We'll make a start. Good morning, everyone. My name is Rohan Hockings. Welcome to the PYC Therapeutics fourth quarter investor webinar. Before we begin today's call, I must make the following Safe Harbor Statement, reminding you that today's discussion will contain forward-looking statements that involve risks and uncertainties. These risks and uncertainties are outlined in our filings with the Australian Securities Exchange. As such, actual results may differ materially from what we discuss on today's call. We disclaim any obligation or intention to update these statements in the future, and I also remind you that today's call is being recorded. In terms of the agenda for today's discussion, the primary purpose is to address the board and management changes that have occurred over the course of the past month.
As we dig into what has happened there, it will become clear that there are a range of secondary objectives in relation to what we want to discuss today. If we unpack the first bullet point on the page here, I think the basic synthesis of the situation is that the company has failed to meet expectations of our performance over the course of the past month, and what I want to be very clear is that the company understands the immediate need to restore confidence in the company in the public markets. I think it is very important that shareholders understand that what has occurred has got nothing to do with the technical progress in the company's scientific programs.
What I want to do is to dig into the detail in relation to where each of the programs is today and what the upcoming milestones are for each of those programs going forward, where the issues and the differences in views at the Board level did occur relate to the company's commercialization strategy and the consequent implications for capital allocation. The final objective is to be very clear about where we as a company are heading. On the back of that, I think to give the synthesized view there so that you can orient your thinking in relation to today's presentation, the two key points to make here are that the company is pushing all four programs through clinical development and is open to, but not beholden to, a licensing transaction around one or both of the ophthalmology assets.
So those are really the primary objectives and topics that we want to discuss. If we circle back to the top now and have a look at the changes that have occurred to the Board and the management of PYC, as I mentioned beforehand, the company understands very clearly that we have not met the expectations of the public markets in relation to the course of the company's conduct over the past month or so. I think what has happened here relates, as I mentioned before, to the commercialization strategy and the consequent downstream capital allocation decisions. The company is balancing a couple of different competing objectives here with a view to delivering the patient impact that drives the organization and the consequent shareholder value increases that will be derived from successfully launching the drugs in the company's drug development pipeline.
The dynamic variables that we've got to deal with here as we look at all of the different options that are available to the company relate to opportunities to out-license the company's assets, the timing and the quality of the terms that are appearing in that regard. That's balanced against the continuous variable that we get in the capital markets of our ability to translate the technical value that is being created through the delivery of milestones in each of those programs into the creation of shareholder value that is recognized in the stock price. What we have to do there is to get ahead of the 24-36-month forward plan and understand how we're going to integrate all of the different options that are available to the company into the concrete go-forward plan.
What we struggle to do there is to create an alignment into the appropriate integration of those different options. And I think the very regrettable dimension is that that's spilled over into the public domain. The company now understands that we need to make changes at both the Board and the management level in order to ensure that we don't see a situation like this play out again. And so what you have seen are some of those changes that are occurring already at the board level. We will continue the process of board renewal through the remainder of this year. There are additional changes coming to ensure that the Board has the depth, breadth, and independence required to navigate the company's future stage of growth as it moves to a late-stage development company across multiple assets.
So that's effectively what has happened in relation to the divergence of views and what has occurred there. The go forward plan is very clear, but what I might do at this point is to open up for any questions or comments from the audience in relation to what has happened before we move on to the scientific update and do the same through the course of that.
Standard city planning process?
I think it's better rather than litigating exactly who was aligned to the views. What I potentially can do is give you more color in relation to the different views. At one end of the spectrum, you have got a need for emergent commercialization of some of the assets and a desire or a willingness to extend the company's capital runway by deprioritizing or potentially pausing clinical development programs to pursue the highest intrinsic value milestones within the pipeline, and I think at the other end of the spectrum, you've got a view that the data and the industry is heading towards us. We have a lot of milestones coming over the course of the next 24 months. We don't necessarily control in the acute sense the timing of those business development and licensing transactions, and we should continue to develop all four assets within the company's drug development pipeline.
And so the plan, as we have aligned as a company, is very much towards the latter. So that should give you the clarity as to the go forward position there. What I might do is just get anyone who's asking a question from the crowd to use the microphone just for the benefit of people online. I don't know if anybody online has any questions there. Garrett, if you have got a microphone or any other questions from the audience while we wait for Garrett to get those ready?
That's the one that seems to be.
Yeah, I think we've touched on that one though beforehand. Have you not got the questions online?
That's just.
Okay.
But I really have just.
Wait one second.
Thanks.
So my question's about the Board, Rohan. You mentioned that there'll be ongoing renewal. Will you have anything more to say about that today, or is that for to unfold into the future?
Look, the point that I wanted to make today in relation to the Board renewal is that the process is active and that we expect the changes to be made before the end of the year. So I think rather than get too far ahead of those, it's better to comment or give more color in relation to exactly what is happening as they materialise. But effectively, what we're looking for, as I mentioned before, the depth, breadth, and independence within a Board of four to five members to be able to guide the company on that next phase of its development, both through the multiple different commercial opportunities that are coming to hand, but also as we move multiple drug candidates through to late-stage clinical development.
Maybe just piggybacking off the last question, are there any specific talent gaps or kind of strategic priorities when you think about the new Board that you'd be looking to address?
Look, I think the primary objective there as we map the attributes of the different Board members, the characteristics that we're looking for there is very much focused towards all of those different commercial opportunities that we have in front of us today. And so if you think about, and we'll go through shortly and outline what the milestones are within the programs that are going to drive the increases in the intrinsic valuation, those are also the triggers for commercialization activities at the asset level. And then we've got at the corporate level, existential questions around whether or not we ultimately are inevitably an American company, how long we wish to exist as an Australian company, could we go all the way through to a drug development launch as an Australian company as well. So there are a lot of complex questions very much on the commercial side.
We've got largely the technical elements of the development under control. There are further changes that need to come at the management level, and we have implemented those in terms of also building out the skill sets to make the recommendations on the commercial dimensions to the Board. Also, from a clinical development planning standpoint, because of the high velocity nature of the assets through clinical development in the context of unmet needs, we needed to build out the CMO capability within the polycystic kidney disease and Phelan-McDermid program specifically. And so we've made some changes at the management level there to bring on board the expertise required to do that. That's really the combination of the skill sets between executive and Board that we're looking for. I'll just check online. We've got questions in relation to why did I resign? Funding all of the programs is the issue.
So how are we balancing the potential for capital raising, shareholder dilution versus deals? If you cannot get the share price moving to better reflect value, then question mark. Which of the four programs was earmarked to be potentially paused? Do I still plan to leave the company and other remaining members of The Board aligned, or are there still differing views on the most viable strategic pathway? Okay. So the approach to the out-licensing, I think we've touched on that one before. In relation to my resignation, I think there is the what that is seen in the public communications. What we see less of is the how and the why. And I think there was an opportunity for the company to provide more color in relation to those divergent views that we've just spoken about.
When I go out and raise capital for the company, as we did earlier this year, we set out a very clear roadmap for how we plan to create patient impact as our primary purpose as an organization and deliver the downstream consequent commercial uplift in valuation for shareholders associated with that patient impact. If there is going to be a fundamental change to the strategy of the company, we need to have the appropriate decision-making processes in place in order to navigate that, and we need to communicate that very clearly to the market. There has to be a very strong rationale why we are going to do something different to what we have suggested to the markets we are going to do, and as we spoke about beforehand, there were different views in relation to how the company went forward here.
I don't think there's anything unusual about that that is in the ordinary course of board conversations about strategic direction. And I fully accept and understand that we have not seen the translation of the technical milestones into shareholder value recognition that we would have liked to through the course of that period. And so I think there is a natural inclination and a tendency to want to tap the brakes in that context. And I don't think that that is the right thing to do here. I think that the company has got a whole host of milestones on the technical side that are going to create a lot of opportunities for the organization. A lot of work had gone in already to creating multiple different pathways to support the company's future growth in relation to the access to capital question that came afterwards.
So it was really, I don't think a function of the fact that there were different views. That is fine. It's the ability to reconcile those views into an integrated pathway and to do that in the context of the private realm as a public company. I think that is very important. So it really comes down to that in relation to the rationale for why I stepped away. I thought there was a material risk that the company went down a pathway that was not aligned to where I see the organization heading. In relation to the funding of all of the programs, as I mentioned before, the complex part here, and there are obviously commercial sensitivities that sit behind it, so we can't go into full detail in relation to what is occurring, but the company has multiple different options.
It's a continuous assessment of the relative merits of dynamic variables, both in the equity capital markets, but also at the asset level from a business development and licensing standpoint. There is a huge amount of appetite on the part of the industry as a whole to see PYC's drug development programs go forward, it's not the access to capital issue. It's the nature and timing and terms of the inflows of capital that were creating problems for the company. In terms of which of the four programs was earmarked to be potentially paused, the real understanding here is that it's the larger indications that are driving the primary interest on the part of the industry as a whole. The pharmaceutical industry gravitates towards programs that have a potential valuation of $5 billion or more annually.
They are the assets of greatest interest to our large pharma partners, and so consequently, it's the polycystic kidney disease and Phelan-McDermid programs that fit the bill in that regard. I think in particular, the polycystic kidney disease program is attractive because it's already a clinical stage asset. I think there are many reasons to believe why Phelan-McDermid syndrome, and you've seen the announcement go out today, we'll have a conversation in relation to that very shortly, has got a very high potential to impact that patient population as well, so it was really a matter of prioritization of the polycystic kidney disease program specifically, but with a view to supporting those larger development programs. Do I still plan to leave the company? No.
I think the resolution that we have as an organization in relation to the go forward plan, the fact that we are continuing to develop all four programs and that we will work to ensure that the options that were available to us continue to be available to us in relation to charting a strong path forward has meant that I have been willing to commit to the organization to see through a really critical 24 months of the organization's growth to the end of 2027, and that's been communicated to the markets as well. Is the Board now aligned, or are there differences in view in relation to the strategic pathway? I think the Board is aligned.
I think what you saw generally was a mobilization and alignment of the broader shareholder base in relation to the direction that was put to the capital markets at the timing of the last capital raise. I think there is an understanding of the attraction of all of the assets in the company's pipeline. Not only that, but the portfolio theory benefit that comes from having a multi-asset pipeline. And I think there is also an appreciation that we are very close to milestones that will drive an uplift in the value of those programs, certainly at the intrinsic valuation level. And we understand our job is to translate that through to the market capitalization level as well. So we do have alignment in that regard.
How do we envision our position in the global biotech landscape over the next five years as an independent commercial company, a license or a potential acquisition target? Yeah, I think that's a good question. So to jump ahead and look down to the company's commercialization and capital management plan at the minute, we understand very clearly what the drivers of valuation in the pipeline are. And we have four human efficacy readouts that are really the primary contributors to that coming over the course of the next 24 months. So understanding those is where we as a company are heading. And I think it's always important for a biotech organization to have a very clear view of how they are going to develop their assets independently.
And at that point, you create the opportunity for inbound commercialization partnering arrangements on attractive terms for the organization, knowing that you don't fully control the timing of those outcomes. So our view here really is to continue the development of all four assets in the pipeline. We have a preference, and I think very clearly, if we can't do anything about closing the gap between the intrinsic valuation and the market capitalization, you are going to prioritize the business development commercialization opportunities. And as I spoke about before, the preferred assets for us to out-license right now are the ophthalmology programs. And the reason for that is the magnitude of the increase that is coming in those larger indications within the very near term is greater.
That's risk that we want to retain for our shareholder base to see that translated through to an increase in the valuation of the company. In terms of the pathway and the longer run to commercialization, are we shifting from equity to licensing? Look, it's a continuous balance of those. So what we are doing is we are looking at the cash runway. We have found a way to extend the existing cash runway into fiscal year 2028. That gives us the time to push through the commercialization opportunities to deliver the technical milestones that are going to drive optionality from a commercial out-licensing standpoint. It's very clear that there is frustration that we have not been able to translate those technical milestones into shareholder value, and the longer that that persists, the more that we are going to bias towards a business development or licensing outcome.
We are certainly doing the work in order to create those opportunities. I think that's why we are building out the management team's capability from a commercialization standpoint, because there is a lot of work that goes into development of those inbound licensing opportunities across four assets in the pipeline. Even with a view to a polycystic kidney disease deal that waits until we have that definitive data from the multiple dose study. I think the important thing for shareholders to realize is this is an industry with long lead times. It's not as if we snap our fingers and we have an outcome available at the back end. If you are thinking about licensing opportunities in 18 or 24 months' time, you need to be engaged with the industry today.
So there is really a lot of work to be done, even in the context of a medium-term aspiration for out-licensing of those assets. Are there discussions with larger pharmaceutical partners for licensing co-development or commercialization rights? Yes, they are ongoing in terms of our dialogue with partners or potential partners in relation to effectively all of the assets in the pipeline. There is a primary interest at this point in time in retinitis pigmentosa type 11 because of the availability of clinical data and preparations for the implications of the Type D meeting with the FDA that is on the very near-term horizon and is likely to give counterparts the certainty in relation to where the finish line is for that asset that they require to enter into meaningful licensing conversations.
The other asset, as we spoke about before, just because the magnitude of the opportunity and the excitement in the indication of a disease-modifying approach is so high, is the polycystic kidney disease program. And so we have a continual dialogue with large industry partners in relation to that asset, despite the fact that we are not looking to out-license it immediately. These are the preparatory conversations that are going on in relation to once we have the data in hand on the total kidney volume and the kidney functional eGFR endpoint in 12 months + time, we are prepared and the industry understands those assets as a whole. So they are very closely watched clinical trials in that context. Question on key supply chain dependencies for clinical commercial scale manufacturing. Are there any risks for tariff exposure points? Look, not really.
I think we benefit as a modality from a very simple synthetic CMC process. It's transferable. It can be moved from our current location of manufacture into the U.S. at any point in time. There are many different contract drug manufacturing organizations who offer the ability to synthesize these drugs. It's a very well-understood process. So we're quite nicely insulated in that respect. Other questions on what's occurred? Otherwise, we will move forward to the more exciting part of the presentation. No? Okay. I don't think there are any more. Oh, there's one more has come through. Are there any other competitors working on similar research for the same assets? And will PYC pursue a U.S. stock exchange listing such as NASDAQ? What is the planned structure and timeline? How will this impact existing Australian shareholders in terms of liquidity, currency, and reporting?
Yes, there are competitors, as you would expect, I think, in very attractive commercial indications, particularly where the genetics of the indications are so well understood. It's not unique to us, the attraction of the much higher propensity for success in clinical development of drugs targeting mutations in single-gene diseases, monogenic indications. So if we look at the pipeline by asset, if we look at RP11, we know that Biogen had an AAV gene therapy for RP type 11 that, as far as we understand, has been discontinued. We know there is another company called Epic Bio who were looking at, I believe, an RNA therapeutic approach for RP type 11. And I think from the latest update on their website, we don't see any active development in that program either.
There were competitors there, but RP11 is the first asset to have entered into clinical development with a disease modifying or addressing the root cause, the PRPF31 deficiency in these patients. It is by far and away the most advanced asset with a disease modifying potential in that capacity. In ADOA, there are two competitors, both of whom sit in earlier clinical development than PYC. Again, there is an AAV gene therapy approach by a company called Neurophth Therapeutics, and there is a naked RNA therapeutic approach by a company called Stoke Therapeutics. We are very clear in relation to the potential competitive advantages of PYC's approach in these indications that we are looking to bear out in clinical development. In terms of polycystic kidney disease, the field is a little bit broader here.
If we focus on the potential disease modifying approaches, I think everybody is aware of the acquisition by Novartis of Regulus for their Faribursin microRNA targeting approach. We have other players in the space in relation to the disease modifying approach, including Vertex Therapeutics, AbbVie, GlaxoSmithKline, also in early or mid-stage development for drugs targeting polycystic kidney disease. And there will be a host of others in stealth mode that we don't know about, many, many more in preclinical development given the attraction of that indication. And we have, of course, the existing approved therapy in the form of tolvaptan, marketed by Otsuka Pharmaceutical.
In relation to Phelan-McDermid syndrome, the two primary competitors, and this time sitting more advanced in clinical development than PYC, we have another Australian company with whom many of you will be familiar in the form of Neuren Pharmaceuticals, who are in the process of conducting a phase three for a small molecule IGF1R modulator. And we have a company in the U.S. called Jaguar Gene Therapies, who are again looking at the AAV gene therapy approach there. So hopefully that gives you a nice synthesis of the competitive landscape. Where we really see the differentiation of PYC in this regard is twofold. It's the link from a strategic standpoint between the pathogenetic mechanism, the haploinsufficiency, and the RNA therapeutics.
There was a really beautiful article by Stanley Crooke posted recently on the attraction of the RNA therapeutics for upregulation of target gene expression in the context of haploinsufficiency specifically, but gene insufficiency more generally, looking at the different ways that we can do that reflects very much the mechanisms of action that we see in PYC's pipeline, the work that we were doing seven or eight years ago to get ourselves so far ahead of the rest of the field in that regard. The second primary differentiator for PYC is on the Achilles heel of the RNA therapies, getting more of the drug to the target cell, the delivery technology that facilitates the competitive advantage there. Okay. If PMS competitors are more advanced, why is PYC progressing? Are you that confident in your point of difference? Yes, I think is the answer there.
I think the company has an opportunity to introduce key opinion leaders from around the globe who can give you an independent perspective on this, and we are looking to do that in the near term. We were contacted by one of the KOLs in PMS after the presentation at the last webinar was given in Barcelona at the PMS Foundation Day, who described the data as frankly amazing. That was before we'd seen the additional point of evidence that's come out today. If you think back, that data came from the brain cells that were derived from the children with Phelan-McDermid syndrome, showing that we can restore the missing SHANK3 gene expression, that that SHANK3 protein that is restored is localizing to where it needs to be within the cell.
And not only that, but the cells are communicating to one another at levels that are much higher than what's seen in the untreated PMS organoid models in that context. So some very exciting differentiation in that regard. What I think is the key here and the point that we watched a video last time around that one of the KOLs in the field is making, Phelan-McDermid syndrome is a neurocommunicative disease. It's not a neurodegenerative disease. The neurons are there. They're not dead, but they're not able to properly communicate with one another. And so if you think about what this drug does, it restores the protein that enables those cells to communicate with one another. This offers a differentiated potential with respect to disease modification in this indication.
If you think back to the video of the child with Phelan-McDermid syndrome, you will have seen that clinical observation of the phenomenon of regression, patients losing skills that they have previously obtained and the devastating implications of that for the patient families. You start to see why the attraction of a disease modifying approach that addresses the underlying cause of the disease is so differentiated in that context. Yes, we do see very clear differentiation for PYC. What I think will be really nice is to have independent experts within the field talk to you about that differentiation. We're looking to do that in the very near future. Okay. A lot of questions in relation to that, but hopefully everybody's comfortable in relation to what has happened.
I think the synthesis here really is that we understand that we have not met expectations and that we have an immediate obligation to restore the confidence of the capital markets in the company. I think the important point is for everybody to understand it was not driven by any technical issues in any one of the company's pipeline development assets. Hopefully you understand that it was on the commercialization strategy and consequent capital allocation on which sensible minds can differ. These are complex areas, and we have had a difference of opinion. I think that that bit is part of the ordinary course of business. The real difficulty here is it spilled out into the public domain, and I think what we saw there is that the company has outgrown its Board.
And so we had a need to evolve the Board structure specifically and also to build out the executive team to ensure that the company is set up for success in the medium and longer term, that all of the bodies of work that go into preparation for the big opportunities that sit behind each one of these assets are being mobilised independently and concurrently. And so that's exactly what we intend to do. You will see further communications coming from the company in relation to the additional Board evolution, but hopefully you understand what we're looking for there.
It's to build out the commercial capabilities of The Board specifically and to bring that independence of thought with a four- to five-person board that can really guide the company's transition and deal with the complex questions in relation to how are we going to go about ensuring that this value that we're building in the drug development pipeline is being translated? Do we need to bring on board U.S. partners in that journey, both from an industry standpoint, also potentially investors? Is the ASX the appropriate listing for our organization? What is the longer term future of PYC, not just in relation to the four assets in the pipeline today, but remembering that we have a platform technology in relation to assets five, six, seven, and eight, so there are complex questions, issues in front of the company.
In many respects, that's as a function of the success that we have seen in relation to the pipeline to date. And I think the very disappointing part about what happened, there is a lot of biological and execution risk in drug development companies. What you don't want to do as an organization is to introduce additional governance risk. And I think that's exactly what we have done. And what we've got to do now is address that and make sure we've got a very clean path for the company to move forward. Hopefully you have the color in relation to where we've landed as an organization and what we're pursuing. We'll go into some more detail in relation to how the milestones within each one of the pipeline assets are then going to drive those commercial opportunities that we see. This can be interactive as well.
So if you've got a question in the room, please feel free to put up your hand and I'll continue to try and monitor the chat as we go through. So if you look at where the company's programs are today, we've put polycystic kidney disease here at the top to focus on the largest indication that we're pursuing. Hopefully everyone is reasonably clear that we have a combined phase I-A , phase II-B study that is currently ongoing that sits ahead of a single registrational phase II study, 12-month study that sits behind on that anatomical surrogate endpoint of the size or the total volume of those patients' kidneys, with a 24-month confirmatory endpoint of that accelerated approval process based on the function of the kidney.
What we're looking to demonstrate is to show movement in the I-A, Ib study in relation to those endpoints so that we're getting a mirror of that registrational data set, giving the industry very high conviction that we are going to be able to reproduce in the larger patient population, probably about 200 patients in that registrational study. Can we see in 40 or 50 patients in the I-A, Ib movement on total kidney volume and eGFR in particular, with the upstream urinary biomarker of urinary PKD1 protein level? That's really the objective where we've progressed to here. The I-A, Ib is split into three parts, part A, part B, part C. Part A is being conducted in healthy volunteers.
What you've seen in the ANZSN or the Australian and New Zealand Society of Nephrology presentation is the safety data from the healthy volunteers in cohorts one to three was presented very recently. Where we're at today is we are partway through dosing in cohort four, and we should have some information in relation to the highest dose cohort, that optional dose cohort by the end of the year. The part for me that was very encouraging about the industry's progress recently is we have seen one of our competitor companies, competitor peer companies, I should really say, using the same modality, PPMO, via the same intravenous route of administration, demonstrate safety data in a different indication, myotonic dystrophy. So that's why they're not competitors for us, but rather peers for a 15 mg per kilogram dose of PPMO.
So a very, very similar molecule administered via the same route of administration with a more frequent dosing administration at five times the dose that we're envisaging administering in the polycystic kidney disease patient population, demonstrating clear safety tolerability, not being plagued by the issues that implicated their Duchenne muscular dystrophy program from an electrolyte disturbance standpoint and the consequent questions of what's going on in that kidney. So I think that bodes very well for PYC, but obviously the even better part was that we saw the same thing in cohorts one, two, and three of the healthy volunteer population in part A of our study. In addition to completion of cohort four in part A, you know that we have also progressed to dosing patients in part B of that study.
Before the end of this month, we hope to complete dosing within cohort B1. I think we do need to calibrate everybody's understanding that part B in patients will be slower than part A. I want to explain the reason for that. Patient identification and meeting of the eligibility criteria for the study is tricky, much trickier than the healthy volunteers. The first thing that we need to do is genotype the patients or sequence their DNA to confirm that their mutation is in the PKD1 gene, because there are different genes that drive polycystic kidney disease. PKD1 accounts for about 80% of the total patient population, but we need to confirm that the patients have got a mutation in PKD1. That's about a six-week process from the time that we obtain the tissue sample from the patient for the genotyping.
Once we've confirmed that the patient has a PKD1 mutation, we then have to send them for an MRI to confirm that they meet the Mayo Imaging classification criteria for the size of the kidney, knowing that we are conducting that trial in patients who have Mayo Imaging classification types C, D, and E, so larger kidneys. If they have type A or B, that's too early stage for us. It's not that the drug won't work for them, but it means that we're not as able to see that signal quickly because the kidney is already quite large and small changes in volume are relatively easily detectable. So at the minute, because the Australian clinician population don't use MRI to monitor disease progression, we're seeing about a 70% failure rate on the MRI.
So we have to go through that whole process end to end for 20 patients in order to recruit the six that we need for the cohort and the dose escalation. Over time, we will be able to build ourselves up a bank of patients, so it will become quicker as we move through to the later stage cohorts. The other big point that I want to make in relation to this study, we have a tendency in Australian life sciences to get very prescriptive around when specific milestones that are going to drive evaluation uplift are going to occur, and we need to be very careful about doing that here.
I think because we saw Novartis acquire Regulus as a company at the end of a three-month multiple ascending dose study where PYC will be very soon, there is great hope and expectation about what we might see in that study. But I would encourage all of you to go back and have a look very closely at the Regulus data set because it is a very subtle shift in relation to the separation of the placebo or natural history groups from the interventional groups. There is a lot of overlap of that data, and I think everybody needs to temper their expectations in relation to exactly when that's going to occur. The data that I'm much more excited for is 12 months' worth of exposure.
Really, from six months onwards is when you're giving yourself scope to see the differentiation, clear separation between the natural history placebo group and the interventional arms of that study. So that's where we've got to in polycystic kidney disease. I think things are progressing very nicely indeed. I think the team, the clinical operations team under the leadership of Paula Cunningham, that program have done a really beautiful job of progressing that asset. And there is obviously a huge amount of focus in relation to where that program is going. This is one of the assets where we have a continual dialogue with multiple industry participants because there is such a strong degree of interest in where we're going.
It's really that 12-month data in the multiple ascending dose study at the higher dose cohorts, cohort two and three in particular, that's really what's going to trigger the opportunity there. Putting that in context, we are in no way shying away from the fact you are going to see data through the course of next year because it is an open label study. So as that data comes to hand, it will be going out into the public domain, and I think what the Regulus transaction tells you is you don't need to see much in order to get a multi-billion dollar transaction away in the context of this particular indication because of the extent of the patient need and the size of the market in the event that you have life-changing impact for those patients. What we are looking to do is not to replicate that transaction.
We are looking to create data that takes us a full change beyond that by not going three months through the clinical trial and extrapolating over a nine-month window, but rather delivering 12 months' worth of data. But there are some patients required in relation to that, but I think the rewards will be worth the journey. The Phelan-McDermid syndrome program, I am very excited about. I think there has been a gross underappreciation of the potential in this indication. And I think if you think about the two key pieces of data that we spoke about before, have we got a quantitative cure in cells for this condition? Can we restore the missing gene expression back to wild type levels seen in unaffected individuals in a human brain cell, the cells in which this is occurring?
Does that give you downstream functional rescue of the communicative deficit between those cells? If you think about the quality of the answer that we have generated in that regard, if you then look at today's data and you see that the drug is safe and well tolerated, all doses assessed in the dose range finding studies in the non-human primates, meaning you can administer lots of drug to the non-human primate, and that is the best species for predicting what is going to happen in the human. If you then see a strong biodistribution or lots of drug in the target tissue in the brain, you're feeling very confident in relation to where that program is heading.
But to go one step further downstream and to see target gene modulation, SHANK3 modulation in the non-human primate that is giving you the link back across to what we've seen in the patient derived models, that is a really high conviction preclinical data set in that setting. And if you then look to the benchmarking, if you want to go to the next step again, look at the benchmarking to a drug that is effectively the same size, same backbone chemistry, just a different sequence of letters that's being delivered. And here I'm talking about zorevunersen or the Stoke Therapeutics drug for Dravet syndrome.
If we can benchmark all of those key preclinical parameters, the potency of the molecule, the safety, tolerability, the biodistribution profile, knowing that the route of administration is the same, that the target cell is the same in the target tissue, that the phenotype is the same, that it's language and cognition that really matters to those children, and you've seen the data for zorevunersen on the language and cognition endpoints in their phase I-II study, and that that is supporting a multi-billion dollar valuation for Stoke Therapeutics. The other thing to take heart from here is, look at the change in the market capitalization over the course of the last four or five months in Stoke, five to six X from the lows, around $5, the company trading up around $30 today, so it can happen quickly.
It really is based on the data that has been generated behind that and presumably the industry interest as RNA therapeutics are really coming into the forefront in that regard. We're not alone in relation to the difficulties that we're facing as a company. I think the very exciting thing here is Phelan-McDermid syndrome is a larger indication with a broader interventional window than Dravet syndrome. There is a lot going right in that program. What you'll see here, the next major milestone is actually human safety and the early efficacy data, recapitulating that. We're going to be moving that asset into clinical development next year. It's a very, very exciting time in the context of that program as well. In RP type 11, the focus is really on the transition to a registrational trial. It's got two dimensions to it.
One is working with the regulator to define the finish line. And that's the Type D meeting that we're scheduled to conduct very soon. The other dimension is looking at how we're going to integrate what the regulator is expecting in terms of an approval for the drug with what's happening in that phase I-II study and the open label extension as we push patients beyond the 12-month pathway, very similar to what we spoke about in polycystic kidney disease, but giving ourselves a mirror of the proposed registrational trial design in the phase I-II study. So we can build very high conviction that we are on the pathway to an approval. With that in hand, coupled with the outcome from the regulator, that is really the opening of the transactional window for that asset. So it's coming very soon.
I have encouraged Sri, who's driving that FDA engagement, just to temper the speed of the execution of the Type D engagement. I'm very comfortable if that moves to initially we guided to this quarter, but if that moves to January or February, there is a particular question that we want to ask the FDA in relation to our proposed primary endpoint, which we're very high conviction is going to be mean change in LLVA. So we've got a very good understanding already of what we're likely to get out of that meeting with the FDA.
What we're looking to do is to engage the regulator, given the macro trend and the strength, the appetite for looking at unconventional ways of getting these gene therapies for rare disease, gene therapy in the umbrella term there, to patients with a desperate need very quickly. What can we do to work with the FDA to understand flexibility in relation to the pathway to market there? We will come out with a further update in relation to that data set before the end of the year. You have those two milestones in the very near term, data from the ongoing studies, the open label extension studies coupled with the proposed FDA engagement timeline, and then very soon thereafter, the outcome of that FDA meeting.
In ADOA, you've very recently seen that we've finished the dose escalation study in the single dose format in patients, and we're now moving to a global multiple dose study. This asset is 12-18 months behind RP11. What you're really looking for here is the data that will be coming in the second half of next year, once patients in the multiple dose study have been on drug for 12 months or more. Some very exciting, early, very early efficacy data that was announced at a conference very recently. I think really the key thing from the dose escalation study to take away is the safety tolerability profile. We just need to see that profile mature in terms of greater exposure to the drug and a larger number of patients as we move through the multiple dose study.
And from there, it's very much a recapitulation of what we're looking at in RP11, understanding what the regulator wants to see in terms of the registrational pathway and ensuring that we've mirrored that in the phase 1/2 study to give us the conviction that we are going to launch into that registrational trial. What then are we going to do about the situation in relation to valuation? What we have in front of us within the next 24 months are many, many milestones that give us the opportunity to drive a full change in the intrinsic valuation of the company. And so if you look through those, I don't intend to go through them one by one, but you can see there is a lot of human efficacy data on this page. And you are aware that human efficacy data is the currency of the realm.
In addition, PYC has got the opportunity to close the gap between our market capitalization today and our intrinsic valuation, and we have just seen the green shoots waving through the RNA therapeutic space in particular in the U.S., a real change in sentiment over the course of the last couple of months and possibly even in biotech in the Australian market as well, so it's been particularly unfortunate timing in relation to the issues that PYC has seen over the course of the past month, but there is a very clear window to turning that around, both in terms of closure of the gap between market capitalization and intrinsic valuation today, if you think through the probability of success that the company is being ascribed by the capital markets, it is very, very low for each one of these programs.
That is not commensurate with the evidence that we're putting out to you in relation to the probability of success of each of these assets. It's also not commensurate with the feedback that we are getting as a company, either from industry, but I think particularly encouragingly from the KOLs. On the industry front, you obviously have to wait to get full conviction for the deal to materialize. As we spoke about before, that can take time. What I think the company can do a better job at is making available those global experts in each one of these indications to walk you through with an independent lens what is the very special feature about each one of these drugs and how does the data generated to date inform what's going to come. We'll be looking to do that going forward.
In relation to the commercialization strategy, as we spoke about before, we are very much open to finding a partner in relation to the ophthalmology programs, precisely because of the issues that we've spoken about from a value recognition standpoint. It tilts the balance very much in favor to that business development and licensing approach. I think the thing that we have to be careful of is the precise timing of those transactions is not entirely within our control. It's largely a counterparty-driven process. And so we've got to be prepared to continue to develop these assets. I think the lovely thing about those ophthalmology assets is that PYC as a company has the wherewithal to launch them commercially independently. So we don't need to be beholden to an industry partner in relation to taking those programs forward. There is certainly the option to do it.
There is certainly a preference to do it with the right partner on the right terms. But we are not going to rush into that transaction, and we are not going to accept sub-fair value terms in relation to those programs in order to out-license them, given that we have a very strong opportunity to take those assets further ourselves and very high conviction in the programs as well. What we need to do then is to work on the value recognition side and potential other ways of enabling the company to go down further, deeper into clinical development across all of its assets. We have some very interesting options and opportunities emerging in that regard. I will stop there and see whether we have any other questions or comments. Go room first. Hi, Rohan.
In your introductory remarks, you made reference to the cash runway that you have running through to a certain date, and I didn't catch it or write it down. Can you repeat, please?
Fiscal year 2028. Okay.
And just with that, what does that assume with regard to clinical development across all four programs, or is that with the assumption that you're prioritizing PKD and PMS?
No, that supports the commercialization and capital allocation approach that I've spoken about here, which is all four assets into development. There's an open question around the precise timing of the transition to the RP11 pivotal, but that's to be worked out on the back of clarity from the regulator in relation to exactly where the hurdle is for a drug approval in that indication. So it's supporting the activities that deliver the milestones that you saw in the table on the preceding page.
Just another quick one on PKD. You know, I think historically you've spoken to that program as being such a large indication that it would be difficult for PYC to stand alone commercialize. Is that view being maintained? Would you be looking for a commercial partner there, or is that something you're kind of starting to rethink?
I don't think there are any changes there. I think really the company's understanding of the pathway there, as you know, it's just such a high prevalence indication with such a broad spread and distribution of the patients in the U.S. in particular, that it would be very difficult for a company of PYC scale. I mean, impossible for a company of PYC scale today. There's obviously water under the bridge to flow through.
But I think the way the company has always thought about that asset in particular is that the partnering, that it will be better launched in the hands of a partner, a large pharmaceutical company in particular. I think it would take to launch that asset appropriately, that there will be two opportunities to do that. One, at the end of the Ib data, when you've got that 12 months' worth of drug exposure at the proposed therapeutic dose in hand, and then you will have it again if you decided to fund that pivotal study independently. And then at the time of the new drug application, you would have a, I think, an ultra-competitive process. I think the understanding at the minute is that you're going to have an ultra-competitive process at the end of the Ib anyway. So there are two good options there.
I don't think we have matured the thinking sufficiently yet to work out which of those two might we pursue or be inclined to pursue.
Reveals my poor understanding, but you've caught me out with the cash to FY2028. Have you rethought any expenditures in order to achieve that deadline, or have I just got the date wrong?
No, it's really it just relates to the only change there is in relation to taking the time to digest from the FDA what comes back from that Type D meeting in RP11 and the upfront costs associated with the launch of that registrational study. Really, if you shifted those back from the first half of next year to the second half of next year, you would then see the cash runway extend into FY2028. We don't have any questions in the room.
We'll go to some of the ones that are coming through online. Can we please give some color to Mr. Tribe's position? He seems aligned to longer-term valuating inflection points before doing deals. Large holding, is he likely to be patient enough to wait? Look, I can't really comment in relation to intentions of individual shareholders. I think those questions are better put to the individuals involved. Regarding the RP11 trial on previous investor calls, we'd express the expectation that a higher dose would likely yield a better outcome. Have any findings been published on the 75-unit dosing on a previous investor call that was stated that there'd been an extension study that would include some participants in the RP11 SAD and MAD, and the dosing would be 75 and 120? What's the status of the extension study?
That's a good question, actually, and one that I wanted to update you on. Yes, we have got data published in relation to the 75 microgram patients. I think the opportunity here is for us to update the market in relation to the longer-term outcomes of the multiple ascending dose study, and that will come before the end of this year, as we've spoken about beforehand. We also have rolled those patients in that multiple ascending dose study over into an open label extension trial. So those patients are continuing to be dosed at 30 µg and 75 µg. There was a window in between the end of the multiple ascending dose study and the start of the open label extension. There are some patients who didn't have drug for a period of up to eight months.
That just creates a little bit of a difficulty in terms of charting the 24-month progression of those patients, knowing that they've had drug exposure for a window, then drug off for a window, and then now they're back to the drug-on standpoint. So we've got to do some work in relation to interpreting that data. In relation to the proposed increase to the 125-microgram dose, this was on the back of not having seen any adverse safety tolerability problems in the phase I-II study and wanting to ensure that we weren't leaving the putt short as we went into the registrational trial. When we proposed the dose extension, the open-label extension trial to the FDA, we had feedback that we had clarity in relation to the path at dosing at 100 micrograms.
But if we wanted to dose at 125 µg, we had some additional non-clinical studies that we needed to do, in particular focused on the detection of drug in plasma at those high doses. And so rather than go back and do that, given that we had seen data at 30 and 75 micrograms that suggested we're in the pharmacodynamic range, the conversion has gone on with the time pressures in mind of moving those patients through to an open label extension study without too long a dosing gap. We are continuing that open label extension at 30 µg and 75 µg. So there's no intention at this point of continuing to escalate to 125 µg. We've got some further questions in relation to individual shareholdings. It's the view of many that our valuation will only be driven fairly by U.S. investors who understand the science.
What can we do about bringing them on board as they won't be buying small lots on market? Look, we are engaged with U.S. institutional investors, and as I mentioned before, the company has done a lot of work to create optionality in relation to access to future capital from counterparts who can potentially bring something beyond just the capital to the company. There is a lot of interest on the part of U.S. specialist investors in PYC. I think there is a lot more familiarity and comfort with looking at data sets on the part of specialist investors out of the U.S. in particular, and so there is shared enthusiasm on the part of what this company has and where that's going over the course of the next 24 months in particular, as we've spoken about, so we have optionality there.
What we haven't done is form the view, those existential questions that I spoke about earlier in relation to, firstly, balancing out the need to push each one of the commercial opportunities and to create the optionality that we're seeking there. Secondly, to determine if we were going to go for additional capital inflows, where might that come from and what implications are there of going down that pathway? Obviously, with the additional question of what could we do in relation to the terms on which that capital flowed into the company? Are there other potential strategic players who would have an interest in PYC at this point in time? So that's what I meant. There are lots of options available to the company. What we've got to work out is how we integrate all of those options into a forward plan.
So we don't have a plan today to draw capital from U.S. institutional investors. We don't have a plan to go to the Nasdaq at this point in time. But we are very clear in our understanding of the obligation to act in the best interest of all shareholders and to ensure that if we cannot close this valuation gap in the very near term through the delivery of the technical milestones that support the enhanced probability of success of the assets, we are going to have to look at other ways of getting shareholder value recognized. And one of those that will be considered is in relation to a potential pathway to a U.S. listing. What is nice to know is that we have got the option for that in the event that the company chose to go down that pathway. Will this be available to replay?
Yes, I think we will be able to make that available to you. Michael, I think you've raised a hand, but if you wouldn't mind just typing the question into the chat, that will be easier for us rather than taking you off mute. Any other questions in the room? See whether Michael gets his question into the chat. Doesn't look like that's coming imminently. Oh, hang on. If a PMS trial were to start today, when could we expect to see behavior rescue reversal of regression based on expected trial design? Look, an interesting question. It's got a couple of dimensions to it. It would be dependent on which endpoint you're looking to see the movement.
What we typically look for here are early potential indications that the drug is working, and then later look for the outcomes that are more aligned to the critical elements of the phenotype for patients with Phelan-McDermid syndrome, and talking to the clinicians in this space, it's very clear that what's important to the patients is language and cognition. On those endpoints, you're looking at a 12-month+ exposure of drug in the patient to really see the full benefits of that because the patient needs to be given the opportunity to acquire skills in the context of having the drug on board, so it does tend to take longer in that context. There are some potential markers of earlier movement that we could look at. These are in the process of being explored by different clinicians, particularly in the U.S. out of Mount Sinai and Rush University.
We are working with those clinicians to see whether or not we could get an earlier signal in that regard, whether or not potentially even between three and six months we might be able to see something there. The other dimension here relates to the dosing at which you're administering the drug. The starting dose and the dose escalation protocol in the clinical study is informed by what we've seen in the GLP tox studies that are about to follow. That's where the absence of a maximum tolerated dose in the NHP data that's gone out to the market today is very encouraging. It's suggesting that we've got quite a lot of headway in terms of the therapeutic index, which means that the starting dose in the patient might be higher, which means that you have a higher propensity for an earlier read from an efficacy standpoint.
But I think it is important, again, that everybody understands the complexity of what's going on here. We want to run the phase one, two studies in PMS patients in four- to eight-year-old children, earlier stage of disease progression, because those are the children in whom we typically see that decline that we've spoken about, the regression. That means we need to reverse engineer into the GLP tox studies juvenile animals. So we've got additional work to do now in juvenile non-human primates to enable the clinical protocol to progress into the patient population that we're looking to intervene in directly.
In addition to that, the enthusiasm and excitement around the KOL community on the back of the RNA therapy for Phelan-McDermid syndrome has meant that we've had some clinicians volunteer to run what they call a lead-in natural history study, where we bring patients in prior to launch of the interventional clinical trial to map their progress over a 12-month period to see whether or not they are acquiring skills or whether they have already entered the regression phase of losing the skills that they had previously acquired, which is obviously very important for determining where you think that patient should be in relation to their response to the drug. So we are starting to do all of this work in the background as well to prepare ourselves for that very early efficacy signal.
Again, I'd encourage you to go back and have a look at the Stoke data in Dravet syndrome. It's a different gene, and so you can expect there will be some differences in relation to how early that signal is seen. But certainly, by 12 months, they've got a very good handle on the data. And more recently, you've seen the 24- and 36-month data show further separation and maintenance of the improvement in those children, which I think holds great hope for the Phelan-McDermid syndrome patient community. When can we expect to see some biomarker indications on polycystic kidney disease? We're in the final processes of validating the assay today. The assay will be run on both the healthy volunteer urinary samples and also those that are being collected from patients.
But I expect that you're going to see something in relation to that in the first half of next year. That's really the time frame. So it's getting very near given that we're approaching the end of this year already. I think, though, that the focus has really shifted to the total kidney volume and eGFR endpoints. There is just, there's a lot of variability in urinary PKD1 measures. And again, I'd encourage you to go back and have a look at the various datasets that's in the public domain about just how much variability there is in relation to the baseline expression of urinary PKD1 to start with.
But also the test-retest variability is in the order of 35%-40%, meaning that if we measured anyone's urinary PKD1 protein on a given day, it could vary by up to 40% if they came in a week later. So in the context of that amount of noise, detecting your signal in small sample sets is very challenging. So just be careful not to ascribe too much weight to it. But having said that, there will be data available, I'm sure, in the first half of next year. Okay. We've got some hands raised, but we can't, unfortunately, take you off mute individually. So if you do have a question, we'll give one final opportunity to type it into the chat. Any other questions in the room while we wait for those online? No, I don't think there are any others coming.
So look, it hasn't been the company's finest hour. And I want to be very clear that the company understands and accepts that and the responsibility for turning things around in terms of rebuilding the trust and confidence of the public markets. I think there is an opportunity to do that very quickly. I wanted to make sure that everybody understood what had happened and in particular understood that what occurred had nothing to do with the technical merits of the scientific progress in relation to each one of those programs. It's also very important, given that this did play out in the public domain, that you have a very clear understanding in relation to what the company's view is on the issue that drove the problem, how we are going to develop our pipeline going forward, how we are thinking about the commercialization approach and capital allocation.
And so the company is aligned now in relation to the development of all four assets in the company's development pipeline. I think it is an incredibly exciting window in terms of what's coming. What we clearly have to do, though, is a better job at translating the technical progress into shareholder value creation. And it has been an acutely frustrating window where I think you can see why the temptation to tap the brakes has occurred. But really, for me, given the excitement of what is coming and the direct proximity that I have to those industry conversations around these assets, it's really a time to tap the accelerator, uncomfortable as it may be. It is a very, very exciting pipeline of drug development candidates. The industry, as you can see, is moving towards RNA therapeutics. It's moving increasingly towards RNA drug conjugates as well.
The data is just getting better and better. It is coming towards us. If we can continue to execute well, if the data continues to go our way, there are some very big things coming for PYC in the near term. We've got a lot of work to do on our side now, because if you look at that 24-month window and what's coming, the preparatory work for the execution of those milestones is happening today. What we must do is have a board structure and an executive management team who are capable of generating the best outcomes from those commercial opportunities by setting the platform correctly. That's very much what we're focused on. You will continue to see an evolution of the company's makeup in that regard so that we're properly prepared for what's to come.
Is the company, we have had a couple of questions come through. Is the company working on a fifth drug? No, not at this point. We're very much focused on the four in the clinical pipeline. Is there scope to outlicense the delivery technology? And I think you got a question on notice in relation to the decline of AAVs within the industry and the strategic shift of Big Pharma away from it and whether or not that has driven any further interest in PYC's delivery technology. And the answer, the frank answer to that at this point is no, it hasn't. Unusually. But I think it's because there is so much focus now on the assets. People are getting their head around the individual assets that we haven't pushed and we haven't had inbound interest or even time for inbound interest in relation to the delivery technology itself.
Perfect. All right, well, thank you very much, everybody. We look forward to updating you in the very near term in relation to the additional changes that are going to occur, and I think even more excitingly on the technical milestones that are coming in the near term in relation to the pipeline, so we'll have a chat then.