Syntara Limited (SNT) Earnings Call Transcript & Summary

Good morning, everybody. My name is Michael Woods, and it's my pleasure again to host the briefing for Pharmaxis, this time on PXS-6302. I'd like to welcome back many of you who probably participated in the briefing on Tuesday. And for those that didn't participate in that briefing, we are going to post the recording of the briefing on the Pharmaxis website, IR section, over the coming couple of days. So you'll be able to catch up on that if you choose to do so. In that session, we heard some very detailed overview of the oncological applications of PXS-5505 in cancers that have proved really difficult to treat with existing chemo and immunotherapeutics and have generally very poor prognosis. That's primarily due to the extracellular matrix fibrosis, either contributing significantly to cancer symptoms or potentially providing some kind of protection against those therapeutics. And in each case, the inhibition of LOX enzymes is postulated to allow for reduction in symptoms, and enhanced performance of existing therapies is either combined or in myelofibrosis as a standalone therapy. Today, we're going to be exploring another of Pharmaxis' drug candidates, PXS-6302, as a topical agent to treat fibrosis, we're all more familiar with, which is scarring, both cosmetic as well as significant functional impairments for patients. Firstly, we'll hear from Gary, who will give us a recap on why Pharmaxis is looking into scarring, and before moving on to Dr. Mark Fear and Professor Fiona Wood, to tell us a bit about their research into this. So I'll pass over to Mark -- to Gary, and then after Gary, I'll introduce Dr. Mark Fear and Professor Fiona Wood in more detail.

Thanks, Michael. I'll just share my screen and some slides. So just for those -- apologies for those of you who have joined us on Tuesday, just for a couple of minutes just to recap on Pharmaxis and the sort of the stage the company is at the moment. So we are a clinical stage drug development company. We have had a long-term research program, a multiyear program, which has looked into a particular kind of chemistry aiming oxidase chemistry. And from that come a number of targets that looked at diseases where inflammation and more likely fibrosis have played a key role. And we think through the collaborations we've had with scientific and academic groups worldwide. We've developed a world-leading position in this particular kind of lysyl oxidase inhibition. The drugs we produce are all small molecules. They are irreversible inhibitors of the enzymes, the lysyl oxidase. And they're all first-in-class and best-in-class drugs there as well. So there's nobody else in this field that's ahead of us in lysyl oxidase inhibition. So we are forging a path, and that's why we've ended up with a lot of collaborations like the one you'll hear on this morning because we have drugs which can be used to test hypotheses about this enzyme in human disease. And from that research program have come 4 studies, 2 of them already in progress and another 2 planned to start recruitment later this year. And that really puts us as a company, a very exciting stage for investors to evaluate, understand some of the science here and look at the short-term data that's going to come from these clinical studies that will drive value for investors. So I mentioned before that we were leaders in lysyl oxidase chemistry and biology. And I'll leave the chart on the left-hand side to Mark to introduce you to because Mark will talk far more eloquently than me about the role of lysyl oxidase enzymes in fibrosis and scarring and how that pertains particularly to scarring of the skin. We have 2 drugs. The first one, 5505, was talked about on Tuesday. And I encourage you, as Michael said, to look at the recording of that if you weren't able to join us on Tuesday. We had 3 different centers from the U.S. and Australia talking about the application of this drug 5505 in treating fibrosis is associated with cancers, myelofibrosis liver cancer and pancreatic cancer. That's currently in a study in myelofibrosis. The other one which we're going to be talking about this morning, 6302, is a drug which comes from Pharmaxis' own research that comes out of our labs that are based just outside Sydney. This is a topical drug. So it's going to be applied to the skin as opposed to be taken as a tablet. And it's a very recent pattern. So this is something which has come out of our development pipeline very recently is patented in 2019. So we've got a lot of ] ahead of it. And I think as you're going to hear a really exciting potential to help patients with a variety of different fibrosis of the skin and scarring in particular. So that leads us really to those 4 trials before I hand over to Mark and Fiona to talk more about the last 2 studies. The studies we talked about on Tuesday were in 5505 in myelofibrosis and hepatocellular carcinoma, a form of liver cancer. The addressable markets for both of those cancers are large. The existing chemotherapy in myelofibrosis, albeit it doesn't actually treat the disease itself, it treats the symptoms that come from the disease, already selling $1 billion a year. And we're now in a Phase II study. We're recruiting 24 patients, and that we should have data on that by the end of this year. So that's a really exciting prospect for us as a company that we might make a significant difference to those patients and then be able to go on to develop that further to become a therapeutic. The liver cancer one is being done by a group in Rochester, New York. They've done a lot of preclinical work in liver cancer and shown that if you add an antifibrotic, particularly our 5505, on top of their existing chemotherapy, then the cancer is much more responsive to the chemotherapy. So that by breaking down the fibrosis, you allow the drug in, and then that helps the chemotherapy work better. In the animal models of liver cancer, we see big improvements in survival in those patients. So that's starting to recruit next quarter. It will be 18 patients. We'll have data by the end of next year. So there are 2 trials that we'll talk a little bit about this morning and the science behind them are in scarring. And I'll leave that to Mark and Fiona to talk about. But I just wanted to address the issues that having a company that's going into cancer and fibrosis and associated with a number of different cancers, why did you end up in scarring? And I guess the answer to that is that the science led us there. And in particular, if Fiona and Mark came to us and said, this is a really interesting enzyme in this particular area. And what about collaboration on it. So we've had a multiyear collaboration with Fiona's group over in Perth, one we're very proud of, and we're excited about the work that they've done that you'll hear about. And when I started to look into this, I mean, scarring is, I mean, if you only will talk, I'm sure, about the unmet medical need here and the impact of scarring on patients. But also when I started to look at what other treatments were available and the other companies that were operating in this space, there's really very, very little that addresses scarring. There's quite a lot of development work in terms of wound healing. But when it comes to scarring, there's not very much new and it's crying out for a pharmacological approach to treating skies. And then when you look at the numbers, there are something like 100 million patients per year. who have operations that end up in scars. So clearly, the number of people out there who are looking for treatments is enormous. And I think we're starting at the early stages of this, but we're really hoping to see some clinical proof that there will be some signs of efficacy that come out of these next studies that give us the emphasis and the encouragement to go on in this area. So with that, I'll hand back to Michael.

Thanks, Gary. And I think I'd just like to also highlight that it's not just the number of people getting surgeries each year, but this has the potential, as you would have seen in that third trial for existing scars that are greater than 1 year old still to be treated, which I think opens up an even larger market. In any event, I'd like to now introduce Dr. Mark Fear, a senior research fellow in the Burns Injury Research Unit at the School of Biomedical Sciences c Western Australia. And Dr. Fear has conducted the preclinical work on the Pharmaxis' LOX inhibitors and will cover the science of scarring and potential LOX inhibition benefits. And then followed by Professor Fiona Wood, who leads the Burn Service of Western Australia and is a Director of the Burns Injury Research Unit at the University of Western Australia. Professor Wood is leading the clinical trial programs into PXS-6302 that Gary mentioned and will cover the clinical applications of LOX inhibition and the unmet need in the clinical development strategy. Following the presentation by the 2 researchers, we will then have a period of Q&A with some analysts, which I'll introduce after the presentations. Thank you.

Okay. So I'm assuming everyone can see that. Okay. I'm going to talk about the PXS-6302 treatment in the amelioration of the scar. So as Michael said, I've worked with Fiona at the Burn Injury Research Unit in WA and have done for the past 15 years or so. I'm just going to introduce some of the background as to why LOX is a good target in scarring and then present some of our preclinical data using PXS-6302 to improve scars. So when you get an injury, there's a process of sort of overlapping process that result in healing. So you get initially the platelets and you get [sccernible] hemostasis and stop the bleeding. And that triggers an inflammatory response. And this all happens. You can see across the top there, very early within minutes. And the inflammatory cells come in, they clean up the wound and also create a whole bunch of factors that stimulate the next part, which is kind of the formation of the new tissue to repair what's been lost. So you have essentially 2 layers to skin. There is the epidermal layer that is on surface layer, and that forms the barrier and this would sort of migrate over across and form a complete barrier to restore the surface of the skin. And underneath you have the dermis and this is what provides the platform for that to actually happen. So in the dermis you have these cells fibroblasts. They produce a lot of collagen, a lot of matrix. And once they produce that, these cells on the surface can migrate over the top of that and close the wound. And so what you're left with at that kind of early stage is a lot of fibroblasts in here producing a lot of matrix and a closed wind. And once that wound closes, obviously, it's not susceptible to infection. But this looks very, very different to the surrounding skin primarily because that matrix that has been produced to kind of promote healing is very different to the normal skin matrix in the tissue around it. And that happens depending obviously on the size of the wound over a kind of period of days and weeks. And then once you've got wound closure, there's a kind of process of remodeling and this really continues for life so it's sort of cut off is around 18 months and you think you've got a stable scar. But even in stable scars, this process of collagen -- turnover in collagen production kind of continues forever. And primarily, the reason scars look different and the reason they're stiffer and they feel different to normal skin is all about this layer here and the collagen that's produced by these fibroblasts. So the more that collagen you have, the thicker the bundles, the more densely packed it is, the tighter crosslink it is the worst the scar. So there's kind of a whole range, obviously, from normotrophic scars, which actually look quite similar to the normal skin, all the way through to hypertrophic scars, which are raised and red and really obvious. And then obviously, you have even fibrotic disease where scars actually grow outside of the boundaries. And this process, as I said, takes months and years and so I'm going to talk about a little bit more now. So looking at these kind of 2 layers of the skin, so a normal skin you have the surface and then underneath the collagen is kind of oriented in a whole bunch of different ways and that provides a lot of kind of tensile strength and liability in all different directions. What you have in scar is this collagen is much more densely packed. There's a lot more of it, and it's really tightly bundled and quite often in the sort of parallel bundles. So this doesn't give you that same kind of pliability because -- and strength because all of the strength is in one direction. So I kind of hopefully sort of emphasize the importance of collagen in scarring we're just talking about. So here's the fibroblasts here, which is responsible for collagen. So these cells or the cells producing collagen. And there's a whole bunch of stages within the cell where they slowly develop from procollagen through to triple helix that's actually secreted. And then outside of the cells in the actual matrix and the bit that we're kind of interested in, the collagen still gets processed even further some then get cut off. And the very final step of this collagen once is in the matrix is down here at the bottom, and it actually gets cross-linked and this cross-linking is what's causes what's catalyzed by lysyl oxidase. So the lysyl oxidase enzymes cross-link this collagen and that essentially makes it very, very stable, pretty much insoluble and very hard to remove. And so this is where PXS-6302 is effective. So PXS-6302 is an irreversible inhibitor of lysyl oxidase. So that blocks this kind of cross-linking process, and will reduce that stability of the collagen. And so in normal skin, you kind of have a balance. So you have your soluble sort of normal collagen and then that gets cross-linked and you get that really stable insoluble collagen, and that's balanced, that activity of LOX is balanced with kind of degradation. So some of that cross-linked collagen will be with MMPs and metalloproteinases. They will start to degrade the collagen back to the soluble. And you get this kind of balance between synthesis of insoluble, back to soluble and that's what gives you your normal skin balance. And then when you get scars formed or as scars are maintained, you have an increase in LOX activity and increase in that cross-linking. There's more of that insoluble stable collagen. The degradation is less. So the balance is just shifted, and that's what causes the loss of pliability and the increase in collagen and the poor scarring. And so obviously, with PXS-6302, you inhibit the LOX, you decrease the activity, you decrease the cross-linking to kind of shifting that balance back now to increasing degradation. So over time, those scars will remodel and you'll increase the degradation of that insoluble collagen back to soluble, you change the balance and that should shift the balance back more to normal skin, which is what we want. And so just to run through some of our sort of preclinical data. So this is just looking at cells in culture, just to demonstrate something that we're pretty confident that inhibiting LOX does actually reduce the collagen and cross-linking from fibroblasts. So we just take fibroblasts, these are human fibroblasts in a flask in the lab, and we can add the inhibitor PXS-6302 or LOX inhibitor and then measure how much collagen is produced and look at also the number of crosslinks that are produced. And this just shows as we increase the dose of the inhibitor, we reduce the amount of hydroxyproline. It's just a measure of collagen. And we also reduce the cross-linking, and this is kind of seen in these pictures here. So on the left is the control, which the green is actually just there are some collagens. We stained the collagen with label. And you can see there's a lot of it, and it's actually quite parallel in its secretion, and that obviously is reduced significantly when we treat them with LOX inhibitor. And I think as Gary kind of mentioned, this is a topical drug. So we had to demonstrate obviously that this penetrates skin. So the simple way to do this is a French cell. So you have the donor chamber. And in here, we have the PXS-6302 cream. And then we put a piece of human skin in between this and the bottom chamber, and then you can take samples from this bottom chamber over time. And obviously, as the 6302 penetrates through the skin, you start detecting it in this lower chamber. And what we saw is, over time, you get an increase of concentration of PXS-6302 passing through the skin, and this is human skin again. So we know that the drug is actually readily absorbed into the skin and readily crosses the skin barrier, which is really important because delivery, I think, has been one of the big issues in terms of having effective treatment for scar. And so moving into a couple of preclinical models. So we've done 3 preclinical models. Our first is a small animal model, and this is an excision injury, so surgical injury, a full thickness, so through both the surface layer of the skin and the bottom layer of the skin, where the dermis is. And then we treated once a day for 28 days with PXS-6302, and then you look at the scars at the end of that experiment. And again, as you can see from that graph, clearly, as we increased the concentration of 6302, we're effectively decreasing the cross-linking. And these pictures of the scars kind of show a nice histology. You can really see that parallel kind of straight collagen in here in the control, which is significantly diminished in the treated group when you compare that. So you can really see a change in the histology of those scars as well as changes in the collagen and the cross-linking which we measure. And so moving into a large animal. So this is the sort of standard preclinical model, is a porcine model. And this again is an excision injury. So a surgical injury. These are larger, say, 10 square centimeter full-thickness injuries. And these obviously, the porcine model type is a lot more similar in healing to humans. That takes a lot longer. So this is treating for 10 weeks. Again, once a day topical treatment and then looking at the scars at the end of that time. And what you can see, so across from left to right, is increasing concentration of the drug. And you can clearly see just from visually how these scars are improving with treatment. And this graph just shows similarly. So we provided these photos to a number of plastic surgeons who were blinded to the treatment group, and they rank these scars to compare their quality. And obviously, as you can see, so they're increasing quality. So the lower the score, the better scar outcome. And as you can see, that was improving. It's been a sort of dose response fashion. So that's already promising from that porcine model. And then I'll just talk a little bit about we've also done a burn model. So this is a burn injury, deep dermal burn injury. And again, topical once per day treatment after time to heal so after the tissue has re-epithelialized. And what we were really interested in here was actually the strength of the tissue. So one of the possible concerns about changing the cross-linking and the collagen deposition and remodeling would be that you actually alter the tensile strength than the physical properties of that scar. So I've got a stress-strain curve on the right there of a control and treated. And essentially, the slope is kind of a measure of pliability. So the longer that slope or the more shallow the slope, the better the pliability. And you can see there's a slight shift to increased pliability when you treat with the drug. And the peak of that curve actually kind of dictates that is the tensile strength of the tissue essentially. So what you don't want is a reduction in that peak because that would suggest you're weakening the tissue through treatment. But you can clearly see that the peaks are very similar for both treated and control. So we've got something where we've got very similar tensile strength, so we're not losing strength in the scar issue with its healing, but we are improving the pliability. So it's softer and more pliable. And so just to kind of sum up the data that I've shown you. So clearly, we can inhibit the target enzyme in scar tissue. We've demonstrated that we can improve scar appearance, and these are assessed by surgeons blinded to the treatment. So pretty confident in these changes in appearance and we've done that in small and large surgical injury models. And we've also shown that in a much larger deep dermal burn injury model. And the data we have today suggests there's no loss of tissue strength, but there is an improvement in pliability, which is probably the key. The appearance and the pliability are the key properties of scar that matter to patients. And so how it looks and how it feels, and we seem to be getting improvements in both those assets. And I think what was really important from that first slide I showed you is -- we think this has the potential not just to treat at that time of wound healing, where you've got sort of weeks to months of healing, but potentially to treat established scars because that production of collagen and that shift in producing stable collagen persists for a lifetime as far as we can tell. So there's an opportunity not only to treat in the weeks and months after injury, but potentially years post injury. I think -- are you going to present from here, Fiona, do you want me to?

Yes. Yes, keep the slides going. Thank you. So I'm going to just go from the more clinical side of things now. So thanks, Mark, yes. So could you change, right thanks so much. I mean we've seen-- I think marks a very well established scarring is a significant issue that we can change. But I just thought I'd like to show you some of the real scarrings that we've seen. We're not talking about always just cosmetic scar. Scarring I often feel is more than skin deep and it has a profound effect on people over their life. And as we've indicated, it's persistent, it turns over. That gives us an opportunity for improvement in treatment, but it also means that this person has to bear this for life as you can see in this small child here with a burn injury on the chest and up into the neck. That child will never move normally again. So it has a profound effect on your total body function as well as in certain circumstances you can see on the other side the clinical photograph there, the scar going beyond the zone of injury, that's expanding. And so -- and then with that expansion comes the itch, the pain, the scarring that influences the capacity of the persons to function and to sort of ignore them, if you like. So it's more than just what something looks like it's what it feels like and how it affects the rest of your body. And so what we're trying to do is understand how can we unscar the scar, how can we change that phenotype of the fibroblast back to a normal skin phenotype or back in that direction. And we know, as Mark said, that there's an interplay between the cell and the matrix around it. So if we can change that matrix, we can change the cell functionality and change that scar quality and move back towards normal skin over time. Thank you. So we now treat a patient with a skin loss. And I think I can talk about skin whole day. We talk about skin and see what it does because it does so many things. Certainly, it gives us our waterproof layer, a barrier to infection. But it's also involved in -- a bit of indeed involved in bone and hemostasis and linking that with the sunshine and the immune system, why do we blush. It is internally involved with our nervous system. So there's all this functionality that when it gets damaged is impacted. And so how deep the burn of the injury is depends on how you treat. And so when we go all the way through the full thickness of the skin, we're having to try and work out where can we borrow Peter to pay Paul, how can we harvest on sites, move that skin from a non-injured area and put it into the injured area, how can we facilitate the healing of the major word as you see in this adult patient here with an 80% body surface area burn, well, yes, we can survive such massive injuries, but it comes at a cost, and that cost is scarring. And it influences the functionality going forward with respect to this as the scar develops, we are sort of crowds out, if you like, or damages the capacity to develop sweat glands, hair follicles. So the other functionality of the skin other than the wear and tear barrier and the waterproof barrier that become compromised, it comes compromising it's immune response, et cetera, and we have to protect from sunshine. And so one of the commonest injuries we see here is a injury. With our cell based therapies, 80% of our children with this particular injury have no visible scar, but we see changes underneath the surface. And we see those changes influencing systemically that individual. So we've got a standard of care if you like, on how we can repair those wounds, but we have a real clarity of understanding of how that isn't delivering a regenerative pattern. It's not delivering normal skin. What we do is we have a scar repair, and that scar repair has a significant influence for life. Thank you. And one of the key things, which I thought I'd put on the table, we can discuss as we go forward this morning is the time to healing. And I think that sort of this whole LOX inhibition pathway is that we've got inflammation. We need information to heal. But when inflammation becomes extreme, it drives that poor scar outcome, and that inflammation is perpetuated, the longer the wound is open. So by modulating this and reducing the time to healing, we can reduce the scar. And that is one of the very few things that we absolutely categorically naive in this space is that we can reduce the time to healing, we can reduce the scarring. Thank you, Mark. I'll come back to that later. So what is our current standard of care? And I'm sorry about this sort of like this busy kind of slide. But I wanted to go through this in a real depth because what we have right now, as you've heard from Gary, actually, is quite limited. The one thing I know is that if I get a wound healed within 10 days, and only a very small percentage of people will have a scar. If that wound isn't healed until 21 days, then 74% of people will have a scar. And that scar is for life. We may be able to modulate it, change it, but it's for life at this point in time. And the scar, as we've heard, goes from our immature hypertrophic slightly scars, which we can improve with topical therapies, potentially. We've got -- we have to define the scar for our treatment. So we've got linear scars, surgical scars. In many people, they may fade to a reasonable level, but there are hundreds of millions of people with surgical scars that haven't improved to a reasonable level. And we've got then the keloid scars, the scars that then go beyond the zone of that injury. And that could be a minor, it could be a major situation. And then the burn scars. And the burn scars hyper -- rather a very characteristic hypertrophic response that is associated with the itch and the pain, et cetera. So what is it that we do about it? Number one is we try and heal as quickly as we can. Number two, then we need to look at the surface of the skin and see what we can do. And so basically, what we have in our toolbox at this point is silicone sheeting with a small molecular weight. Silicone topically has an impact on some scars some of the time. It's a trial and error. We put it on under -- sometimes under pressure garments, and I'll come back to that or sometimes just in the topical crew it will have an influence, as I say, in some people, some of the time. It will hasten the maturity but it does not eradicate the scar. And it only does that in certain individuals. And in other individuals, a small percentage should probably coming up to 8% to 10%, it causes a reaction and we have to stop it. When this -- in some instances when this gets out of control, historically, steroid was the only thing that we could use. And so we would use that steroid. But now we have laser therapy. And so we have a capacity to fractional laser to alter the scar by using the laser, which initiates microthermal zones. And sort of it's a bit like in my head space. It's a bit like in those older ones amongst there's a bang and the thump in the top of the television to get the very horizontal hold going. It's a bit of a sledgehammer to crack a nut. But we're learning all the time on how we can control those microthermal zones to get the right kind of balance so we can remodel the scar. Pressure garments is another thing we use very widely. But does pressure in itself influence the scar. And this is something that I feel is debated long and hard. Pressure garments facilitate edema control. By controlling the edema, you control inflammation, you can have a positive effect. But that's in the short term. In the long term, the pressure garments influence the oxygen transfer across the surface and at the cellular level, does it change the mechanobiology? Is it a combination of these things? And again, it's -- well, it's not something that is foolproof and works with everybody all the time. And so we've played by -- we tend to use pressure garments when the scar is a vascular response when the scar is red. And then we pushed that pressure until the redness starts to dissipate and then we pull back on the pressure. I think it's interesting that we measure our scars in terms of what they would like. Are they red or purple or angry -- or sort of the vascular response? How florid is that? What the pigment load is like? Are they pale? Are they dark? What does it feel like? Is it lumpy? And is it pliable? And so all these things -- these subjective things come together to give scar management -- scar assessment, and we're trying very hard to look at assessment scarring that we can use to become more objective rather than subjective about this because that's one of the things that is a bit of a problem. And certainly, there's all sorts of things that people use cryotherapy as occasionally, again, in certain circumstances used in keloid scarring can change the healing pattern, but not widely used. Things like introducing bleomycin and other oncology drugs into keloid scar is not widely used interferon. Again, it's because we haven't got something that is reliable. We've done research looking at steroids in keloid scars versus calcium channel blockers, and we find that 50% of these scars will return within a year, even with steroid, which is considered the state-of-the-art treatment. And so just going through with what we have straight away, trying to heal quickly, uses topical silicon, pressure, if we need it and escape control injection with steroid and laser. And that's the standard of practice and then you start to get more complex things with scars that are out of control. Thank you, Mark. This is just to show you that we can change things and we try and monitor our changes in our -- and we've got a suite of tools that we look at scanning the surface. And this is using OCT, optical coherence tomography to look at just under the surface without taking histology and comparing the impact of our laser on hypertrophic scar here you see on the shoulder, on the upper arm. And we're trying to understand how we can change that scar and this shows the vascular pattern of the blood supply within the scar trying to drive it to a normal pattern as compared to the normal skin. And so these are some of the research, one of the research tools that we use, as I say, trying to get some objectivity around this whole space. Thank you, Mark. So we have an unmet need. We've got an unmet in time, one, prevent the scar. Two, control the scar. And the holy grail is can we unscar the scar? Can we change that scar phenotype back to a regenerative phenotype? And this matters because these scars have symptomatic pain, itch, movement. The skin no longer flows over the underlying tissue structures. You may not be able to move your hand or your elbow or whatever normally. So you have that functional impact as well. So we really want to understand how we can control that extracellular matrix to drive a regenerative phenotype, not just in the acute phase but way down the track as well. And then the other thing is how can we integrate if we repair a flap, we bring -- take out the skin cancer, we bring a flap tissue in there. How can we integrate that so that we don't have a scar around the edge and underneath? So the integration of new tissue constructs. So that brings us to the trial. We've done the first in human on our normal skin, and we move and go forward from that. And now we are using the topical cream in the scars that are established scars greater than 1 year previously from injury, 10 square centimeters. And with our first cohort, we've recruited our first 8 patients. And we're taking serial pharmacokinetic blood and biopsies -- punch biopsies of the skin before and during this whole procedure out to 2 months, we have our first patients just arriving at the 2-month mark. And we'll be tracking these first 8 patients very carefully, as you can see here with the checks, with the boxes, with the blocks of time. Our next cohort, which we just put out a Facebook Expression of Interest. So we started our patients coming forward. So for us to survey is to make sure that they are suitable to include in the trial. And this 42-patient cohort that we will commence in April are randomized. Our first, 8 all have the drug. Our next 42 patients will be randomized into drug versus placebo. They are less intensely followed, as you can here, in terms of bloods and biopsies. But we will be driving this out again to 3 months. And so our recruitment path will be April, May, June. So we will be finishing the trial by these established old scars in the sort of July, August, September. And then we will be moving into our acute work as well. So the part 2 with -- in our acute work is looking at our burn injury patients, can we stop it happening in the first place. So we'll be looking at 2 to 3 weeks. The epithelization has been achieved. The wounds have healed, but then the maturation and the remodeling starting. So this will again also be a randomized controlled trial with a 3-month follow-up. Clinically, I can -- we can assess at 6 weeks, and we know whether that person is going to develop a scar or not or become -- will develop a scar, a troublesome scar. So we will be in a position with our 3 months follow-up to know that 3 months is when our scars are at their worst, and then they tend to mature after that. So in there, in this situation, we'll be bringing in scar scanning, a 3-dimensional scar scanning technology, ultrasound histology, POSAS is the patient and observer scar assessments. And so that looks at both the symptoms and the appearance of the scar from the patient perspective and from the observer such as myself. And so the other thing is how many of these patients will then go on to have -- require secondary interventions such as steroids and lasers. Laser is our third therapy these days. And so that's the next trial that will sort of roll along flowing on from our chronic established our work. Thank you. And I think that's where we can answer all the 4 questions you have for us.

Thank you very much, Professor Wood and Dr. Fear. Now I'd like to introduce our Q&A panel. We have Scott Power from Morgans. We have David From Edmonton Partners and Chris Kallos MST Access. So those will be the panelists. We'll start the process with about 15 minutes of Q&A or maybe 20 minutes of Q&A for Fiona and Mark, and then we might bring Gary in, and we can extend the Q&A to more prime access level questions as opposed to just the clinical program. So do you guys want to get started? Perhaps Chris, you are not on mute, do you want to start with the Q&A?

I can start. Professor Wood, I guess, the question for me in the other trial, which is the criteria is quite objective. How do you go about choosing or standardizing scarring? I imagine there are many varieties of skin types and types of scars. How do you go about standardizing that for the purpose of this trial?

The first 8 patients have all got quite -- have got a range of scar. And what we're looking at is the scar in context of that individual. So we are aware of the pigment load of the individual influence, the time from injury, all these different things, the data points that we're capturing because what we're trying to find out as we go forward is which scar type is actually the most receptive. And the individual variation is actually fundamental for us to build that knowledge base. So rather than trying to get everybody with a same or less scar, what we're looking at is anyone who has a 10 square centimeter scar and put it into context of that individual. So we feel in our way forward. And I think we will -- that way, we will be in a position to understand what kind of -- what patient is the most likely to be responsive. And I think that's a lot of work to do in the future as well, looking at men versus women, age. We know that collagen turnover is slow in older people than the younger people. So does this -- is this more effectively younger than older? That kind of thing that we will build this knowledge base as we go forward.

I guess the follow-up question to that is, does that become harder with keloid scars?

Keloid scars are hard to stop. And I think we're in a position that and these particular trials, we are not going for keloids in the first instance. So I can tell you these scars are not keloids what we're researching because they are so complex. I think that's an opportunity for the future, but then that will be a separate cohort. Does that be reasonable, Mark, because cellular differences are quite significant?

Yes. Yes, the whole pathophysiology is different. So yes, I think there's definitely potential for 6302 in keloids, but we would have to do that as a separate distinct trial, not as part of a broader scarring trial.

Sorry. And the third part of the question is, given that we're focusing on established scars, can you perhaps talk about the time line of the current trial? What are the next steps?

In terms of the current trial, it's -- we're looking at an improvement over a 3-month period. Mark, do you want to talk about heavy water, which has guided us in that space?

I can talk a little bit. So we have actually done some measures in humans of collagen turnover. So we're pretty confident. So we did this partly for within this trial as to whether LOX might be effective in this type of scar. So we have actually measured collagen turnover in established scars and some of that is actually in patients who are enrolled in this study. So we'll hopefully be able to kind of look at collagen turnover and how that matched to whether the treatment is effective in established scars. I think in terms of the time line, were you sort of asking more about the time line of?

It sounds like as Professor Wood said you're feeling your way in terms of the indication, when do you think you'll have a clearer idea of what specific subsegment when you stratify the scars, where the next steps may be. So what's that sort of time period?

I think -- sorry, I misunderstood the question. Certainly, from already, I guess, there is, in some quite complex scars, there is an indication of improvement if you could feel and see a difference. And so I would anticipate that the -- putting keloids to one side, we will have -- my observation is we'll have an impact on scarring. And the time you will apply the cream for how long and all those things are what we will be working out. But from a perspective of the scars, at this point, our indication is that they are responsive. And so I don't think that's the issue. I think it's more the -- how long you give it for and just -- and maybe in certain circumstances, it requires longer. Yes, that's what -- and it may need 3 months instead of 2 months, that sort of thing.

Yes. Can I squeeze one last one? Obviously, it's early days, and we're talking burns and acute settings on track from possible combination of this product would say, something like a ReCell for burn injuries?

Okay, that's an interesting one because it's the type of scar we are looking at which patients do require that scar modulation. And so at the 6 weeks mark, we would be looking at introducing this as in patients who have ReCell or more complex reconstruction. Our issue is can we -- in the acute work start that 4 weeks earlier so we drive down that upswing. And so yes, we will be looking at this across the board of complexity in our acute work as well.

Great. That's it for me. I'll let someone else have to go.

Maybe David next.

Thank you both of you for lovely presentations. So I mean, it's been said that human wound repair is one of the most complex biological processes that cures during our lifetimes. So many finally tuned in time, molecular and cellular pathways involved. It's actually kind of remarkable that the repair process can occur without more malignancies, I think. So just reflecting on the safety profile of PXS-5505. I'm really interested in your thoughts on how you see this treatment as part of therapy that targets just one part of that repair process, albeit downstream in the cascade, but I'm just interested in your thoughts on the balance of everything going on.

Can I just start on that one? So you're absolutely right and largely in terms of sort of therapeutic development for wound healing, people have focused a lot on the actual wound repair itself. And that is an infinitely harder space because there's so much going on, whether it's TFB, CTGF or all these other factors and the balance of the factors and the inflammation and all of them happened. So that has really been a really complex challenge, whereas I think what's nice about this is you don't necessarily that point. This process of collagen remodeling and stability and processing happens pretty much forever. So you can let the wound heal, if you only can do the surgery and the intervention, you get the best peeling you can, and then you can treat with a LOX inhibitor, right. So you're avoiding that complexity and even the toxicity of a wound environment where a lot of compounds and stuff probably are going to be less effective and certain biologicals have been shown to be less effective. So I think what's nice about this is you kind of miss that really complex where there's so many different processes happening simultaneously and you actually treat it when the scar is actually just really focused on remodeling of the dermis. So yes, I think it's kind of a more, it's a better time to intervene because there's a lot less complexity.

That's great. Scott, do you have any questions? .

Yes. I don't have anything. Fiona and Mark that was a terrific presentation. I'm so just looking at the results, which we're likely to get out in late June 2022, you'll be getting -- you'll be having a really good look at some of the efficacy measures in the scar structure. I'm just wondering what a good result looks like. We're starting off with a 10-centimeter scar what would be a good result for you that would make you sort of really impressed and hopefully move it forward towards a registration.

From my perspective, I think I tick in there. If the patient thinks it's better and wants to continue using it and try it in other areas, that's success. We spend a lot of time in this space. And as you saw, we kind of with the silicon, pressure garments, all this sort of thing. And if we have a therapy that the patient thinks has improved their scar then that is the biggest tick we can have because they're the people that wear it. Having said that, then there's all sorts of other things that we need to look at, whether it's the scanning and I'll hand over to Mark to look to respond with respect to histology and all that kind of -- the structure of the skin. So we can back it up with -- that sort of thing point of fact is if somebody would continue to use it and then POSAS process, their assessment of their scar has improved, that's our biggest tick. Will that be fair, Mark.

Yes, for sure. And I think just to be clear with this, so we are treating 10 square centimeters, but a lot of these patients have much larger scars. So we are only treating a part of the whole. So it must give an opportunity to really see a difference because these are established scars and from an appearance perspective you can kind of see the impact of the treatment in the context of the larger scar for a lot of these patients. So I think that gives us an opportunity to see a difference.

I guess you're also looking at assessment of more objective assessments as well of the quality of the scar?

Yes. So that's Fiona, sort of alluded to the 3D scanner, I think that's really being able to measure the volume of the scar over time, I think, is really critical. So we'll be starting that with this randomized cohort of actually measuring that in 3D, which will give us a really objective measure of how and how the controls and stuff of the scar. So that should give us some really nice data around that.

And just one other question, if I can. Just the rationale for using the 2% cream versus the 3% cream, which seemed to perform significantly better than the 1.5% cream.

So we did in an initial study, we did dose escalating up to 4%, and 2% and 4% look very similar in terms of their levels of inhibition. And we have actually measured inhibition indeed. So one of the reasons I think we are keen to minimize the dose is because then we can treat the large area. So particularly for large burns, some of these patients might have 60% to 70%. So clearly, if you have 60% of your body covered in a cream, that's a pretty large dose. So we wanted to minimize, but still obviously get effective inhibition. And we have measured that in this first 8 patients, and we are getting effective inhibition at 2%. So we're happy with that. But yes, we weren't really concerned in terms of the dose we could have gone up to 3%, 4% for these small areas we're treating, but it was more looking to the future and being able to cover a whole arm with the cream not sort of have to worry about the total dose that a patient was receiving. And as I say, our measures of LOX inhibition look really good. So 2% seems to be just as effective.

A question came up from the audience. So just before I perhaps hand back to David, it's sort of relevant to what you were talking about, Mark. And that's about the safety profile and whether the agents are systemically absorbed and how -- whether there's a sort of length of use that you've established is safe.

So that's part of, obviously, this first trial. This will be the longest we treated. We have had some patients out to 3 months and without any issues. Certainly, there's no rise in systemic levels, and with once daily application over 10 square centimeters. So everything we've seen and obviously when we do pathology bloods at every appointment as well, and none of those have shown any kind of indications of systemic changes in liver or kidney or whatever. So all the data we have at this point would suggest that, yes, it's safe and you can do it for a long time, but we'll continue to collect that, obviously, over the coming kind of 50 patients and be sure that we can sustain that.

And maybe I'll just jump in there just briefly. So that what we're doing now with collection of all these data sets is up for then going to a regulatory body with for an IND, so we could go to the FDA for IND and we've got a lot of the information now on producing GMP material that we've already done, and they're collecting patient level data. And as you rightly say, the level of systemic exposure to the drug versus what's in the skin. And Martin now that you want to have something which has a bigger safety margin as you can so that you can use it on a bigger skin area as you can because a lot of these patients do have scars to a much larger area. So that's where we're heading with this. So we should be ready to go back to the FDA with an IND in -- within the next few months once we've seen data coming out of these first 8 patients that have come from the study.

Great. Thanks, guys. David, over to you.

So just getting back to what you were saying before. So it sounds like if you think about common traits of the scar for wound healing being rapid re-epithelization, dampened immune system, delayed collagen deposition and the ability to remodel. And this treatment is really focusing on the latter 2 I assume. Does it -- is it something that you would then assume that patients will be using for life? Or does it form -- do we get to a stable point and just bringing it back to the trial, the 3 months, I mean, I guess, 90 days is where we typically talk about scar synchronization. But is it possible that with the reduction in the collagen matrix formation, you might expect that time might be elongated for scar synchronization and would you expect that to be a longer term follow-up in these patients perhaps as an extension on the trial?

Yes. So that was quite a long question. There's quite a lot of questions, I think. But I'll see what I can remember. In terms of the follow-up, yes, I think we need to follow these. So the moment, they're getting treated out to 90 days, and that's their final appointment. But actually, LOX isn't replenished very fast. So even when you start putting the drug they don't get LOX activity for quite some time afterwards. So we would imagine that the remodeling will continue for quite some time after you stop taking it. So yes, we need to look at these patients a bit further down the track because they may actually continue to get improvements related to their treatment, even though they stopped. No, I don't imagine they would need to take this for life. I kind of showed in that shifting that balance. So you would imagine if you shift that balance forever, that potentially would be deleterious rightly if you would start to get seeing a problem. So you would imagine there's kind of some optimal, at least maybe different for different people, and the extent of the scar. You would imagine there's a point where you would want to stop in that balance. So what we kind of know is the fibroblast that produce all that collagen are very sensitive to the matrix they sitting. So actually the stiffer and worse that matrix is the more they produce. So what you would imagine is as that matrix gets less stiff and remodeled, they stop producing as much. And we know that happens physically. We don't know that happens in response to LOX inhibition at the moment. But we know that happens with response. So that's kind of how we would hypothesize this is that the matrix gets remodeled much more like normal skin types. So I guess, I mean stress strain, the Young's modulus and it's trends are comparable.

And so what you're saying is that if you were to continue indefinitely, you might see that a growing disparity in those measures? Is that what you -- and are you still looking for some kind of a steady state where you're any other sort of changes?

Potentially, if you treat it indefinitely, you could start to change that stress strain curve, that would absolutely be a possibility. We don't really know the answer. Would there be a plateau where the body stops responding and just or responds. So one of the things we did measure quite early on was we talk we stopped cross-linking the collagen where lot of cells just produce more collagen to compensate them, and that doesn't actually happen, certainly doesn't happen over the short term, in a week or 2. And so we've tested that in the lab because that was one of our concern, whether they would then respond. If the matrix becomes so do they then respond. We don't really know we haven't got to test that. But I think that would be a really long term, but you might reach a plateau where they respond or you may just reach a plateau where it doesn't matter how you keep inhibiting it just.

And I'll just to add to that. From a clinical perspective, where we've got a significant scar that is not responding, we would sometimes do what we call a Z-plasty. And that means we change the direction of the skin and as I said, we close it the other way. And in doing so, we change the tension and the mechanobiology of the surface. And in that circumstance, we see the hypertrophic scar resolving, and it usually is between the 6 and 12 weeks, we see that response and it doesn't recur. So I think we have clinical practical sort of observational evidence, if you like, that when you change the mechanics of it of the skin envelope, you can actually then change the phenotype of the cells that are driving it. And so in my head, that's why we've been looking at this 3-month time frame. Change something in 3 months, can you keep it changed for life? Can you unscar the scar to that point and then that will be stable, and that's what we're looking for. So this -- it's not coming from out of the blue. That's how I'm trying to say. It's coming from practical observation of what happens when we do more complex things like surgical intervention.

Professor Wood, can I just ask, sorry, David, go ahead.

No, I was just saying thank you for that good answer.

Professor Wood, can I just get your comment on the experience you've had with the first day patients that have gone through the trial? Anything you can sort of pass on to the audience?

I think -- so from my participation, sometimes you could see a difference, and it's like, am I wanting to see different series it's real. But certainly, there are a couple of our first say that if I look away and I feel a surface, I can mark the edge. I can feel the edge of the area I've treated. Not in all of them. And I'd say it's very early and you don't want to say it, well, it works and it's fantastic or anything. But clearly, there's something happening. And I can't think probably half at this point, but they're all at different time points because we're going through. But it's really interesting. And anything is can I feel this difference because it's a different cream that's being put on the surface. That's why the randomized trial is going to be really important. The carrier versus the drug as well because am I feeling just that kind of moisture change or am I feeling a real change. And so certainly, it's encouraging it would be I wouldn't put my hat and my coat on that [ .

In the nice things we're talking is pretty well tolerated. So I mean, the important thing is that we're going to be able to get 3 months data on all these patients, and there are going to be some controls in there. So come the end of the year, we get to enter August, September, hopefully, we'll see in an overall sense. I'd just like to stress the exploratory nature of this as well. I mean we are throwing market looking at all kinds of endpoints and measures and skin types. They've explained how we're exploring the impact of different types of scars and different things. This is collecting an awful lot of information that allows us to plan the next stage and go on for it. I think we're all very hopeful that we'll see a positive change in the scars. And then it will be a question of trying to identify at least of which cars in particular, should we trial this in? Where should we really go that we can make a difference? Because I think then maybe Mark and Fiona can comment, but the history of trying to run clinical trials in scarring is littered with probably trial design problems in trying to control the patient groups and trying to work out how do you actually measure an effective drug that's going to match what the FDA or the TGA are going to say, okay, yes, that's a treatment that we're willing to approve.

Right. Perhaps we have probably time for one more question, so I might see whether Chris, do you have one more question you want to ask of the team before I move to a couple of questions from the audience and then hand over to sort of questions that might be more fund access related than specifically for Fiona and Mark.

Just the last question around the design of the trial. Now the -- given the exploratory nature would empowering of the way forward, what kind of strength of data would you need to sort of plan next steps here given the limited number of patients so it's been vague, but I guess in terms of getting next steps or getting guidance on where to go to next with the indication, how strong a signal would you be looking for across how many patients of that type?

I think I'd be guided. I mean Fiona said it earlier on, if you've got a significant number of patients saying, "I want to carry on and it makes a difference," I think the collaboration between us and the University of Western Australia would be really digging in deep the thing to try and work out, okay, where is that improvement and what makes sense to go next? We've talked a little bit this morning about some of other types of scars. So one of the biggest probably areas of unmet need is in keloid scarring globally, which occurs mainly in African and Asian skin. And there's very little that we can do for those patients at the moment. And if the prospect of maybe being able to surgically excise the keloid and then stop it recurring. That would be also an interesting place to go. So I think, yes, if we can see something happening, and we're clearly modifying this comment, we'll be taking approaches so you can count the number of crossroads in the course. And mechanistically, I think we'll know, yes, it's working at that level. And then are we structurally seeing changes in the scarring and are patients noticing it? If that's a yes, then we'll be very encouraged to keep going. I think that has a potential huge benefit.

That's great. Thanks, Gary. Perhaps I can sort of bring the 2 questions from the audience together into one, which is really looking forward. And I go to some of what you were just talking about, Gary, taking what's really a Phase I into a Phase II and beyond. What's the sort of the future road map here from a Phase II study and also a regulatory approval process, particularly in Europe and the U.S., where it doesn't look like there's a predicate treatment to compare to. And you'd obviously have to be going through some kind of potential pivotal trials. So that's just at a high level, talk through what subject to success in the trials going ahead with Fiona and Mark at the moment, what future development pathway looks like for this.

Yes. So certainly, the next -- these 2 trials that we're talking about, if you can remember, there's another one after this looking at patients with burn injuries. Those 2 trials will generate a significant amount of data. And with that, my hope is that we'll be able to go to a regulatory agency, TGA, FDA, EMA and talk about patient selection and endpoints that they would see as being enough to give us approval. So the next trial design is really has to be a heavy regulatory input into it in terms of angling towards what do regulators need to see. I know -- I think I know what myself and Mark and Fiona would like to see. We just -- if the patient say it works, it works. That, however, it doesn't always tick all the boxes for the regulators. So we need to really consult with them. But the beauty of what we're doing now is generating data that allows us to have a really good scientific based evidence, based discussion with them as opposed to, well, 9 out of 10 cats like this one. So that's what we're going to do kind of thing. It really gives us a huge ability to do that. So as I mentioned, we're we'll use -- we'll be probably having an initial, what we call a pre-IND discussion with the FDA once we've got the data from the first 8 patients and the safety information that allows us to go there. And then that develops into a full IND for a specific clinical trial application once we've got the data from all the patients going through. And that will be an exciting step forward, which should happen towards the end of the year.

Great. Thanks, Gary. I guess at that point, it's probably a nice segue into any more format specific for general questions around the agenda that we've worked for today. So may be David or do you have any more general questions for Gary before we...

Yes, I could ask one. So it's really interesting stuff. I mean the idea of reducing fibrous capsule development around the medical implant in my former life is actually a serious issue, too. And I just wondered because obviously there's implications to electrode tissue interface signal to noise ratios, impedances, all of these different things. There's a huge industry built up around that, and some of them involved slow release of various drugs, whatnot. Have you considered other applications of this technology, for example, a slow release formulation that could be used with implants?

We haven't yet. I think we see this as proof of concept. And if we're really making a difference, then it obviously opens up a lot. We had study teams come to us and talk about the postsurgical closing of surgical wounds and the additions that they get inside them and abdominal surgery things like that, which all could be potentially target for a topical LOX which is maybe putting an implant or is a spray that you do before you close the wound. I think there's a number of different ways we're going. So we'll be certainly inviting Mark and Fiona to come with us and talk to professionals from other walks of life to sort of look at the data that's coming out and the scientific understanding of what we're actually doing to see the applications in other areas. So I don't want to get ahead of ourselves. I think we just see data from this and then explore. But clearly, there's a lot of opportunity there.

Related to that, I think it was mentioned earlier that there is quite a durable risk inhibition to the LOX from the drug. About how long do you see or is there evidence of how long you see that duration extend far beyond the application of the drug.

I think the nice thing from Mark, maybe a comment on this, but one of the concerns we had was you're applying something which is reducing cross-linking collagen in the scarring process. So if a patient then is on the drug and then has an injury and needs to go in for surgery, what you do. And I think the nice thing is once you start treatment, the actual inhibition of the enzyme within the skin drops off pretty quickly. So you're not going to interfere in wound healing for a repeat injury. So that's one of the safety issues we have to look at. Mark, would that be fair?

Sort of. So the inhibition does last for a while because LOX is not synthesized very quickly. So because it's a reversible inhibitor once you actually prevent LOX is not a sort of uptake of and an upswing of LOX expression. So for -- it will be in the weeks, I think, post inhibition all full restoration activity will be in the weeks post your last.

From that perspective, it wouldn't -- it's not a functionally active in the early parts of wound healing. So we still -- there's early phases.

Also be very different if you had to bring because your body will synthesize a whole lot of LOX as part of the wound healing process. So I'm talking about is restoration of activity in an established scar which is a very different context.

Great. Thanks. I think we've got just enough time for maybe 1 or 2 more questions. So maybe, Chris, do you have something for Gary in general.

I think most of my questions have been answered. In terms of, sorry, Gary, in terms of -- on the financial side, in terms of funding, future funding for similar programs, what's the capacity for fund access to expand the clinical trial program into, say, topical?

Yes. So we are funded to get to data in the current study and the myelofibrosis data they're ongoing. So once we see data from those, then the company would have options in terms of looking at collaborations with other industrial partners or going back to the markets again as well. I think in our -- Chris, in biotech, we're driven by data at the end of the day. I think our -- if you look at our valuation at the moment, it doesn't really reflect where we are as a company in terms of the clinical development trials we have ongoing. But the data changes that. So we are funded through the data, and that fundamentally changes the perspective of the market.

Right. Maybe one last question.

Professor Woods, you are fairly clear with your timelines in terms of the recruitment for the trial. That was my observation of the way you presented the data or the way the trial is panning out. So is my observation correct that you don't have an issue with recruiting the patients for the next 42?

I think the next 42 is a different group. And so we've gone to a public expression of interest. We have people approaching us by e-mail all the time trying to because things that they hear about what we're doing. And so our original aid are very much more intensive and there was screened very rigorously. And we did -- I did put the a lot of biopsies and a lot of blood tests on them. So they were a group that are very vested. And I think that going forward, in the next 42, the in-cost on that next 42 patients is a lot less. And so I don't perceive that we will don't anticipate any issues because there is a lot a people again. I think the other thing is that scars are big enough 10 square centimeter as a minimum. And so we will see in this next 42, they won't be just our burn patients, who are well known to us, there'll be a much broader group of people.

Great. Thank you, Dr. Wood and -- Professor Wood and Dr. Fear. Gary, do you want to make any closing comments before we close this briefing session?

No, no, just to thank Mark and Fiona for spending their valuable time to share [indiscernible]. We live on our collaborations in effect. And I think we're[indiscernible]scientists of this caliber to come and work with us. We couldn't do anything without them. So thank you both very much.

Great. And thank you, too, David, Scott and Chris, for your time and questions, which hopefully have served to inform the participants on this call. And as with the call on Tuesday, I understand after a couple of days, this will also be posted on the IR part of Pharmaxis' website for future reference or other people that weren't able to participate in the entire thing or at all. So thank you very much, everyone. With that, I'd like to draw this session to a close.

Thanks, guys.