PYC Therapeutics Ltd

ASX:PYC

Earnings Call Transcript 2022-Q1

[Rohan Hockings, executive]

Hello, everyone, and welcome to the PYC Therapeutics First Quarter Investor Call. My name is Rohan Hockings. I'm going to be guiding you through today's presentation. And before we begin, I just want to make you aware of 2 things. Firstly, this call is being recorded or used by the company at a later point in time. And we also need to read a forward-looking statement disclosure that I'll just share with you. So before we begin today's call, I'd 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. That's the formal forward-looking statement disclosure, which is a part of the materials that have been released to the ASX in support of this morning's call. So I'll leave it on that page for a moment. If you can please just raise your hand or type any questions that you have into the chat function, I will try to group them by theme and address them towards the end of the meeting as well as those that have been submitted before through the info e-mail address. And I just wanted to outline before we begin, we'll be changing the format of today's presentation from previous presentations. We will have a 10 to 15 minutes or a shorter overview, briefing that I'll give, and then we'll move quickly into the Q&A session to allow you to direct the conversations to the point of particular interest. And I think the reason that we're able to do that is the story is very much consistent with what you have heard over the course of the past couple of years. We need to update you on progress that we've made both within our most advanced program, the investigational candidate for retinitis pigmentosa type 11 and also in terms of the breadth of the pipeline. So I will walk you through a presentation on both of those dimensions and then throw it open to the floor for questions. I think the overarching synthesis, and it will be familiar to those who follow certainly the U.S. life sciences market, but increasingly the Australian life science market as well, it has been a very difficult macro environment for biotech companies over the course of the last 12 months. The pendulum has swung hard from 1 of the best markets and valuations that the life sciences industry has seen to 1 of the worst. So it's been a very challenging external environment. But within that context, we have made very strong progress internally within PYC. So I thought I'd just leave you with the core message for today. I think everyone is aware, certainly those who followed the company for some time now, that we are a precision medicine company, and we operate in the field of RNA therapeutics. We have a combined platform that underpins our technology. Firstly, a facilitated delivery that addresses the fundamental challenge in precision medicines of getting sufficient amounts of drug to the target sales of interest. And the second platform that we have is an RNA therapeutic design capability. So we join those 2 elements of our platform together to create a next-generation RNA modality called peptide conjugated oligonucleotide, we refer to as PPMO. I think the overarching vision has been articulated several times. So in this meeting, I've actually shortened the time frame of the focus to look at what's the actual immediate ambition of the company. We are looking to become a platform technology with a clinically validated modality. That's where we're really hitting in the shorter term. And what we have done is to define 3 core milestones with respect to the first element of that, which is to become the clinical stage company. One of the key interim stage gates that we are going to progress through on our journey to those first-in-human studies. And here, we are referring to the company's most advanced asset, the RP11 or retinitis pigmentosa type 11 investigational candidate. Last year, we set out 3 milestones that were critical on that transitional journey from a preclinical company to a clinical stage company. The first 1 was to ensure that we have established a well-tolerated dose of the investigational candidate in non-human primates. And you'll see if you look back at our releases from late last year in Q4, we have achieved this. The second 1 that we needed to undertake was to engage the U.S. FDA through the pre-IND process to align on what the pathway to the IND filing in the transition to first-in-human savings look like. And that has been pegged as a first quarter activity, and we expect to be in contact with the market very soon in this regard with respect to the outcome of that engagement. And finally, the milestone that was set for the second half of the year is the submission of that IND to the FDA. That will, in turn, enable us to progress into those first-in-human studies. And I think the key message here is that we are on track to achieve all milestones within this year. We don't have any update to the time line and are not anticipating any changes in the near term. I think that's quite important because just winding back, to give everybody the context for what we are here to do, there are many companies who are exploring what we refer to as naked antisense oligonucleotides. So the drug modality on its own without any facilitated delivery technology, PYC was faced with a choice when we looked at our modality as to whether or not we went with the well-established and validated naked antisense oligo that is used by companies such as Ionis, Stoke, [indiscernible] Therapeutics or whether or not we wanted to explore the oligonucleotide in combination with the facilitated deliver technology. And given that delivery remains the fundamental challenge within the field, we have opted to go for the novel next generation of this modality. And I think people should understand that, that comes with a certain degree of risk because this is innovative in the sense that it has never been done before. No one has ever administered a PPMO in a human eye. And so we are in the process of characterizing all of the dimensions of the PPMO modality in a nonclinical setting to give us the color and information that we need to progress into clinical development. So it's genuinely cutting edge in that sense. That brings with it a degree of risk because we're entering into the unknown. And in many respects, that demonstrates the progress that we've been able to make over the course of the last 12 months, in particular, with advancing to this point because we are removing risks by providing answers to the critical questions that go into what the profile of the investigational candidate is going to look like in humans. So at what dose? Is it safe and tolerable? What does the pharmacokinetic profile of the molecule look like? All of these different dimensions are relevant to what are our prospects of success in the clinic and ultimately to a market entry. So very pleasing and encouraging progress in that regard. I'm sure there will be questions towards the end on the progress of the RP11 asset. So I'll leave that there for now. The other dimension in which we're adding value is in the breadth of the pipeline. So the RP11 program represents depth and the approach to, and then subsequently clinical validation of our technology. And the second element to our operations are the breadth. So how many programs have we got running? What are the indications that we have selected to pursue? And which target tissues do they exist in? Now here, we are looking to expand and have been expanding our pipeline, both within the eye, leveraging the information that we're understanding following an intravitreal route of administration for the RP11 program to enable those fast follower programs. And for those who follow the company, you'll be familiar with our ADOA or OPA1 program that is the second asset in the pipeline, but also into novel target tissues that sit beyond the eye as well. In particular, we have an interest in the central nervous system and the systemic application of the drug for treatment of diseases that occur in different organs that are best access by the blood stream. We have a specific focus on monogenic diseases. And this is a critical part of the company's strategy, and I think it's very important that investors understand this. The reason they've pursued these monogenic diseases, which tend to be associated with what they call orphan indications or indications that affect a small minority of the population individually, although collectively, they are quite prevalent. It's because when you have a single mutation in a single gene that underlies the causation of a particular disease, the ability and confidence that you have to predict a meaningful intervention for that patient is far greater than if you look at a polygenic disease or a disease that is not fully characterized in terms of the mechanism that is causing that disease. And it's likely that the mechanism is a complex interplay between a bunch of different factors, both genetic and environmental. And I think that makes a lot of sense. So if we have a really good understanding of why a disease is occurring and have identified with a high degree of conviction the specific gene that is driving that disease process, it logically follows that you have a far greater prospect of success in clinical development, given the certainty that, that provides with respect to the ability to unwind that process. The second reason that we do that is a lot of these orphan indications have genuine unmet needs. So these are settings in which there are no treatment options available for patients. And what that creates is the potential for a faster path to market because it creates the possibility that you can reach market with 2 clinical trials as opposed to the conventional 3 trials. So if you think about the 2 dimensions that are most relevant to valuation or biotechnology company, when you run a risk-adjusted net present value model, they will be the probability that you reach market and the speed with which you get there. That is obviously, once you have looked at the size of the target market that you're addressing as the critical third variable there. So that's the underpinning rationale for why we have prioritized these monogenic indications. And I think the combination, it's also worthwhile pointing out that if those assets have got a higher propensity for success in clinical development, what that means is that the information that you're gaining in your nonclinical evaluation is more important because you are adding a higher propensity for success in that setting. And therefore, through the removal of risk, you are building value earlier than you were capable of doing in those more complex polygenic disease processes that we spoke about. Where it really does come down to an assessment of whether the therapeutic is affected in the clinical setting to provide the certainty in the answer that you're looking for. So that's the rationale for what we are doing in the context of the pipeline expansion. You'll see us continue to focus on identifying and progressing indications that have got a highly validated biological underpinning. And specifically, you have got a monogenic cause or a single gene mutation, mutation in a single gene that is causative of the patient's illness. Why is this worthwhile? Well, because some technologies that have the ability to scale very quickly and having in a clinical setting are highly valuable. They are amongst the most, if not the most, sought after assets in the life sciences industry. Because they combine that certainty or the higher degree of certainty that you get in the context of the industry with the scalability and the ability to impact multiple patient lives and the commercial implications that flow from that. So if you have a look at where PYC is focusing its efforts and how they link directly to that ambition of becoming a clinical-stage company with a validated -- clinically validated technology that has that scalability that we've spoken about, you get the best dimension of the RP11 program. And here, we've got the stage that we have currently progressed to in [indiscernible] and where we are hoping to progress through the course of 2022, that is through the initiation of a combined Phase I/II clinical trial, first in human studies and the same with respect to the broader pipeline. And then we have a strong desire to expand the pipeline beyond those programs that are currently identified on this page. So you see both in the CNS and then via systemic route of administration, we will look to add additional assets into the pipeline. That will be the focus. I think of the first half of the year, the second half of the year, the attention will turn back to the RP11 program. as we get the interim readouts from our GLP toxicology studies that are the enabler for the submission of the IND and the transition to the first-in-human study. So if you look forward then to or what are the milestones that are going to occur in 2022 that take progress towards these outcomes? The key driver for us is to ensure good execution in the RP11 program. So for us to become that clinical stage company, that involves 2 sets of clinical studies. The first 1 is a natural history study or a non-interventional study. And here, we're looking at the baseline progression rates for loss of visual function in patients with RP11. So that we fully understand what the disease progression looks like in the absence of therapeutic intervention. And the reason for that is to give us a benchmark for the next milestone that you see here, which is the initiation of the interventional trial. Now that comes in the second half of this year. I think the very exciting thing for us is that this is the first disease modifying investigational candidate for this indication. So it brings great hope for the RP11 patient community and the PYC staff and investors alike. I mentioned before that we'll be adding additional programs outside of the eye. We've spoken previously about the CNS candidate. I know that's a topic of interest, and I'm sure there'll be questions coming on that. We've got some more information to provide in that regard as well, but I'll leave that in the Q&A. And critically, the generation of the nonclinical efficacy data in support of these additional programs. Now remember, in the monogenic indications that you're going to see added to the pipeline, it is the nonclinical setting where you're capable of adding a substantial amount of value because of that higher propensity for success in clinical development and the more rapid path to market. So that's an overview of what we are looking to do. I wonder whether it might be possible for people to raise their hands as well. I was just in -- maybe I will -- I've got a couple of questions coming through on the chat line. Just trying to work out what we're doing here. We'll start with addressing those.

[Rohan Hockings, executive]

So Matthew's question is, if clinical validation is required to be sought after and you're aiming to start trials in Q4? And how long after that -- how much longer after that can we expect validation? Can we provide some color on executive departures and whether it's tied to or has impacted your U.S.-based awareness and partnership opportunities? And when are we looking to disclose the CNS targets?

So I think the first question is, clinical validation is obviously the highest form of validation that you look for as a life sciences company other than commercial validation once the asset has entered market. So it is clearly a very important milestone for the organization. You can achieve high degrees of nonclinical validation as well. And so that's why we look at all of the different models to evaluate the therapeutics that we are progressing into the clinical trials to give us a sense of what is the probability that we are likely to succeed in that setting. That's really what we're looking to do there. So validation comes in many forms. Obviously, we are looking to have an impact on patient lives. That is the ultimate objective for this company. And so clinical validation is an important part of the journey. But the nonclinical validation that we have already achieved and the conviction that we have in the nonclinical data is what is encouraging us to move those assets forward. And as I spoke about, that links back to the indication selection and the underlying strategy to prioritize the monogenic diseases. In terms of executive changes, I think we've addressed that previously. So we're not going to address specific circumstances on this call, whether it's tied to or has impacted U.S.-based awareness and partnership opportunities, I think it's clear that we have decreased our commercial presence in the U.S. with a focus on advancing the asset from a technical perspective. So we have retained and continued to build out our technical team in the U.S. I don't think it has limited our partnership opportunities. It just means that we have to do more from the Australian office. When are we looking to disclose the CNS targets? I think this is a focus because of commentary that was provided last year with respect to the nomination of targets in the CNS. And the update that I can give here is we have filed the intellectual property protection that we were looking for, for the 2 CNS candidates that we spoke about last year. And so we mentioned in particular that we had a focus on autophagy induction as 1 pathway in neurodegenerative diseases and another was neuro information. And so what the IP filing does is it enables us to identify the targets that we're pursuing in that context. In the former instance that is [ Becklin ] 1. And in the latter, it's near neuropilin 3. So we have made some significant progress and have some very nice data to underpin that IP filing. The reason that we haven't spoken about it publicly is because it doesn't form part of the organization's priorities moving forward.

And the reason for that is, if I'm going to stand up in front of you and say that we're very excited about the monogenic diseases because of the extent of the value that can be added in the nonclinical setting, I think we also have to accept that the ability to add that value in the complex of the polygenic or more complex indications is necessarily lower. And so they have a longer path to market, a more arduous path to clinical development, a multiyear development pathway that significantly exceeds that of the monogenic programs, and they also have a longer path through clinical development as well. So in the context of a significantly lower piece success and you only need to look at the success rates that have been seen in indications like Alzheimer's disease over the last 20, 30 years to know that it's an ultra high-risk venture to be entering into that domain, coupled with the time taken and the depth of expertise and understanding in the context of a very, very complex disease pathway. I don't think that's an asset that we want to be prioritizing in the near term. Where they will become of interest to the company again, and in this respect, we are sports for choice because we have a whole bunch of assets in the discovery domain that we can choose to progress through at different rates, is when monogenic assets that are directed towards the same target tissue have been developed in the nonclinical setting. And when we understand the properties of those drugs, and in particular here, I'm talking about the biodistribution or which particular cell types within that target tissue is the RNA therapeutic capable of entering and engaging target in. That then gives you more conviction if you know that you can enter into the cell types in which those diseases are occurring. And so from there, those programs will leverage the validation that is occurring in the monogenic indications and have a much clearer path on a sort of a piggyback style of model into clinical development. I should also click back -- sorry, I've been reading live and went straight to those, but I'll revert to the calls that have -- the questions that have been submitted to the info line as well and perhaps we'll alternate between the 2. So the next question here, just focusing on the time, we're 20 minutes through already, has the strategy to access U.S. capital markets changed given the poor conditions there? I think everybody who has had an ambition to visit the U.S. capital market has had to take a step back and think about what they're doing. And so I think certainly, the timing and nature of that visitation has changed, yes. And at this stage, what we are doing is really taking a step back and looking at the different avenues that are available to us from a commercialization and access to capital perspective, and canvassing a far broader range of options than having a singular focus on a U.S. listing. Is there a trade-off between doing business development deals with partners and accessing capital? And if so, where do we sit on that trade-off with our products? Yes, I think there certainly is. It's clearly front of mind for us. The question as to whether or not we are looking to out-license assets and take an upfront payments that enables us to invest elsewhere in our pipeline or whether we wish to continue to fund those assets into and through clinical development. And if we are going to do that, what the alternative source of capital looks like, primarily a need to visit the equity capital markets through that process? We are constantly evaluating those trade-offs, and they are constantly changing because the nature of the assets themselves is dynamic as the extent of the validation increases of those assets and the more that we know about each 1 of those programs and how that informs their propensity of success in the clinic, the risk reward proposition is changing in that context, both in the eyes of the counterparty, but also in the eyes of PYC. And so it really comes down to a consideration of the terms and the ability to create multiple opportunities around multiple assets to determine which is the most attractive route for us right now. And I think it's another reason why you see the focus on the pipeline because I don't think we would like to be in a position where we were forced to enter into a deal with any 1 particular asset. Another question, are there any discussions about getting independent research on PYC for investors? Yes, this has been a clear focus for a considerable period of time now. Obviously, without any outcomes in this regard, because I think it would be very helpful for generalist investors and the Australian market, in particular, to have a simplified version of the story and an independent assessment of the technology. So we have had active conversations for quite some time. Unfortunately, I think as people are aware, the general understanding of life sciences, but specifically precision medicines and nonclinical stage precision medicine companies, is fairly limited within Australia. So we have had the conversation across 2 jurisdictions, and I think it is an important piece of the puzzle getting that coverage in place. But we have been unable to succeed in having the coverage initiated at this point in time, largely because there's a feeling that the generalist investors in Australia are not going to do the work required to take a meaningful position in a life sciences company at the nonclinical stage of development. So I think things are getting easier for us as we make the progress towards a clinical stage company. We still have active discussions in this regard, and I'm hopeful that, that will yield something soon. The next question that's come through is, has the company done any deeper analysis on what each product is worth if they make it to market? And if so, how conservative or robust are the assumptions? Again, yes, it's very important for PYC to have its own internal view on the valuation of each of the assets. And I don't think it's a particularly difficult calculation to make. We basically touched on as we went through the different dimensions that are relevant to the company's strategy and prioritization of different programs. If you think about the RMPV model, and I think that's probably the most appropriate to prioritize future cash flows and value those at a discounted rate back into today's dollars, it really requires an understanding of what is the size of the addressable market. And what does the reimbursement look like within that market. I think we've given a lot of color on that. We don't likely to give -- we don't like to give direct guidance and nor does the exchange like us to give direct guidance on valuations. But I think we've given significant input on the variables that are relevant to a relatively simple calculation of what valuation looks like. So we know that there are between 5,000 and 8,000 patients with RP11 in the Western world. We know that most of those patients are addressable because there is a long time period between the age of onset of disease and the age at which blindness occurs typically in the patients 40s or 50s. And we think that all patients who have got residual function are likely to benefit from or certainly those who have a haploinsufficient mechanism, which is, again, the vast majority of patients, are likely to benefit from VP-001. And so size of the target market, if you split that out between the U.S. and the non-U.S. populations because you achieved slightly lower reimbursement in the non-U.S. populations, you multiply that by the orphan drug pricing. There's an argument that you have ultra-orphan drug pricing here, but I think just stick to conservative assumptions for now, and that's USD 180,000 per patient per annum. That's the size of the target market. If you then discount for the time period taken to get to market, and I think we've given some color on what that looks like, I know there are other questions directed towards that later on as well, it really comes down to the probability of success. We have also given the market, if you look back at our previous Investor Relations communications, a lot of color on the propensity for success in generic medicines and the men dealing inheritance patent genetic medicines specifically. We know that industry success rates are around 10% to 15%. And we know that the propensity for success for genetic medicines in monogenic disorders is around 5x that. So it creates a very attractive and robust valuation for those assets. It's also borne out by the peer characterization. So if you look at other assets that have a first-in-class disease-modifying nature for an orphan indication, and here, we're looking at assets like nusinersen or SPINRAZA, you will see that the impact is borne out or I think even possibly a better example of the [indiscernible] drugs for DMD that were coinvented by Sue and Steve. You see that you get a nice triangulation on the valuations that we're getting out of those models as well. I'll come back to the online questions for now. Why do we think that the market sold the share price down from $0.18 last year? And do you feel the upcoming milestone price back at $0.18? I think the share price sell-down from late last year is largely driven by the macro environment. If you have a look at the valuation of peer companies, that's peer companies, both in RNA therapeutics, but just in the industry more generally. There's no doubt that the valuations are off, substantially off, specifically in the U.S., but I think you're starting to see it flow through to the Australian market. In conversations with the bankers in the U.S., it's a really hard time in life sciences right now, really, really hard. And it swung from -- at the first quarter of last year being really the kind of peak in terms of what the industry has ever seen in terms of valuations and the rapidity of the deal flow, companies entering into the NASDAQ through an IPO, also reflected in the BD deals as well. There was a euphoric feeling amongst the industry. I think it's probably fair to say that valuations went too far the other way, and they have swung very hard back in the opposite direction now to very much doom and gloom and again, in conversations with the U.S. bankers, it does not seem like things are going to change in the immediate future from a macro perspective. And I think if you compare and contrast that back now to the internal situation within PYC, we have made very strong progress in the time. So I think there's an additional sense of frustration here for us because we didn't -- our boats did not float with the rising tide of early last year, but we have certainly seen the tide to take us down. As you pointed out, we've lost half of our market capitalization. So look, there's a sense of frustration associated with that, but it is what it is. We need to deal with it. Do we think the 3 upcoming milestones are relevant to getting us back to $0.18? I can't speculate on what the market is going to do. What I can say is we can pay our meaningful outcomes for the reasons that I spoke about previously. Nobody has ever taken this modality into a human before. So in characterizing that we have got a PK profile that links to a target product profile of the drug, then that will ensure patient compliance. So here, we're talking largely about the dosing interval. What we would ideally like to see here is an interval between dosing of greater than 3 months, preferably to up towards 6 months. I think 3 months is acceptable. I think patients will have 4 intravitreal injections a year. Possibly for the pediatric population, that will be more of a difficulty, but I think that will be tolerated. It would be ideal if we can see that up towards the 6-month and 2 doses per annum. I think that would be a great outcome. It's clearly relevant now that we do make the transition to a clinical stage company because that in and of itself is a very important milestone. I think people find the story a lot easier to understand certainly for platform technologies, when you have a very clear use case of, okay, I understand that you've got a platform, but what does that look like in terms of your ability to access the market? And so I think it likely will get a lot easier for us in terms of those investor conversations and the ability to reach not just life sciences specific investors, which I still think we need to do because I think that will be an important validation from the Australian market perspective, but also to get some follow-on investment coming from the generalist investors. Where it takes us in terms of the share price? I don't know. The next question is, is the interventional trial for RP11 part of Phase I? Yes, that's another great thing about moving into an unmet need in an orphan indication is that we are not going into healthy volunteers in the Phase I. In the combined Phase I/II, we will be entering into a study in the context of 11 patients, and there will be a secondary objective of defining some form of efficacy readout. Obviously, the primary objective there is to establish the safety of the molecule, but we are looking for insights on the efficacy there as well, which brings forward, again, from an investor perspective, the milestone that you're looking for that really gives you conviction that the asset is going to in the market. So that's good there. A follow-up question coming here on how long we expect the trials to take? I know that was a question that was submitted online as well. The current design of the study is for a 24-month combined Phase I/II and for a 24-month combined Phase II/III. And so there's a question there as to whether or not we can likely procure CEP290 studies overlap the start of the Phase II/III with the Phase I/II. I'm not going to commit to an answer on that today. What I suggest we do is come back and have a deep dive with our Chief Development Officer, Glenn, who's got the expertise in the clinical trial design, and we can walk investors through exactly what that looks like. If you think what else sits on there, there's a conventional 10 months, although with a priority review, 6-month review window for the new drug application that sits on the back end of those trials and then you've got the enrollment period that sits on the front end. So that's roughly the overview. We've got a question from George McColgan of what other monogenic diseases PYC has looked at. We obviously can't disclose that because we need to have our IP in place before we are willing to say anything publicly about those assets that have made it into the pipeline. Although there were 2 that we were looking closely at. And in fact, we have generated some very nice data for one, but unfortunately, we were gazant from an IP perspective by 1 of the major global pharma companies. So I don't think there's any harm in disclosing that. We were very interested in progranulin as a target. And unfortunately, that hasn't made it into the pipeline despite the fact that we have oligos that have a very nice upregulation effect in that context. It was looking very promising indeed. This is 1 of the difficulties in the industry is there's an 18-month lag between when companies filed provisional patents and when they enter the public domain. So we don't know what other people are working on, and it's imperative for us in that context to retain a focus at the front end of the discovery pathway. So this is part of the unseen in the organization now. Everybody focuses on what's going on at the back end. The market does not even see the body of work that's going in at the 18-month front end to ensure that we've got an asset in an attractive indication that can achieve the therapeutic intervention that we're looking for and that we have got proper IP protection in place for. Fortunately now, we've had a very clear focus on monogenic diseases for some time. We've done a lot of background work in a bunch of different indications, all of which we have identified as being very attractive, and I expect to see us progress additional programs into the pipeline through the course of 2022.

The next question, we're flicking back online now. I'm just trying to keep up with [indiscernible]. Does the age of the patient affect the rate of eye degeneration of conducting the natural history study? I expect that actual RP11 human trials will have patients on varying ages. So is this picked up in the natural history study for comparison? Yes, that's a good question. So what's known about the rate of progression of RP11, and obviously, there are a bunch of different parameters that go into the assessment of visual function, is that there's roughly an 8% decline in function in patients per year. So that's the kind of shorthand answer there. Patients have got different ages of onset for the disease. And this is probably largely informed by the extent of the expression of the wild-type the PRPF31 a little. So very good validation of the mechanism that PYC is pursuing in this context. So I think it's important to remember that the start of the disease process is variable between patients. For some patients, the disease will start at age 60. For other patients, it will start at age 6. The rate of decline once the progress of the disease has begun is relatively consistent across the patients. But it is important for us to get a spread of patients with respect to where they sit on that decline curve. So that we're not characterizing extremely well 1 particular part of the curve, you can understand if it's an exponential rate of decay, it will flatten at the start and at the end of the disease course. That we have got a good curve characterized for patients from a range of different stages of the disease. That would give us the best curve against which we can then compare the interventional study.

You mentioned updating the market on the pre-IND FDA progress very soon, but that was in the context of talking about the whole year 2022. Does very soon mean days, weeks or months? Look, we picked it as a Q1 activity. So I would suggest that we're probably in the realm of weeks in that context before we have wrapped up the process and in a position to communicate the outcome of that 2 market. The next question is, does the company have enough funds to get through the next 12 to 24 months? The short answer to that is yes. If you look at the most recent financials, we had $45 million in cash at the end of January, and that will obviously be plus 7 months of entitlement to the R&D rebate. So you're looking at about $50 million there. And the net burn of the company is in the order of $25 million. So, very easy to do the math there. We are funded on the current projections of the cash runway into Fy '24. So we do have that, which is why we have been afforded the time to step back from what's going on in the U.S. capital markets and think about, okay, what options have we got here? How can we create attractive outcomes in the context of where the company is at and where the company can get to within the context of our cash runway? And I think that's another thing to point out. We have a much, much lower cash burn than our U.S. peers, about 1/4 of companies that are at a similar stage of development. And the reason that we can do that, we are a small and nimble organization, we do obviously have the benefit of the R&D rebate environment here in Australia. But I think that is something to be remembered if the commitment of the organization to patient outcomes that is enabling us to achieve that. People are working really hard. We see these assets to the scientist generally has been a difficult period because looking at the work they are doing and the market's response to it, there is a clear asymmetry. And we are now at the point where we are close enough to a clinical study that we can feel the prospect of changing somebody's life. So there's a refreshed sense of motivation. I think it's been a really nice job, I see Glenn online, from the U.S. team of ensuring that we have the progression of information that is required for the translation of our technology. Very, very exciting to take a novel modality into humans for an indication for which genetic counseling is the current approach to therapy within the course of the next 12 months. So despite what's going on in the macro environment, I think there's a lot of hope internally as well.

That we just coming through one more [indiscernible] side, just trying to see where we got to here. I've touched on the time lines for the RP11 trial. Biotech industry has generally shown a significant risk off over recent times. Can you comment on this? Do you see any green shoots? Yes, I think that's entirely right. I think you see a whole bunch of generalist investors moving out of the space and a complete shutdown, almost complete shutdown of companies that are accessing public listings and capital in the U.S. So it has certainly been a very, very difficult time. And if you look at the nature, it's starting to emerge in the Australian media now 30% to 40% off in the industry. It's much, much more severe than that in many contexts in the U.S. So it has been a very, very difficult time. Do we see any green shoots? No, not right now, is the answer to that. And I don't know how long it's going to take. But capital markets can remain subdued for long periods of time. So we are planning for that and taking that as a base case. Hence, the response earlier on, okay, well, how are we looking at the trade-offs between monetizing assets versus visitation in the capital markets, and both obviously have their relative pros and cons. Most recent procure failure of sepofarsen show any clinical -- sorry, does recent procure failure of sepofarsen to show and a clinical benefit in a Phase II/III trial have a negative contagion effect on RNA as a therapy in the eye, particularly when targeting the retina? Has that been part of any discussions with the FDA? Have you had any opportunity to outline PYC's points of difference? So look, this is obviously very disappointing. First and foremost, for the LCA10 patient community to not see the follow-through of the results that was seen in the early clinical studies, albeit not in all patients into the pivotal. And also, I think, very disappointing for the researchers who've invested a decade or more in the development of that therapeutic because a very elegant body of work was done in support of that. I was watching recently a presentation by Andre Grant who was involved from an academic perspective in the early stages of that work and a lot of really good work was done. So it is very disappointing from their perspective. I have not yet looked closely at the data. So I've seen the headline failures, but I have not reviewed the indication in any depth. Whether it has any negative contagion effect on RNA therapeutics in the eye, look, it's an RNA therapeutic buying intravitreal injection for inherited retinal dystrophy. So there are clearly parallels there, and I think that is a cause for us to take stock of the situation and look more deeply at those readouts. At the same time -- so certainly, it would have been our preference for that to have succeeded. I think that would have been a very good outcome for us and shown a clear validation of the modality of albeit a slightly different variation of the modality in the context of a very similar indication to that which we are pursuing. Having said that, I think there are very clear differences, and those differences have guided our path over the course of the last 3 years. So the first 1 that I'll draw your attention to, and if you go back and have a look at our previous presentations, you'll see that we steered clear of leber congenital amaurosis from an indication perspective -- indication selection perspective or strategy perspective because we think the phenotype is very severe. And so the prospect of making a meaningful difference in the context of patient lives when they have very, very few photoreceptors, viable photoreceptors to begin with, makes life a lot harder. We think the RP phenotype is much, much better suited to an RNA therapeutic because of the slower rate of disease progression. Now the trade-off there is it is a 24-month window for the evaluation in the clinical trial. That means that you've probably got a longer duration to see a sufficient decline to show the deflection. Hopefully, the deflection created by the investigation of candidate in that context. But I think the indication selection is much better in RP than it is in LCA. So there could be a question of whether or not the patient is ever capable of responding to therapy to begin with, and that was certainly part of our rationale in avoiding it. The second 1 is the fundamental challenge in the field remains delivery. And this goes back to the choice that we made. I guess to be really clear on the point that I was making through the introductory presentation, we can choose to go with the negatively charged phosphorothioate chemistry in the assets all of those, if we want. Because when you patent the RNA therapeutics or the oligo, you take all of the backbone chemistries, you're backbone chemistry agnostic. What you are patenting is the sequence of the letters of the oligo itself. So if we wanted to do exactly what Ionis, Procure, Stoke and others are doing, we can. It's open to us to develop that even in parallel to show the advantages of the PPMO. The reason that we have gone with the PPMO is because it is effective at much lower concentrations. So if you do a quick compare and contrast of the efficacy of the VP-001 candidate, we see levels of exon skipping around 40% in the patient-derived models at a concentration of 5 micromolar. And if you have a look at the Procure data, we're probably more interested in seeing as the industry has moved to the 2 prime MOE chemistry now, the sepofarsen was 2 prime MOPS. But let's focus now on the MOE. For the USH2A asset, the nonclinical data set for Procure shows 17% exon skipping up 50 micromolar of the drug. So I think you see the power of the facilitated delivery there. That's the competitive advantage. It's more that. It's between 1 to 2 orders of magnitude more potent on the back of the facilitated delivery. And I think without having looked at the data, 1 of the big questions is going to be whether or not they were capable of getting sufficient drug to the target cell in order to correct the phenotype. And that's assuming that there were enough viable cells at the time of treatment that they could actually recover or maintain sight in that context. Has this been part of any discussions with the FDA? No, the discussions with the FDA are very much focused on our own therapeutic modality and our own therapeutics. We don't need to reference the competitive landscape in that context. Have you had an opportunity to outline PYC's points of difference? I think that's probably more a market-facing discussion rather than a regulator-facing discussion. What's our strategy, if any, to establish third-party confirmation of PYC's peptide delivery platform? And is this important? Yes. I think that's a good question. It's not a priority for the organization because we have made a strategic pivot from being a delivery technology on a fee-for-service model for other people's drug cargoes to the advancement of our own drug cargoes, end-to-end ownership of a therapeutic asset and responsibility for the development of that asset. And that's why we have a translational team in the U.S. Having said that, it would be nice to partner with others. You are just limited in the diversity of the cargo classes where the peptide delivery technology is likely to be the best solution. So there are all sorts of chemistry and other considerations that go into whether or not a specific drug cargo or a specific counterparty can be quickly conjugated or joined to our delivery technology to get the benefit of that facilitated delivery. It's more complex than it seems on face value. So there's -- there will be a limited pool of people for whom their cargo can immediately be conjugated to our delivery technology, and that's probably the primary driver of why you haven't seen us do a delivery deal to date. You then really do need to have a compelling data pack, the validation that we spoke about earlier in the nonclinical setting, in the context of relevant models. So for us in the eye, we've got that. We are beginning to develop it in the context of the CNS and also upon systemic delivery for other target tissues of interest, but we don't have anywhere the same amount of data in those tissues that we have in the eye. So you need someone who was working on the right type of cargo in the right cellular layer in the right organ. And so that just very quickly narrows down the potential pool of counterparties. Having said that, we've got conversations with counterparties who are in that domain. And so we have active discussions with those guys. For us, it's as much about ensuring that we're maintaining focus because there's always something else that you need to do in order to bring the 2 components of the drug together. And so it's really just a trade-off. Are we getting -- first thing, do we have the bandwidth to do it? Or are we better off just focusing on our own internal work? And secondly, due to the terms of the commercial agreement, reflect fair value for PYC. And if we can check both of those boxes, then we are very interested in doing it. How are we managing the risk of being overtaken by much larger, well-funded competitors in the race to lodge IP protection of the assets, in particular, as we start moving towards more popular targets? This is a hassle, so as I mentioned before and I mentioned the targets so we can mention who took the IP that we were hoping to protect ourselves. It's Roche. And they've done a very comprehensive micro walk on the target change. So it hasn't left any room for us to come through with our own IP. Yes, this is a constant risk for us. And so how we're managing that is to maintain activity at the front end of the funnel. The problem with that is that's time and efforts that is not reflected in shareholder value. Because it's not until those assets mature, at least to the point that we can publicly talk about them, we can't expect to get value for them if we haven't told the market what we're doing, but at the same time, we can't talk about them because we don't want to prejudice our ability to capture the IP that we are looking for. So look, biotech part, there are many competitive tensions, and that's just 1 that we're dealing with. We have decided to continue to make that investment. So we do active drug discovery work. We've built ourselves a very nice pool of potential candidates to convert into programs, and we're right in the process now of prioritizing those programs and working out which ones we are going to focus on as pipeline assets. Are we briefing any funds brokers to get some support for the share price, which is higher on the back of good news? I think it's a very similar question to the 1 that came up beforehand. The answer is yes, we do maintain an active external dialogue. I think if the question is, could we do more? I think, again, the answer is yes, and we're going to need to, I very much agree that we have made good progress and it hasn't been reflected in the market cap. A lot of that does have to do with the macro environment, but we still need to address it. And so what you will see from us is, in the very near term, a clear explanation of why we think our assets are differentiated, and how we have compiled the information and the validation in the nonclinical setting that gives us conviction that we've got something differentiated in the clinical setting. And so what we're really trying to do there is, if you are very clear and simple communication of what we think the relevant information is to go into a calculation of that success, the critical variable that drives the valuation of the organization. And if we can do that properly and we can do it across the different assets that we have in the pipeline, you can then look back at where those assets are in the development stage and particularly importantly, where the RP11 program is as it approaches first-in-human studies. And you can run your valuation calculations. And you can have a look at the difference in the intrinsic valuation versus the market capitalization. We need to spread that story. So we'll be very much focused on that for the rest of the year. Could we give shareholders an insight into the current state of the U.S. operation, the numbers employed, the individual roles and the future direction for 2022? Yes, we can. So as I mentioned at the outset, we have got a very clear focus on technical progression in the U.S. at a minute. So if you remember, we went over there for 3 reasons. The first 1 was for technical capability, but under the guise of the regulatory engagement. So translational drug development capability, the ability to efficiently move assets into clinical development. That's the first. Second, BD opportunities; third, Investor Relations opportunities and access to the capital markets. I think the focus is very much on number 1 and lesser focus on number 2 right now. In terms of number 1, who have we got over there. We've got half a dozen employees headed by Glenn who's on the call. So Glenn as our Chief Development Officer. We have expertise in drug product, drug substance, toxicology, clinical studies and executive support. So a team of half a dozen that are very much focused towards the technical development side of things, and we expect that organization to continue to grow. Could we explain the contribution made by PYC's U.S. directors during the last 12 months and give an insight into what they can bring to the company in the future? The 2 U.S. directors that we have are Mike Rosenblatt and Jason Haddock. With respect to the contributions that they make, Jason's skill set comes very much from a finance and commercial background. And I think Mike provides the complementary skill sets with that very broad industry experience, but more focused towards the technical side. So I think that the 2 of them are very complementary in that context. They also bring to PYC the voice of the industry. So people who have been there and done that. And as you know, we've got a extensive drug discovery capability here in both Western Australia. We've now got the translational ability and the clinical development capability in the U.S., but that's a more recent addition. So that guidance from the industry as we continue to build out the organization as we move down the value chain is really important, and that's really where I expect those guys to contribute for us going forward. It's certainly been a good job of joining with them to date. In the 2021 AGM presentation, we were told that the management of the 2 markets, U.S. and Australia, were more complex than first thought. Could you please give more depth concerning this in the company's current view on a dual listing? So again, we've touched on the dual listing previously. I think it's really a matter of timing more than anything else. I think we understand that ultimately, the capital market that we need to be accessing is in the U.S. And when I say ultimately, it's probably in the near term as well. In terms of the complexities there, it's not easy to take an already public entity on to an exchange in the U.S. It's far more complex to do it with a company that's already listed than it is with a private entity because you lose control of the valuation throughout a series of capital raisings that usually support the public listing. So if you look at, say, that you've got a company that takes a Series B as a private funding round, as a private company, and then we'll undertake a pipe or private investment in public equity as a precursor to an IPO. You often see a rerate in the valuation between those 2 events, quite significant and on the back of a very short time span and no technical rationale for why that valuation change exists. It's much more directed towards the commercial dimensions and the liquidity. So if you're looking for and what you were seeing in the good times in the market back last year where 2x rerates between the pipe, the crossover funding round and the IPO, you don't have control of that with an entity that's listed on a public exchange already. The pricing is already being set in a different market. And so I think the management of that and in particular, then the arbitrage opportunities that, that provides for sophisticated life science investors evaporates. So you're not going to come into the pipe round with a guarantee that you'll get the 2x revaluations of the IPO because you are not controlling the listing price. And you can say, well, you're not controlling listing price. Anyway, they often are because there will be a follow-on subscription from the U.S. life science investors into the IPO at higher pricing, but they may then allow themselves to be backfilled by other investors if the demand for the book is strong. So it's in that transition window. You need to make sure you're getting set with the U.S. institutional investors who are going to provide the support and the run in the aftermarket to the valuation that you're looking for. So you need to deal with them. But when they've got easy options that are coming through that are American companies that are private, there's a lot less complexity for them in entering into a transaction with those counterparties than there is an Australian company that has a public listing. So it just needs to be managed and very, very carefully thought through. All right. That's it. No more questions. So I'll give anyone a couple of minutes more. That's good that we've got through all of them. And I think -- I guess to wrap up, the forward view of what's coming. We've spent the first quarter of the year really getting quite tight internally on what 2022 looks like, what we're hoping to achieve there. I think it's been really clear in the RP11 program for quite some time. And I do think that transition to a clinical stage company is a fundamental determinant of value because clinical stage companies with scalable underpinning platform technologies, in areas of strong macro growth in high demand. And we're heading right for that space. I think we're executing very well. We are maintaining the time lines. There's obviously difficulties managing in a COVID-driven world, but we have not had any major hiccups at this point, touch wood, that would give us any cause to think that we are not on track for clinical development, IND submission and transition to first in humans at the end of this year. So if we can maintain that, and we can turn our attention then to, okay, that's great, that's the cornerstone program, and we've got a high degree of conviction on the pathway there, what can we tell investors about the value of the scalability of the technology? And in particular, can we replicate the strategy and the benefits that we see in that program through indication selection in our programs? At the same time as maintaining a realistic assessment of what the company can do. And so if you ask what I want the pipeline to look like at the end of this year, it's probably only 3 assets. I think that's manageable. I'd like 2 of them to be in the eye. I'd like a new target tissue for the third one, for 2 reasons: one, to give us some negation just in case there is something crazy about RNA therapeutics in the context of the retina. I think that's unlikely and I don't think ProQR's result does provide guidance that, that is the case at this stage for the reasons that we spoke about earlier. But from a risk mitigation perspective, I think it's important that we have got another target tissue to pursue. And I also think from a scalability perspective, showing that we can move beyond the eye is really important as well. So it provides both downside protection and the ability to attack the upside. That will be a very exciting time for us. We'll need to run a fourth asset coming along behind the others just in case anything on to what happens in any of those programs so that we have a ready-made replacement ready to go. We will continue to invest in the discovery side. We have got active conversations on the business development side. Whether or not we decide to pursue those will come down to whether or not we can define terms that are sufficiently attractive for PYC to take away resources from our existing programs or to add further resources to undertake that body of work. So yes, look, it's been a great effort. There are many hands that are lending in right now. It is quite an intense environment to operate in. It's difficult for us internally to see the share price decline at a time of such significant progress. However, it's the same to many in the industry, and I don't think there's any point complaining about it. We just need to take the ball by the horns, get out and do something in that regard where we're going to focus in the near term. Once we've got that pipeline build out going and we've nominated those additional candidates in the context of monogenic indications, we're going to be feeding the information out, hopefully, in a very simplified format. But with the supporting technical detail that shows you why people get excited when they look under the hood of this company, to communicate what's different about the tech. What's different in the nonclinical setting that gives us that heightened confidence that we are going to be able to change somebody's life in the very near term as we move into the clinical setting. So keep an eye out for those, and we look forward to updating you on the Q2 call. Thanks very much, everyone.