Operator: Good afternoon. Welcome to the Avacta Group PLC Investor Presentation. Throughout this recorded presentation, investors will be in listen-only mode. Questions are encouraged and can be submitted at any time by the Q&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. 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 like to hand you over to the management team. Chris, good morning.
Chris Coughlin: Good morning. Thanks, Lilly. Thank you to everyone who is joining us today. Brian and I are thrilled to be bringing you our interim results. Without further ado, let me dive in. We are advancing our next-generation pre|CISION platform. This is a tumor-activated peptide drug conjugate that can deliver our payloads with optimized kinetics using a specific mechanism that is highly innovative and new in the peptide drug conjugate field, which is a mask and release. pre|CISION masks a potent payload behind that peptide that's cleavable only by FAP. FAP 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. Our lead asset, FAP-exatecan, or AVA6103, that we'll take a deeper look at.
Chris Coughlin: It's the first of this next-generation peptide drug conjugate. 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 potential for pre|CISION, it was really limited in the original clinical look at exatecan back in the late 1990s, early 2000s. It was limited by both its potent toxicity, 90% of patients had severe neutropenia, but it was also limited by its PK. That's where these advances in pre|CISION came from. We'll talk a little bit about these inventions that led to this clinical program. The phase I FOCUS-01 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 topoisomerase I mechanism works.
Chris Coughlin: 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, deruxtecan, has nice activity. We have, out of our next-generation pipeline, two shots on goal that are coming to the clinic. AVA6103, as you can see there, we have published 5 and a half months after the trial started. We have published our initial clinical proof of mechanism data. 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 Enhertu. We are going to be updating these as we move towards our ESMO presentation. ESMO begins, as you know, in just 8 days. Our second of the next generation is AVA6207.
Chris Coughlin: We believe that this is one of the first dual-payload peptide drug conjugate programs out there. We will be presenting a little bit later this year the candidate selection and all of the data that goes into that. This is the clinical candidate selection, so the final drug will be presented in the H2 2026. 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 has been de-risked in patients. pre|CISION, the first generation of pre|CISION is AVA6000. We have demonstrated 3 important aspects in this program. The first is we have optimized the safety, and the payload was concentrated. We have published these biopsy data showing 100 to 1 concentration of the payload in the tumor versus the plasma.
Chris Coughlin: One of the key toxicities that we see with the payload, Dr. Rubinson, in the clinic is cardiac failure, and it is incurable. So, the bar for the evidence to list that lifetime maximum in the clinic was quite high. We have published the data leading up to that. We are very proud. Lots of factors there, and we will be presenting additional data. We have also seen durable RECIST responses in our lead indication in salivary gland cancer, even, again, at the lowest levels of FAP expression, which we published back at ASCO and BIO International 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 September, we published the proof of mechanism data with AVA6103.
Chris Coughlin: We are going to take you through some of the key data slides here today. The dual payload will go through candidate selection. That is coming. The AVA6103, the efficacy readout will be in the H1 2027, but we will commit today that the tumor PK will be out year-end or very early in 2027. We do have ongoing multiple discussions with multiple pharma partners. The IP estate is building. As Brian will describe a little bit further, we are looking at a potential NASDAQ dual listing during 2027. So the next generation of our pre|CISION 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. So this innovative drug class achieves a robust efficacy, but using small molecule chemistry.
Chris Coughlin: We'll take you through a little bit of how our scientists invented this. What are the three goals? First, it's to release the payload in a tumor-selective manner. This is really to address some of the key toxicities that we've seen with both ADCs and PDCs similarly. The second is to protect normal tissues, and that's through this masking effect. We've seen this and shown it clinically with AVA6000, that we can protect normal tissues. We alter the biodistribution of the payload by using the pre|CISION mechanism. Finally, and this was big for the next generation, we modulate the PK of the payload. Recall back, I mentioned that exatecan 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.
Chris Coughlin: We want, with a single dose of our drug, to deliver just like an ADC, with controlled exposure in the tumor. 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. The pre|CISION 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. It's about a third to a half of what you would spend to manufacture an ADC. The pre|CISION platform, it has a very large market opportunity. About 90% of all solid tumors express FAP.
Chris Coughlin: This was a large experiment that we did, study that we did, both internally with immunohistochemistry, but also with our collaborators at Tempus, looking at about 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. What I can tell you is that we have not found a single solid tumor that does not have very robust expression. That represents a very large market opportunity. There isn't a single pre|CISION medicine that will work for every one of these, which is why IP and managing that pipeline delivery, again, with capital efficiency, is critically important for Avacta going forward. What do we mean? Let's unpack a little bit about first generation versus next generation, the whys and the hows. The first is why.
Chris Coughlin: Well, let's look at the first generation. This was a direct peptide link between the payload, doxorubicin, and the peptide. You can see the actual chemical structure of the drug there. The peptide 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 cleave this peptide. It turns out that this direct peptide link is actually a highly efficient substrate, and so it enables very rapid cleavage. The main mechanism of metabolism of this drug when it enters the human bloodstream is actually cleavage within the tumor. We had to do a couple of things in order to get a drug like exatecan to work. The first is that we needed to slow down the cleavage.
Chris Coughlin: We know from a very old theory, it is called the Norton-Simon hypothesis, was published back in the 1970s. We know that we need, for some of these enzymes that are important in DNA metabolism, we need at least 3 days of coverage. We need to shut that enzyme down for 3 days, and that just is not going to work with an 8-hour half-life. That is where the capping group comes from. The capping group that we have introduced, you can see over there 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. We want the tumor to hold onto the drug. Otherwise, it gets eliminated by the kidney pretty quickly.
Chris Coughlin: The second part, and these 2 inventions work together, but the second part is a chemical linker that is essentially to mimic that part of doxorubicin that sits in the active site. We have invented and borrowed some of these. There are multiple chemical linkers that have been used in the ADC field and small molecule field. What we found in these inventions and in investigating this is that we can get very variable speeds of release. That is 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 so we can dial in the PK that we want. Controlled release enables 3 important things. The first is, we get very much so greater PK control. We now know that we can keep the drug right in the active site.
Chris Coughlin: We can have the tumor take it up and be a reservoir. 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. Because we have multiple linkers and it allows the drug to sit outside of the active site, we have now been able to really expand the pipeline potential here and get many more, large number of small molecules to work with pre|CISION enabling. That brings me to the Avacta pipeline. We do have 3 programs that are now deploying our pre|CISION platform. Our first 2 next-generation programs, AVA6103, which is releasing exatecan. You can see the indications as we have talked about already.
Chris Coughlin: This one is working through its dose escalation period of the phase I trial. Our next milestones with this one, as I mentioned, we are going to be publishing the tumor PK. That started at cohort 3. That will be in late Q4 or very early in the days of Q1 2027. We will not be dropping data in at Christmas time, but either late in Q4 or very early in Q1. The efficacy data then will be in H1 2027. As I mentioned, this trial started in March. First data came out in 5.5 months showing the proof of mechanism, and we are looking forward to those few updates. The dual payload, which we have not disclosed the indications, we will show you some of our ideas later.
Chris Coughlin: This one is combining a potent topoisomerase I inhibitor along with one of the key resistance mechanisms targeting DNA damage. We will be looking at announcing the payloads, and then all of the data that is going to be supporting that clinical candidate selection, that will all be in the next eight weeks, essentially, as we move towards the end of 2026. Then some really important updates that we have on faridoxorubicin, our first-generation drug. This one, we are going to be updating that lead indication in head and neck cancers, the salivary gland subset. We are going to be looking across the phase I-A and the phase I-B data. We will be updating in the H2 of 2026, as ESMO starts in eight short days. Some really important data will be coming for both faridoxorubicin.
Chris Coughlin: Critically important, we are going to 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. We will also be updating AVA6103 preclinical as well as a trial in progress at ESMO. Lots of important data will be coming out in Madrid in just a short period of time. Taking a look at the pre|CISION platform as a whole, we have designed pre|CISION, and especially the next gen, to look at four key opportunities that we think we can make the drug conjugate aspect look a bit better. The first is payload release. We know with the ADCs that one of the challenges are these organ-specific toxicities because of the non-specific protease cleavable linkers. These are lung toxicity and liver toxicity, pneumonitis, hepatitis.
Chris Coughlin: Because we get tumor-specific release by FAP, we are not seeing any of those toxicities now deep into AVA6000 and as well through the first several cohorts of AVA6103. We have no pneumonitis, no hepatitis, and importantly, as I mentioned for AVA6000, no cardiac toxicity. We can now use a dose-dense regimen to treat resistant disease. 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 the antibody, but also the safety of the payload as some of it is released in plasma. The whole idea with the next generation was to really keep that payload out of the plasma. The internalization dilemma.
Chris Coughlin: With an ADC, payload is released following the slow process of internalization because it is targeted to a tumor antigen through that antibody. 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 is important that in salivary gland cancer, every single patient has FAP-negative tumor cells. FAP is only expressed in the stroma. That indication and just the number of patients that we see that durable tumor shrinkage is critically important in that program. Tumor penetration also critically important. It can take up to 24 hours to see that payload release within the tumor, whereas we see it within minutes with the PDC. We have a very rapid Tmax in the tumor. We actually get a very nice Cmax.
Chris Coughlin: in our animal models. All of that, importantly, is delivered with small molecule chemistry and manufacturing. That saves a lot of money as we move towards the GMP manufacturing of our drugs. Let's look at the clinical trial for AVA6103. As I mentioned, we have both the standard arm, which is in every 3 weeks there at the top, and we have the every 2 weeks arm at the bottom. This is the dose-dense regimen. In bold, below the dose levels, you can actually then compare that 50% increase in the dose intensity that we get with the every 2 weeks arm is critically important. We can keep this one going as long as we continue to see that very favorable safety profile that we have described with the proof of mechanism data.
Chris Coughlin: 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 7 if the safety allows. These oncology trials, especially using the Bayesian design, the BOIN 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 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 going to 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.
Chris Coughlin: 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 2 different programs. First, in HER2. This is an ADC that uses a very similar payload, deruxtecan, compared with our exatecan. The dose levels are very similar, first 3 dose levels in the Enhertu trial and first 3 dose levels in terms of payload dose with the AVA6103 trial. Exatecan, it's important to note that the MTD in pretreated patients was dose level 2 in our trial. By the time we moved to dose level 3, we were looking at a 50% higher than the maximum tolerated dose. The safety that we're presenting here is the safety that is published at that MTD.
Chris Coughlin: Now we're 50% higher, and you can see there, we have no neutropenia. This is the most important barometer. The neutrophils are part of the immune system. 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. We see no neutropenia through these first 3 cohorts. We were thrilled by that. It really shows that we're able to keep the drug out of the peripheral blood. We do see a single grade 1 case of thrombocytopenia and then nausea and vomiting through the first 3 cohorts, and a couple of cases of grade 1 anemia. So a really favorable safety profile. We're thrilled with this despite, again, giving 50% higher dose of payload above the MTD of exatecan, the payload in the clinic.
Chris Coughlin: Now we are going to turn to what we think are some of the most important data, which is really understanding the pharmacokinetics and starting with the plasma PK and really understanding what is going on in the patients through sampling in the bloodstream. I am going to take you through first here the chemical reaction that we are measuring, because again, this is not a made-up drug. This is a drug that needs to go through a cleavage event by a resident enzyme, FAP, that exists in the tumor. What happens, you can see here, this is just a schematic of AVA6103 describing where the capping group and the linker are and how exatecan sits outside of the binding pocket. The drug fits nicely then into the FAP binding pocket. We cannot measure this.
Chris Coughlin: This is 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 two reactants or two products of this chemical reaction. The first is released exatecan, and the second is the released peptide. Importantly, I mentioned that released exatecan has a very short half-life in the clinic, only 8 to 9 hours. It was one of the things that was very challenging in its initial development back in the late 1990s, early 2000s. Even shorter half-life, though, is our released peptides, only 2 to 3 hours.
Chris Coughlin: 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 going to be released into the bloodstream at very low levels. We drove those assays way down to a very low limit of detection of 0.1 nanograms per mil. What we are going to do next is look at exactly what the animals were telling us and what the preclinical data told us, of how this drug was going to work in the clinic. The first, I am going to take you through the four colors here. It is a very busy figure, but if we break it down by colors, I think you will see that the drug is designed exactly to behave as we have chatted about.
Chris Coughlin: Each dot here represents a small group of animals, and we are looking at both plasma as well as tumor in this figure. Let us start with the joined-up drug, which is in gray and navy blue. Gray is in blood, and navy blue is in the tumor. The joined-up drug, AVA6103, we get a nice peak there at number 1, as soon as the drug is infused into the bloodstream. It drops down then very quickly to a pretty low level, and what is 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 5 days later in the tumor. That is where we are creating this reservoir.
Chris Coughlin: We want the drug to sit right in the tumor and be able to reload the tumor from the low level that is in the bloodstream. Now we are going to look at the product of the reaction, which in this figure is exatecan. So the released exatecan 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 are now able, over the course of those 5 days, to slowly release the exatecan. What you can see is, if we look way out to day 5 there, we still have it being released above the IC90 of exatecan. Now, the IC90 is, it stands for the inhibitory concentration where 90% of tumor cells in a dish are being killed by exatecan.
Chris Coughlin: It is a key factor that we use to describe the potency of a drug. This one is somewhat low because exatecan 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 is step 2, but that we do not get that in the bloodstream. That is over there at step 3. So in very light teal, we see that the exatecan, it comes out in that initial burst of cleavage that we see in the tumor. It comes out into the bloodstream, and it disappears within 2 to 4 hours. The whole idea there is that masking.
Chris Coughlin: The drug itself, AVA6103, is not going to cause the toxicity, but it is that released exatecan, and we wanted it to disappear very quickly from the bloodstream. So, we use this figure. This is exactly what we designed this drug to be, and we are going to 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 critically important. So, now we are going to move into the clinic. This is the first figure. This is the first cohort of patients in the trial and understanding the PK. 3 important observations is, first, we see a rapid decline in navy blue of the plasma level of the joined-up drug, AVA6103, or the peptide drug conjugate.
Chris Coughlin: Importantly, it is going to be retention in the tumor, but also that slow rate of clearance that we have seen, and that is the capping group, was designed 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 exatecan is still being detected. It has to be being produced somewhere. It is being produced in the tumor, and that is based on our preclinical data that we showed in the previous slide. We are getting that reservoir, navy blue in the tumor, but we are also getting dark teal. We are getting that drug being produced within the tumor. Probably 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.
Chris Coughlin: It is detectable 2 days after that dose was administered. It is actually the highest level. You can see there, the confidence intervals are going to overcome each other, but the absolute value there of the peptide, it is detected 2 days later. It is both of those products being produced, that is going to be cleavage that is occurring within the tumor, given that reservoir. The next step that we are going to do is pull these last 2 slides together and understand, is our modeling happening in the clinic? Are we seeing, is the drug doing what we designed it to do? That is this busy figure, looking across the 3 dose levels, 1.5, 3, and 4.5, and there are 4 different lines in each of these. Let me walk you through.
Chris Coughlin: We are going to look at both what we anticipated and modeled in the animals, and that is going to be in the solid lines. Then what we see in the clinic is going to be in the dashed lines. In dark navy blue is going to be AVA6103, the parent drug. Then in light teal is going to again be the released exatecan. Let me walk you through a couple of factors here. We look back, this is the figure that we just looked at 1.5. This is the first dose level. It is 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? That is because mice have about tenfold, 10X times the soluble FAP in their bloodstream.
Chris Coughlin: We do see in the animals that little peak that happens in the plasma. Similarly with AVA6000, we saw this in that program as well. We just do not see that peak in humans because we do not have very much FAP in our bloodstream. So 1.5 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. We do see this figure of the extended exposure of the peptide drug conjugate, and that is driven by a single patient. It is exactly what we saw though in a very low FAP model, is that we see sort of that extended exposure. That is exactly what the cap was designed to do, was to prevent that rapid kidney filtration of the drug.
Chris Coughlin: We were incredibly encouraged by observing this in that second dose level. You can see there, we do get, these are log scales, but we do get that nice dose responsive increase, slight increase in the plasma level of exatecan. But we also get that nice increase and spot on with what we modeled with AVA6103. If we move to the 4.5 mgs per meter squared, spot on with what we expected from the animal studies. You can see there the rapid decline of AVA6103, dashed lines in patients in the plasma down to the lower limit of detection out 2 days. But we are still getting that sustained release of exatecan. This is exactly what we expected to see as we continued that dose escalation.
Chris Coughlin: These findings are really increasing our confidence that this non-clinical to clinical translation is performing exactly as intended. We ask those who have been following us to think back to all of the animal models that we have published where this drug is really nicely shrinking both low FAP, high FAP. That will be some of the next data along with the tumor PK that we have guided will be late this year. Last data figure that we are going to look at here. We compared the known PK of the release of deruxtecan from Enhertu. This is essentially using AI to recreate these data sets from the published data within Enhertu and its release of deruxtecan versus what do we see with the release of exatecan from AVA6103. We are looking at the first three dose levels for each of these.
Chris Coughlin: The message here is that we are seeing about estimates three times lower release in the plasma of the payload than was seen with equivalent doses of Enhertu. Why is that important? 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 AVA6103, as opposed to, and in PK figures like this, when you stop the lines, that was when you stopped detecting it above the lower limit of detection, which is depicted there at 0.1 nanograms per mil. You can see at dose level 2, which is in the very light green, as well as dose level 3 in the rusty color of exatecan, or I am sorry, of deruxtecan released from Enhertu, we still detect that out multiple days later.
Chris Coughlin: Low levels, but even those low levels in the plasma can create some of those toxicities. We are thrilled with how AVA6103 is behaving in the clinic thus far, and this slide sums that up. We have a very favorable safety profile of AVA6103 in the clinic, compared to both conventional exatecan as well as Enhertu. We think those are two really important comparators as we start to measure what this drug is doing. 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 have been doing this a long time, 20 years now, and this is really the best preclinical to clinical translation that I have seen in my career.
Chris Coughlin: This remarkable consistency really increases our confidence that AVA6103 is performing exactly as we intended, and that our robust preclinical data will translate into the clinic. We think AVA6103 is really, it is 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 2027. 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 similar capping group, so we are going to create that reservoir, similar peptide, which is going to be cleaved by the FAP enzyme. Importantly, the invention here is around the self-immolative linker.
Chris Coughlin: We still have the ability to guide the PK and how slowly or how quickly, should we want it, will the linker allow those payloads to be released. The first way that we are going to implement this in the clinic is really to use it to go after resistance mechanisms. There are some patient populations out there, some well-known resistance mechanisms that really predict for high unmet need in the clinic, and that is exactly where we have decided to go first. The combination mechanism of action, the two drugs that are going to be released from that single pre|CISION event, are going to be the combination of a highly potent topoisomerase I inhibitor. This one, again, induces single-strand breaks. This is the exact drug class that irinotecan comes from.
Chris Coughlin: We are going to hit one of the most important resistance mechanisms out there, which is the DNA damage response. Bring forward one of these drugs. We have 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. 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. 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.
Chris Coughlin: These unmet needs, ATM loss, SLFN11 loss, MSI-high, cyclin E1 upregulation, we know that these are patient populations really looking for new approaches, easily measured in the clinic, and there is a large set of diseases there. We are now working through some of 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. Really looking forward to publishing 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 8 weeks, the latter part of 2026. With that R&D update, let me turn it over to Brian for the financial results that we are here for.
Brian Hahn: Thanks, Chris. As we recently announced, the oversubscribed equity placing and subscription of GBP 12.5 million, this helps strengthen our financial position to support these R&D programs as we move them through the development process. This was the third oversubscribed placing subscription we have completed this year, raising GBP 10 million in March and GBP 9 million in June from institutional and existing shareholders. Cash and short-term deposits at 30 June was GBP 20.27 million, up from GBP 16.9 million at year-end, and cash held at 31 August was GBP 10.6 million. It is 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.
Brian Hahn: 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.
Chris Coughlin: Thanks, Brian. Let's summarize now. I want to take a look lastly before we get to the questions on what's coming next. What have we accomplished this year, and what is coming next? As you can see there, we have five really important updates that will be coming. To be honest with you, it's about 8 weeks left in 2026. We will be presenting with 6103 at ESMO. This will be a trials-in-progress presentation with some important preclinical updates. We're really excited about those. That's about 8 days away. As I guided to, we are going to have that tumor PK. We've mentioned that that started at cohort 3, and we are going to be looking at that late Q4. We won't drop data at Christmastime or in the very early days of 2027. We will be updating data there.
Chris Coughlin: With our dual payload, which we're super excited about, really going after some areas of really high unmet need, using this platform to really address high unmet needs, 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 the Q4 of this year. Then finally, some data that we know everyone has been waiting for is the salivary gland cancer with AVA6000, the salivary gland cancer progression-free survival. The ESMO updates is going to be so much more than that, though, with this program.
Chris Coughlin: This is going to be our first opportunity to really look very long-term in the AVA6000 program, understand there's many patients that have been on for quite some time, and understanding, again, going back to the basics of drug, really understanding the PK, how durable is the FAP mechanism, and really studying that not just in the animals, but really studying it in the patients and understanding a bit more of the biology there. A number of big updates still coming by the end of the Q4. We will be looking at, again, then in 6103, that efficacy readout in the early parts of 2027. The expansion cohorts will be designed and begin there. Lots of work over the next several months, but the next 8 weeks look to be very busy for Avacta. We're really excited about a number of the pieces here.
Chris Coughlin: So, with that, let me bring the formal presentation to a close and turn it back to Lily. Let's answer some questions.
Operator: Thank you, Chris, Brian, for the overview of the interim results and the business update. 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?
Chris Coughlin: Well, as we announced yesterday, at ESMO, we are going to have two important presentations. Let me start with AVA6000. 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 critically important, especially in the PDC, where we haven't had big durability just yet. The team has really been focused on the regulatory aspects of this program. We disclosed previously that we had a successful end of phase I 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 of the health authorities, and then present those data from our setup trial.
Chris Coughlin: So, the phase I-B and combining it with the phase I-A, it's really important to show that we're ready to move forward. We're very happy now to be at that stage of finalizing those datasets. Some of those datasets are going to support the pivotal trial. So, it's important now that we present that dataset, that subset of patients that would be eligible for the trial. 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 the conversations and the advice and the design, what is that subset that would be eligible for the trial?
Chris Coughlin: This is based on not just prior therapy, but histology of the disease, the ECOG, or the performance status of the patients. We are going to disclose all of this. This is going to allow us to plan for that enrollment. We are also looking very long-term, as I mentioned, at PK safety, rolling all of that out long-term. It is critically important that we not just show durability of efficacy, but that we show why. What is the PK there? 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 does generally translate to better outcomes for patients. Oncology drug development here, it is a long game. I have been doing this for a long time, but it is a long game.
Chris Coughlin: The first question we ask the PFS is, "How long can we control the tumor?" We are going to answer that at ESMO. We know that so many have been waiting. But the bigger question then becomes, "How long do I have, doc?" That is the overall survival. The important point that we announced is in the design of the pivotal trial, only PFS is needed for approval. We have to show non-detriment, so we cannot make the overall survival shorter. But the key data for the approval of the drug will be the PFS. That is an important dataset that will be coming. I know that is long, but we think that this is going to be really a platform-validating set of data that will be coming.
Chris Coughlin: There is some important biology that is coming out of this trial that actually will impact and show us some things that will impact next gen, like AVA6103.
Operator: 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 AVA6000 program?
Chris Coughlin: Yeah, good one. Let me assure everyone first that the program is advancing right on track. We know that there is the perception of the delay in this one, because it has taken a long time to collect the PFS data. Like I mentioned, we base our predictions of when data will be available based on some of the observations that we made. Now, it really does translate in oncology, when you are collecting PFS data, the preliminary look at the PFS in the phase I portion, we anticipated it could be 9 months, and that was ESMO of 2025, 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 I-B patients, and that was back at ASCO and BIO.
Chris Coughlin: That was back May and June of this year. These were sort of the first looks in the expansion cohort. These datasets did show us some really similar efficacy in terms of tumor shrinkage. The waterfall plot that we showed was very similar to what we saw with the phase I-A patients, and the PK in those first 2 cycles were critical. At ASCO, we also showed the cardiac safety. At ESMO, now we are really looking long-term, and PFS in the joint patient set, in the patient set that is going to 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 a short time away.
Chris Coughlin: We will be in Madrid soon, and we believe that there is some good datasets coming in both of the presentations. They are going to be very meaningful for both the program, as well as the platform.
Operator: That is great. Just turning here to the next question. You have hinted here to a biology presentation at ESMO, platform data. What will we be looking at, and why is more biology needed?
Chris Coughlin: Let me answer this one two ways. The first is, the biology studies at ESMO are going to be both in patients with AVA6000, but also AVA6103, and some of it will surround the role of the enzyme, FAP, that we rely on. We need FAP to cleave the drug. It is a mask and release. We are really trying to understand more about durability of responses, and the tumor shrinkage that we have seen with AVA6000. How does the enzyme behave in patients and in our models, and how can we use the models to make predictions for AVA6103 and whatnot?
Chris Coughlin: There is 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 are doing with pre|CISION, which is we are leveraging a tumor-specific enzyme, FAP, to cleave a peptide and release the drug. They are two pretty different approaches, but similar. The pre|CISION platform is based on that concept of mask and release. Other peptide drug conjugates do not use a masking approach to spare the normal tissues, and they do not use this release mechanism. We think the tumor-specific release and the masking capabilities are really some of the most innovative, and they are quite unique to pre|CISION. 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.
Chris Coughlin: We believe these datasets are critically important not only for the program, but the platform. To note again, it is going to be across both of them. As I have mentioned before, biology leads to new IP. If we think about the second reason to look at more biology, the controlled release mechanism, it started with some biology questions, and 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 that brings us to brand new IP. As we have committed to, once we Much more coming in the next 8 weeks.
Operator: That is great. Just turning to the next program, AVA6103. 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. I will ask a few more frequent ones in the submitted questions. Just next question here we have got is, for AVA6103, it appears that enrollment is going well. Can you comment on this? Are the dosing cohorts still lining up with the Enhertu trial?
Chris Coughlin: Yeah, enrollment is going very well. We are thrilled with how that trial is progressing. We mentioned previously, we have completed four dose levels with respect to enrollment. As you know, the collective experience with AVA6000, until a trial shows something on proof of mechanism, it is tough. It can be tough days. But we were thrilled that we really saw, as we showed you, from the first cohort, that 6103 was really doing what we designed it to do. We have not seen that kind of challenge in enrollment. Our CMO, Dave Liebowitz, and his team, they are doing a fantastic job in a challenging space. We have four dose levels, two arms in parallel, and all of that has been completed in 6 months. Just terrific execution by Dave and the clinical team. We have both the every 2 weeks and the every 3 weeks in parallel.
Chris Coughlin: Dose level 3 is where we started collecting biopsies. Let me just note, it is important to note the differences between 6000 and 6103, the statistical design. We get a lot of questions about the Bayesian design, BOIN. It allows flexible dosing, it allows backfilling of cohorts, mandatory biopsies starting at dose level 3, and none of that was permitted in the design of the 6000 trial. So we do continue to progress and advance this trial. We are still lining up, and we are going to be comparing with the doses of Enhertu, but also conventional exatecan. We think that that is important. There were single agent responses to conventional exatecan in the early days. So we will continue those comparisons, and the flexible BOIN design really allows us to make some important decisions during the conduct of the trial.
Operator: That is great. 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&D spotlight that biopsies are now mandatory. How does that work?
Chris Coughlin: Yeah, so once again, we started collecting those at the third dose cohort level. We use the backfill mechanism. It is 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. These collection requirements, the mandatory biopsies really did not start until that third dose cohort. We get asked, "What does backfill mean?" Backfill means that a patient who is not granted a slot in the main dose escalation cohort can be treated at that lower cleared dose level. The trial is moving rapidly. The biopsies were, it did not move in until dose level 3, but it is going well right now. So yes, we are guiding that. We are hopeful end of year.
Chris Coughlin: It's possible it leaks into the early days of January, but we are collecting. We already have a few in our back pocket. We are really excited to be showing tumor PK. It's a really important part of this program.
Operator: Thank you. Just moving on to the next question here. Your CMO also suggested previously that the trial might stop at dose level 5 or 6. Is that true? How does the dose selection work, and how does this BOIN design work?
Chris Coughlin: Yeah, that'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 AVA6000 at tolerability. We hit unacceptable toxicity, but 6103, we are knee-deep, and we will not be stopping until we see. Maybe we should do an Avacta Academy on Bayesian stats. It's a very different trial design, but suffice to say, no, we will not stop early.
Operator: That's great. The next question here we've got is on AVA6207. At the Q4 AVA6207 announcement, will you have a development-ready candidate or further optimization still to complete? What safety and efficacy criteria must it meet, and which steps towards IND submission and first patient dosing are funded today?
Chris Coughlin: Yes, definitely. We will have a development-ready candidate. There are multiple steps before we get to those more expensive places, but the year of IND-enabling studies, we have to manufacture the drug. Once we start the manufacturing, 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 that we have a patient population that it is relevant for. So, a lot of data coming. This program is really our first one that is designed to attack those key resistance mechanisms. So, the clinical planning here is critical and is going to 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.
Chris Coughlin: 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.
Operator: Perfect. 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?
Chris Coughlin: We very much understand the intense interest around updates on our partnering discussions. But as I am sure everyone can understand, keeping the status and the details of ongoing discussions confidential is just as important to successful partnering as it is waiting for clinical data to mature for a successful trial. We have multiple conversations that are ongoing under confidentiality, so we cannot disclose anything there until there is something to be announced. I can say that we continue to have productive conversations, both under CDA, but also with multiple partners not yet ready to sign a CDA with us. It is important that we do the right deal at the right time. We know that one of these deals could bring in quite a bit of non-dilutive funding, but it is important to note that these deals always give away key pieces of our IP estate.
Chris Coughlin: Again, back to doing the right deal at the right time. What I can also add here is that we are 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 keep everyone updated as we move forward. Some of the new data coming are really important to some of these conversations, so I will stop there.
Operator: That is 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 is next for the company?
Chris Coughlin: Sure. Thanks, Lily. Appreciate it. Indeed, thank you to everyone here on the call for your continuing interest and supporting Avacta. This is an incredibly exciting time for our company. We have made huge progress in advancing the pipeline. It is centered around our unique pre|CISION technology. We have made some big advances. We are 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. 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 8 weeks in front of us. Five key data outputs. Every program will have news coming in the next 8 weeks, and we are looking forward to sharing some really important updates from the company in that timeframe.
