Avacta Group (LSE:AVCT) — Interim Results

0:01 Good afternoon, and welcome to the AVACTA GROUP PLC investor presentation. Throughout this recorded presentation, investors will be in listen only mode. Questions are encouraged and could be submitted at any time by the q and a tab situated on the right hand corner of your screen. Simply type in your questions and press send. Due to the significant attendance on today's meeting, the company won't be in a position to answer every question received during the meeting itself. However, the company can review all questions submitted today and publish responses where it's appropriate to do so. Before we begin, I'd like to submit the following poll. I'd now like to hand you over to the management team. Chris, good morning. Good morning. Thanks, Lily. Thank you to everyone who is joining us today. Brian and I are thrilled to be bringing you our interim results. And without further ado, let me dive in.

0:47 So we are advancing, our next generation precision platform. This is a a tumor activated peptide drug conjugate that can deliver our payloads with optimized kinetics using a specific mechanism that is is highly innovative and and new in the peptide drug conjugate field, which is a mask and release. Precision masks a potent payload behind that peptide that's cleavable only by Fab. And Fab is a protease that is abundant, in solid tumor stroma, and it's near absent in healthy tissue, which allows us then to widen the therapeutic index of highly potent payloads that are otherwise limited, by their toxicities in the clinic. And so our lead asset, FAP exotecan or AVACTA six one zero three, that we'll take a deeper look at. So it's the first of this next generation, peptide drug conjugate.

1:46 This is a FAP activated, but it's... Importantly, it's a controlled release, version of exatecan. When we initially looked at this potent payload, as a as a potential, for precision, it was really limited in the original clinical, look at exothecan back in the late nineties, early two thousands, it was limited by both its potent toxicity. You know, ninety percent of patients had severe neutropenia, but it was also limited by its PK. And so that's where these advances in precision came from. We'll talk a little bit about these inventions that led to this clinical program.

2:31 The phase one FOCUS o one trial has been dosing since March across six indications: gastric cancer, colorectal, cervical, small cell lung, hormone receptor positive breast cancer, and pancreatic. Probably our favorite of these various indications are the GI cancers, where we have really good evidence that the TOPO-one mechanism works. And as an added benefit in gastric cancer, we have evidence that a similar mechanism in an ADC in HER2 that uses a very similar payload, doruxtacan, has nice activity. We have... Out of our next generation pipeline, we have two shots on goal that are are coming, to the clinic. AVACTA as you can see there, we have published five and a half months, after the trial started. We have published our initial clinical proof of mechanism data.

3:28 We will take you through, some of the more, I would say, meaningful slides in today's presentation. We also have shown significantly higher tumor concentration. These are our preclinical studies. Selectivity and activity versus in HER two. We're going to be updating these as we move towards our ESMO presentation. ESMO begins, as you know, in just eight days. Our second of the next generation is AVACTA six two zero seven. We believe that this is one of the first dual payload peptide drug conjugate programs out there. The... We will be presenting a little bit later this year, the candidate selection and and all of the data, that goes into that. This is the clinical candidate selection, so the final, drug will be presented, in the second half of twenty twenty six.

4:23 Also, the data, that will support, moving towards that IND and launching the IND enabling studies. Why does our next generation win? Well, it wins because it's been derisked in patients. So PRECISION, the first generation of PRECISION is AVACTA We've demonstrated three important aspects in in this program. The first is we've optimized the safety, and the payload was concentrated. We've we've published these biopsy data showing a 100 to one concentration of the payload in the tumor versus the plasma. We've also shown excellent cardiac safety. You know, one of the key safety features or one of the key toxicities that we see with the payload doxorubicin in the clinic, is cardiac failure, and it is incurable.

5:17 And so the the bar for the evidence to lift that lifetime maximum, in the clinic was was quite high. We've published the data leading up to that. We're we're very proud. It it... You know, lots of factors there, and we will be presenting additional data. We've also seen durable rhesus responses in our lead indication in salivary gland cancer, even, again, at the lowest levels of FAP expression, we published back at ASCO and BioInternational in May and June of this year. So updates on all of these programs will be coming in the next couple of months before the end of the year. So the timeline there at the bottom. In in September, we published the proof of mechanism data with AVACTA six one zero three. We're gonna take you through some of the key data slides here today.

6:11 The dual payload will go through candidate selection that is coming. The AVACTA six one zero three, the efficacy readout will be in the first half of twenty twenty seven, but we will commit today that the tumor PK will be out year end or early... Very early, in 2027. We do have ongoing, multiple discussions with, multiple pharma partners. The IP estate is building. And as Brian will will describe a little bit further, we are looking at, a potential NASDAQ dual listing during 2027. So the next generation of our precision medicines, this peptide drug conjugate drug class, we are aiming to deliver activity that is more robust than the ADC class, which is probably one of the most, successful classes of drug in oncology right now.

7:09 So this this innovative drug class achieved the robust efficacy, but using small molecule chemistry. We'll take you through a little bit of of how our scientists invented this. And what are the three goals? So first, it's to to release the payload in a tumor selective manner. This is really to address, some of the the key toxicities that we've seen, with both, ADCs and and PDCs, similarly. The second is to protect normal tissues, and and that's through this masking effect. We've seen this, and shown it clinically with AVACTA six thousand that we can protect normal tissues. We alter the biodistribution, of the payload, by using the precision mechanism. And finally...

7:55 And and this was big for the next generation. We modulate the PK of, the payload. Recall back I mentioned that exothecan had a real PK problem in the clinic. It has a very short half life, so it had to be dosed daily, which is incredibly inconvenient for patients. And so we want with a single dose of our drug to deliver just like an ADC with controlled exposure in the tumor. And what we found is that we do get a nice, Cmax. So we get a nice hit of payload, in the tumor right up front. And so the precision next gen controlled release PDC platform is designed then to achieve all three of these goals using our innovative small molecule chemistry. The added benefit of this being a small molecule is that we save a lot of cash, on the GMP manufacturing.

8:49 It's about a third to a half, of what you would spend to manufacture an ADC. Now the precision platform, it it has a a very large market opportunity. About ninety percent, of all solid tumors, express FAB. This was a a large experiment that we did... Study that we did, both internally with immunohistochemistry, but also with our our collaborators at at Tempest looking at about a 160,000 human solid tumors using these combined methods. We didn't do immunohistochemistry, which is a bit more labor intensive, but the RNA analysis looked across all of these tumor types. And and what I can tell you is that we have not found a single solid tumor that does not have very robust expression. And so that represents a very large market opportunity. There isn't a single precision medicine that will work for every one of these, which is why IP and and managing that pipeline delivery, again, with capital efficiency, is critically important for AVACTA going forward.

10:04 What do we mean? Let's unpack a little bit about first generation versus next generation, the whys and the hows. So so the first is is why. Well, let's let's look at the first generation. This was a direct peptide link between the payload, doxorubicin, and, the peptide. And you can see the actual chemical structure of the drug there. The peptide is is in gray, and the payload is in light teal. Couple of things to note here. Doxorubicin has a chemical structure that sits nicely in the active site of FAP, and that is required, for FAP to be able to to cleave, this peptide. It turns out that this direct peptide link is actually a highly efficient substrate, and so it enables very rapid cleavage. So the main, mechanism of metabolism of this drug when it enters the human bloodstream is is actually cleavage within the tumor.

11:04 And so we had to do a couple of things in order to get a drug like exothecam to work. The the first is is is that we needed to slow down the cleavage. We really know... We know from a a very old theory. It's called the the the Norton Simon hypothesis. It was published back in the seventies. We know that we need for some of these enzymes that are important in in DNA metabolism, we need at least three days of coverage. We need to shut that enzyme down for three days, and that just isn't gonna work with an eight hour half life. And so that's where the capping group comes from. The capping group that we've introduced, you can see over there in in navy blue. The capping group is designed to hold our peptide drug conjugate in the active site of FAP and create almost a reservoir within the tumor. So we want the tumor to hold on to the drug. Otherwise, it it gets, eliminated by the kidney, pretty quickly.

12:06 The second part, and and these two inventions work together, but the second part is a is a chemical linker that is essentially to mimic that part of doxorubicin that sits in the active site. And we've invented and and and borrowed some of these. You know, there's multiple chemical linkers that have been used in in the ADC molecule field. And what we found in in these inventions and and in investigating this is that we can get very variable speeds of release. And so that's why we call this controlled release. Now for exatecan, we needed to create sustained release. So we needed to really slow it down. But we have various levels, and and so we can dial in the PK that we want, of any given next generation precision medicine that we make. And so this controlled release enables three important things. The first is, we get very, very much so greater PK control. We now know that we can keep the drug right in the active site. We can have the tumor, take it up and be a and be a reservoir.

13:15 The second thing is that we can control the release in the tumor. As I mentioned, we can get it to release very quickly. Or in the case of exatecan, we can get that to slow down given the very short half life of this drug. And because we have multiple linkers and it allows the drug to sit outside of the active site, we've now been able to really expand the pipeline potential here and get many more... You know, a large number of small molecules, to work with precision enabling. That brings me to, the AVACTA pipeline. We do have three programs, that are now deploying our precision platform. Our first two next generation programs, a v a six one zero three, which is releasing exothecan.

14:01 You can see the indications as we've talked about already. This one, is is working through its dose escalation period of the phase one trial. Our next milestones with this one, as I mentioned, we are going to be publishing the tumor PK. That started at cohort three. That'll be in late fourth quarter or very early in the days of of the first quarter of twenty twenty seven. We won't be dropping data in at Christmas time, but... So either late in the fourth quarter or early that... Very early in the first quarter. The efficacy data then will be in the first half of of twenty twenty seven. As I mentioned, this trial started in March. First data came out at... In five point five months showing the proof of mechanism, and we're looking forward to those, few updates.

14:51 The dual payload, which we have not disclosed the indications. We'll show you some of our ideas later. This one is combining potent topo one inhibitor along with one of the key resistance mechanisms, targeting DNA damage. With that one, we will be looking at, announcing the payloads And then all of the data that's gonna be supporting that clinical candidate selection, that'll all be, in the next, eight weeks, essentially, as we move towards the end of twenty twenty six. And then some some really important updates that we have on faridoxorubicin, our our first generation drug. This one we're gonna be updating that lead indication in head and neck cancers, the salivary gland subset. We are gonna be looking across the phase one a and the phase one b data. We will be updating, in the second half of twenty six. ESMO starts in in eight short days, and some really important data, will be coming for both ferredoxorubicin.

15:56 Critically important, we're gonna be looking long term, there with that update, really understanding, how patients have been doing, that have been on the trial, for quite some time. And then, we will also be updating AVACTA six one zero three preclinical as well as a trial in progress at ESMO. So, lots of important data will be coming out, in Madrid, in just a a short period of time. So taking a look at at the Precision platform as a whole, we've designed Precision and especially the NextGen to look at four key opportunities that we think, we can make, the drug conjugate, aspect look a bit better. And the first is is payload release. We know with the ADCs that one of the challenges are are these organ specific toxicities because of the nonspecific, protease cleavable linkers. These are lung toxicity and liver toxicity, pneumonitis, hepatitis.

17:00 And because we get tumor specific release by FAP, we aren't seeing any of those toxicities now, deep into AVACTA six thousand and as well, through the first several cohorts of AVACTA six one zero three. We have no pneumonitis, no hepatitis. And importantly, as I mentioned for AVAC six thousand, no cardiac toxicity. We can now use a dose dense regimen, to treat resistant disease. And so the idea here is that by increasing the dose density, putting those doses closer together, we actually increase the amount of payload that we can deliver. That is limited in the ADC field by the PK of of the antibody, but also the safety of the payload as as some of it is released in plasma.

17:49 And so the whole idea with the next generation was to really keep that payload out of the plasma. The internalization dilemma. So with an ADC, payload is released following, the slow process of internalization because it is targeted, to a tumor antigen through that antibody. But our peptide drug conjugates have a very simple extracellular release. FAP is an extracellular enzyme expressed on the cancer associated fibroblast, and that simple release results in the killing of FAP positive and FAP negative cells. It's important that in salivary gland cancer, every single patient has FAP negative tumor cells. FAP is only expressed in the stroma. So that indication, and, you know, just the number of patients that we see that durable tumor shrinkage, is critically important in that program.

18:43 Tumor penetration, also critically important. It can take up to twenty four hours, to see that payload release, within the tumor, whereas we see it within minutes with the PDC. So we have a very rapid, t max in the tumor. We actually get a very nice c max, in our animal models. And all of that, importantly, is delivered with small molecule chemistry and manufacturing. That saves a lot of money as we move towards the the GMP manufacturing of our drugs. So let's look at the clinical trial for AVACTA six one zero three. As I mentioned, we have both the standard arm, which is an every three weeks there at the top, and we have the every two weeks arm at the bottom. This is the dose dense regimen. And in bold, below the dose levels, you can actually then compare that 50% increase, in the dose intensity that we get, with the every two weeks arm, is critically important. And we can keep this one going as long as we continue to see that very favorable safety profile, that that, we have described with the proof of mechanism data.

20:00 As we move through the dose escalation, this will only be limited by toxicity. We will be escalating... We can even escalate beyond dose level seven if the safety, if the safety allows. You know? So these these, oncology trials, especially using the Bayesian design, the Boyne design, really allow us, to be flexible with dose levels, and respond to safety as we see. These arms are enrolling in parallel. It really does increase our ability, to to treat patients, and to move towards, all of the data collection that we see there. On the right hand side, you can see we've sketched out a number of, expansion cohorts. We're gonna determine, based on the data, make a data driven decision, which of these, will move forward once we've identified, the dose in the trial.

20:55 So if we look first, at the time that we reported data last month, we had completed and analyzed, the data, including the PK data for, the first three, cohorts in the trial. And we're comparing here with, two different programs. First and HER two. This is an ADC that uses a very similar payload direct scan compared with our Exitucan, and the dose levels are very similar. First three dose levels in the Enhertu trial and the first three dose levels. In terms of payload dose with the AVACTA six one zero three trial. And then exotecan, it's important to note that the MTD in pretreated patients was dose level two in our trial.

21:44 And so by the time we moved to dose level three, we we were looking at a 50% higher, than the maximum tolerated dose. And the safety that we're presenting here, is the safety that is published at that MTD. So now we're 50% higher, and you can see there we have no neutropenia. This is the most important barometer. So the neutrophils are part of the immune system. They're they're part of the white... One of the key parts of the white blood cell component, of the bloodstream. We can't transfuse neutrophils. They are the infection fighters, and we see no neutropenia, through these first three cohorts. We were thrilled by that. Really shows that we're able to keep the drug out of the peripheral blood. We do see a single grade one case of thrombocytopenia and then nausea and vomiting through the first three cohorts and a couple of cases of grade one anemia. So a really favorable safety profile. We're thrilled with this despite, again, giving fifty percent higher dose of payload above the MTD of of exothecam, the payload in the clinic.

22:59 And so now we're gonna turn to what we think are are some of the most important data, which is really understanding the pharmacokinetics, and and starting with the plasma PK and really understanding what is going on in the patients through sampling in the bloodstream. And I'm gonna take you through first here the chemical reaction, that we are measuring. Because, again, this isn't this isn't a a a made up drug. This is a drug that needs to go through a cleavage event, by a resident enzyme, fat, that exists in the tumor. And so what happens... You can see here. This is just a schematic, of AVACTA six one zero three describing where the capping group and the linker are and how exatecan sits out outside of the binding pocket. So the drug fits nicely then into the fat binding pocket.

23:53 We can't measure this. So this is the, the the reaction complex that is formed, and the speed with which that reaction occurs, again, is determined by the gray portion there, which is the linker. That gets broken down, as you can see there, all the way over on the right hand side, and we release now reactants or two products of this chemical reaction. The first is released exothecan, and the second is the released peptide. Now, importantly, I measure... I I mentioned that released exothecan has a very short half life in the clinic, only eight to nine hours. It was one of the things that was was very challenging in its initial development back in the late nineties, early two thousands. Even shorter half life, though, is our released peptides, only two to three hours. And so in order to measure this in patients, if we get the drug... If the drug is doing what we designed it to do, these are gonna be released into the bloodstream at very low levels. And so we drove those assays way down to a very low limit of detection of point one nanograms per mil.

25:01 What we're gonna do next is look at exactly what the animals were telling us and what the preclinical data told us of how this drug was gonna work in the clinic. So the first... I'm gonna take you through the four colors here. It's a very busy, figure. But if we break it down by colors, I think you'll see, that the the drug is is is designed, exactly to behave as as we've chatted about. So each dot here represents a small group of animals, and we're looking at both plasma as well as tumor in this figure. So let's start with the joined up drug, which is in gray and navy blue. Gray is in blood, and navy blue is in the tumor. So the joined up drug, AVACTA six one zero three, we get a nice peak there at number one in... As soon as the drug is is infused into the bloodstream.

25:54 It drops down then very quickly to a to a pretty low level, and what's happening there is depicted in navy blue. The drug is now being taken up by the tumor. And what you can see there is that we get joined up drug out five days later, in in the tumor. So that's where we're creating this reservoir. We want the drug to sit right in the tumor and be able to reload the tumor, from the low level that's in the bloodstream. Now we're gonna look at the the the product of the reaction, which in this figure is exotecam. So the released exotecam in the tumor is in dark teal, and in the bloodstream is in very light teal. What you can see here now is in, the released exatecan in the tumor, we're now able, over the course of those five days, to slowly release the exatecan.

26:49 And what you can see is is if we look way out to day five there, we still have it being released above the I c 90 of exatecan. Now the I c 90 is... It stands for the inhibitory concentration where 90 of tumor cells in a dish are being killed by exatecan. It's a key factor that we use, to sort of describe the potency of a drug. This one is somewhat low because exothecan is such a potent drug, but it was critically important in the design of this drug that we get multiple days of coverage. Again, back to that Norton Simon hypothesis. We get multiple days of coverage within the tumor, and that's that's step two, but that we don't get that in the bloodstream. And that's over there at at step three. So in very light teal, we see that the exiticcan, it comes out in that initial burst of of cleavage that we see in the tumor.

27:47 It comes out into the bloodstream, and it disappears within two to four hours. And the whole idea there is that is that masking. So the the drug itself, AVACTA six one zero three, is not gonna cause the toxicity, but it is that released, exothecan, and we wanted it to disappear, very quickly, from the bloodstream. And so we use this figure. This is exactly what we designed, this drug to be, and we're gonna use this figure as we move into the clinic because understanding is the drug doing what we designed it to do in the patients is is critically important. And so now we're gonna move into the clinic. This is the first figure. This is the first cohort of patients, in the trial and understanding, the PK.

28:36 And and a couple... Three important observations is is first, we see a rapid decline in navy blue, of the plasma level of the joined up drug, AVACTA six one zero three or the peptide drug conjugate. That's importantly, it's gonna be retention in the tumor, but also that slow rate of clearance, that we've seen, and that's the capping group, was designed to, to affect both of those for us. We also see in the patients here a very low sustained release of exatecan in the plasma. Now recall, the half life of exatecan is only eight to nine hours. So as you're getting out days after the dose was administered and the exatecan is still being detected, it has to be being produced somewhere. It's being produced in the tumor, and that's based on our our preclinical data that we we showed in the previous slide.

29:27 We're getting that reservoir navy blue in the tumor, but we're also getting dark teal. We're getting that drug being produced, within the tumor. Probably even even more important because of that really short half life is the slow sustained release of the peptide. Now the peptide is detectable, in the bloodstream of the patients. It's detectable two days, after that dose was administered. It's actually the, the highest level. You can see there, you know, the confidence intervals are gonna overcome each other, but the absolute value there of the peptide, it's detected two days later. So it's... Both of those products being produced, that's gonna be cleavage, that is occurring, within the tumor given that reservoir.

30:16 Now the next step that we're gonna do is is pull these last two slides together and understand, did our... Is our modeling happening in the clinic? Are we seeing... Is the drug doing, what we designed it to do? And that is this busy figure, looking across the three dose levels, one point five, three, and four point five. And there's four different lines in each of these. Let me walk you through. We're gonna look at both what we anticipated and modeled in the animals, and that's gonna be in the solid lines. And then what we see in the clinic is gonna be in the dashed lines. And dark navy blue is going to be AVACTA six one zero three, the parent drug. And then in light teal is going to again be the released exothecan.

31:03 And let me walk you through a couple of factors here. We look back. This is the figure that we just looked at at 1.5. This is the first dose level. It's actually pretty spot on with what we anticipated. We get asked the question a lot, why do we see this little peak, of the light teal in the animal modeling? And that's because mice have about 10 fold... 10 x times, the soluble fat in their bloodstream. And so we do see in the animals that that little peak, that happens in the plasma. And similarly with AVACTA GROUP we saw this in that program as well. We just don't see that peak, in humans because we don't have very much fat in our bloodstream. So one point five mgs per meter squared first dose level worked out quite nicely. When we move to, the next dose level, we have a very interesting observation, one outlier, in the trial that we call out there, and that we do see, this figure of the extended exposure of the peptide drug conjugate, and that's driven by a single patient.

32:04 It's exactly what we saw, though, in a very low FAP model is that we see sort of that extended exposure. That's exactly what the CAP was designed to do was to prevent that rapid, kidney filtration of the drug. So we were incredibly, encouraged, by observing this, in that second dose level. And you can see there, we do get these are log scales, but we do get that nice dose responsive increase, slight increase in in the the plasma level of exatecan, but we also get that nice increase and spot on with what we modeled with AVACTA six one zero three. Now if we move to the 4.5, mgs per meter squared spot on with what we expected, from the animal studies. And you can see there, the rapid decline of AVACTA six one zero three dashed lines in patients in the plasma, down to the lower limit of detection out two days, but we're still getting that sustained release of exothecan.

33:09 And so this is exactly what we expected to see as we continued that dose escalation. And so these findings are are really increasing our confidence that this nonclinical to clinical translation is performing exactly as intended. And we ask, you know, those who have been following us to think back to all of the animal models that we published where this drug is is really nicely shrinking, both low FAP, high FAP. And that will be, some of the next data along with, the tumor PK that we have, that we have guided will be, late this year. And so last data figure that we're gonna look at here, we compared the known, PK of the release of to can from Enhertu.

34:00 And this is essentially using AI to recreate, these datasets from, the published data, within Enhertu and its release of dirux to can versus what do we see with the release of exetican from AVACTA GROUP Now we're looking at, the first three dose levels, for for each of these. And the the message here is that we're seeing about, you know, estimates three times lower release in the plasma of the payload than was seen with equivalent doses of Enhertu. Why is that important? Well, you can see, our exposure, just as we saw in the animals, the exposure in the bloodstream disappears, pretty quickly with those first three dose levels of AVACTA six one zero three as opposed to...

34:56 And and in PK figures like this, when you stop, when you you you stop the lines, that was when you stopped detecting it above the lower limit of detection, which is depicted there at point one nanograms per mil. And you can see at dose level two, which is in, the the very light green, as well as dose level three in the rusty color of exotecan... Or, I'm sorry, of doruxtecan released from in HER two, we still detect that out, multiple, days later. Now low levels, but even those low levels, in the in the plasma can create, some of those, toxicities. So we are thrilled, with how AVACTA six one zero three is behaving in the clinic thus far, And this slide sums that up. So we have a very favorable safety profile of AVACTA GROUP in the clinic compared to both conventional exothecan as well as in HER2. We think those are two really important comparators as we start to measure what this drug is doing. Now the comparison of the preclinical model PK and the clinical trial PK demonstrates just a really exceptional alignment for the first three dose levels. I've been doing this a long time, twenty years now, and this is really the best preclinical to clinical translation that I've seen in my career. So this

36:26 remarkable consistency really increases our confidence, that AVACTA six one zero three is performing exactly as we intended, and that our robust, preclinical data will translate, into the clinic. We think AVACTA six one zero three is really... It's performing exactly as intended, and the dose escalation continues. The biopsy data will be coming soon, and the efficacy data as we get into the first, parts of of 2027. So turning back to the pipeline, an invention that we were extremely excited about, from our chemists and our biologists was to adapt this next generation platform, develop new linkers that actually had a couple of different pods where we could attach two different payloads.

37:23 Now similar capping groups, so we're gonna create that reservoir, similar peptide, which is gonna be cleaved, by the FAP enzyme. But importantly, the invention here is around the self immolative linker. We still have the ability to to guide the PK and and how slowly or how quickly, should we want it, will the linker allow those payloads to be released? The first way that we're going to implement this in the clinic is really to use it to go after resistance mechanisms. And so there are some patient populations out there, some well known resistance mechanisms that really predict for high unmet need in the clinic, and that's exactly where we've decided to go first.

38:15 And so the combination mechanism of action, the two drugs that are gonna be released from that single precision event are going to be the combination of a highly potent topo one inhibitor. This one, again, induces single strand breaks. This is the exact drug class that exotecan comes from. And we're gonna hit one of the most important resistance mechanisms out there, which is the DNA damage response. And so bring forward one of these drugs, we've we've looked at a number of them and published some of that information. What that allows us to do, in planning the combination clinical development is really to look at that mechanism of action.

39:01 We know that there are cancer cells that harbor specific genetic changes, in the DNA damage repair pathways, and we know that they would be highly sensitive to this particular combination. And I... You know, very helpful to us is that these genetic changes are actually very simple to measure in the clinic, and this becomes sort of the next level of precision medicine for us. And these, you know, unmet needs, ATM loss, Schloffin 11 loss, MSI high, cyclin e one upregulation, you know, we know that these are patient populations really looking for, for for new approaches, easily measured in the clinic. And, you know, there's a large set of diseases there. We're now working through some of the the preclinical studies that will help us to focus in on exactly what are those patient populations that would be the most sensitive, to this particular mechanism.

40:00 Really looking forward to publishing, a a very large amount of the data here, and selecting this candidate, to move into IND enabling studies. All of that will happen, in the latter part... Well, within the next eight weeks, the latter part of twenty twenty six. So with that r and d update, let me turn it over to Brian for the financial results that we're here for. Thanks, Chris. As we recently announced the oversubscribed equity placing and subscription of 12,500,000, this helps strengthen our financial position to support these R and D programs as we move them through the development process. This was the third oversubscribed placing subscription we've completed this year, raising 10,000,000 in March and 9,000,000 in June from institutional and existing shareholders.

40:54 Cash and short term deposits at June 30 was 20,270,000, up from 16,900,000 at year end, and cash held at August 31 was 10,600,000. It's also worth highlighting that we have been actively engaging with a number of specialist institutional investors who have a deep understanding of the biotechnology sector. We are particularly pleased to have been invited to formally host investor meetings at the Jefferies Healthcare Conference in London next month. This represents an important step in broadening institutional awareness of our platform and communicating its significant potential to a highly relevant investor audience. We believe these efforts will help strengthen our investor base and position us for greater success as we advance our plans for a dual listing on Nasdaq. Thanks, Brian.

41:39 Let's take, let's summarize now. And I I wanna take a look lastly before we get to the questions on on what is... What's coming next. What have we accomplished, this year, and and what is coming next? So, as you can see there, we have, five really important updates, that will be coming, to be honest with you. It's it's about eight weeks left in in in 2026. And so we will be presenting with a v six one zero three at ESMO. This will be a trials in progress presentation with some important, preclinical updates. We're really excited about those. That's about eight days away.

42:26 As I guided to, we are gonna have that tumor PK. We've mentioned that that started at at cohort three, and, we are gonna be looking at that, late q four. We won't drop data at Christmas time or in the very early days, of of 2027. So we will be updating data there. With our dual payload, which we're super excited about, really going after some some areas of of really high unmet need, you know, following... You know, using this platform, to really address high unmet needs, where where could we go next for patients? We will be looking at disclosing, those payloads there. We will be presenting at the triple meeting and the candidate selection data late in in the fourth quarter of this year.

43:17 And then finally, some data that we know everyone has been waiting for is the the salivary gland cancer with AVAC six thousand, the salivary gland cancer progression free survival. The ESMO updates is going be so much more than that, though, with this program. This is going to be our first opportunity to really look very long term in the AVACTA six thousand program, understand there's many patients that have been on for for quite some time. And understanding... Again, going back to the basics of drug... Really understanding the PK, how durable, is the FAP mechanism, you know, and and and really studying that not just in the animals, but really studying it in the patients and understanding, you know, a a bit more of the biology there. So a number of big updates still coming in...

44:10 By the end of the fourth quarter. We will be looking at again then in 06/01/2003, that efficacy readout, in the early parts of twenty twenty seven. The expansion cohorts, will be designed and begin there. So lots of work, over the next, several months, but the next eight weeks, look to be very busy, for AVACTA. We're really excited about, a number of of the pieces here. So with that, let me bring the formal presentation to a close, and turn it back to Lily. Let's, let's answer some questions. Thank you, Chris Brian, for the overview overview of the, interim results and the business update.

44:55 Now let's turn to the questions which have been sent in for the management team. We have had a very strong response, and thank you to everyone who has submitted a question. Given the length of the presentation, let's just focus on a few that were not addressed yet. Can you expand on what data will be presented at ESMO? It seems that everything has already been presented. What are we looking to learn at the meeting? So so as we announced, yesterday, at ESMO, we are going to have, two important presentations. So let me let me start with AVACTA six thousand. We are going to be presenting the final... The PFS data for the salivary gland cancer indication. I know we've been waiting for that. Durability is is critically important, especially in the the PDC where where we haven't had, you know, big durability, you know, just yet.

45:48 The team has really been focused on on the regulatory aspects of this program. We disclosed previously that we had a successful end of phase one meeting with the FDA. That meeting went well. We received good advice on the pivotal. There are aspects of the pivotal trial that we still have to decide in the company with the help help of the health authorities and then present, those data, from our setup trial. So the phase one b, and combining it with the phase one a, it's really important, to show that, you know, we're we're ready to move forward. We're very happy now to be at that stage of of finalizing those datasets. And some of those datasets are gonna support the pivotal trial. So it's important now that we present that dataset in that subset of patients that would be eligible for the trial.

46:40 As you know, we've shown many patients in different subsets of salivary gland cancer. For example, some have had very extensive pretreatment, but we know that these patients would be excluded from the pivotal trial based on our conversations with the health authorities. So what we're going to be doing at ESMO is really understanding and presenting who are those patients that based on, you know, the conversations and the advice and the design, what is that subset, that would be eligible for the trial? And this is based on not just prior therapy, but histology of the disease, the ECOG or the performance status of the patients. And so, we're gonna disclose all of this.

47:25 This is gonna allow us to plan for that enrollment. We're also looking very long term, as I mentioned, PK at safety, you know, rolling all of that out, long term. It's critically important that we we not just show durability of efficacy, but that we show why, you know, what is is the PK there. You know, I I I should mention that we know that the wait, for the PFS data has been long, perhaps painful, but it is a paradox in oncology. Longer the wait, it just generally translate to better outcomes for patients. Oncology drug development here, it's a long game. I've been doing this for a long time, but it's a long game. The first question we ask, the PFS, is how long can we control the tumor?

48:14 We're gonna answer that at ESMO. We know that so many have been waiting. But the bigger question then becomes how long do I have, doc? And that's the overall survival. The important point that that we announced is in the in the design of the pivotal trial, only PFS is needed, for approval. And so the, we have to show nonbetramine, so we we can't make the overall survival shorter. But but the the key data, for the approval of the drug will will be, the PFS. So so that's an important dataset that will be coming. I know that's long, you know, but but we think that this is gonna be really a platform validating, set of data that will be coming. There's some important biology, that's coming out of this trial that actually will impact and and show us some things that will will impact next gen like AVACTA six one zero three.

49:13 Thank you. Just turning to the next question. It has been noted that the pivotal design... Trial design is agreed, and we have had so much data already presented. Why has this program not advanced, and what are we waiting for in the AVACTA 6,000 program? Yeah. Good one. So let me assure everyone first that that the program is advancing right on track. We know that there is the perception of the delay in this one and because it's taken a long time to collect the PFS data. Like I mentioned, you know, we we base our, predictions of when data will be available based on, some of the the observations that we made. Now it it really does translate in oncology as... Know, when you're collecting PFS data, the preliminary look at the PFS in the phase one portion, we anticipated it could be nine months, And that was ESMO of of 2025 that we...

50:09 So a year ago. Now why has it taken so long? Well, PFS takes a long time, and you have to wait for the patients to progress. We did disclose some of the early data in the phase one b patients, and that was back at ASCO and bio. That was back May and June of this year. And so these were sort of the first looks, in the expansion cohort. And and these datasets did show us, some really similar efficacy in terms of of tumor shrinkage. You know, the waterfall plot that we showed was very similar to what we saw with the phase one a patients. And the PK in those first two cycles were critical. ASCO, we also showed the cardiac safety. But now at ESMO, now we're really looking long term.

50:58 And, you know, PFS in the joint patient set, in the patient set that's gonna be relevant for that pivotal trial, safety, efficacy, long term PK, looking at FAP expression in a couple of different ways, taking that long term view. So my advice here is stay tuned. ESMO is is a short time away. We will be in Madrid soon, we believe that there's there's some good datasets coming, in both of the presentations. They're gonna be very meaningful, for both the program, as well as the platform. That's great. Just turning here to the next question. You have hinted here to a biology presentation at ESMO, platform data.

51:43 What will be... What will we be looking at, and why is more biology needed? So let me answer this one two ways. The first is, the biology studies at ESMO going to be both in patients with AVACTA 6,000, but also AVACTA six one zero three. And and some of it will surround the role of the enzyme, FAP, that we rely on. So FAP is... You know, we need FAP to cleave the drug. It's a it's a mask and release. We're really trying to understand more about durability of responses and and the tumor shrinkage that we've seen with AVACTA six thousand. How does the enzyme behave in patients and in our models? And and how can we use the models to make predictions for, you know, AVACTA six one zero three and and whatnot. There's, there's a big key difference, between targeting a tumor antigen, which is essentially using the antigen as a destination, a location, for a drug like an ADC, And then what we're doing with Precision, which is we're leveraging a tumor specific enzyme, FAP, to cleave a peptide and and release the drug. They're two pretty different approaches, but but similar.

52:58 And so the precision platform is based on that concept of mask and release. Other peptide drug conjugates, don't use a masking approach, to spare the normal tissues, and they don't use this release mechanism. And we think the tumor specific release and the masking capabilities are are really some of the most innovative, and and they're quite unique, to precision. So a deeper understanding of the biology of FAP, and some of this will come out at ESMO, preclinical and clinical, like I said previously. And and we believe these datasets are critically important not only for the program, but the platform. And and to note again, it is gonna be across, both of them. And as I've mentioned before, biology leads to new IP.

53:50 And so if we think about the the second reason to look at more biology, the controlled release mechanism, it started with some biology questions, that led to some of the most important IP for the company. We have to continue to evolve. We have to continue to understand, how the platform works, and and that brings us to brand new IP. And and as we've committed to, once we have new IP, we will be disclosing. And and so much more coming in the in the next eight weeks. That's great. Just turning to the, next program, AVACTA six one zero three. We have had a number of questions coming in on the trial design, the data that were reported recently, and also the data to come.

54:38 I'll ask a few more frequent ones in the submitted questions. But just the next question here we've got is, for AVACTA it appears that enrollment is going well. Can you comment on this? Are the dosing cohorts still lining up with the ENHER two trial? Yeah. Enrollment is going very well. We're we're thrilled, with how that trial, is progressing. We have... You know, we we mentioned preview... We have completed four dose levels with respect to enrollment. As you know, the collective experience with AVACTA until a trial shows something on proof of mechanism, it's it's tough. It can be tough days. But, you know, we were thrilled that, you know, we we really saw from...

55:24 As we showed you from the first cohort, that six one zero three was was really doing, what we designed it to do. And so we have not seen that kind of challenge in enrollment. Our our CMO, Dave Lebowitz, and his team, they're doing a fantastic job in a in a in a challenging space. You know, we have four dose levels, two arms in parallel, and all of that has been completed in six months. Just terrific execution by Dave, and the clinical team. We have both the every two weeks and the every three weeks, in parallel. Dose level three is where we started collecting biopsies. It's it's also... Let me just note. It's it's important to note the differences between six thousand and six one zero three, the statistical design. We get a lot of questions about the Bayesian design, BOIN.

56:17 It allows flexible dosing. It allows backfilling of cohorts, mandatory biopsies starting at dose level three, and none of that was permitted in the design of the six thousand trial. So we do continue to progress and advance this trial. We are still lining up, and we're going to be comparing with the doses of in HER two, but also conventional exotecan. We think that that's, important. There were single agent responses to conventional exotecan, in the early days. So we'll continue those comparisons. And, you know, the flexible boing design, really allows us, to make some important decisions during, the the conduct of the trial. That's great.

57:04 We have spoken quite a lot about the tumor PK understanding that the tumor biopsies were later in the trial. When will we see the biopsy data? Your CMO, Dave, mentioned in one previous r and d spotlight that biopsies are now mandatory. How does that work? Yeah. So once again, we we started collecting those at the third third dose cohort level. We use the backfill mechanism. It's occasional that a patient, that enrolls in the main dose cohort would consent, to a biopsy. There are some pretty solid rules around where biopsies can be mandatory, and so that is both institutions as well as FDA. And, you know, so we... These collection requirements, the these... You know, the the mandatory biopsies really didn't start until, that third dose cohort. We get asked what does backfill mean? Backfill means that a patient who's not granted a slot in the main dose escalation cohort can be treated at that lower cleared, dose level. And, so the trial is moving rapidly. The biopsies were sort of, you know... It it didn't move in until dose level three, but it is going well right now. And so, yes, we are guiding that, we're hopeful end of year. It's possible it leaks into the early days of of January, but but we are we are collecting. We already have a few in our back pocket.

58:32 So really excited to be showing, tumor PK. It's a it's a really important part, of this program. Thank you. Just, moving on to the next question here. Your CMO also suggested previously that the trial might stop at dose level five or six. Is that true? How does the dose selection work, and how does this Boyne design work? Yeah. It's a good question. We've gotten this one by email. No. We will not be stopping until we define that MTD. We stopped with AVACTALES at tolerability. We hit unacceptable, toxicity, but, six one zero three, we are are knee deep, and we will not be stopping until we see. Maybe we should do a a AVACTA Academy on the Asian stats. It's it's a very different trial design, but to suffice to say, no. We will not stop early.

59:23 That's great. The next question here we've got is on a v a six two zero seven. At the q four a v a six two zero seven announcement, will you have a development ready candidate or further optimization still to complete? What safety and efficacy date, criteria must it meet, and which steps towards IND submission and first patient dosing are funded today? Yes. Definitely. So we will have a development ready candidate. There are multiple steps before we get to sort of those more expensive, places, but the the year of of IND enabling studies. We have to manufacture the drug. Once we start the manufacturing, that, that drug actually goes into the preclinical models, the toxicology models. We really have to be convinced at both a PK and an efficacy level, as we move and and that we have a patient population that it's relevant for. So a lot of data coming.

1:00:18 This program is really our first one that's designed to attack those key resistance mechanisms. So the clinical planning here is critical and is gonna be ongoing in the months of the IND enabling studies, in parallel with that. We have to find the right patient populations. We have to find the right centers. But the beautiful part of this one is it is a true precision medicine approach. And so we know who are the patients that are likely to respond here. Perfect. We have, thank you. There are a number of additional questions on business development. One has been asked multiple times. Are you in formal diligence with any potential partners even if unnamed, and what milestones would trigger a deal? We, we very much understand, the intense interest around, updates on our partnering discussions.

1:01:10 But as as I'm sure everyone can understand, keeping the status and the details of ongoing discussions confidential is is just as important, to successful partnering, as as it is, you know, waiting for clinical data to mature, for a successful trial. We have multiple conversations that are ongoing under confidentiality, so we can't disclose anything there, until there is, something to be announced. I I can say that we continue to have productive conversations both under CDA, but also, you know, with with multiple partners not yet ready, to sign a CDA with us. It's important that we do the right deal at the right time.

1:01:58 We know that, you know, one of these deals could bring in quite a bit of nondilutive funding, but but it's important to note that, these deals always give away key pieces of our IP estate. So, again, back to doing the right deal at the right time. What I can also add here is that we're very fortunate to have a highly experienced and strategic board, who are very supportive of the management team, in this aspect of the business, and we will we will keep everyone updated, as we move forward. Some of the new data coming are really important to some of these conversations, so, I'll, I'll stop there. That's great. Thank you, Chris, Brian. That is a long list of questions for today. Chris, would you like to sum up with a few words on where AVACTA is now and what's next for the company? Sure. Thanks, Lily.

1:02:53 Appreciate it. I... And and, indeed, thank you to everyone here on the call, for your continuing interest and and supporting AVACTA. This is an incredibly exciting time for our company. We have made huge progress, in advancing the pipeline. It's centered around our unique precision technology. We've made some big advances. We're very well positioned. We have a solid financial basis, two programs in clinical development, many upcoming milestones, and a truly innovative preclinical program in our dual payload. It... That program is designed to go after some of the toughest to treat cancers, by attacking one of the key resistance mechanisms. Look. We have a very busy eight weeks in front of us.

1:03:40 Five key data outputs. Every program will have news, coming in the next eight weeks, and we're looking forward to sharing some really important updates from the company in that time frame. We have never been in a better position, I can tell you. We are just weeks away from several key datasets that will impact not only the programs, but the precision platform, which forms the basis of all of our IP, as a whole. And so I can say we are so excited, really looking forward to delivering these datasets, which will deliver value, through this... You know, we have a potentially transformative period, coming up for AVACTA and our patients.

1:04:26 And we're looking forward to a number of these updates, and the company continues to make, just remarkable progress, and thrilled with where we are. That's great. Thank you for updating investors today. Can I please ask investors not to close this session as you'll now be automatically redirected to provide your feedback in order that the management team can better understand your views and expectations? This may take a few moments to complete, and I'm sure will be greatly valued by the company. On behalf of the management team, we'd like to thank you for attending today's presentation, and good afternoon to you all.