Earnings call transcript: PYC Therapeutics Q3 2025 focuses on pipeline potential

PYC Therapeutics Ltd held its Q3 2025 earnings call, emphasizing its pipeline development and strategic market opportunities rather than specific financial results. The company’s stock saw a minor decline of 0.81%, continuing a challenging year that has seen shares decline 42% year-to-date. With a market capitalization of $1.74 million, InvestingPro analysis indicates the stock is currently trading near its Fair Value. Despite the lack of immediate financial data, PYC Therapeutics highlighted its innovative approaches and significant market potential in rare diseases.

Key Takeaways

• PYC Therapeutics focuses on developing treatments for rare diseases with significant unmet needs.
• The company is advancing multiple clinical trials, with human efficacy data expected within the next year.
• Innovative RNA therapy aims to address root causes of genetic diseases.
• Stock price experienced a slight decline, reflecting cautious investor sentiment.

Company Performance

PYC Therapeutics is concentrating on its robust pipeline, targeting diseases such as Polycystic Kidney Disease (PKD) and Phelan McDermott Syndrome (PMS). The company aims to leverage its precision medicine approach to address these conditions, potentially tapping into large market opportunities. While no specific financial results were discussed, InvestingPro data shows last twelve months revenue of $0.68 million, with a current ratio of 4.77 indicating strong liquidity position. The focus on clinical advancements and strategic growth remains clear, though the company’s overall Financial Health Score remains in the weak category.

Financial Highlights

• Revenue and earnings per share were not disclosed during the call.
• The company highlighted potential market sizes, with PKD exceeding 15 billion USD annually.

Outlook & Guidance

PYC Therapeutics expects to deliver human efficacy data across three key programs within the next 12 months, with the next earnings update scheduled for September 25, 2025. The company is exploring potential partnerships, particularly for its RP11 and PKD programs, as it continues to de-risk its pipeline through comprehensive studies. For deeper insights into PYC’s financial health and growth prospects, InvestingPro subscribers can access the detailed Pro Research Report, offering expert analysis of key metrics and growth drivers.

Executive Commentary

Rowan Hawkins, CEO, emphasized the company’s patient-centric approach: "We create the type of drugs that we would want to take if we were a patient with these diseases." This reflects PYC’s commitment to developing first-in-class therapies with the potential to transform treatment paradigms.

Risks and Challenges

• Regulatory challenges remain a hurdle, with ongoing engagements necessary to advance clinical trials.
• The lack of immediate financial data may cause investor uncertainty.
• The success of clinical trials is critical to future growth and market penetration.

PYC Therapeutics’ Q3 2025 earnings call demonstrated a strong focus on pipeline development and innovation, with the company’s strategic positioning in the rare disease market offering promising potential despite current stock fluctuations.

Full transcript - PYC Therapeutics Ltd (PYC) Q3 2025:

Rowan Hawkins, Host/Presenter, PYC Therapeutics: Good morning, everyone, and welcome to the PYC Therapeutics third quarter investor webinar. My name is Rowan Hawkins, and I’ll be your host this morning. For those of you who are present at the second quarter webinar, you’ll be pleased to know that I’m back in rude health. I have regained the ability to talk underwater, and I’m very much looking forward to getting through a lot of content with you today. But before we begin, I do have to remind you that today’s webinar is being recorded and to read the following safe harbor statement reminding you that today’s discussion will contain forward looking statements that involve risks and uncertainties.

These risks and uncertainties are outlined in our filings with the Australian Securities Exchange. As such, actual results may differ materially from what we discuss on today’s call, and disclaim any obligation or intention to update these statements in the future. Like many biotechnology companies, PYC exists with the sole purpose of changing patient lives. But to understand where PYC is different to other biotechnology companies, you need to understand a little bit more about the potential for impact in those patient lives and why PYC has such high conviction with the assets that it has in development in its pipeline that it is going to make a meaningful change in the lives of those patients. It’s important to understand a little bit more about the the patient journey in each of these indications, what’s important to the patient, and what evidence that we have to suggest that we are going to be able to have a meaningful impact with the drug that addresses the root cause of these diseases.

And remembering that each one of these drug candidates is the first drug candidate that directly targets the root cause of these disease indications. We need to have a look at the available evidence from the non clinical setting in order to understand what impact are we likely to have in the patients and how are we going to measure that. This is particularly important background in the context of the two larger indications in the company’s pipeline, polycystic kidney disease and Phelan McDermott syndrome. Because in these indications, unlike the ophthalmology indications, the preclinical models of the diseases suggest to us that there is not only the potential to stop the disease from progressing, but there is actually the potential to reverse or partially reverse the disease phenotype. So these indications are especially important in that context, we’re going to have a look into some more detail in relation to both of those two programs today.

That will then be followed by an assessment of how that translates into potential patient impact. This is critical at the minute because you know that all four of PYC’s pipeline assets are going to read out on the human efficacy dimension over the course of the next twenty four months. But in particular, the three clinical stage assets are all going to provide data in this realm over the course of the next twelve months. And so we’ll frame what those milestones look like, what to expect in relation to each one of those, what the company in particular is looking for on that patient impact dimension. And then at the end of the conversation, we’ll have a discussion around how that translates into the propensity for success for each one of those assets, which largely dictates the creation of intrinsic value and how different milestones that the company is crossing within the very near term creates optionality for the organization in relation to how that value is recognized.

So we’ll go through, from an agenda standpoint, a brief introduction to the company for those who are new to the story. I will outline the forward view of the next twelve months, what’s happening in each of the programs, and we’ll have a particular look at a milestone in relation to the polycystic kidney disease and Fatal McDermott syndrome program occurring within that window, touching on each one of those points that I’ve just alluded to before we open up for a Q and A. Please do put your questions into the chat section of the Zoom, and we will endeavor to address each one of those at the end of the conversation. So for those of you who are new to the story, PYC Therapeutics is a precision medicine company. We are focused on the creation of disease modifying drugs for patients who have a severe disease and who don’t have any treatment options available to them today.

To give you a simplistic analogy in relation to the difference between a disease modifying drug and a non disease modifying drug, because that is a central part of the conversation for today, if you think of an orchestra playing being a normal cellular function In the context of a disease caused by gene insufficiency, it is akin to removing the conductor of the orchestra. So there is one thing and one thing only that is going wrong with that particular cell in the context of the single gene diseases that we’re going after. But what’s happening downstream of that is there’s gross dysfunction throughout the orchestra as a whole. So the cellular dysfunction is disrupted. An accessory pathway drug may act on one section of the orchestra or band and try and correct what is going on, Whereas a disease modifying drug is directed towards replacing the conductor so that everything downstream of that change is restored back to normal functioning.

So we use a precision medicine to increase gene expression or replace the conductor in the orchestra in diseases that are caused by not having enough of a particular gene being expressed. The company has coupled this with an additional technology that addresses the Achilles heel of the precision medicine platforms, which is that they don’t get to where they need to be very effectively. Precision medicines are excellent once they are inside a cell, but the challenge for the industry as a whole has been getting them to the right target cell and then across the cell membrane so that they are able to exert their effect on the inside of cells. The company has used the combination of those two platform technologies to create three clinical stage assets that are first in class and have best in class potential. And as I mentioned before, we will see human efficacy data coming for each one of those four programs over the course of the next twenty four months.

There are five highlights of what the company does. The first one being that we create the type of drugs that we would want to take if we were a patient with these diseases. These are drugs that are addressing the root cause of single gene diseases. So in the context of one thing and one thing only having gone wrong, the drug is directed towards fixing that one particular thing that has occurred. We are doing this at scale in patient populations in the smallest instance that affect around one hundred thousand people globally, in the case of retinitis pigmentosa type eleven, or blinding eye disease.

The largest indication in polycystic kidney disease affects tens of millions of patients worldwide. These are, albeit they are called rare diseases, they are at the more prevalent end of the rare disease spectrum. Because we focus on diseases in which one thing and one thing only has gone wrong, single gene diseases, These drugs have the highest propensity for success in clinical development, five times higher than the industry standard. We like to push that risk curve even higher by validating each one of the drugs in the context of what we call a patient derived model. Here, what we’re talking about is because it’s a genetic error that is occurring in the patient and it’s a quantitative error, not having enough of a particular gene expressed, if we take a tissue sample from the patient and reverse differentiate or send that tissue sample backwards to a stem cell, we then have a platform from which we can create ourselves a little mini organ of the particular organ that is going wrong in that disease indication, be that an eye, a kidney, or the brain.

And we can assess whether or not we can firstly quantitatively restore gene expression back to wild type or unaffected levels, and then go downstream to see whether we can correct the functionality of that cell as well. So this is more akin to engineering or drug design than it is to science or drug discovery. And we can gain additional conviction before we’ve even moved into the clinic in relation to whether these drugs are going to work on the back of seeing that quantitative rescue and functional rescue that we’ve spoken about. Fortunately for the company, all of that work is behind us, and we are now very much focused on the translation of that preclinical work into the clinical efficacy signal. So as I mentioned before, we have three clinical stage assets.

Each one of those is going to read out on the human efficacy dimension over the course of the next twelve months. And there is also a lot of excitement building around a near term milestone in the Fallon McDermott syndrome programme. We’ll touch on in more detail why that is. So turning our minds to what is coming up and how does that frame the probability of success in each one of these programmes and consequently the intrinsic valuation of the company. We’re focusing here firstly on the polycystic kidney disease program.

And so we’re going to talk in some detail in relation to the outcome that you see on the right hand side of the screen here, the open label multiple ascending dose study data. This is when we are seeing drug exposure in the kidney in patients over an extended time period that is likely to give us meaningful insight in relation to the efficacy of that drug program. And this is where we’re going to come back to here at the end of the conversation to talk through value creation. Our recent commercial activity in the space is giving us a benchmark from which we can assess value of the asset and then push beyond that as we deliver, moving through into the second quarter of next year, the most mature data set in relation to a disease modifying drug that has been seen in polycystic kidney disease. That will run all the way through to the fourth quarter of next year, at which point we will have mirrored the single registrational study that sits on the other side of that 1b trial, twelve months’ worth of data looking at the total kidney volume.

And we’ll go into more detail on that clinical endpoint shortly. In the nearer term, we will present at the Australian and New Zealand Society of Nephrology Conference that is occurring next month, the safety data from the ongoing Phase 1a1b study. The second milestone that we’re going to talk about in detail is the only non human milestone in the pipeline. That is a preclinical data set in the context of the Phelan McDermott syndrome programme. You recently saw data from patient derived neurons or brain cells that have come from children with Phelan McDermid syndrome, the ability to quantitatively restore the missing gene.

So we can answer that question of whether or not we can put the conductor back into the orchestra. We’re going to look today at some of the assessments of whether that has functionally restored the orchestra’s ability to play or rescued that deficit. That data is very soon to be complemented by data from nonhuman primates or monkeys, looking at a couple of different important dimensions. The first one, safety tolerability of the drug candidate. The second one, by distribution.

How much drug is present within the cells that are affected by this disease indication? If we’ve already answered the question of can we restore gene expression and functional rescue in the brain cells, in the ex vivo or in vitro environment in cells, basically, the next key question then becomes, can we successfully deliver that drug candidate inside those cells? Those two together give us very high conviction that we have the ability to have a meaningful clinical candidate that will change the lives of patients with PMS. But what we are also going to do to build that conviction further, as we release that data set next month, is to benchmark it to a clinically validated peer drug candidate. This is a drug that is targeting a different indication, but it is a similar indication.

So it’s caused by a different genetic deficit. But the reason that we are so interested in it is this drug candidate, the peer drug candidate, is clinically validated. It has moved the needle for children with a different neurodevelopmental disorder on the language and cognition endpoints that are so critical to the Phelan McDermott syndrome patient population. So if we can then show in nonhuman primates that our drug candidate is similarly or better tolerated than that drug candidate, if we can show that we have more drug in the key regions of the brain than that peer drug candidate, if we can show in the human cells that the concentration required to see efficacy is lower than that peer drug candidate, we will give ourselves a very strong read through in relation to our propensity for success as we move that asset into clinical development on the right hand side of the screen in the second half of twenty twenty six. So those will be the focus areas of today.

I’ll come back and touch on the progress being made in the ophthalmology candidates when we wrap up the conversation and the commercial relevance of each of those. So if we dig into the polycystic kidney disease drug programme in a little bit more depth, the reason that we are particularly excited about this drug candidate is a combination of four features, All of which drive to the point of patient impact. The first one is, as we’ve touched on before, this is a high prevalence indication. This disease, albeit rare, is the most prevalent rare disease. The most prevalent single gene disease, monogenic disease, and a primary driver of chronic kidney disease.

Polycystic kidney disease affects one in every one thousand people, or zero point one percent of the population. So there are a lot of people who are affected by the disease. From a patient journey standpoint, the median age of renal transplant is 55 for those who have a loss of function mutation. So in relatively young in life, we are seeing patients undergo a very significant operation. In the lead up that window, they will be losing their renal function.

And in the window after that, they will be on immunosuppression as a consequence of having had the organ transplant. So it’s a disease that causes very high morbidity, and in fact, also accelerated mortality. Ninety five percent of that patient population does not have a treatment option available today. This is a severe and unmet urgent need. If we look at the animal models of polycystic kidney disease, we know that restoring the missing gene expression, polycystin-one in this case, responsible for causing the disease, can actually lead to not just stopping of the progression of the disease, but actually the potential for disease reversal.

And so the huge excitement, the great hope for patients with polycystic kidney disease is if we can design a drug that addresses this root cause of the condition, the potential for impact there is far greater than any downstream or accessory pathway drug. If we look at the size of the market, that handful of patients, or the five percent or so, who are served by an available current therapy, one of those accessory pathway drugs that we’ve just spoken about, we know that we have a very large market. From a commercial standpoint, polycystic kidney disease is a US15 billion dollars per annum, or larger, target market to go after, as confirmed by the sales of Tolvaptan of US1.5 billion dollars despite addressing just five percent to seven percent of that patient population. So there are a lot of people affected by this disease, as I mentioned before, in the tens of millions if we expand the aperture to look at patients worldwide. What’s going wrong?

What is the one change that is affecting these patients? It’s a loss of function mutation in one copy of the PKD1 gene, polycystic kidney disease one gene. What is happening as a consequence of that spelling error in the DNA is that that one copy of the gene is creating an unstable copy of messenger RNA. So as the DNA is creating RNA and subsequently protein, you are losing one half of the protein creation cascade that is required to maintain normal cellular function. So it’s this missing PC1 or polycystin one protein that is the missing part of the orchestra.

PYC double o three acts at the RNA level to restore that missing PC1 expression. The first drug to directly target PKD1 to restore PC1 protein expression. What’s happening downstream of the orchestra? It’s partially known all of the different parts of the orchestra that are going rogue as a consequence of not having the conductor. But what we know is that it’s the apex regulator that fully restores the balance required across all of those pathways to ensure normal renal architecture and normal renal function.

The animal models of this disease are very interesting. If we look at a mouse model of a polycystic kidney, on the far left hand side is what a wild type or unaffected kidney looks like at 16 of age. If we have a look at what a polycystic kidney looks like, so here we’ve switched off one copy of the PKD gene, You can see that kidney, even at 13 of age, is much larger than the kidney on the left hand side. And the reason for that is because it has a large number of very small cysts throughout the entirety of the kidney. If we leave that animal for a further six weeks in the context of not having that second copy of polycystin, you can see that the kidney becomes grossly dysmorphic.

You can see those cysts have grown, become fluid filled. They have started to destroy the architecture of the kidney, and consequently, that kidney’s function. The incredible thing about this study is if we allow the kidney to grow to thirteen weeks without having a functional copy of polycystin, but then we switch the gene back on, at 16 of age, the kidney will look like it does on the far right hand side. So we have restored the architecture here. This is a regenerative change, reversal of the disease.

And you can see the quote on the right hand side there. This leads us to observe a previously underappreciated phenomenon of regenerative capacity: renal plasticity. The ability of the renal tubular epithelial cells to regenerate and restore the harm that has been done by this disease process, if we can replace that missing PC1 protein. It also gives you a very good cue as to why we are looking at total kidney volume as the endpoint that we are most interested in. Because the human disease mirrors what’s going on in the context of this animal model, you can see that the polycystic kidney is far larger than the kidney on the left, resembling the kidney with normal anatomy and function.

What we are looking to do is to see not only whether the size of the individual cysts, but the size of the kidney as a whole can either be arrested, or in a perfect world, ideally reverted back towards the normal size that we see in individuals who are unaffected by the indication. You can also see that downstream of the anatomical readout is the confirmatory functional readout. So how good is the kidney at doing its job? What’s going on in relation to the size of the kidney is as these cysts increase in number and size, become fluid filled, they are putting pressure on the normal renal tissue that is left around them. And as they squash that normal renal tissue, you’ll see in very late stage disease, patients very rapidly decline in what we call their estimated glomerular filtration rate, or the ability of the kidney to filter the blood.

And so the idea here is that if we can see early movement on the volume of the kidney, that will be a lead indicator of the downstream benefit in relation to the function of the kidney. And so you can see why the FDA have designated twelve month anatomical surrogate on the volume of the kidney as the approval threshold, but then require those companies, the sponsors, to run that study for a further twelve months, twenty four months in total to look at the function of the kidney. Ultimately, that is going to be what’s important to the patients in that context. If you think about why this approach and no others, the apex regulator here, the conductor, is doing so many sophisticated things with the orchestra at once that it is possibly the only way to make a meaningful intervention in relation to this disease coupled with that potential for reversibility that we see from the animal models. You start start to see why the scope for patient impact is by far greater in the context of a disease modifying approach than it is if someone was to pursue an accessory pathway or a downstream approach that focused on one particular area of the kidney at once.

So it leaves us with two questions. The first one is: Can we restore the missing gene expression? And the second one is: Can we deliver that drug inside the target cells within the kidney? So here, we mentioned before the use of patient derived models. We have taken cells from a patient who has polycystic kidney disease.

So they have that DNA error in the PKD1 gene that is leading to a loss of one copy of that PC1 protein. And what we have done here is we have given an escalating dose of PYC003, the drug candidate, and we have measured what is the change in PC1 expression as we increase the dose of the drug. What we can see here is a really lovely dose dependent upregulation of polycystin as we are increasing the amount of PYC003 that we are putting on that patient’s cell. We know that this crosses the absolute disease correction threshold. We know that patients who have even ten percent to twenty percent more functional PC1 have on average twelve more years of renal function, renal transplant at the age of 67 as compared to 55.

So if you can restore PC1 protein back to 85%, as in here, of wild type expression levels, we expect that to have a very profound impact on the patient, with the great hope being that’s mirroring what has been seen in the mouse models of the disease, where it’s not only stopping disease progression, but we may potentially see some reversal as well. What that doesn’t answer is how much of the drug can we deliver to the target cells. And this is where the nonhuman primate or the monkey studies come in. This is the missing piece of the equation in the context of PMS that we’re going to answer very shortly. We have answered this question already in the context of polycystic kidney disease.

What you see here is each unit of the drug is denoted by a pink dot. So you see the kidney that has received no drug, the PBS control on the right hand side here, it doesn’t have any pink dots, as you would expect, because it hasn’t been given the drug. On the left hand side, you see a kidney that is lit up like a Christmas tree. It has pink dots everywhere. When we zoom in to the individual cellular level, we can see that all of the renal tubular epithelial cells, the cells that are affected by the PC one protein insufficiency are not sorry, have been effectively transduced by the drug in this case, both in the cortex and the medulla of the kidney.

So those two pieces of evidence combined give us very high conviction in relation to what is about to happen. You know that we are progressing through single ascending dose studies in healthy volunteers. We’ll be back to the safety review committee this month to push to the highest optional fourth cohort in that healthy volunteer setting, part a of the phase one a. We are also about to dose the first patient in the part b of that study. Once we have moved through and completed the single ascending dose study is when we are into the repeat dose format.

We’ll be starting in Q4, but delivering data in Q1, Q2, Q3, Q4 next year. We’ll touch on at the end of the conversation the measurements of the total kidney volume in those patients throughout the course of next year is going to be absolutely critical here. TKV and eGFR later. In the context of the second indication that has a very near term readout that has a meaningful impact on the probability of success of the program, Phelan McDermott syndrome, there is a lot that is the same about PMS, as in polycystic kidney disease, and in fact, each one of the indications that PYC is pursuing. You all know that PYC specialises in diseases that are caused by one copy of the gene acquiring a mutation that causes it to be non functional.

So the other remaining copy of the gene is still present, but it’s not creating enough protein for the cell to function normally. So you see that here, it’s a different protein that’s affected, but the concept is identical. Instead of the polycystin one protein, here you’re looking at the shank three protein. We normally have two copies of the gene, each producing one unit of protein. That protein will sit in the neuron or in the brain cell, and it will anchor other proteins that will act as receptors and potentiate the signal or the communication channel between neurons.

So it’s a it’s a protein that is responsible for helping neurons’ brain cells communicate with one another. And what happens downstream is we have normal communication throughout the different regions of the brain that coordinate our thinking and activity. In Phelan McDermott syndrome, we have a deficiency of that shank three scaffolding protein that causes a loss of the communicative ability for these neurons. Similarly to polycystic kidney disease, the mouse models of Phelan McDermott syndrome suggest that there is some potential for reversibility of this indication. And so what we’re going to do here, the question has been put, we don’t know yet in humans because we haven’t seen a disease modifying drug readout on the efficacy dimension.

But you’re now going to listen to a professor of pediatric neurology, Elizabeth Barry Kravitz, talk about the potential for reversibility of this indication in humans. The first ten seconds or so is her answering a different question. So just bear with us for the first ten seconds, and you’ll hear her be put the question in relation to reversibility of the indication.

Elizabeth Barry Kravitz, Professor of Pediatric Neurology: To take care of patients is to make sure that your insurance approves anything that gets approved that looks like it might benefit you.

Interviewer: Thank you. We have another question that is asking essentially if it’s, you know, ever a hope of restoring developmental skills that were lost via regression. I know that we can never, you know, guarantee something like that, but is there any hope there?

Elizabeth Barry Kravitz, Professor of Pediatric Neurology: Well, that’s an interesting question. You know. I mean, typically in neurodegenerative diseases like Niemann Pick or Batten’s disease, we tell people that once it’s lost, it’s gone. And the reason for that is that the neurons are dead, and so we can’t get them back. But I don’t think that’s really the case in PMS.

I mean, don’t have any evidence that neurons are dying. They’re just not functioning. So if we could make them function better, I think theoretically you could. I think that’s the reason why we see in a lot of the older patients we see these ups and downs where there’s a regression, but then they kind of bounce back. And they may not bounce back all the way to where they were before the regression, but there’s a lot of ups and downs.

And then sometimes there’s a regression and then there’s not a bounce back. But certainly there are lots of experiences with regressions that reverse. And so I think that’s because the neurons are all there, and somehow they just become better functional of maybe because of whatever treatment the patient is taking or just because there’s variation in functionality over time. And so what that suggests to me is that if we got the right treatment that optimized the functioning of shank or that replaced the function of shank in the cells that we could potentially see reversal of of regression.

Interviewer: I think we have some hints of that also in animal models of, you know, testing in older animals that seem to show some benefit. So that’s that’s great. Thank you for that.

Rowan Hawkins, Host/Presenter, PYC Therapeutics: So you can see there the commentary in relation to the absence of cell death. The point around this is not a neurodegenerative condition. This is a neurocommunicative problem. So the neurons themselves are there. They’re just unable to communicate with one another because of the absence of that scaffolding protein that helps them communicate to one another.

I wanted to illustrate what that phenomenon of regression and why the potential for reversal of it is so important to you. And so here, we are very grateful to Keurashank and to the patient family who have given us an insight in relation to what does that look like at the human level. So we’re going to now have a look at another video that gives just a short couple of minute overview of the developmental journey of a child with Phelan McDermott syndrome. So I will just put us back on mute here.

Abby, Parent of PMS Patient: Hi. I’m Abby. My only child, my son, Darice, has Phelan McDermott syndrome. The toughest part of this diagnosis for us has been experiencing regression. Despite Darius’s genetic diagnosis, he was doing quite well.

At age two, Darius was able to put silverware away. Notice here when he’s done putting away the first batch, he says more as he returns to get more. Darius could also feed himself with a spoon. At three, Darris could drink water from a regular cup without spilling. You’re so silly.

And he was pretty great at shooting a basketball. Yay. Good job, buddy. But sadly, one by one, Darius’s skills and interests and all the potential he had in life were robbed from him. Around the age of six is when all these skills began to vanish.

Where does the spoon go? Where does the spoon go? No. Try again. The spoon no.

You have to use your eyes. You have to use your eyes to look. Good job. Oh, buddy. Can I have the cup?

Can you swallow what’s in your mouth? Can I have the cup, Darius? Can I have the cup? Additionally, he craves motion even if it’s not productive, like pacing back and forth in the house with no particular rhyme or reason. Although we’re unable to pinpoint any specific event that may have happened or caused this regression, it happened, and it’s heartbreaking.

I was driven to join in the formation of Kira Shank with other similarly situated parents with one goal in mind, to accelerate research, to help my son, Darius, and all others that suffer with this dreadful condition a chance for a brighter tomorrow.

Rowan Hawkins, Host/Presenter, PYC Therapeutics: There’s a lot in that, I think, and in particular it brings home the urgency of the creation of treatment options for these patients. What I wanted to focus on today specifically is the link between the two videos, this concept of regression and restorative potential, whether or not we could address it. You can see what I’m talking about even though it’s been at the cellular level largely to date, how that translates in terms of the potential for patient impact. What is it that’s important to the patient, and how much of an impact do we think we can have in the life of that individual? That’s really the key here and the differentiation between drugs that address the root cause of these conditions.

You heard professor Barry Kravitz talking about if we could find a treatment that replaced the functionality of the shank protein. That’s exactly what PYC double o two is. It’s an RNA therapy that restores shank three gene expression back to wild type levels. And so what we’ve done here, we know that we can do that in the context of the human brain cells, but we wanted to go downstream to have a look at the functionality of those cells and the communication between the neurons after having restored that gene expression. So what the PMS team have done is they have taken cells from an individual.

We did not take I want to be clear here. We did not take brain cells from a child with PMS. We took blood cells from a child with PMS, reverse differentiated them into stem cells, and then used those stem cells to create neurons or brain cells. We grew those neurons on a plate, and we put them through an assay or some technical changes that illuminated them as red when they were communicating to one another. It’s showing you when the neurons are sending the signal to the neuron immediately adjacent to them.

And so what we’ve done now is to address this side by side, looking at the neurons from the child with PMS in the absence of treatment, how much red is glowing or how much communication is there between the neurons in the absence of treatment with PYC double o two, and what does that look like following treatment with PYC double o two. So I’m going to play the video in the absence of treatment first. You may have to look quite closely at your screen, but you should be able to see some flecks of red, in particular around the top of the screen, as those cells are trying to send that communicative signal to the cells next to them. If you look at the comparison of what that video looks like with the one post treatment, You’ll start to see why we’re so excited about the potential of this drug candidate. Because the neurons are firing in a coordinated fashion, the signal will move out of the aperture of the screen and it will come back shortly.

You can see that there is a lot more activity on the right hand side than what we’re seeing on the left hand side. So to know now that we have the power of a patient derived model, and we have not only a quantitative rescue for the genetic deficit, but that that does transpire downstream in relation to functional rescue as well. To know that we can go into a rat and achieve enough drug at safe and well tolerated levels to modulate the shank three gene expression in the rat. We got lucky, and the human oligo actually works to change the target gene expression in the rat. And to know that we have that same readout coming in the context of the nonhuman primate, which even better recapitulates what goes on in humans, you can see how we’re able to give ourselves a very high conviction position in relation to what is coming as we move that drug into clinical development next year.

And I think sometimes when we hear about scientific developments, and we hear the commentary on it’s still this many years away from clinical development and, of course, all the associated risks, of which there are many in drug development. They are by far the most manageable in the context of these single gene diseases. This program is moving extremely quickly, and it’s not a matter of having to wait for tomorrow in order to get that readout. Really, what we need to do now is start bringing the patients in who are going to be in the clinical trial so we can get an assessment of what their function is every three months for a twelve month lead in window to have a look whether we can make a meaningful deflection in the context of that particular patient’s progression. Because as you can see from the video with Darius, depending on which age you intervene at, where that patient’s at, at what point they were going to experience that heartbreaking phenomenon of regression or losing those skills, it’s going to be difficult to see the signal even in the context of a drug that has a very profound impact in that patient population.

So there is a lot of preparatory work going on now. You’ll see the data coming out with the comparison to zorivonesin, the other RNA therapeutic administered via the same route for the same target cell in the same target tissue manifesting in the same phenotype as patients with PMS, that will give us a very strong read in relation to what is likely to happen when that drug does get into patients in the second half of next year. So a very exciting window in relation to PMS. We have spoken about and before touched on the human safety side of the equation in polycystic kidney disease. What I wanted to do now was to just touch on the commercial opportunity in relation to the polycystic kidney disease program.

You are aware that Novartis bought a drug from a company called Faribirsen. In fact, they bought the entirety of the company for a couple of billion dollars on the back of three months’ worth of data in a multiple dose study. PYC will eclipse that data point in the end of the first quarter of next year. And unlike Regulus, who had to stop their multiple ascending dose study because they hadn’t completed the chronic dose GLP tox studies in nonhuman primates, we will continue to dose those patients throughout the entirety of next year. So we will deliver not a three month cut of the data, the full twelve months that mirrors the registrational study that follows.

And so we will be decreasing the risk associated with that program by a fold factor, the flip side of which is increasing the propensity for success and the associated intrinsic valuation of the asset asset by a fold factor as well. It’s very clear that the company has optionality in relation to the timing of a potential partnering transaction indication. If you think back to the conversations that we’ve had previously in relation to the important dimensions of a partnering transaction, they are threefold. Firstly, to ensure that you are on strategy for the counterpart. The second one, to ensure that you have a strong hypothesis.

The third one is to accompany it with compelling clinical data. I can tell you that we are on strategy for a large number of global pharmaceutical companies. You have just been through the strength of the hypothesis in relation to why we believe restoration of the polycystin one gene is going to have a meaningful impact in the lives of these patients. You have seen the quote suggesting that it is not just the best, but possibly the only way to meaningfully intervene in polycystic kidney disease. We are within a stone’s throw of generating the human efficacy data with some very important safety data coming out later this month and early next month in terms of the totality of the presentation of what we’ve seen to date.

So it’s an incredibly exciting window within the polycystic kidney disease program. We are also in a very exciting window in the family McDermott syndrome program. The propensity for success is going to be materially increased on the back of the data that is coming next month in the event that that is successful. The reason that you see nothing to the right hand side there is because once you have the non GLP safety tolerability readouts in the nonhuman primates, when you go into the GLP tox studies required to progress into humans, it’s unlikely that you’re going to see something different from what you saw in the non GLP studies. So the increment of risk removal is happening very early, and then the next outcome that you’re going to get is human safety.

If we can accompany the human safety with a near term human efficacy readout, we’re going to be in a very strong window there. Effectively, the company will be in a similar position to where it is in polycystic kidney disease in the second half of next year. In addition to that, we have some important engagements with the regulator, the FDA in particular, through the Type D meeting to finalise the registrational study design for the RP11 asset. And we will also release an update on the data from those patients who have been tracked out for eighteen to twenty four months within this window, mirroring the proposed registrational study or the twenty four month timeframe that we have aligned on through the Type B meeting with the FDA in that context. In August, we expect to finish the single ascending dose study in patients with ADOA.

That data will be presented in September and again in November at the Neuro Ophthalmology Society of Australia meeting and again at the Royal Australian New Zealand College of Ophthalmology meeting in November. That asset will then be progressed into a repeat dose study. If you think back to the journey of the RP11 program, we got some early hints of efficacy in relation to the single ascending dose study, and those were confirmed as we moved through to the open label multiple ascending dose studies that followed. So similar to PMS and PKD, the ADOA asset is around twelve months behind where we’ve currently got to in the RP 11 program. So this is a very, very rich pipeline in terms of the news flow that’s coming.

There are a lot of very meaningful human efficacy signals that were within reach. All three of those programs are going to cross that threshold, and the company is also traversing the milestones that are creating optionality in relation to how the shareholder value that is being created here is going to be realized. So a very exciting and busy time for the organization as we look to integrate that into our commercial strategy as we’re yielding these very important human efficacy milestones over the course of the next twelve months. So with that, I will stop and open up for q and a. I might get you, Andrew, to just use the microphone if you’re gonna read the questions out.

Andrew, Q&A Facilitator, PYC Therapeutics: Question around the the next dosing, the the b one dose in the kidney trial, whether you expect to see any efficacy in that.

Rowan Hawkins, Host/Presenter, PYC Therapeutics: So the b one dose in the PKD study is the first dose in the patient population. We are mirroring the same dosing protocol that we went through in part a of the study in the healthy volunteers. Zero point four milligrams per kilogram of body weight is the dose that we’ll be administering to those patients. I think the issues in relation to seeing an efficacy signal from that patient cohort are twofold. Firstly, albeit that it is in within the proposed therapeutic range based on the nonclinical modeling and scaling through to humans, it’s at the lower end of it.

That’s one problem. It’s probably subtherapeutic. And the second point is because it’s a single dose study, we don’t yet know. We know from the REGULUS trial that three months is probably enough to see movement, but we don’t yet know whether a single dose is enough to engender that movement. REGULUS molecule has a shorter half life for a person than PYC double o three, but they gave seven doses in the course of that three month study.

So I think it’s probably overly optimistic to see something in the context of b one. I think the one point two and two point four milligram per kilogram b two and b three cohorts are much more likely to yield an an outcome in that regard. And I would temper expectations, particularly on the TKV endpoint in relation to potentially the first quarter of next year in the repeat dose setting before we expect to see that.

Andrew, Q&A Facilitator, PYC Therapeutics: And just a clarification on the registrational study for PKD. Is TKV sufficient for this accelerated approval, or are we looking for EGFR on that?

Rowan Hawkins, Host/Presenter, PYC Therapeutics: Yeah. That’s correct. So the pathway that has been designated for an accelerated approval is a commercial approval in The US, specifically, on the back of the anatomical surrogate endpoint or total kidney volume. The drug is approved at that point, and then the approval becomes unconditional once the twenty four month confirmatory data on eGFR has been released. But there is authorization to commence marketing between those two milestones.

Andrew, Q&A Facilitator, PYC Therapeutics: And in terms of patient stratification for the trial, is there any focus on younger patients with less damage to the kidneys or older patients with a small spheres of progression?

Rowan Hawkins, Host/Presenter, PYC Therapeutics: The bias there is to patients who are more advanced. And the reason for that is the kidneys can tolerate quite a lot of anatomical damage before the function becomes distorted. You know that you can donate your kidney and that you have adequate renal function with one kidney, suggesting that you can have 50% loss of the tissue in two kidneys before you notice any functional difference whatsoever. So because we are trying to prove that secondary link to EGFR, and if you look at the EGFR decline in patients, it doesn’t start manifesting until very late despite a much more linear growth on the size of the kidney on the TKV endpoint. So what we’re doing there is we are biasing towards the later stage patients where we are going to see movement or hope to see movement on that EGFR endpoint.

How well validated are NHPs as a preclinical model for target tissue concentration for PKD and PMS? NHPs are both the most toxicologically relevant and also from a biodistribution standpoint or pharmacokinetic relevant species for modelling of humans. So it’s the best that you can get. We know that we share both from a physiological perspective and also an anatomical perspective a large amount of our DNA with nonhuman primates, so they are considered the gold standard species in terms of prediction. For polycystic kidney disease, the biodistribution has been well validated in the context of delivery to the kidney.

Although, we will confirm that by measuring the plasma concentration of the drug and the urinary concentration of the drug as well to reverse infer what the concentration is going to be in the context of the human kidney. In Phelan McDermott syndrome, there has been a large number of population health studies run by both Stoke and Biogen who have confirmed that rats are actually highly predictive of nonhuman primates, and nonhuman primates in turn are highly predictive of humans.

Andrew, Q&A Facilitator, PYC Therapeutics: Probably a question just your thoughts generally on FDA and, you know, involvement and changes in the regulator.

Rowan Hawkins, Host/Presenter, PYC Therapeutics: It’s certainly a dynamic time, excuse me, in relation to personnel and organizational changes that are occurring at the regulator. From the PYC standpoint, we’ve been very, very fortunate with respect to consistency of the personnel who are managing the FDA’s engagement with each one of our programs. And I think the synthesis of the June 6 conversation in relation to the potential registrational path for r p eleven was actually very positive. What we are seeing is a benefit associated with the views evolving views of the FDA in relation to precision therapies or gene therapies for rare diseases specifically for all of the reasons that we’ve been through today. This particular area of accelerating gene therapies for patients with a rare disease has come as one of the focus areas for the FDA, and we are seeing an enhanced degree of flexibility over and above what we were expecting in relation to the potential registrational pathway in that context.

So aware of the changes that are happening at the macro level, and I think, fortunately, the beneficiary of a very smooth experience with the FDA to date.

Andrew, Q&A Facilitator, PYC Therapeutics: Question just to confirm the size of the the markets of the four diseases being targeted.

Rowan Hawkins, Host/Presenter, PYC Therapeutics: So each one of the indications is a commercially attractive market. We pursue patient populations that exceed 5,000 patients in the Western world. So if you combine that with orphan drug pricing, you’re looking at markets that individually are worth north of $1,000,000,000 per annum. If we look at the size of the two larger markets that we’re going after, you have seen there the inference from tovaptan and the market penetration and the yield revenue yield associated with that drug candidate. You can see that PKD is a $15,000,000,000 plus a year indication.

And if we take the data from Keuershank, twenty thousand patients with Fehler McDermott syndrome in The US, if we adopted orphan drug pricing of around $200,000 per patient per annum as a median level, you’d be looking at a $4,000,000,000 market in The US alone. There is a very strong argument to suggest that pricing for a drug that had a profound impact in language and cognition in the context of a pediatric population should attract much higher pricing than the median orphan drug price. And then you’ve obviously got the rest of the world to consider there as well. So I think you can accurately infer that there is a 5 to $10,000,000,000 a year market opportunity in the context of Phelan McDermott syndrome. In the context of the ophthalmology programs, they are smaller and probably reflect 1 to $3,000,000,000 per annum markets for RP 11 and ADAOA, respectively.

Andrew, Q&A Facilitator, PYC Therapeutics: What what is currently outstanding to on the RP eleven’s trial or RP 11 program before you can commence the registrational study? And and and when is the likely commencement of the

Rowan Hawkins, Host/Presenter, PYC Therapeutics: What what is outstanding in relation to it? Oh, what is currently outstanding? Okay. So the in relation to the RP 11 program, it’s really up to us to set the timing for engagement in the type d meeting of the FDA. So the

We’ve done the type b meeting, which is to get a high level structural alignment. But what you want to do before you start enrolling the registrational study is to get firm alignment on every dimension with the FDA. So it’s a matter of moving from the high level detail down to the refined detail. What we are waiting to do in relation to that is two things, to continue to look at the data from the phase one two in relation to nomination of the primary endpoint. You can see from the Miura GTX J and J asset for RPGR getting the primary endpoint right is very important.

So we wanted to take the time to think that through in some detail before making the nomination there, ensure that we have got the secondary endpoints right, and then determine whether or not we wish to have a conversation with the FDA around any proposed accelerated approval pathway or changing in the threshold of approval. So once we have refined our views in relation to each one of those, we’ll be back to the regulator to confirm the final registrational study design. But I think we have a pretty good understanding already of what that is going to look like.

Andrew, Q&A Facilitator, PYC Therapeutics: I have a final question here. Just a general comment around the activity of, you know, partnering discussions and some some thoughts on timing around around any potential transaction.

Rowan Hawkins, Host/Presenter, PYC Therapeutics: Yeah. It’s asset specific, I think, the first thing to say. So if we look at what the company would like to do, our preferred asset, we’re contemplating partnering, would be around the RP 11 program. And so I think a key input there is to obtain that regulatory certainty in relation to the registrational trial pathway. So I think that, coupled with the phase one, two data that we’ve generated to date, is likely to be sufficient to crystallize partnering opportunities for us.

And then the question there is in relation to terms and whether or not we’re looking to achieve a global partnership or a regional partnership. That was a very interesting transaction, potential precedent transaction that came out this week between Viridian Therapeutics and Kissei Pharmaceutical. I think it was a $70,000,000 US upfront and a 20 to 30% royalty coupled within the order of US $320,000,000 of milestones for a Japanese regional deal for a rare blinding eye disease. So quite a nice benchmark for us there. We, as I have spoken about before, we continually engage with the sector in relation to the potential for finding a partner who can bring something to the table in relation to that program and also meet the needs of the company from a broader corporate development standpoint.

ADOA, I think, is a little bit too early. I don’t think we’d like to license that asset until we get human efficacy data. That will potentially be in the second half of next year before we’re in a position to do that. I think the complicating factor there is that often companies who have an interest in rare blinding eye diseases would like to take two of them rather than just one. But I think from a company value maximization standpoint, we’d be looking at establishing a more robust human efficacy signal than what is capable to be achieved in a single ascending dose study format.

In the context of Phelan McDermott syndrome, I think it is really opened by that nonhuman primate data that is coming next month because the CNS as a therapeutic area is a much more active domain than ophthalmology, and because we have got these precedent molecules like sorivumers and in Dravet syndrome, nusinersen or spinraza in spinal muscle atrophy, that gives counterparties a lot of conviction. And obviously, it’s a much larger target market to go after as well. So I think that window is open there in the event that we wanted to partner early. But we would obviously have to temper the expectations in relation to the upfront given that that asset has not yet gone into clinical development. But a very nice precedent transaction, again, if you look at the Biogen Stoke transaction for rest of the world rights around zoruvenirsen.

They achieved a 165,000,000 upfront. I think it was in the order of half a billion dollars of milestone and sales royalty in the teens, 10 to 20% region for rest of the world. So ex US rights for their Dravet syndrome drug candidate, albeit that was with phase one two data in hand. And then in polycystic kidney disease, it’s really with the company to determine what is the right opportunity to partner that asset. It’s clear that it could be partnered now in the event that we wanted to, but it’s very clear that the more value that we contribute to that asset by derisking it, human safety and human efficacy data that’s coming is going to build the commercial terms very substantially.

Here, I think you have a lovely precedent transaction from Regulus in relation to where we could expect to see see the commercial terms in the event that we see movement on the total kidney volume endpoint by the end of the first quarter. And I think here, you have to take into account the preclinical differentiation of the PYC double o three asset and the very different corporate and commercial environment that PYC is in today as compared to where regulars were when they did that transaction. But I think the far more interesting thing is what is the fold change in the deal terms that can be achieved by taking more risk off the table, giving the full mirror of that registrational trial by going through to q four of next year. And in the context of an open label study, you, the shareholders of PYC, are going to continually see updates in relation to what is happening on that total kidney volume and eGFR endpoint throughout the course of next year. So it’s gonna be an incredibly exciting time in that program, albeit we have an opportunity to partner early.

I think the preference should be rare to partner late. No? All good on the question front. Alright. Well, thanks very much, everybody.

I hope that has been informative for you. We will look forward to giving you an update as these milestones proceed in Q3, a very busy time for the company, and then again at the Annual General Meeting for the Q4 update. Thank you.

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