirmed PRPF31 loss of function mutations. So what we are saying here is that it's in the context of the early-stage patients that we are likely to be able to see our signal earliest, and therefore, that will inform our progression through to late-stage studies that has got very clear precedent in other ocular indications and should not have any implications with respect to restrictions on the label or the patient population who are likely to be able to use or benefit from the drug candidate.

How will AI impact PYC's development pipeline?

That's quite a broad question. AI at this point in time is shaking up the drug discovery industry in a very significant way. I think it largely remains to be seen exactly how that will play out where the best applications of artificial intelligence are throughout the course of drug discovery and development pipelines generally, not just for PYC.

We know that it's going to have a very significant impact. There is a lot of noise around AI, and we're in the window where we are sifting through that noise to find the true value-adding applications of the technology. We are a part of that process through our collaboration with Google Cloud. And we have ongoing activities that should help us respond to it, not just on the back foot, but getting on the front foot to see how we can use AI to get ahead of the curve here, coupled with the existing knowledge and capabilities that the organization has.

Has perimetry ever been used as an approvable endpoint with the FDA in other blinding eye diseases?

So there is a -- no is the answer to that now, but there is a very strong push towards microperimetry as the right endpoint for patients with retinitis pigmentosa. And in fact, Sri was at a conference over the course of the weekend run by the Foundation Fighting Blindness. There is very much a concentration of effort on this particular endpoint in the context of retinitis pigmentosa specifically amongst other companies that are pursuing different forms of RP. So RP, the phenotype, but caused by underlying different genetic mutation within this indication.

There is a very strong push and deposition to the regulator to accept microperimetry as a registrational endpoint. And it seems to be the endpoint on which we are closest to getting the FDA to accept a novel endpoint in the context of a late-stage trial. And coupled with the enhanced flexibility that the regulator is demonstrating towards accelerated approval pathways, novel endpoint, surrogate markers of disease progression, I think that's entirely appropriate that we're moving there.

So PYC is part of the bodies that are making the representations to the FDA. There are, of course, other examples of companies such as Spark Therapeutics and LUXTURNA, who have had a novel endpoint in the form there of the multi-luminance mobility test or the maze, have had their drug approved on the basis of one of those novel endpoints.

Regarding RP11 trial progress, understand waiting on approval for 75-microgram dosing. Do you have approval at present to progress straight into the MAD design? Or are you waiting on FDA approval to progress into multi-dosing?

So here, we have the approval, all relevant approvals, to progress to the 75-microgram SAD cohorts, so we're not actually waiting on approval there. In fact, 2 of those patients have already been dosed and we are hoping for the third patient to be dosed on Monday. We'll come out and confirm once we have locked that away.

Sri and Clare, our 2 colleagues in the U.S. who are leading that effort are doing an outstanding job on the execution of that clinical trial, and we are not far away from generating data for those patients. We are now also preparing for initiation of the MAD later this month and patient dosing there.

So we are moving at speed in both the SAD and the MAD and we are going to be getting data coming from both sets of patients in the near future.

Final one on RP11. As you have an IND, is there any plan to expand to U.S. sites within the SAD/MAD study or you won't enter U.S. sites until the registrational trial?

So the RP11 program is solely being conducted in the U.S. right now. So it's only involving sites in the U.S. There is an expansion to include additional sites, all of which are also in the United States, through the progression of the SAD and MAD and it's actually going the other way. What we are looking to do now is see whether or not we can enroll geographies and jurisdictions outside of the U.S. for the registrational study.

Are there cost benefits for being first-in-class for Phase III?

Not really. The primary benefit for entering into a registrational study with a first-in-class drug comes at the back end of the process when you're launching that drug in market. I think we've given some illustrations previously. It's worth people having a look at the uptake of other first-in-class RNA therapies for rare disease. SPINRAZA provides a very nice example here.

Typically, what we see is a very steep uptake curve, which is not surprising. Patients are literally waiting for these drugs. You can see even up to 80% of peak sales being reached within 12 to 18 months of product launch. So that's the primary advantage that you get there.

The other benefit from a sponsor standpoint is that when you are a first-in-class drug candidate in the context of an unmet need, when there is no approved therapy, it's a genuine unmet need, such as RP11, there is no standard of care against which to compare your drug. So you are really looking to compare your drug against the absence of treatment, which is why we are running these natural history studies concurrently so that we can get a better understanding of how quickly the disease is progressing in a statistically significant manner or a manner that enables us to generate statistically significant data showing the delta between the treated and the untreated groups in that context.

Any progress update with AlphaFold project, noting announcement from Google DeepMind overnight predicting the structure of an interactions between biological molecules interacting, including proteins, DNA, RNA and small molecules that could function as drugs.

So what the question refers to here is there's been a new release of the AlphaFold technology, AlphaFold v3 has become available this morning or published and it is extending the ability to move from modeling the target protein that we are looking to have an interaction with to the peptide, small molecule, smaller component that we are looking to have that interaction.

So no, it's a bit fresh, that one, for us to be providing an update on how that's relevant to us. Isomorphic clearly leading the field in this context and will take some time for that to flow through before we can respond to it.

But what I will say is that we are likely to -- thank you, Carol, look to include the latest iteration of that software in our activities in collaboration with Google Cloud.

If other responses can be seen from the first round of injections that have been completed already, would that help your confidence RP11 is working? Or is it the upcoming MAD and SAD trials?

I think what is being referred to there is the historical data from the patients who have already been dosed in the SAD. What we've touched on here is those patients are likely to take a lot longer to give us that signal. So we're obviously continuing to follow up those patients. We are certainly hoping that we start to see patients from within the SAD convert under the expanded access protocol to a multi-dose format. That would be very helpful there.

But I think we probably have got a pretty good handle on where those patients are at for now. We obviously want to see what the impact of the drug is in the context of a longer period of time.

So yes, that data will be very helpful for us. But I think the most promising prospect going forward, given what we've seen to date, is in the higher dose cohorts where we're getting more drug to the patient retina in the context of an earlier-stage patient with a focus on this dimension in which the endpoint is moving the fastest in the context of visual fields.

Do we prefer outright sale of an indication or partnership or income stream?

Look, the typical structure in relation to licensing deals in the biotech industry is a transaction that has got 3 components. There is an upfront component of cash paid from the licensee to the licensor.

There is a series of what we call milestones that's paid, again, from the person licensing the drug to the person who has licensed it to them through different milestones of development, often tied to clinical development milestones, but typically back ended to include sales milestones as well.

And then there is a royalty, usually for these types of deals in the low double-digit categories.

So we get a bit of an exposure to both anyway. You get the upfront component and then you obviously get the back end, the at-risk component or what is referred to as biobucks.

We are in a position where we're just going to evaluate any potential deals and the term sheet for them that come across the desk of the organization moving forward. That will be looked at on their merits. That will be looked at in the context of the company's own modeling in relation to the intrinsic valuation of those assets, which reflects very much the assumptions that we've spoken to you about today.

Very high probability of success for these molecules. Very attractive commercial markets in the event that you're launching first-in-class drug products for an unmet need.

How are we giving the safety trial patients the option for additional treatment correlate with the multi-dose study?

And so look, it'll end up being very similar in terms of the data that's being generated for those patients. We'll be looking at a very similar dose interval in that context. So it effectively becomes additional patients who are going through a repeat dose format and for whom we are capturing data on a regular basis. It's just expanding out the sample size in that context.

And it's also fulfilling our obligations to patients who have enrolled in that single ascending dose study and given us the benefit of seeing whether or not the drug candidate is working in that context. So this is an obligation that we have back to those patients.

Have we selected the candidates for cohort 4? Yes. Select for early-stage? Yes.

Yes. So we -- that's the refinement of the inclusion criteria. Those inclusion criteria are now live with respect both to the higher dose SAD cohort, also with respect to the MAD cohorts that will be enrolled and hopefully dosed later this month, early next. So yes, we are looking at those earlier-stage patients.

Is the Nasdaq in your immediate sight? Not in the immediate sight as it relates to the next 12 months. Any transition to the Nasdaq would be a 12-month or more process. So at this point in time, it's not a high priority for the organization.

Value recognition for shareholders is. So we very clearly need to do something about the communication and the understanding of the impact of these milestones. We think we have a lot of work to do there. I think you can see that by the delta in valuation to us versus our U.S. peers. We don't want to see a situation persist where we are continuing to trade at a very significant discount to those peers, especially in the context of the quality of the data that we are putting out here in some very attractive markets for the reasons that we've discussed.

So as I mentioned before, Plan A is still deliver, deliver, deliver, get an understanding recognition of the value that has been created through this critical window where we know it is the peak window in terms of value recognition.

Plan B is look to create licensing opportunities around individual assets so that we can demonstrate the value of what we have created in the context of a partnering transaction. Effectively, the trade-off you're making there is dilution at the corporate level versus at the asset level.

Now what we would be looking to do there is to reinvest the upfront money and pushing deeper into development with the candidates that are targeting larger indications, and that will fundamentally change the commercial leverage around the table when it comes to transacting on those assets.

That's it for the Q&A today. Any other questions in the room? Hang on one second.

[Unknown Analyst]

I'd like to ask with the patient where you think it's worked, did the testing show up changes first? Or did the patient walk into the clinic thinking there's a bright golden star on the horizon sort of thing. Did the patient pick it up first? Or did the testing pick it up?

[Rohan Hockings, executive]

Yes, it was the patient. So very nice that the quantitative assessment of the patient correlated with what the patient was reporting with respect to an improvement in the visual function.

So the patient first noticed that they were finding it easier to read the computer screen. And this patient's occupation requires them to spend a long time at the computer screen reading the computer and had a series of other observations in relation to how her activities of daily living or visual function were affected by receiving treatment with the drug.

So that was very, very encouraging. A very well-educated and articulate patient who was able to convey the impact of their experience very eloquently to the treating clinician there.

And there is a lot of excitement as a consequence on the part of the clinicians. There is a very strong desire, the point that we spoke about beforehand, to try and correlate the patient-reported outcomes with what we're seeing in the quantitative assessments. And that will help us understand exactly where we need to look in relation to the progression to the late-stage studies that's scheduled for next year. Pat, can you give the microphone. Thank you.

[Unknown Analyst]

And what was the time frame from dosing to the realization or the patient's sterilization?

[Rohan Hockings, executive]

Look, the data that you have seen is from a 4-week follow-up and the patient was scheduled to come in again at 12 weeks. But because of the patient-reported outcomes, we brought the patient in for an unscheduled visit at 8 weeks and conducted the same assessment. The 4-week and the 8-week quantitative data correlated and so that provides a very nice package in that context.

It's somewhere between dosing and the 4-week visits that have occurred for the patient. So it's very early, right? Very, very early.

Yes. And I think just to put it in context, looking at some of our peer companies that are developing investigational therapies for other forms of IP, they are looking at and highlighting much lesser impact on microperimetry than what we're seeing in this context. So in that context, looking at a slowing of the rate of progression, but seeing a delta between treated and untreated eye. Here, as we touched on previously, what we're actually seeing is an improvement in the sensitivity within the microperimetry designated area for evaluation.

So very encouraging, but we need to see it in a larger patient population. So we need to see half a dozen of the patients showing that. And in particular, what we want to see is some of the patients from the multiple dose study showing it as well. The SAD patients are -- I mean, that's terrific, right, and we should be converting those patients through to multi-dose format. But we want to see maintenance of this improvement in visual function over a sustained period in the context of repeat dosing with the drug. That's why the data that is coming between now and the end of this year is so critically important for us.

We've got another one -- another couple. What is considered early stages for RP11? Is it just night blindness? Or does this cohort include those who have lost some peripheral vision? Yes. Yes, it is. It does include those patients who are starting to lose their peripheral vision as well. So with RP11, it's typically a disease of childhood, but we do see what we call a variable age of onset of the disease. So some patients don't present until they're older. Despite the variability in the age of presentation, once diagnosed, there is a very consistent rate of disease progression from that point.

And so for earlier-stage patients -- and you can see them reflected in the inclusion criteria. If you go back and have a look at the presentation at ARVO, understand that it's difficult to get involved in some of the technical measurements here, but effectively, what we're doing is we are including patients who have a minimum preservation of their peripheral visual field left. So we've effectively set a cutoff in terms of the visual field and we are accepting anybody into the trial who's got more peripheral vision than that threshold.

And so that will include some patients who have progressed and lost some of their peripheral vision. It will also include other patients who are at a much earlier stage of disease progression, and the fundamental impact of the disease today has really been loss of the night vision or dark adaptation.

Will this session be available online? We'll see what we can do with respect to making the recording available. But if you e-mail the company's info line, we'll send you a link to the presentation.

Okay. So in summary, if we just go back up to the headline message, really today was an opportunity to hopefully share some of the great enthusiasm and excitement that exists within the organization and increasingly around the organization. It is very gratifying to hear back from the ophthalmology community their excitement in relation to what we are seeing in relation to the RP11 drug.

Also that is starting to translate into momentum behind the ADOA drug candidate. There is a lot of interest amongst the clinicians to take that drug candidate and create what we call a pipeline in a program, expand that into other indications where we have a strong degree of suspicion that improving the presence and quantity of OPA1 within the cell is going to improve the ability of those cells to resist whichever phenotype that we're looking at in that context. So that is terrific.

There is, obviously, building momentum in relation to the polycystic kidney disease program. We have passed through that critical milestone that we spoke about at the last investor presentation in relation to establishing that, that drug is safe and well tolerated in nonhuman primates.

We're very much in the lead up to the GLP tox studies, where we hope to repeat those outcomes before submitting the regulatory submission to take that program into humans. It is not going to be a long time between initiating those first-in-human studies and starting to have a look at some biomarker and anatomical surrogate efficacy endpoints in that context as well.

So massively, massively exciting period for PYC. We are on track for fulfilling the multi-year aspiration that we have set out to shareholders for progressing these 3 first-in-class and potentially disease-modifying drugs into humans.

The company's focus has now shifted. It's progressed. Whilst we bring the second and third assets into humans, the first asset has progressed even further within human development. The focus for the company now within this 24-month window, of which we are through nearly 6 months already, is to establish clinical proof of concept behind each one of those 3 assets. Following that is progression through a pivotal study and gearing up for commercial product launch before we submit the new drug applications that are currently anticipated to begin in 2028.

Very, very exciting time for the organization. We are at the pointy end. You are going to see a whole bunch of readouts throughout the pipeline. But in particular, there is a lot of excitement around what is going to happen in these SAD and MAD patients that you are going to see the data on between now and the end of this year.

Thank you very much for your time. We look forward to updating you through the course of the next quarter in the form of the ASX announcements and then holding another investor session in Q3 to update you on progress.