Avacta Group Plc

Good afternoon and welcome to the Avacta Group Plc investor presentation. Throughout this recorded presentation, investors will be in a 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 of today's meeting, the company won't be in a position to answer every question it receives 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. and now that time 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. We are advancing our next generation precision 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. Precision masks a potent payload behind that peptide that's cleavable only by sap. and FAS 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, FAS Exotecan or ABA6103 that we'll take a deeper look at. So it's the first of this next generation peptide drug conjugate. This is a FAP-activated, but importantly, it's a controlled-release version of ExaTcan. When we initially looked at this potent payload as a potential for precision, it was really limited in the original clinical look at ExaTcan back in the late 90s, early 2000s. It was limited by both its potent toxicity, you know, 90% of patients of 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. The phase one 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 TOCO1 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, duroxacan, has nice activity. We have, out of our next generation pipeline, we have two shots on goal that are coming to the clinic. ABA 6103, 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. 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 preclinical studies. Selectivity and activity versus in HER2. 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 ABA6207. We believe that this is one of the first and many other 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 second half of 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's been de-risked in patients. So precision, the first generation of precision is ABA 6000. We've demonstrated three important aspects in this program. The first is we've optimized the safety, and the payload was concentrated. We've published these biopsy data showing 100 to 1 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, Dr. Rubison, in the clinic is cardiac failure, and it is incurable. and so the bar for the evidence to list that lifetime maximum in the clinic was quite high. We published the data leading up to that. We're very proud. 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 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 ABA 6103. We're 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 ABA 6103, the efficacy readout will be in the first half of 2027, 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 IT estate is building. and 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 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 and oncology right now. So this This innovative drug class achieves a robust efficacy, but using small molecule chemistry. We'll take you through a little bit of how our scientists invented this. And what are the three goals? So 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 And that's through this masking effect. We've seen this and shown it clinically with ABA 6000 that we can protect normal tissues. We alter the biodistribution of the payload by using the precision mechanism. And finally, and this was big for the next generation, we modulate the PK of the payload. Recall back, I mentioned that Exotecan Thank you for joining us. Thank you for joining us. to manufacture an ADC. Now, the Precision platform, it has a very large market opportunity. About 90% of all solid tumors express fat. 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 Thank you for joining us. 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 IT 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. So the first is why. Well, 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 in gray, and the payload is in light teal. A couple of things to note here. Doxorubicin has a chemical structure that sits nicely in the active site of fat and that is required for fat 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. So the main mechanism of metabolism of this drug when it enters The human bloodstream is actually cleavage within the tumor. And so we had to do a couple of things in order to get a drug-like exit he can to work. The first is that we needed to slow down the cleavage. We know from a very old theory, it's called the Norton-Simons hypothesis, was published back in the 70s. We know that we need, for some of these enzymes that are important 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 going to 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 navy blue, the capping group is designed to hold our peptide-drug conjugate in the active site of FAPT. and create almost a reservoir within the tumor. So we want the tumor to hold on to the drug. Otherwise, it gets eliminated by the kidney pretty quickly. The second part, and these two 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. and we've invented and borrowed some of these. You know, there's multiple chemical linkers that have been used in the ADC field and small molecule field. And what we found in these inventions and investigating this is that we can get very variable speeds of release. And so that's why we call this controlled release. Now, for exit CCAN, 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 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 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 Exotecan, 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 ABACTA pipeline. We do have three programs that are now deploying our precision platform. Our first two next generation programs, ABA 6103, which is releasing ExaTcan. You can see the indications as we've talked about already. This one 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 the first quarter of 2027. 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 2027. As I mentioned, this trial started in March. First data came out in 5.5 months showing the proof of mechanism, and we're looking forward to those few updates. The dual payload, which we have not disclosed the indications. We'll show you some of our ideas later. This one is combining Potentopo-1 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 going to be supporting that clinical candidate selection. That'll all be in the next eight weeks, essentially, as we move towards the end of 2026. And then some really important updates that we have on pyridoxal rubicin, our first generation drug. This one, we're 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 1a and the Phase 1b data. We will be updating in the second half of 26, as most starts in eight short days. and some really important data will be coming for both varidoxorubicin. Critically important, we're 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. And then we will also be updating ABA 6103 preclinical as well as a trial in progress at ESMO. So lots of important data will be coming out in Madrid in just a short period of time. So taking a look at the precision platform as a whole, we've designed precision 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. And 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. And because we get tumor specific release by FAP, we aren't seeing any of those toxicities now Deep into ABA6000 and as well through the first several cohorts of ABA6103, we have no pneumonitis, no hepatitis, and importantly, as I mentioned for ABA6000, 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 regimen, 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. And so the whole idea with the next generation was to really keep that payload out of the plasma. The internalization dilemma. 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 fibroblasts. 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. 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. So we have a very rapid Tmax in the tumor. We actually get a very nice Cmax 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 GMT manufacturing of our drugs. So let's look at the clinical trial for ABA 6103. 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, and 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 we have described with the proof of mechanism data.

As we move through the dose escalation, this will only be limited by toxicity.