Joining. My name is Rohan Hockings. I'm the managing director of PYC Therapeutics, and I'm gonna be your host on today's special edition of the Investor Update. Before we begin, I'd just like to kick off by letting you know, firstly, that this call is going to be recorded, and secondly, making 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, and 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.
And so the focus of today's call, and it, it really is quite an informal conversation, so please feel free to interrupt through typing into the chat any questions that you have or issues that you'd like clarification on. If we're going too deep or not deep enough, please point that out, and we'll try and adapt in response to the level of understanding through the audience. The basic objective of today, it's not a PYC 101. We will touch very briefly on what the company does, but we want to focus very much on the results released to market yesterday, because they play a very important role in guiding the prospects of success of our second drug program, a first-in-class investigational drug for patients with a blinding eye disease called autosomal dominant optic atrophy .
I think that very much orientates the conversation for today. So we've got a lot of conviction and comfort that we are on a path to a high-impact medicine here, and not just a high-impact medicine for patients, but also a high-impact medicine for investors, because we apply some very aggressive commercial filters at the start of the process to make sure that we are only working on challenges that will bear a substantial financial return in the event that we are successful. What we wanted to do was to make sure that everyone has fully understood the implications of the data that was released yesterday, the outcome of some non-human primate studies that very elegantly show an integrated profile on the three dimensions that we are most interested in in this drug.
Those are whether the drug is safe and well-tolerated, whether the drug has got a nice half-life or durability profile in the retina, and critically, whether the drug is effective at modulating the gene that is missing in patients with ADOA. There are really two levels to understand the results from yesterday. The first one is the simpler level, and it's in itself quite meaningful. It is simply to communicate that we have just achieved in non-human primates exactly what we want to achieve in the human studies that are about to begin. That takes on particular meaning when you understand that non-human primates share about 98% of their genome with humans.
We have just shown that we are able to increase expression of the OPA1 protein in the target cell, retinal ganglion cells, in the non-human primate retina at a safe and well-tolerated dose. We don't yet have the full PK study results, but we know from the VP-001 molecule, PYC's first drug, for another blinding eye disease, that this class of therapeutic has about a 20-day half-life in the non-human primate retina, which lends itself to a 100-day dosing interval in patients. Patients only need to be dosed around 3, maybe 4 times a year, which is very convenient from the patient perspective. So that these drugs really have an ideal profile, from the patient perspective, and it is a really impactful outcome when you consider all of those dimensions together.
The data, however, goes to another level when you look a little bit more deeply at how this piece of information integrates the data that we have already generated in these patient-derived models. To give you a quick recap on what the patient-derived models are, this is a relatively new innovation in drug discovery and drug development. It's only really come about in the last five or 10 years, and the sophistication of these patient-derived models is now going through the roof. So that these are very quickly becoming the gold standard tool in non-clinical development to give insight on whether a drug is likely to be effective in clinical development. And so what we do here in the generation of these patient-derived models is we take a skin sample from patients who have ADOA.
So we've got some cells that have got the genetic defect that we're interested in addressing. And we send those skin cells, that we call fibroblasts, backwards in the evolutionary chain into what we call an induced pluripotent stem cell. And this stem cell has the ability to turn into any different type of cell in the human body. So it's, it's quite a powerful starting point when you're trying to create a disease model, and this stem cell will as well have the genetic deficit that we are looking to correct, because it came from a patient with ADOA. And now, having turned the cell backwards into a stem cell, we're now gonna turn it forwards, not, not back into a fibroblast, into a skin cell. We're not so interested in that.
We're gonna turn it forwards into the cell type that's affected in ADOA, a retinal ganglion cell, so the cell that exists in the retina of the patients that is responsible for communicating the visual signal that is created by the retina to the brain, which will process that visual signal. So you think of it very much as the connecting cable that sits between the retina and the brain. And the reason that we want that cell is we've now created a model from a patient with ADOA of the cell type affected in ADOA, in which we can see the deficits observed in ADOA. And so you, you start to understand from that description why this is such a powerful model for the evaluation of the efficacy of a therapeutic.
We build ourselves a retina in a dish, in which we can assess the efficacy profile of the drug. And the key that I really want to communicate across to you today is that the level of protein upregulation of the missing protein, OPA1, in the non-human primates, is the same level of protein upregulation that we can achieve in the patient-derived models, in order to fully rescue the ADOA phenotype in the context of those patient-derived models. Now, this is a really, really elegant non-clinical path. It's the pinnacle of non-clinical data, and I want to just walk through very slowly a recap of what autosomal dominant optic atrophy is from the patient perspective, so we understand the implications of why this drug is such an important new therapy, but also to look more closely at the underlying genetic cause of the disease.
Because that sets a very nice platform for an understanding of how the PYC-001 molecule works, and the data that we've been able to demonstrate in the non-clinical setting in support of the propensity for success of this molecule in clinical development. And I think it is important to remember as well, just to triangulate yourself in the commercial context here, yes, it's early in the drug development course. We understand that. But remember, in precision medicines, especially RNA therapies for monogenic disease, assets, even at a very early stage of development, transact for significant sums of money.
So if you have a look at, and we've alluded to previously, the Vertex and Entrada deal , that was an asset that was significantly earlier in development than the ADOA program that PYC is developing, so much earlier than PYC-001, by at least 12 months, and that was purchased for $250 million upfront. And if you look at the recent collaboration with GlaxoSmithKline and Wave Life Sciences, they paid $170 million upfront in cash, plus milestones equating to $500 million-$1 billion, and a 10%-20% royalty on future sales of that drug. So these are very, very attractive commercial products, even at an early stage of development.
The key question that the BD counterparts, and also therefore investors, are interested in is: What is the quality of the non-clinical data pack that's been generated, and how does that give conviction that we are going to see both human safety and efficacy when we get into clinical development? Because if we can understand that in great detail, we already know that launching a first-in-class disease-modifying drug for patients who have no treatment options today, is both an attractive thing to do from a humanitarian perspective, it really moves the needle from wanting to make a difference in patient lives, but also as a direct derivative of that, it's very impactful from a financial perspective as well. And we understand that in the context of the orphan drug pricing, ADOA represents approximately a $2 billion per annum market with very, very high margins.
Okay, so I'll pause there. We don't have anything in the chat so far, so I'm going to continue to progress just by giving you an introduction, firstly to the patient journey in ADOA, and then we'll get on to a bit of a deeper understanding. We've communicated to you, and I think you're aware, that the disease is caused by a deficiency of the OPA1 protein, but we're then going to walk through, okay, but what exactly does that do? How does not having enough OPA1 protein in the retinal ganglion cell impact the function of this visual cable that is communicating the message from the retina to the brain? So firstly, in relation to the prevalence of this indication, it affects slightly more than one in 35,000 people.
But the loss- of- function mutations, the mutations in the OPA1 gene that give rise to a defective copy in one of the two OPA1 genes, affects around 85% of the patient population. So the 1 in 35,000 there that we are talking about represents the addressable market for PYC-001. ADOA itself is actually slightly more prevalent, but there are some different mutations and pathogenetic mechanisms that impact a small percentage of the patient population, and unfortunately, those patients are not going to be eligible to receive PYC-001 because it has a very specific mechanism of action in addressing the underlying cause of the disease in the majority of patients.
Now, most of these patients are diagnosed in childhood, around the age of seven years old, and you can see on the, f rom the images on the right-hand side, it's the central vision of the patients that is impacted first. So you see that in the middle image here on the right-hand side. They'll present to their doctor and ultimately be referred to an ophthalmologist, and there'll be a fairly typical appearance of the retina, sometimes confused with glaucoma, but less so in the pediatric population when the clinician dilates that patient's eye. And so when increasingly now we're seeing patients undergo genotyping or genetic testing to confirm the diagnosis, and so you actually see increasing rates of diagnosis of ADOA in the patient population. And just a reminder here, anyone who's familiar with the PYC strategy will know that we focus on the highest propensity indications for success in clinical development.
Just recently, we have obtained a fuller understanding of exactly how much more likely drugs targeting monogenic diseases or single gene diseases are to be successful in clinical development, and the current estimates stand actually a little higher than this, somewhere between 5 and 8 times more likely to succeed, which has a very significant impact on the understanding of the stage of development and the commercial success profile for PYC-001. Now, we know that these patients have a mutation in one copy of the OPA1 gene that leads downstream to a loss of one of the two copies of the OPA1 protein that are produced from copies of those genes. One copy of the OPA1 protein is enough for every cell type in the body, not for the retinal ganglion cells, because they have a very high energetic burden.
If you can imagine pushing that signal that is generated from the photoreceptors in the retina all the way through to the brain, every time light photons are hitting the retina, requires an enormous amount of energy. So the genetic deficiency is actually present in every cell in the body, but it's only these very high metabolic rate cells that are manifesting any deficiency whatsoever, because they need more energy than any other cell type in the body. And so OPA1 protein, understanding what its role is, is actually key to understanding the data that we've generated in the patient-derived model, and we're going to come back to that lately. But you'll hear us hang on a lot about the impact on the mitochondria in the cells. So this funny-looking sausage thing that you see here is actually the cell's engine room.
This is the unit that is producing what we call ATP, which is the fuel source, the energy source for the cell. They normally look like these nice, long sausage structures that you can see here, with a thin and tightly integrated internal morphology. What that helps them to do is to produce this energy currency, the ATP, which makes the cells strong. They're fit, and they're very resistant to any cell stresses, so they don't die easily.
If you can imagine, the impact of losing one of your retinal ganglion cells is that one of the fibers in that cable, much like a copper cable, gets broken, and so you lose the ability to communicate the visual signal from the part of the retina that that retinal ganglion cell was responsible for delivering to the brain, and consequently, that's why you're seeing that part of the visual image drop out in these patients. The OPA1 protein is a mitochondrial membrane protein. It sits in the membrane of these mitochondria, and it enables them to have this beautiful, well, somewhat elegant, sausage-like morphology, and to functionally produce the energy currency of the cell.
And so if we transition now from the unaffected biologics across to what the biologics look like in ADOA patients, yes, we know that we've lost one copy of the OPA1 protein, so we're expressing about somewhere between 50% and 70% of normal levels, and what that does is the OPA1 protein is not present throughout the mitochondrial membrane, and so you're losing this nice integration of the internal morphology of the mitochondria, and they're appearing more like tennis balls rather than the typical sausage-like structure. That means they're not as efficient in consuming oxygen, respirating, and producing this ATP. We're getting less ATP produced, which means that the retinal ganglion cells are more sensitive to cell stress, and when they're stressed, they undergo a programmed death pathway called apoptosis, and they basically enter a suicide pathway, and they die.
These cells do not get replaced in the retina, so once you've lost that fiber in the cable, that part of the visual field is still being generated in the retina, and it's still capable of being processed in the brain, but you've lost the connecting signal between the retina and the brain, and you don't get that back. That's what's causing those patients to go blind. It is a little bit of a, you know, high school biology refresher, but you'll see why it's very important when we revisit the impact of those patient-derived models later on. Now having a look at, all right, well, what does PYC-001 do to address this deficiency? We've just had a look at the bioenergetic cascade in the unaffected individual who's got two copies of the OPA1 gene.
That means they're making two copies of the RNA transcript and two copies of the protein. We know if we go upstream from that deficient protein, what's actually responsible for this disease, it's a mutation somewhere in one copy of the DNA of the OPA1 gene, which is leading to what we call a loss-of-function mutation or an unstable RNA transcript. So the RNA transcript is made with the mutation, but it very quickly decays before any protein can be made from it. So it's lost, and we're only creating or translating protein from one copy of the transcript, which is leading to only one copy of the OPA1 protein. We've just been through the cascade of the bioenergetics, so I'm not going to touch on that.
But here, if you zoom out and have a look at not what's going on at the cellular level, but what's going on in the retina as a whole, here you see these are the photoreceptors up the top that are creating the visual signal. They are passing the image on into the retinal ganglion cells, and it's these fibers of the nerve that are going off to form the optic nerve and taking that signal from the back of the retina all the way through to the brain. What does PYC-001 do? Well, it localizes to the good copy of the OPA1 gene. It doesn't actually do anything with the mutated copy of OPA1 at all.
What it does is it goes and binds to the wild-type copy or the functional copy of the OPA1 RNA transcript, and it makes it easier for the what we call the translational machinery, or the part of the cell that is responsible for making protein from RNA, makes it easier to access the start site that initiates that translational process. So we're actually using the one copy of the RNA transcript to now get two copies of the OPA1 protein. So this is great because now we're starting to restore OPA1 protein levels towards what we see in wild-type patients, unaffected individuals. So this is what we mean when we say this is the root cause of the disease. It's actually completely rectifying the deficiency of the protein that is triggering off this disease cascade that we just...
What that should mean is that we get to this side. We restore the internal morphology. We restore external morphology back to these long, sausage-like structures. That means that the ATP can be produced in larger amounts. That means that the cells are fitter and will reduce that cell death, and they won't undergo apoptosis when they're stressed, which could mean that the patient retains vision. So that's a synthesis of the underlying disease cascade. It is a little bit deeper, but I think it will help you soon to understand what's going on. All right, take a quick breath there. We'll just have a chat. Does anyone have any questions so far? Please do feel free to type them into the chat periodically if we do. If not, we'll move on to what we've done in non-human primates.
Remember that these are what we call wild-type non-human primates, so these, these monkeys have two functional copies of OPA1. They're not in any way intended to be a simulation of ADOA patients specifically, but they offer some very valuable answers to us in relation to questions that are relevant to likelihood of success for our drug in the clinic. So remember, this is the question our BD counterparts and our investors are ultimately interested in, and also internally, we are very interested in this question as well, because we need to allocate our scientific effort, our time, and our resource dollars to domains that are going to have a high impact for patients and, and consequently for shareholders. It's this question that everybody wants an answer to, but we can't answer that yet because we haven't started the human trials.
But what we can do, and this is a really critical concept for people to understand, in the context of monogenic diseases and these patient-derived models, we can shift the risk curve left. Risk that would ordinarily be accepted in the clinical setting, can be moved into the non-clinical setting because of the high propensity of success and the quality of the non-clinical data that's available to us now that we can make these human eyeballs in a dish outside of a human. We've got a question there. So Brian is asking: So that Entrada asset sale was valued at about twice PYC's market cap at a less developed stage? Yeah, that's right, Brian. So they received $250 million for that myotonic dystrophy asset.
Interestingly, it's also a third-in-class asset, so it's well behind some of the other RNA therapeutic competitors in that domain. If you have a look at Avidity Biosciences and Dyne Therapeutics, they also have a more advanced asset for myotonic dystrophy, so they're a competitive dynamic within that context. Also, about a week after that deal was announced, the Entrada platform, the lead candidate in Duchenne muscular dystrophy, which also hadn't started clinical development, went on clinical hold, and as far as I'm aware, that still hasn't been removed just yet. But you're quite right in relation to the understanding of the financials of that transaction.
The derivative questions that we can answer now that will help inform the answer to this question, and actually very much shape the answer to this question in the context of those dimensions that we've just discussed. Basically, two questions. The first one, can we reach the target cell affected in this disease? And we're going to touch on briefly, but a lot of you are already aware, for the whole precision medicine class, the fundamental limitation on the impact of that class right now is delivery to the target cell, because it is difficult to get big things, like precision medicines, inside of cells. So can we reach the target cell, is the question that, the umbrella question that encompasses these top questions. Then the second question is, can we modulate target gene expression once we're in there?
Can we actually increase OPA1 gene expression at the protein level such that we rescue that pathogenic cascade that we've just been through? They break down into some slightly more detailed questions. Yes, okay, it's one thing to reach the cell, but what we really have to show is that we can reach the cell at a dose of the drug that is safe and well tolerated. No use if we're going to cause more harm in administering the drug than the benefit we're going to do. We want the dose that is administered in order to achieve high levels of drug inside the target cell, still to be safe and well tolerated, specifically in non-human primates, because they are the, what we call, the most toxicologically relevant species for humans.
So they're the species that gives you the best insight on whether a drug is likely to be safe and well tolerated in human development as well. And then the next two questions are the correct expression deficit. What we're looking for here is an increase in the OPA1 gene expression. We did not know that we were going to be able to achieve that in the context of a non-human primate, because this... Remember, this is a human genetic medicine. It's designed specifically for the human genome. Yes, the monkey is very similar. They don't always show efficacy of human drugs, even in the context where those human drugs are, in fact, effective in humans. So we were hopeful that we might see some changes in the OPA1 gene expression, but we had no guarantees that we were going to.
What we were going to rely on was the concentration of the drug in the retina in order to link us up to the patient-derived model to fully answer this cascade of questions. But it's much better when you can get that gene upregulation of the target gene, because it's not just telling you how much drug is in the retina, it's telling you how much drug got inside the target cell in the retina. So it's overcome that delivery challenge, and has and then gone downstream to modulating the target gene expression. So it started to answer questions that are usually refined to the domain of the human genetic model.
These were wild-type monkeys that were not affected by ADOA, so we had no prospects of answering this question of whether or not we'd see an impact on the disease itself, because the monkeys did not have the disease. So here, we are reliant on those patient-derived models that we spoke about, and that's why the data that we'd already generated is so important. So we have another question here: Would you expect an even greater affinity in humans, giving the engineering of the oligo is for the human genome? Yes. So that's exactly right. We didn't do a lot of optimization of the oligo in the context of the non-human primate cells.
So what we did do before we went into the monkey studies was look at whether or not we were likely to see a PD or an efficacy impact from the drug in the monkey studies. But what we did see there was that we didn't achieve the same levels of efficacy in the non-human primate cells as the human cells, but because we were going to do these studies anyway from a safety, tolerability, and durability perspective, we thought we would leave the efficacy evaluation to the in vivo tissue sample. So we knew that it was going to be harder to achieve target engagement and gene modulation in the non-human primate than we anticipate it will be in humans.
The drug is less effective in non-human primates than it is in human cells, but we were still hopeful that we might see a signal there. So that's quite right. Yes. Now, the next page, if I can get to it. Right. Yeah, just a reminder here, this is a really nice quote. I've been saying it for years, but I'm a lightweight in the industry, and nobody takes any notice when I do, so I'm reliant on quotes from others who are CSOs of $100 billion companies. This is George Yancopoulos, who's quite an outspoken figure in the community. "While everybody else was so hyped and giving Nobel Prizes for CRISPR and all that, we realized those weren't really the limitations.
The limitations were really delivery." This is a very, very poignant observation from someone in the field, who's basically saying: Look, there's been a hell of a lot of effort directed towards the things that you can do when you can get inside cells, and that's because in the lab, we've got all sorts of tools at our disposal to get things inside cells. But it's ignoring the fundamental challenge when you move to the in vivo environment, that you don't have those same tools available. So he has articulated very nicely here why Regeneron have focused so heavily on the delivery side, and that is what differentiates their company. It's also what differentiates PYC, and it's why this picture is just so beautiful.
You're looking here at the retina of one of the non-human primates from these studies, and what you see stained in blue are the cell nuclei. So these are all of those individual retinal ganglion cells that we've spoken about, lined up in a row in the retinal ganglion cell layer in the retina. What we see up the top here is the arc, so it's quite hard to see against the background, because the stain here is only for the cell nuclei, plus in red for the OPA1 protein, but you're not seeing a great deal of it. These are the fibers, the retinal nerve fibers that are coming from those retinal ganglion cells and moving down toward the optic nerve, where the fibers all band together and form the cable that communicates that signal.
So what we look to here as we transition to the PYC-001 treated group, we're looking for more red in the image. That's what we want to see. We, we could see the same number of cell nuclei stained in blue, but what we want to see is more of this very faint red protein, because there's a, a red immunofluorescence tag that has been attached to a probe for the OPA1 protein here. And, and what you can see... I mean, this is really elegant stuff. If you look at the individual retinal ganglion cells, you can see each one of them expressing more OPA1 protein.
Not only are they expressing more protein in the proximate region of the nucleus, you can now also see it speckled down through the retinal nerve fiber layer as the protrusions of these RGC axons are heading off toward the optic nerve. This is really important because the mitochondria migrate throughout the cell. They create energy along the axon to keep pushing that signal along, the further downstream they go. You can see here, not only has the PYC-001 been able to solve the delivery challenge, not only has it crossed the cell membrane to get inside the cell, the RNA therapy has then taken over. It's exerted its effect on the OPA1 gene expression, and you are now seeing much higher levels of the OPA1 protein present in the retina of these non-human primates.
So this is exactly what we are trying to do in the context of the retina of ADOA patients. This is the underlying cause of autosomal dominant optic atrophy. It's not having enough of this protein stained in red in these specific cells within the retina. So super, super encouraging image and data in that context. In vivo is a term not well known. Okay, thanks, Brian. So in vivo, we just mean in a living organism. So the retina in a dish models are absolutely fantastic for looking at the human genome, to David's question before, and giving you an answer to the question of whether you can rescue those functional deficits.
We're not seeing the mitochondrial deficits and the increased susceptibility to cell death in the non-human primate, because even this level of OPA1 is enough to sustain the function of those cells. This is a wild-type non-human primate. It doesn't need any more OPA1 than what is present in these cells. So what we need from the patient-derived models is that functional insight, but what we can't get from the retina in a dish is the complexity of a living organism. There's no vitreous, the sticky stuff in the center of the eyeball, to help us answer the question of, is the drug going to traffic from the center of the eye to the inner limiting membrane? Can it cross the inner limiting membrane and get into the retina?
Will it get into the inside of specific target cells that we're looking at when it's dosed at a safe and well-tolerated level? So we combine the data from the living organism with the data from the model that more accurately reflects the human disease. And again, that's why this integration of the data around this 1.6-fold level. So this is a 1.6-fold. It visually looks a bit more than that, but when we quantify it, that's the upregulation that we see. This 1.6-fold increase in OPA1 protein expression in the living organism is enough in the context of human genetic models to fully rescue the phenotype, the functional deficits seen in these ADOA patients.
So that's what we're going to have a look at now, but a really, really lovely image, and hopefully, you can understand why we were so excited to see that. Okay, what we should be hoping to see now is plugging in 1.6-fold increase in the OPA1 protein levels now in the ADOA patient-derived model. Will that transform our mitochondrial structure to this nice integrated internal morphology? Will it move us across to this sausage-like, elongated, external morphology? Will it mean that we can create more ATP, consume more oxygen, and see the fitness of those cells improve? And ultimately, will that then lead to a greater resistance to cell death, which is what's going to be stopping the blindness of these patients? Just another question: Was this immunoassay run on all four subjects, were similar results seen in all? Yes, David.
So the results that were published in the ASX announcement are the aggregation of all 4 eyes that were treated with PYC-001. So when you say all 4 subjects, there were... My understanding is there were 2 animals per group, but both eyes were treated, so 4 eyes per group. And the data that you're seeing presented is the data that is aggregated across all 4 samples. So it's holistic in that context. All right, so now we're looking at a patient-derived model, and, we're looking to see the top end of that cascade. So we're just focusing on the, the upper level. We're not going all the way down to the function and the fitness of the cells. We're just looking at the structure of the cells here. And again, you're seeing cells stained here from an ADOA patient with the nuclei in blue.
What we're doing, instead of red, this time we're staining in green for a mitochondrial network protein, so for a protein that sits within the mitochondria and gives you an insight into how well connected those networks are inside the cell. What you're seeing here is a relatively normal looking cell, but you can see in these two cells, you've got a lot of dark areas, where there should be green. The network, the mitochondrial network, is not very well connected. If you give a very low dose of PYC-001 in the same ADOA patient, immediately what you're seeing is restoration of the networks of mitochondria in all of these cells. What this is, is a proxy insight into the infrastructure or the morphology of the mitochondria.
We are seeing here more healthy looking mitochondria in the patient-derived cells, and now we've been able to go downstream. We know that PYC-001 will increase the OPA1 protein when it's administered to patient cells or even wild type cells, but we did not know prior to this that will actually result in a downstream benefit, what the mitochondria look like? So here we're looking at the role, the function of OPA1 within those cells, and whether or not we can have an impact in rescuing the deficiencies that are seen in ADOA patients. So very encouraging data in that respect. Now we're going further downstream to the bottom of the cascade. All right, we've seen that the morphology has been improved, but does that, in turn, translate to an improvement in the bioenergetics?
So again, here, what we're going to be measuring is ATP production and a further downstream readout, which is called oxygen consumption or respiration. Just like you breathe when you're exercising, cells consume oxygen when they are undergoing ingestion as well. What we're seeing in the ADOA patient, without treatment with PYC-001, is they're hitting about the units here on the left-hand side, but a score of about 60 in assessing the fitness or the oxygen consumption of these cells. And then following again a single low dose treatment of the drug, you're seeing about a 50% improvement in the fitness of those cells following a single dose, single treatment of the drug. Importantly, we're seeing it across multiple patient cell lines as well.
So we know that PYC-001 should treat all patients who have a loss- of- function mutation in OPA1, but we want to be sure of that by assessing multiple of these patient-derived models in the lab, just to confirm our suspicion that this drug is going to be effective, effective for all of these patients. Now, this is very impactful data, because what we're seeing here is restoration of the retinal ganglion cell bioenergetics in what we call a mutation-agnostic manner. So these patients have actually got different mutations in OPA1, but you can see the impact of the drug is the same. Remembering that's because the drug is acting on the, the good copy of the OPA1 gene and protein. We've got a couple of questions coming through here now as well. What is the oxygen consumption in a healthy cell?
Yeah, that's another good question. So the question that, I think that's David again, he's asking here is, all right, we're seeing a nice big step change, statistically significant step change in the oxygen consumption of the treated cells as compared to the untreated. But what that's not telling you is, where does the oxygen consumption of a healthy cell, one that is not affected by ADOA, sit? Are we going 10% of the way to disease correction, or are we going 100% of the way to disease correction? And so what we can tell you here, David, we should be generating some isogenic control data, so where we correct the mutation and actually have in the same genetic background what the consumption looks like.
But we know generally there's about a 50% delta between the performance of the wild type cells and the ADOA patients in terms of maximal oxygen consumption. So we're seeing about a that's a 50% upregulation. So basically, in the ballpark of what we're seeing here, it will fit somewhere within the error bars of what you're seeing here. And if you look here, this one is actually about a 50% improvement. So it's actually very close to the PYC-001 treated level. It's taking us very close to all the way back to wild type oxygen consumption and mitochondrial ATP production. So very encouraging in that context as well. All right, so now big step back and a deep breath.
The data is exciting because we've just done in the non-human primate what we want to do in the patient, when clinical trials start next year, but it's more exciting than that when you dig a little bit deeper into it, because the extent of the OPA1 upregulation that we are seeing, 60% increase in OPA1 at a high level of statistical significance, links us across to the patient-derived models, where we see about a 1.5-fold increase in protein at, again, similarly low doses of the drug. That is now demonstrating full functional rescue of the ADOA pathogenetic cascade that sits downstream of that protein deficiency. We gain conviction not just from, restoring protein expression levels, but actually looking at the way the ADOA cells behave in the context of having the increased OPA1 protein level restored.
It is very, very encouraging for these patients, and being able to integrate those two data sets around this common nexus gives us very high conviction in the answer to questions one, two, three, and four. We still can't answer question five yet. We're not going to be able to do that until we progress into clinical development, but we've got an extremely high degree of conviction that we should see correction of this disease in the context of progression of PYC-001 in clinical development. So we're very much encouraged by that.
If you think about the risk curve, we've spoken about this at length, but it is very, very important for patients, sorry, for investors in PYC to understand, whilst the probability of success for industry participants as a whole is very low, somewhere around that 10% figure that is quoted when you start a clinical trial, in terms of the prospects of a successful market entry, we know that we are somewhere between 5-8 times higher than that, just because of the genetic validity of the target. Because we have chosen diseases that are caused by mutations in single genes, we know exactly what is going wrong, and we know exactly what we've got to do to fix it. If you look at the Alnylam retrospective that we've guided you to recently, they are a company that similarly focuses on monogenic diseases.
We know that Alnylam have a 64% chance of successful market entry when they launch a phase I clinical study. That Alnylam data is predicated on the validity of the target. We're not satisfied just with increasing ourselves by 5- to 8-fold. What else can we do to stack the odds in our favor? Well, there are two things. One, we can validate our drugs in patient-derived models. We can make use of these tools that are very recently available to give us an even better insight than any animal model ever could on what is the impact of the drug in the context of the human disease. So these patient-derived models will be lifting that success even further.
If you are able to then solve the delivery challenge, the fundamental challenge for RNA therapies, precision therapies, generally, when you move to the in vivo or living organism environment, you are really starting to give yourself a differentiated non-clinical data pack, and it is through those eyes that our BD counterparts are going to be putting their head above the parapet to want to license one of these assets in-house. It's what makes them such an attractive commercial product. There is no other class of therapy at this stage of development that can confer this kind of profile of success as you move through clinical development. So this is very, very exciting stuff for patients, and that's the bit that we are most excited about.
If you think about these models that we've spoken about, looking at your cells perform in a fundamentally different manner that is linked to the ultimate step in the disease cascade that is causing these cells to die, knowing that these patients lose 40% of their quality of life when they go blind, that is a very, very impactful medicine in that context. So from no treatments available to a disease-modifying treatment with this drug, in the context of this non-clinical pack that we have in support of it, is a lovely position for PYC to be in, and we're very much looking forward to progressing into clinical studies. That's very much where our focus is right now. So we've got a pre-IND meeting scheduled with the FDA on Halloween, so 31st of October.
We will be commencing the natural history study in the fourth quarter this year, look at the disease progression in the absence of treatment. Final step in the puzzle for us, the missing piece in the data, is to repeat those studies that we've just done in a non-GLP, non-Good Laboratory Practice format, in the GLP format, and then that will support the IND lodgment. And to be clear here, not a great deal changes as we transition from the non-GLP studies to the GLP studies. Beyond, there's a very high degree of paperwork involved in conducting a GLP study to ensure reproducibility of the data that is generated. It'll be the same molecule that is assessed, in the context of the GLP studies. We just have a higher degree of execution standard of the studies itself.
We'll be looking at a more refined range of doses so that we can define how much headroom have we got between the dose where we're seeing efficacy, because we're actually seeing efficacy in these studies that we've just done at the lowest dose that we assess. So we're kind of open in the low direction there, and we need to evaluate that further, but we also need to push up a little bit higher, so that we can establish what we call the NOAEL, or the No Observable Adverse Event Level, which will give us some information of how many times over have we got a gap between the minimal effective dose and the maximum tolerated dose.
Once we have those GLP studies to hand, they'll finish in the first quarter, that will enable us to submit the IND submission in the second quarter of next year. We're currently looking, and particularly enthused on the back of this data, at ways that we can accelerate execution of that clinical trial. So we're looking to see whether or not we can actually accelerate to be dosing humans in the first half of next year. We'll come back and talk more once we've had time to consider that a little bit further. So that's it. Hopefully, we've given you some degree of understanding of why we are placing such a high degree of importance on these studies. I hope that has helped you to understand the relevance of them. We are very, very much enthused by the data that we've seen here.
It was beyond our expectations in terms of what we were hoping to get out of the studies, but we were thrilled to see such wonderful images and, in particular, to have seen every single retinal ganglion cell within the images showing the gene modulation. That really does show you the link from a strategy perspective to choosing intracellular protein deficiencies, because remember, in order to save these cells, you actually need to deliver the drug inside every single cell in the retina that you want to save, because the OPA1 protein is used inside each cell. So even if you reach only 90% of the cells, the other 10% are still going to be susceptible to cell death, because they don't have enough OPA1 protein. There's no OPA1 protein sharing between cells in that context.
A wonderful, wonderful data pack, very exciting for patients. We'll be engaging again with Cure ADOA and the ADOA Patient Foundation, as well as Retina Australia and a number of other patient bodies, to take them on the journey with us. We're very appreciative of the support that they have given us to date, and also from the clinicians who really do understand this data and are mobilizing behind us in support of an earlier execution of the clinical study. Very much like the VP-001 molecule and the FDA recognition of the fact that that is an important potential new therapy for patients with RP11, we'll be looking to get Fast Track status and Orphan Drug, Rare Pediatric Disease designation for PYC-001 as well.
How rapid is the deterioration of vision in ADOA, and how does that time course lend itself to clinical endpoint measures in a trial setting? Is it similar to RP, and would we use similar suite of investigational tools? This really nails it. So the issue that we've got now, what keeps me up at night is not the safety and efficacy profile of the drug, it's how are we going to see the efficacy signal in the context of a slowly progressive disease, in the confines, within the confines of a clinical trial? And that's directly what this point is getting to. So firstly, this non-clinical data pack gives us a really high degree of conviction that we've got to accelerate into a registrational trial very quickly.
So the first thing to think about is, once the single ascending dose study is complete, and touch wood, assuming that we establish the same safety tolerability profile that we're seeing in the non-human primates in the human, what we will be looking to do is to be going all in on a registrational trial, because of the underpinnings of this molecule, the quality of the non-clinical data package, just giving you every suggestion that you are going to see an efficacy readout there. The question is right, this is a slowly progressive disease, and it actually does have some variability in the phenotype as well. So we know the onset is in childhood, and the progression is slow. The endpoint in half of patients is legal blindness. The other half of patients have a slightly more moderate form of visual impairment than legal blindness.
So that's the phenotypic variability. The vast majority of patients are likely to seek treatment with the drug, particularly those who are very young and those who are losing the ability to drive, which typically affects those in their thirties, and the older patient population, because they're very keen to maintain any functional vision that they have left. So it's the... The question is, when will those in the teenage years, this is what's been raised by the clinicians, seek treatment? And how do we see the visual signal in the context then of having early-stage patients and also late-stage patients in the clinical trial?
What we're doing here is we are, in addition to the standard suite of assessments of visual function and functional vision, we're looking to see whether or not we can incorporate exploratory endpoints that are currently seeking approval as registrational endpoints, but are not there yet, but that will give us some early insight on whether or not the drug is effective. There's one in particular that I'll draw your attention to. It's called DARC, D-A-R-C. This is called Detection of Apoptotic Retinal Cells. And so what's happening here is the patient attends the outpatient clinic. They have some eye drops put on the eye that dilate the pupil. They have a cannula inserted into one of their veins, and they have a fluorescent dye injected into the bloodstream.
And that dye is attached to a binding protein that will stick to a marker of cell death, apoptosis, called annexin V. And so the blood will carry the fluorescent tag to the retina, and what we're looking for here is the level of fluorescence in the patient's retina as we're looking through that dilated pupil at the back of the eye. And so what you would expect to see here is that the retina of the ADOA patients will light up. There'll be more staining with the immunofluorescence because there will be more cells that are undergoing this programmed cell death pathway.
So that will be very insightful because if we can follow those patients and compare those images to what those images look like after they've received the drug once or ideally in a multi-dose format, we should be able to detect a lot earlier in the disease course, any delta between the treated patients and the untreated patients. That is not yet a registrational endpoint for the FDA, but by the time we get through to a pivotal study, we're hoping that it will be. Even in the event that it's not, it will give us conviction that the drug is, in fact, working. We just need to run the clinical trial for long enough to see it.
So there are slightly different endpoints here to what we're looking at in the VP-001 or RP type 11 clinical trial because the pathogenetic mechanism is different, but it's the same basic approach, which is let's measure everything and see whether we can incorporate some exploratory tools there as well to see the signal early, and then let's invest in running a longer, larger pivotal study. Because if we have the additional conviction in the clinical setting to compound a super elegant non-clinical data pack, we've got very, very high conviction that this drug is gonna have an impact for all these patients. We just need to be patient enough to see it. Remember, the flip side of that coin, slowly progressive diseases, means that you've got a very, very large addressable patient population.
Almost everyone is somewhere on the slope of visual deterioration, that they want to preserve whatever vision that they've got left, and that's the promise of these drugs to stop the disease progression in its tracks. The sooner you start the drug, the more functional vision that you should be able to preserve. Any other questions from anyone in relation to PYC-001? If you wind forward through, even to the middle of next year, we anticipate VP-001 moving to a potentially registrational mid- to late-stage study in July, and we would now anticipate having a second asset in the clinic that is progressing through a phase I, II, and generating safety data, but also initial insights on efficacy, with some very funky tools that may help us to see that signal early. We are then on track for progression of our third asset into clinical development.
That will give PYC three first-in-class and potentially disease-modifying drugs in highly attractive commercial markets. It will be coming thick and fast from a human data generation perspective. We're hoping that that kicks off for the very early single-dose data for the RP11 patients even later this year, as we move through the second and third patient cohorts in the VP-001 clinical trial. There is an enormous amount going on. We have maintained that investment into the quality of data that we're generating into the platform technology that overcomes this delivery challenge. We really feel that we have made some differentiated, first-in-class, best-in-class molecules here, and we're very much looking forward to seeing the impact in patient lives. A particularly exciting time for PYC-002, sorry, for PYC generally, and PYC-001. There's more coming, so we continue to do differentiated science.
I'm very hopeful that we'll be back having some more special editions of the investor webinar to explain more meaningful progressions before the end of the year, so stay tuned. One more question that's come in, in the meantime: "Are potential partners interested in the PYC-001 program, and how are we going to fund it?" We'll take the funding question first. So we've mapped our budget on the basis of realization of the vision and the overarching corporate strategy, so we've been very clear about that. We're going to continue to invest in progression of all three of these programs through to clinical trials and human safety and efficacy data. We started the year with AUD 50 million in cash. We are an incredibly lean organization. So net burn last year of AUD 27 million. We're funded through to FY 2025.
This data must move the needle. It does move the needle in the BD conversations. Hopefully, we can help the ASX to understand it and its impact, and we can drive through to generation of some licensing revenue through, out- licensing of, at this stage, I think, a single asset. We're very keen to hold on to the majority of the assets that we're developing, but you can pretty much see from our current enterprise valuation that we are not getting the recognition that we deserve with below effectively replacement cost at this level. So, yes, I think it very much makes sense for us to out-license an asset. Yes, this is the data that moves the needle for potential partners.
I think you'll find, we obviously haven't had a chance to present this to anyone yet, but we'll be on the outbound emails, today and tomorrow, making sure that all those that we have a live conversation with are well aware of this data. In terms of the timing, it's largely in the hands of the counterparts, but the one thing that PYC shareholders can be safe in the knowledge of, the longer that we hold these assets, the more data that we generate, the higher the upfront component of that transaction when it does come. So we are very, very clearly on the right path here. We are building value as we get there.
I don't know exactly when those transactions are likely to occur, but we will continue to push them in the background, and hopefully, we can find ourselves a partner who is strategically aligned and brings additional value to the program as well, and also helps us get the value of what we've done recognized in the equity capital markets. I'll give you just another minute in case there are any other questions. Otherwise, thanks very much, everybody, for your time. If you do have any follow-on questions, feel free to email through to the company. The renal asset. Thanks, Brian. Not yet. So we'll wait. We are very hopeful that we'll be back communicating with the market before the end of the year in that regard.
So, let us generate the data and get a full understanding of all of the elements that go into making sure we have absolute conviction that we have got something that is really going to move the needle, and we'll come back and talk to you at the appropriate time. I think we're getting very close in that regard. Okay, thanks very much, everybody, and we look forward to keeping you updated as we progress.