PYC Therapeutics Ltd

ASX:PYC

Earnings Call Transcript 2022-Q2

[Rohan Hockings, executive]

Okay. I think we're on time so we might get started. [Operator Instructions] Hello, and welcome, everyone, to the PYC Therapeutics second quarter investor call. My name is Rohan Hockings, and I'll be hosting the call today. Before we begin, I want to go through just a couple of housekeeping items. The first one is a standard safe harbor disclaimer that I am required to read to you, which I will now do. Before we begin today's call, I would like to make the following safe harbor statement reminding you that today's discussion will contain forward-looking statements that involve risks and uncertainties. These risks and uncertainties are outlined in PYC's filings with the Australian Securities Exchange. As such, actual results may differ materially from what we discuss on today's call. PYC disclaims any obligation or intention to update these statements in the future. I'd also like to remind you that today's call is being recorded. Just so you're aware that we have a copy to put on the Investor Relations part of our website for those who are unable to join in real time. I'd also like to invite everybody to use the chat function to submit questions. As we move through to the second half of the presentation, I will endeavor to address all of the questions that are posted in the chat function as well as those that have been submitted online prior to the meeting. So please feel free to share those in the chat function. Broadly today, we've got 3 objectives to get through. The first one is for me to provide you with a framework for understanding what we expect to happen in the future. The second one is to share a sense of excitement in relation to where PYC is at currently as a company. I think everyone is familiar that it's been a very difficult time in life sciences generally and aware that the index has fallen 60% and further in the U.S. But I think it reminds you why it's nice to be part of an organization that is checking the boxes and making material progress in terms of doing what it said it would do on the path to the broader objectives that are set out. And that's very much where PYC is at, at the minute. And it's a continuation of the theme that we spoke about in the first quarter investor call in that regard. And finally, I'd like to give you an opportunity to ask any questions that you may have in relation to the company or its future directions. I think it's really important that we try and provide as much understanding as possible to our investors about where we're at as an organization and where we're headed. So please feel free to frame any and everything that you wish to ask of the organization. We'll do our best to address those. I apologize in advance for my voice. I'll try and make this as much fun as you had on a one-way presentation with a speaker who's at risk of losing their voice, and we'll see how it go. You may just have to bear with me at different moments. In terms of the structure of the presentation, I'm going to walk you through the first 3 pages of the new corporate presentation. And then I'll skip forward to the 12-month forward view at the end of the presentation to allow a lot of time at the end to open up for Q&A. So I will hold the microphone early, but I'm keen to make it as interactive a session as we can. So if you guys populate as we're going through the questions that you've got in relation to each part of the day, we'll come back and address those at the end. The one thing that we didn't do on the first quarter investor call was really wind things back to an outstating appraisal of the company and what we do, and probably for the benefit of those who are more recent entrants to the PYC shareholder register. I think we've got a lot of shareholders who have been with us for a long period of time and who've got a really good understanding of what we do, and that's terrific. But also important that we go back to basics and recap the story for those who are newer entrants to the story and less familiar with it. At our most basic, we are a precision medicine company. And we design RNA therapies for patients who have genetic diseases, and specifically for those patients who don't have current treatment options available. For those who have been around for a while, you'll know that we've got 4 active areas of discovery and development work within our pipeline. We have 2 programs addressing blinding eye diseases in our retinitis pigmentosa type 11 program and autosomal dominant optic atrophy program. And we also have an interest in diseases of the central nervous system and diseases of other organs and tissues within the body, such as the kidney. Those are in an earlier stage of discovery work. And we haven't yet nominated the targets that we're pursuing in that regard, but we expect to be in a position to do so very soon. In terms of what's different about PYC and why we're differentiated and how we think that's the overarching strategy of the company, the fundamental challenge in the precision medicine field remains to this day getting a sufficient amount of your drug into the target cell. It's relatively more straightforward if you've got access to the inside of that cell to be able to modulate the cell's behavior in the way that you want to. So we've made huge progress in the field of the design and development of precision medicines. Not so much progress has been made in the field of delivery of those drugs to their target cells. And here's where PYC has a very significant advantage. We are making molecules that are made up of 2 halves. One is a delivery technology whose job it is to be the chaperone for the precision medicine to traffic to the target cell of interest and deliver that precision medicine across the cell membrane and to the inside of the cell. We leverage that foundational platform to then design the other part of the molecule, which is the precision therapy or RNA therapy itself. Here, we don't intend to make any permanent changes to the cell. We're not a DNA therapy. Rather, we are akin to what has been described as a mini gene therapy. So we operate at the level of the RNA, which means we have a very nice balance between a very durable effect, which affords a patient with very long dosing interval, but also reversibility just in case we have an undesired effect or we push the dose of the drug beyond where we want it to go. It's not a permanent change, and you can wait for the drug to wear off. So it sits at the sweet spot between durability and permanence and reversibility. And as I mentioned before, we're a multi-asset company. So we're not pegged to a single program. We do have a program, our most advanced program is about to enter clinical development first in-human studies for the first time. There's a lot of excitement around that program as a whole. But we have applied this technology, as I mentioned before, in multiple different settings. The first 2 in the context of 2 different bonds of blinding eye disease and then into other target tissues that will demonstrate the full potential and scalability of our technology. I think the really interesting thing here is we play in a very well-defined space. So we look at the very low-risk end of the drug development spectrum. We focus on diseases that are caused by mutations in a single gene and whose pathology is consequently very well understood. So it's a mutation in that gene and that gene only that manifests in the disease condition or what we call the phenotype, the cluster of symptoms or the malfunction that the patient is experiencing. And the great benefit that, that confers to us, we'll touch on again later, is, if you've got a very precise understanding of how the disease is occurring. And with a high degree of conviction that the target gene whose expression you are modulating is the root cause of that disease, then you benefit from a much higher propensity for success as you progress through the development spectrum, and in particular, as you move into clinical studies, which is especially relevant for our RP11 program because that's the point that we are drawing to towards the end of this year.

Just to give the visual depiction of the pipeline here. As I said before, we've got the 4 programs that are moving through at different stages of development. One of the challenges for the organization is ensuring that the best is not the enemy of the good enough. We always have opportunities to fine-tune our molecules and make them better. But at the same time, we have patients who are waiting for these therapies. So we can't sit on them in nonclinical development forever. They need to be launched in order to reach the target market that we are pursuing in that context. So we need to balance the idea that we continue to refine the molecules with the need to get them into patients and move them through clinical development as well. You can see there, top to bottom the different programs that we're working on. I think one thing that surprises people, in particular, when they look at the size of our patient populations that we are pursuing is the commercial value associated with that patient impact. So we are very motivated to create these therapies because these are patients who have no treatment options available to them today. And the follow-on benefit from that is a very high commercial impact because there's a specific incentive that has been put in place by the drug development industry to serve the needs of these patients who have what we call rare diseases or orphan indications. And the reason for that is, despite the fact that these are individually rare diseases, so you see patient populations in the single-digit thousands through the western world, is our target market in the first instance, collectively, they are very common. So 7% of the population suffer from a rare disease. And so the industry has decided we adapt. What we don't need is an N+1 cancer therapy, a subtle progression on what is currently available for patients who have a wide variety of treatment options available to them, but rather, we need to make high-impact therapies that will change the course of disease for those patients who have no treatments available to them at all. And so the way that they have done that is through a process largely driven in the U.S. called the Orphan Drug Act, where they're very heavily incentivized drug makers to pursue therapies for these indications through very high pricing. Most recent assessment, it was up. Approximately $180,000 per patient per annum was the median orphan drug price in the U.S. So this specific objective has yielded a lot of focus and interest in these rare diseases, and that is the space that PYC plays for a number of different reasons. We spoke about the probability of success early, the scope for patient impact, the rapidity of the path to market. So because there is no standard of care available to us, we benefit from a potentially more rapid path to market, looking at 2 clinical trials rather than 3. And then I think a very close link between the attractiveness of RNA therapeutics in a particular context of diseases that are caused by an insufficient amount of protein in the cells. That cluster comes together to really drive the PYC strategy. So that's where we've got to. We build value in 2 ways. One is through progressing these assets towards the target market, and ultimately, revenue generation for PYC in the event that we're successful; and secondly, through scaling our technology to find its most valuable application across those disease indications where it's going to be most relevant. So seeking the full potential of the platform technology. Final page that I wanted to walk through, just to give people who are less familiar with the story in understanding of what we're doing is to touch on the second point that's made here. It's a reinforcement of the notion that I spoke about earlier in the context of monogenic diseases. I think this is something that the Australian market struggles with in particular as well. But the idea that we've got 5x higher prospect of success in clinical development as compared to more complex diseases in which there is a lot going on, that is contributing to the manifestation of that disease, and often with elements of it that are not completely understood. So if you don't know how a cell is misbehaving in order to manifest in the disease process or precisely what's going wrong inside that cell, it's very difficult to have conviction that your therapy to correct that cell's behavior is going to be effective. So we are very focused on those domains where we have what we call high biological validity of the targets. And that leads us very closely to these monogenic diseases. And for those who've been with PYC on the journey for a couple of years now, you'll know we have got a bunch of assets that are directed towards those larger but more complex indications as well. They have been put on the back burner, progressed through collaborations with third-parties in the recent past as a consequence of a strategic review that has really narrowed down our focus on these monogenic indications. So hopefully, the rationale for that is very clear to everyone. I'm going to skip through now. There's an opportunity for you all to read. This has been placed on the AFX platform in preparation for today's call. I really wanted to focus the conversation today and to give you some color on where we feel we're at as an organization and specifically where we're headed by referring to the forward view of what's coming in the next 12 months. And I think as you see from the title of this page, it's a really critical window for PYC, not least because we are making the transition from a nonclinical company to a clinical stage company. And if you wind back over the course of the last 12 months, we said that we had 3 milestones that we wanted to get through in order to really add conviction to the fact that we were going to make an impact in patients' lives. The first one was to ensure that we could establish a safe and tolerated dose of our lead investigational drug candidate in nonhuman primates. And the reason that's important is because that's the most advanced readout that you're going to get outside of a human, of the safety of the molecule because the nonhuman primate is the species that most closely resembles the human. So if you look back to our results from late last year, you'll see in the non-GLP dose range binding studies that we're able to achieve that. The second objective that we had was to engage with the U.S. Food and Drug Administration in the pre-IND meeting to find the path to clinical development of the asset through the IND submission that's going to occur later this year. That occurred in the first quarter of this year. And we were very fortunate that we had a largely aligned view in terms of what needed to happen between the timing of that meeting and the IND submission later that year as well as the proposed first in-human evaluation protocol for the investigational drug candidate. So we checked that box as well. The third and final objective that we set out in that transition was the IND submission itself. So I want to walk you through. What we've got to do in relation to progression through to that IND in the fourth quarter of this year is really to complete our repeat of those non-GLP toxicology studies that we previously completed in the context of good laboratory practice standards. So we are very much expecting to see a very similar outcome to what we've seen in the non-GLP studies there. Those studies have begun. And we are now into the window where we're just starting to approach the first sacrifice of the animals after the single dose that will be used to -- once that has been fully reported and the histopathology evaluation has been completed, that will be used to complete the submission of the IND documentation. It will take several months to collect that information into the IND, in the required format for the IND. That will be submitted to the U.S. FDA. And within 4 weeks, we should understand back from the FDA as to whether or not that has been accepted, and we have a clear path through to first in-human studies. So that's really what we've got to do there. In terms of where we progress to from that point in time, the first half of next year is really devoted towards initiation of those first in-human evaluations. We have a very significant benefit here because we are progressing directly into RP11 patients. So we're not conducting a Phase I study in healthy volunteers, but we're moving directly into the disease context and also a combined Phase I/II study. So one of the topics that is very much front of mind for the organization right now and I think it's going to be front of mind for investors as well as we progress to that point is, to what extent can we pull the efficacy signal, the clinical efficacy signal from the Phase II/III study forward into the Phase I/II study to give ourselves, our investors and our potential investors conviction that we have the greatest prospect of market entry that is possible based on the data that we have generated. So -- and I think the broader context for this is the primary objective of those initial first in-human studies is to establish safety. And there's no getting around that. That's exactly what we will do. But there is an opportunity to incorporate dimensions of the study that will give us some insight on the efficacy of the investigational candidate in those early clinical studies. And that's really what's going to drive the closure of the very significant gap between the company's assessment of its intrinsic valuation and the market capitalization of the organization or where we currently trade at on the securities exchange. So a very, very big, very interesting body of work that's coming. And I think also not to forget that this is the combination of many, many years of work on a journey that is singularly orientated towards changing somebody's life. And so to understand whether or not we are going to achieve that is going to be a pivotal moment for our organization at large. That's really the horizontal cut of what's happening in the lead program. From there, it really becomes about leveraging the platform technology to provide as many of those impactful readouts in as shortest space of time as is possible. So what we want to be doing is really moving through those clinical readouts as proximately to one another as we possibly can. We're currently looking at windows of approximately 18 months between the assets. And we are trying to maintain that and possibly even shorten it in some instances through into clinical development. Because that then starts to demonstrate not just that binary outcome of whether we are successful in the RP11 program, but whether or not we are able to scale what we hopefully see in terms of the efficacy profile across multiple different indications. And as you see in the bottom left-hand corner of your screen there, we're just approaching the point in the company's development where we can demonstrate the applicability of the technology outside of the eye. There are many reasons why we started in the eye. Not least of which is the fact that it's a complex organ with a very significant unmet patient need. So we're talking about in both of the indications that you see on the page here, progressive diseases that ultimately culminate in legal blindness for patients. Both of the diseases have onset in early childhood in many instances. And they ultimately yield a very significant impact in terms of the quality adjusted life of the patient population. So that's a primary driver of it. We also get to control the buy distribution. We have a partially immuno-privileged environment in the eye and have a raft of different reasons why we have chosen to explore the use of the technology initially in the context of the eye. But what we would like to do ultimately is demonstrate the applicability into other target tissues that, as I mentioned before, in particular, the central nervous system, neurodevelopmental disorders in particular, and then look at systemically administering the drug for target tissues like the kidney, where access by the vasculature enables us to modify disease progression or potentially modify disease progression in patients who similarly have unmet needs in diseases of those organs.

[Rohan Hockings, executive]

All right. I'm going to pause there and just have a look at what we've got in the questions that are coming through on the chat. We have one question that came through online before I get to the questions from the chat forum that relate to...

[Unknown Executive]

Whether or not we can actually start recruiting for the patients for the studies now so that we're ready to go.

[Rohan Hockings, executive]

So the first question that came through as a presubmission related to the enrollment windows for the clinical trial and whether there's anything that we can do in terms of activities that we're undertaking now to shorten that window through identification of the patients for participation in that study. And the short answer here is no. And the reason for that is because, in the absence of the IND, we are not able to have our human ethics in place in order to initiate the clinical trial. And we need to ensure that we are following due process in this regard. So no, we cannot and are not reaching out to patients at this point in time. But what we are doing is working with census that have got an inherited retinal disease register. And the big advantage that we get here in terms of the speed of enrollment is that we've got patients who have got a genetically characterized form of retinitis pigmentosa. So these are patients -- and remember, the retinitis pigmentosa is a cluster of different diseases, all of which manifest in a common phenotype. We are looking particularly at retinitis pigmentosa type 11, caused by mutations in the PRPF31 gene. What we can do to expedite that enrollment window is work with centers who are -- who have already identified those patients who have RP type 11 within the broader pool of patients with retinitis pigmentosa. And what that means is we don't have to wait for the genetic testing, and we can expedite the enrollment -- the passage of enrollment of those patients into the clinical studies. So the next question that we have from [ Matthew Walker ]. We've got a couple of questions here. So the first one is, can we please update the cash position and cash flow outlook, i.e. our runway? I know the phase transformational 12 months, which has been used before, but is obviously not reflected in the share price. I know broad market behavior. But why is saying at this time different? And finally, you're hitting some significant milestones in the next 6 to 12 months. Traditionally, what is the value uplift for each stage of change? And are there clear comparisons you can reference? So a good set of questions, [ Matthew ], and thank you for those. In terms of the company's cash position, we're currently sitting on a forecast of starting the new fiscal year, which we are rapidly approaching, with just over $30 million in cash. But we will then have the receivable for the -- rebate for the full fiscal year that we just progressed through. So the current estimate of cash and cash receivables puts us in a position of around $40 million. And if you look at our cash and cash receivables, we should be funded through to FY '24 at this point. So hopefully, that addresses your first question, [ Matthew ]. The second transformational 12 months, which has been used before. Obviously, not reflected in the share price. And you recognize what's going on in the broader of the market at that point. Why is it saying this time different? Firstly, I think it is the macro trend. As I mentioned at the outset, a 60% decline in the broader industry index is a very powerful -- that is an unusually powerful macro trend to be fighting against. So I think whilst we have made significant progress over the course of the last 12 months -- and I think it is worth observing it genuinely does not make sense to me that we could be valued less as a company now than we were 12 months ago if you isolate what's going on in the macro environment. So if you talk just purely the intrinsic view of the company, having characterized our molecule to the extent that we have in those tolerated dose studies that we spoke about previously, also in the pharmacokinetic studies that we have discussed recently and put into the public domain in terms of the trafficking of the drug to the retina and its retinal half-life and the implications of that for the dosing intervals in patients, remembering that this is the first time that this modality is going to be taken into a human eye, it strikes me as very unusual that we can be seen to have a lower valuation today than what we had previously. And I don't think there's any reflection of the data that's been generated nor the progress that's been made over the course of the last 12 months. So yes, I very much ascribe that to what's going on within the broader industry. It's difficult to complain. And I think we have to take on [indiscernible] the fact that we exist in an ecosystem and investors have a choice across multiple different companies around where they invest their money. And so the relative valuation of other companies who have also suffered very significant falls in their market capitalization has become a lot more attractive to those investors. So whilst on the one hand, I don't think it's a reflection of the intrinsic valuation of PYC, it's not, I think, feasible to pretend that it's not relevant to our valuation because of the integration of the company within that broader life sciences ecosystem. So I think we have to acknowledge that the valuations of those companies have come down. And we're also subject to the forces that are driving them down. If you look at the reasons that are driving that sentiment, the first one, obviously, and I think it's very well publicized, is the macro environment and the increased rates of inflation, what that means in terms of the cost of capital and the valuation of companies that don't currently have a top line. And so we are obviously in that position. And we are going to need to fund our operations one way or another going forwards. So we are not immune to those pressures. Secondly, I think you see on the back of a very strong interest, and I think we need to be cognizant of the fact that it was a very strong market towards the first quarter of last year, with the sentiment around RNA therapeutics and their role in the global pandemic in particular attracting generalist investors into the space. In large part, those generalist investors have left over the course of the last 12 months. So there are very significant flows of capital out of the sector, and the funding environment has [indiscernible] that context. But look, I don't think my best [indiscernible] in any way of what's going on inside the company. I think that we have built a significant amount of intrinsic value over that time period. And I think going forward, in the coming 12 months, we will continue to do so. And so finally, you're hitting some significant milestones in the next 6 to 12 months. Traditionally, what's the value uplift for each stage of change? And are there peer comparisons that you can reference? Look, that's a difficult question for the company to give an assessment of the forward view of the valuation. We can do it in terms of the drivers of the intrinsic valuation. That we feel more comfortable with because effectively, what we're doing is we are taking risk out of the journey of the asset from inception through nonclinical development, ultimately clinical development and through to market. But if you look at the variability that we're seeing in some of the peers, so you're asking for at the end of the question here. If you look at other RNA therapeutics companies who are focused on monogenic diseases, and we've previously referenced Stoke Therapeutics is one of them, those guys have been trading in a valuation band of between USD 500 million and USD 3 billion. And so what I think you get there is a sense that those macro trends at the minute are far stronger than the contribution that the intrinsic valuation milestones are making. What's happening, I think, is not so much a reflection on whether or not companies are meeting milestones and able to increase their intrinsic valuation, it's just a stampede of cash for the exits. And so it's really difficult to try and predict then what's going to happen on the back of PYC assuming we're successful continuing to check milestones as we push this asset into clinical development overall for the next 12 months. I don't know is the answer to that question. But what you do know is that we only really have 2 questions remaining with respect to whether that asset enters market. The first one, is it safe in humans, and the second one is it effective in humans. The second one is traditionally considered to be the primary driver of valuation of assets in clinical development. And so you see the underpinning for why the company is thinking so heavily about how we can pull forward inside onto that efficacy dimension into the Phase I/II given that we benefit both from this rapid path to market and also the fact that we're evaluating the drug in the context of patients with retinitis pigmentosa type 11 right from the outset of the clinical studies. So it's not a specific answer. I feel like I haven't possibly given you the degree of clarity that you're looking for. But I think, unfortunately, that's a reflection of the current state of the market in life sciences. Jay asked -- got a question. Will there interim results from the Phase I/II trials? And how long after it starts will that be available? So the answer to that question is yes. We will have interim results available. And there are different parts, part 1 and part 2 of the Phase I/II trial. We are starting with a single ascending dose protocol. And so what that means is we will be dosing a cohort of what is currently designated to be 3 patients at a low dose of the drug initially, because, as I mentioned before, we are optimizing for human safety. And this is the first time that this modality has been evaluated in human eye. So it's absolutely critical that we first do no harm in these patients. There will be a window of observation of those patients following the administration of the drug to the last subject within that dosing cohort. And after that window of observation has elapsed, we will have a review with our Data Safety Monitoring Board of the ability to increase the dose to our mid-dosing cohort. And we will then progress through the same number of patients designated for the mid-dosing cohort and the same observational window that sits at the back end of that before progressing to, again, following a review of the tolerability of the investigational drug candidate in those patients with the Safety Monitoring Board through to the high-dose patient population.

And so assuming that we can progress through the dose escalation protocol that we have set out, that will be on the back of an inferred safety at least in the short term for those patients. Those patients will then be followed for a period of 24 months to get the full and comprehensive evaluation of the safety profile of the candidate as well as the progression of the company to a multiple dosing protocol within the context of the Phase I/II. The initial progression through the single ascending dose sees the dosing complete, not the follow-up safety evaluation that I just spoke about, but the dosing complete for all of the 3 patient dosing cohorts in 2023, assuming that we don't see any issues that are dose limiting in that context. We have another question coming through from [ David Sietsma ]. Has anything changed regarding strategy for capital markets or business development or potential partnerships? Yes, I think that's a good question. And the answer to it is, yes, it has. I think in the context of the valuations that you were seeing early last year and the company's transition plan to a U.S. listing to try and close the valuation gap, on the enterprise valuation gap between PYC and its peer companies that were listed on the U.S. exchanges, we had a very comfortable path to increasing shareholder value and bringing on additional funding to complete our internal aspirations in the context of the capital markets. And I think what you see in the context of the macro trend turning very heavily against the life sciences is a push really not just for PYC but for many companies away from looking to the capital markets to fund their activities to looking more towards business development and strategic partnerships, co-development opportunities, and particularly upfront funding associated with those collaborations to help push assets forward into development. Particularly for platform companies like PYC, I think it's probably softened our outlook. And the other factor that we have here is, I think whilst we're very comfortable internally forming a view on the quality of the data that we have generated in the nonclinical setting and the implications of that for what we are likely to see in the clinic, I think it would be very helpful for the Australian Securities Exchange in particular to see the external validation come through our business development partnership. And so directed towards that end, the management team of PYC are off to BIO in San Diego, and I think not next week, but the following week. And we have got a very good card in terms of representation of the top 15 pharmaco globally to sit down and have a conversation with about these varying matters. There's a lot of excitement about different areas of PYC's technology and a spread of different interest. So for some counterparts, we see deep interest in the ophthalmology programs. For others, the interest is more directed towards the earlier-stage assets in the context of the central nervous system. And for others, again, they're more interested in the platform or the delivery technology and evaluation in the context of alternative classes of cargo. So we have a very broad spread of different discussions ongoing in that respect. And I think that will give us a very good read of where we're at in that regard. So yes, I think it has softened. And then the company is very open to and interested to hear the response to our data across each one of those different dimensions. I think we'll get a good opportunity to do that while seeing the light of people's eyes in San Diego over the next fortnight. So I'll just pause and give people an opportunity. We've exhausted the questions in the platform. I think we've got from -- please feel free to add any questions that you may have. Otherwise -- I mean, hopefully, it is difficult because there's not a very deep understanding of life sciences nor the development journey in Australian capital market. So we have invested, and certainly through the written medium in the context of the latest quarterly announcement, we've tried to give the market a lot of color in relation to where we see the organization as being headed. And I think agreeing with the question that was framed earlier, yes, we have had transformational windows in the past. And I think in many respects, they genuinely have been transformational windows. Remember the 2 major questions in the development of a precision medicine for monogenic disease. Can you reach the target cell, is the first one, in a relevant model of pharmacokinetics? And the second one is, can you modulate gene expression in a manner in which you are seeking to? So for PYC because we focus very much on haploinsufficiencies, these are diseases caused by not having enough protein in a particular cell type. So the question for us is, can we increase the amount of protein or the gene expression in that target cell to alleviate the disease? That is the 80-20 of the question of whether or not you've got a program that is likely to be applicable in the context of that disease indication. There are many, many, many other questions that are relevant that need to be addressed, both in the nonclinical setting and ultimately in the clinical setting where it really counts. But the fundamental components to it are those 2 questions. And so value is built very much early in the development pathway for these precision medicine assets. And then there's obviously a huge valuation up late when you get into clinical development and you see the impact that you can have in those patient lives. And you then get conviction that you were going to enter market. The beauty then in the context of unmet needs and the small patient population who is tied to a disease register is you hit your maximum top line very quickly. The ramp-up curve is very aggressive because the patients are literally waiting for the therapy. So it makes it very commercially attractive as well. And those are -- they say there are 4 questions that are relevant to drug development, 2 of them occur in the nonclinical window and 2 of them are occur in the clinical window. First question you addressed in the nonclinical setting is, does the drug work? Because that's the hardest question to answer. The second one you addressed in the nonclinical setting is, is it safe? You swap the order in the clinical setting because now we're in the context of human subjects, and it's critical that we do no harm, as I mentioned before. The first assessment is whether or not the drug is safe. The second question is whether it's effective. What we are trying to do is as much as possible merge the answer to those 2 questions in the Phase I/II to the extent that, that is reasonable so that we give you, our investors, color on the likelihood that we are going to enter market. And I think really important here is you guys have a look at some of the statistics that we mentioned earlier, the 5x prospect of success in clinical development. I accept it's off a very low base. The industry standard propensity for success from Phase I through to market is around 10% to 15%. But when you start applying those multipliers, you get to a very high rate success. These are very, very attractive markets from a commercial perspective. And remember, gross profit is by far in a way the significant driver of the P&L because of the specific incentives that the industry has decided to put in place for the creation of disease-modifying therapies for patients who currently have no treatment options. So I think we're positioned in a very nice place in that regard. And the question for us really now is how many of these assets and what is the quality of the assets that we can get into clinical development? We've got another question coming through from [ Brian Gilbert ]. Can we get an indication of effect of the drug from the first or second dosing level given that they have the disease? That's an interesting question, [ Brian ]. I think one of the big advantages, and like many things in life, there's a corollary disadvantage that comes with it as well. The first thing that you've got to remember is that retinitis pigmentosa is a disease of relatively slow progression. So it's different to the more severe phenotypes that you see in blinding eye diseases, like Leber congenital amaurosis where patients start life with very few viable photoreceptors, and they lose those that they do have very quickly. It's a very aggressive disease course. When we set about the strategy for PYC several years ago in the indication selection, we consciously chose retinitis pigmentosa. And the reason for that is, the slower the progression of the disease, the larger the window of intervention opportunity, and the less dramatic the intervention has to be in order to rescue what's going on at the cellular level and then what's going on and how that translates through to the function of the organ as a whole. The downside is you've got a relatively longer clinical trial. Because the patient's natural progression, and this is the reason that we are initiating those natural history studies is to fully characterize the rate of decline of functional vision in patients with RP in the absence of treatment. We need to know how quickly their eyesight is degenerating without treatment, to start with. Because only then can we probably characterize can we change that rate of progression through administration of the drug? There are some reports that -- with some of the more advanced imaging tools that we have available to us to date, you can actually have a look within about a 6-month window of whether or not you see statistical significance in terms of what is occurring at the single cellular resolution that you can now acquire within that patient's retina. However, that will not be functionally significant to that patient at that point in time. You will need to have a look at the statistical significance that you see at that 6-month time point and extrapolate that out to 24 months or further in order to see a difference that is likely to have functional consequences for the patient. And I think we need to remember that this is not a proven registrational endpoint for the FDA. That's not the purpose that we would consider incorporation of an exploratory endpoint like these high-resolution imaging technologies. It would be more to give us conviction that the drug is working from very early on in the dosing protocol, as you're suggesting there, and the temporal course after administration of that first strike. So I think the short answer is, yes, there are some things that we can do to have a look in a very short window of time. But they are not uncomplicated. And we haven't resolved or reached a definitive view on those just yet. We'll tell you more about them as we progress through to the early clinical trial next year. Thanks very much, [ Matthew ], for your comments. Once the TAM annual revenue -- so total addressable market, I think we've got there, an annual revenue potential for PYC-002 kidney asset, and how is the competitive landscape looking? That question, I will largely have to take on notice because if we gave you the total addressable market, you would be able to infer the genetic targets that we're looking to modulate. I think it will have to suffice to say for current purposes that it's a significantly larger market than any of the other assets in the pipeline. In terms of the competitive landscape, there are treatments available for this disease indication, but none of them are disease-modifying. There is a potential disease-modifying therapy that is in the early stages of clinical evaluation, but there are some fundamental competitive advantages that we are evaluating for the PYC asset over those early clinical assets. Hopefully, I have given you enough color there to satisfy you, [ Mark ], without giving the game away. I think that's one thing. One other thing that is worth pointing out to shareholders, we are taking a largely more conservative view on communications to shareholders generally than we have done in the past, but in particular, in relation to the announcement of assets in the pipeline. So we're not going to say anything much on what we are doing in those early indications until we reach 3 threshold outcomes. The first one is that we've completed our IP filing in relation to all of the different mechanisms of action that we are looking to exploit for the antisense oligo. The second one is that we have got a preliminary readout that we've got conviction in the bio distribution profile and the fact that we can reach that target cell. Remember that's the fundamental challenge in the development of precision medicine. So if we get an affirmative answer there, we really significantly build out our conviction that we've got an asset that's worth talking about. And the third one, we shift across into either a reporter cell line or a patient-derived model to see whether or not we can modulate the gene expression profile in the way that we want to. And remember, we've got a particular focus on haploinsufficiencies. So really here, what we're looking for is, can we get a 1.5 to twofold upregulation in the gene expression profile? And if you collect those 3 pieces of information, we really think you've got something that's worth talking about, at least insofar as the nonclinical setting goes. Ideally, you get some super imposition of the toxicology profile and a sense that you can dose at a level it is likely to be therapeutically relevant for a human without seeing any significant tolerability or toxicity concerns, that really then starts to form quite a robust data pack. And that's what we're looking to generate in support of the third and fourth assets in the pipeline going forward. And from there, it's really about us condensing the progression window for those assets so that we're really giving our shareholders. The next phase of the investment horizon that we're looking to provide you with is rapid fire sequence of clinical efficacy outcomes that turn in the arts to entry of those multibillion dollar market. If we can do that, if we can give, let's say, 3, not only within the 36-month window, I'm not making any commitments to this point, but let's throw that out there as an objective, I think we put the organization in a really good place to achieve our aspiration of becoming a meaningful player in the precision medicine space, with a differentiated technology in the context of a high-impact patient setting. A question coming through from [ John Gilbert ]. Can you explain the patent filing stage, and what needs to be done to gain the patent? Yes, so I think I can shed some color here, [ John ], in terms of the broad structure of the early status of our patent development. Firstly, in terms of the evolution of the patent itself, how you initiate the claim is through the filing of a provisional patent. There is then a 12-month lead time before that provisional patent is examined at what they call the Patent Cooperation Treaty or PCT. What the provisional patent filing does is it draws a line in the sand in terms of the prior right date. So it's -- you are effectively saying, on that date, we are crystallizing what's available knowledge in the public domain. And we are saying that we've got something new and inventive. And so from there, you've got 12 months to build out and support the data pack in support of the original claims. You can file additional provisional patents. If you're getting more detail in relation to the way that you are evolving your invention and you can actually merge those provisional patents into the PCT. The PCT is the first formal examination of the claims that you are making. You'll often get feedback from the patent office in relation to their thoughts on whether or not those claims can be established. So what we look to do given that we have patents in place for existing elements of the CPPs, but we continue to evolve our delivery technology to get those better as well. Most of the patent activity that we have undertaken over the course of the last 12 months has been in the oligo space. So really, what you're looking at here is the generation of a body of data that supports the concept that we can do something meaningful in the context of a disease process and claims to the methods or the specific sequences of the oligonucleotides that are able to achieve that objective. So what we're really looking to do here, and remembering that we can use antisense oligonucleotides in multiple different ways, to increase, decrease or modulate in other ways, like selection of alternative transcripts at the gene expression level exactly what we want to do. We try and file one patent for each different mechanism of action in relation to modulation of the target gene of interest. And we will then progress through to a PCT 12 months later. So hopefully, that gives you some color there, [ John ]. Where we would expect to be? At the very least, in terms of public communication of what we're up to and certainly public communication of the data, it's really important that we don't release any data publicly until the provisional patents have been filed. Otherwise, what can happen is that your own data can count against you as prior right in establishing the novelty or inventiveness of those claims. Look, hopefully, that has addressed everyone's questions. We seem to be slowing down in terms of the rate of questions that are coming through. But as always, please feel free to send an e-mail through at any time to the info@pyctx if you've got any questions. And if you would like the company to get in contact with you, we're more than happy to do so. I hope that we have communicated some sense of the excitement of what's going on within the organization. We're really getting a sense that we are close to that patient impact that we have long desired. And I think the consequence of that is an increase in the excitement within the organization. We take very seriously the idea that we are the custodians of your capital. We are trying to marry the competing demands of fine-tuning of the molecules that we are making and creating the very best therapeutics for patients, with the need to be efficient and move with urgency to create options for these patients and to let go of the assets when we think they're good enough to go. I think we've struck a good balance today. There's a very, very good article by John Maraganore in one of the major publications recently describing the Alnylam journey in this regard. And I think it's got an enormous number of parallels for PYC shareholders. If you'd like to understand in more detail some of the things that keep us up at night and some of the different topics that are front of mind for us, the different and often competitive forces that we are trying to balance at the Board level, in terms of the overarching strategy and execution of that strategy, it is a really good read, and I thoroughly recommend it. Otherwise, thanks very much, everybody, for your time. We've got a very exciting window at. It's always been a dream of mine to take a therapeutic into clinical development. There is a lot of excitement generated in the patient communities. It's really lovely to hear direct feedback from those guys at -- of their excitement as we move forward. And something that I take in particular conviction from is the input and we -- one thing I should call out, we've had an awful lot of help on this journey. And I do want to acknowledge the input of Professor Ian Constable And Dr. Fred Chen from the Lion's Eye Institute here in Australia. I know that Dr. Mark Pennesi has also been a great help to Glenn and the translational team in the U.S. So those clinicians who've got the research experience have got the ability to look at our nonclinical data set and give us the feedback that we need around how that's likely to translate into clinical development have really been invaluable for us. We are extremely grateful to them. We are very lucky to have those guys on the journey with us. And we are very much hoping that we can manifest the outcomes that everybody is looking for in the clinical development stage that we're about to enter. Thanks very much, everybody. And we look forward to updating you again in the third quarter as we move very close to that IND submission and the progression of the company to a clinical stage organization.