Avacta Group Plc (AVCT) Earnings Call Transcript & Summary

Good morning, ladies and gentlemen, and welcome to the Avacta investor presentation relating to the review of the AVA6000 clinical trials Phase I data. [Operator Instructions] Given the significant attendance today with over 1,600 shareholders and investors attending today's call, the company will not be able to answer all questions submitted during the meeting itself. We have received a significant number of presubmitted questions and the company have reviewed those questions and we'll categorize some responses to those sectors in the Q&A session at the end. [Operator Instructions] The company can review these post today's meeting as well. Before we begin, we'd like to submit the following poll. And I'm sure the company will be most grateful for your participation. And I'd now like to hand over to CEO, Alastair Smith. Good morning.

Good morning, Mark, thanks very much indeed, and welcome, everybody, and thank you for sparing some time today. So this morning, we're going to be presenting a summary of key data from the development of AVA6000, both preclinical and clinical data. And I'm joined by Dr. Fiona McLaughlin, Chief Scientific Officer; and Dr. Chris Coughlin, oncologist, immunologist and consultant to the company. So before we get into the presentation of the data, I just want to set the scene and the overarching takeaway message from the data that we're going to present to you is that pre|CISION works as it was designed to do. And what we mean by works, well we're going to show you data that shows us that a pre|CISION Chemotherapy cannot get into cells. So it circulates in the blood stream in an inert and relatively safe form. We're going to show you data that shows the pre|CISION platform is absolutely specific for this enzyme FAP. So it releases the drug in the tumor microenvironment and not systemically. And we're going to see clinical data relating to AVA6000 that shows a dramatic reduction in the severe toxicities associated with Doxorubicin and the drug that it delivers. So this redefinition of tumor targeting means that we can optimize the dosing of Doxorubicin in chemotherapies more generally and improve the outcomes for patients as well as improve their quality of life based on treatment. And I know Chris will take you through our observations to date. So finally, before we start, I realize that many on the call are not scientists. We'll do our very best to make the data digestible. I'll follow up this presentation with an interview with Paul Hill on Vox markets as well to make sure that we've got the key points across. So first, what is the problem that we're trying to solve? So the fact is the traditional cancer therapies don't target the tumor. They don't differentiate between healthy tissue and tumor tissue. And that leads to damage to healthy tissues to toxicities which ultimately limit the effectiveness of most of these oncology drugs. So there's an urgent unmet need for medicines for cancer therapies that do target the tumor and spare healthy tissues. So our approach to doing that is to use the pre|CISION platform that we'll describe in a lot more detail as we go through today. And the pre|CISION platform is a method of linking a cleavable peptide or a peptide that can be removed and we link that to the chemotherapy, and that prevents, as I said earlier, the chemotherapy from entering cells. And that peptide is then cleaved to release the cytotoxic warhead, the chemotherapy by an enzyme called FAP, and I'll describe that in a little bit more detail on the next slide. That releases the active chemotherapy in the tumor microenvironment where FAP is predominantly found. So pre|CISION modified chemotherapies or pre|CISION medicines are designed to reduce the systemic exposure, which causes those toxicities to enhance the safety and tolerability and therefore, increase the efficacy. So a few words on fibroblast activation protein alpha or FAP because it's fundamental to obviously, the way pre|CISION works and the effectiveness of these pre|CISION medicines. So FAP is an enzyme, as I've mentioned. And the job of enzymes is to chew up or cleave, however you want to say it, particular sequences such as the peptide that we -- our proprietary peptide we call pre|CISION. So FAP identifies that and remove it or chews it up and FAP is a member of a larger family of enzymes, and it's really important that we get the selectivity for FAP in the tumor, and we don't get the other enzymes of which you can see examples that the most troublesome actually is usually PREP, which other -- and Fiona will talk through some data from the literature that shows that it's actually very difficult, and it's the proprietary element of our [ IP ]. The fact that pre|CISION is absolutely specific to [ FAP ] and doesn't get cleaved or chewed up by these other enzymes that typically found all around the body. FAP itself, is found on the surface of cells. So it's what we call an extracellular enzyme, extracellular protein, and it's found primarily on the surface of cancer associated fibroblasts in the tumor microenvironment, but also in some cases, on the tumor cells surfaces themselves and many solid tumors, what we call overexpress or create high concentrations of FAP in the tumor microenvironment. That's typically associated with poor prognosis. So just illustrates and we'll obviously go through a lot more detail in the body of the presentation, but just to illustrate the mechanism of action of the pre|CISION platform using AVA6000 and Doxorubicin as the chemotherapy that AVA6000 delivers. So AVA6000 is a pre|CISION modified form of a generic chemotherapy called Doxorubicin. So we have added -- chemically added the peptide that I've been talking about, the pre|CISION peptide to Doxorubicin. And what that does and what we'll see from the preclinical data, in particular, is it prevents the drug 6000 getting into cells. So the drug circulates when administered to a patient and doesn't get into cells. So unless FAP is present, the drug does not go into cells and it's relatively harmless. In the tumor microenvironment, when the drug gets into the tumor microenvironment through the circulation and the encounters FAP, the enzyme that specifically recognized as the peptide we've added, it removes that peptide and releases doxorubicin and doxorubicin will cross cell membranes and get into cells very quickly. So when doxorubicin is released from AVA6000 by FAP, predominantly in the tumor microenvironment, it very quickly gets into cancer cells, fibroblast and other cells. And that is what causes the cell killing, and we'll talk through the clinical observations that follow from that as we go through the presentation. Okay. Well, I will hand over to Fiona to go through the preclinical data that supports a lot of what I've said and then into the clinical data with Chris.

Okay. Thank you, Alastair. So essential pre|CISION concept is that the [ parent ] molecule, in this case, AVA6000 is inactive until it reaches the tumor microenvironment -- it's selectively by the enzyme FAP that Alastair has just outlined. AVA6000 is not cell permeable. And so it passes to the body and out unless -- and its not taken up in the cells unless FAP is present. So let me show you the data supports those statements. On the left-hand side of the slide, what you see is an experiment in which we take a human cell line that has no FAP and we compare it to the same cell line that's been engineered to express very high levels of FAP. Both cell lines are treated with AVA6000 and we then measure the amount of both AVA6000 and doxorubicin that have been taken up by the cells. Doxorubicin is only detected in cells overexpressed FAP as shown by the red circles and not detected in cells without FAP. AVA6000 in contrast is not detected in either cell type, which supports the hypothesis that AVA6000 is not cell permeable. The second important point is the AVA6000 is exclusively selected to FAP, and it's not cleaved by closely related family members that are widely expressed in the body. This is demonstrated by data presented on the right-hand side, where we have a bar chart, which compares the AVA6000 pre|CISION substrate cleaved by FAP and we compare this in the bottom with a modified version of the substrate in which a different peptide sequences used. As you can see on the top chart, AVA6000 is only cleared by FAP and not other family members, whereas a related peptide CGP-DOX which actually was initially used in most studies looking at FAP activity is also cleaved by PREP, which is more weakly distributed in the body. Moving on now to the in vivo studies, we're looking at experiments in mice. In this example, we use a tumor model, which used cells that come from a patient with Osteosarcoma. That patient was previously treated with [indiscernible] resistant to Doxorubicin. This model was selected because the tumor was high in FAP at the RNA level. After just four doses of AVA6000, we can see significant tumor reduction compared to the control. So here we're comparing the blue line with the black line and doxorubicin in red, at the MTD, so the maximum tolerated dose we can give to the mice has no significant effect on tumor size. In a separate animals study using a pancreatic tumor model called HPAF, on the left-hand side of this slide, the HPAF model expresses very low levels of FAP and there is very little response to AVA6000 again shown in blue compared with the control in black. However, when we use a cell line that overexpresses FAP on the right-hand side, what you can see now is a significant reduction in tumor volume when AVA6000 is administered across a range of doses from 6 to 12 milligrams per kilogram. It's important to point out here that the high dose of 12 milligrams per kilogram contains 4x more doxorubicin equivalent dose than the 2-milligram [indiscernible] that we used in the red line. And again, just to make the point that, that 2-milligram dose of doxorubicin is the maximum that we can get to the animal without inducing and significant body weight loss as a measure of toxicity. So we are clearly able to administer higher doses of AVA6000 than we can with doxorubicin alone at tolerable doses. So taken together, our complete preclinical data package supports the concept to AVA6000 delivers DOX directly to the tumor microenvironment, increasing the effectiveness of doxorubicin and further supports the clinical development of AVA6000.

Thanks, Fiona. Thanks very much. So there we just heard a summary of extensive preclinical data. Now we're going to hear from Chris how that translates into the clinic. Thanks, Chris.

Thanks, Alastair. So as we look at the clinical trial data, for AVA6000 together, let's focus on the three key aspects of AVA6000 that we see in the preclinical data. So first, AVA6000 was designed such that it cannot enter cells intact and thus it shouldn't cause the usual toxicities that we see with doxorubicin in the clinic. Second, pre|CISION is specifically cleaved by FAP, which is only located in the tumor microenvironment. And thus, the release of the active moiety, the doxorubicin should be highly specific for tumors. And then finally, given this exquisite specificity and also looking at the mouse experiments that Fiona just showed us, we should really be seeing greater antitumor activity in patients with high FAP enzyme activity. Okay. Let's take a look at the clinical trial together. So let's look at the first slide here, Slide 11. We're describing the trial design and there are a few key aspects of the trial that I want to highlight for us here. So let's start at the top of the slide, the Arm 1 dose escalation. This is the arm that has now completed enrollment, and this is the part of the trial that's using in every three weeks dosing regimen. You'll see the dose levels of AVA6000 in each of the boxes, they are representing the cohorts. Those are in bold. And then in finer print, in the brackets, you can see we've indicated the molar dosing of doxorubicin associated with each dose level. So recall, AVA6000 is a composite molecule. It's doxorubicin plus pre|CISION. So I think it's helpful to characterize how much actual doxorubicin is in each dose level, as Fiona mentioned, with the animals. And this is in the brackets there. For reference, the standard dose of doxorubicin in the clinic is 75 milligrams per meter squared given every three weeks. And so as you can see there, it's only the first two cohorts of 80 and 120 mgs of AVA6000 that are lower or similar to this dose level. Once we've escalated to that third cohort, the 160-milligram per meter squared dose, we're giving more doxorubicin that is standard, about 1.5x in that first dose level there of 160. Again, in the brackets with each dose escalation, also to mention, we're giving more doxorubicin than would be administered in the standard regimen. You can see that there with the 108 to 135 and escalated from there. The green check marks in this particular arm are indicating the dose cohorts that form the patient population that we're going to discuss in the data released today. Next, if you want to let your eyes wander down the slide, you can see Arm 2, where we are continuing the dose escalation with an accelerated every two weeks regimen. So this addition to the trial is based on the favorable safety profile that we're going to show you in the next few slides. This is with AVA6000 again in the first arm delivered every three weeks and looking across these two arms of the Phase I trial. So both the every three weeks and every two weeks, we're going to present finally a comparison of the cumulative dose that would be administered over 12 weeks. This is just allowing us to illustrate how the every two weeks arm is able to deliver more drug over time than the every three weeks arm. And so those bold numbers underneath each of the dose levels, you can see, let's compare the 160 dose level. In a 12-week regimen, we're going to give 640 milligrams in the every three weeks. But in every two 2 weeks, we're going to be able to give a 960 dose level. Based on the safety profile that we're seeing in the every three weeks arm, it is possible that we will not identify a maximum tolerated dose. We have to continue to enroll and look at the every two weeks. And thus, we will identify, as we indicate there, the recommended Phase II dose from the two arms. And so this second arm, the every 2-week arm is currently screening patients in the United States. At the bottom of the slide then, you can see the patient population that was planned to enroll in the trial. We have several diseases included here as Alastair mentioned, there are multiple solid tumors that are known to be positive for FAP. Secondly, patients must have adequate organ function, acceptable performance status and be prepped for the trial. And then finally, prior cancer therapy has a limitation on the amount of doxorubicin the patient may have received prior to the trial. And that's given that we know that this drug has cumulative toxicity. You'll recall as well that standard dose doxorubicin is given for only 6 cycles or 18 weeks at that 75-milligram per meter square dose. And this is important because one of the key hypotheses going into this trial was that patients could be treated for longer timeframe, so longer than those 18 weeks. And this is based on the anticipated lower exposure to the active version doxorubicin and thus, lower toxicity. So we've categorized our hypotheses, and we're ready to take a look at the data from the trial. So let's move on to Slide 12. This is where we're going to first describe the patients as a group. Again, this is the every three weeks arm. And what you can see here in the patient population, we created 40 patients across the -- levels of 80 to 385, and there are 13 patients that are still ongoing. On the left side, in the left table here, you can see the baseline characteristics. These are pretty standard for oncology Phase I trials. We do see a mismatch of male and female trials, and this is in general in patients with a number of gastrointestinal cancers, which we see in this trial. And then the mismatch of the performance status is actually quite expected and anticipated in such a population of patients with prior treatment. So if we look at the right-hand slide or the right-hand table on Slide 12, we're now describing the cancer history for the patients. And first, given the enrollment criteria, there are various cancer types in the trial. You can see there, we're treating soft tissue sarcoma, the GI cancers that we expect both colorectal and pancreatic, and then there's a large number of cancer that are in the other bucket each with only one enrolled in the trial thus far. Below that, what you can see in the second part of the table is that the patients enrolled are heavily pretreated. They have a median of three prior lines of therapy. What that means is that most of our patients have already received a number of prior cytotoxic dose regimens, which contributes to our assessment of the efficacy and the trial thus far and that most of the patients with these multiple cytotoxic mechanism you can see there from Platinum, Topo-I, the various different cytotoxics. These could be considered chemorefractory and as we have progressed in the trial, we note here that the range of number of therapies is as low as 0, and this is a recent development in the trial, where the enrollment criteria for the last cohort and the every two weekly dosing regimen has been modified to a select set of high-FAP disease settings as well as to allow patients without prior therapy in the metastatic setting. So now that we've set the population, let's move on to Slide 13. We're going to look at the toxicities observed in the trial in two ways. In this first instance, and let's consider all of the toxicities reported in the trial and not break them down yet into the individual events. We're going to essentially look here at the observation of toxicity in general as a function of the severity. We look at the grades here. Grade 1 and 2 would be considered to be those mild to moderate toxicities, very annoying to patients, but in general, they don't limit the dosing of patients. It's when we get to the severe and life-threatening which are the grade -- these are the grade 3 and 4. This is where we see toxicities that are going to now limit our ability to continue to dose this cytotoxic drug. It's important here, as we note, the cohort levels, again, to mention cohorts 1 and 2, which are indicated in light pink, are actually those standard dose and a bit lower than standard dose doxorubicin cohorts. And as we achieve -- as we reach cohort 3 here at 160 milligrams per meter squared and above, these are the elevated dose doxorubicin. So we're essentially giving more doxorubicin than what the patient would have received had they received standard dose. The key observation in this slide is that we're seeing a distinct dose response in the first cohorts of the trial where if we look at the first cohorts, there's little to no severe toxicities, the grade 3s and 4s up to 160. And we're really only seeing the mild moderate toxicities here. And the grade 3 and 4, the more severe toxicities are starting to pop up at the higher dose levels. It's also important to note here that cohorts 5, 6 and 7, those in the blue outline box are still ongoing. And so there are still 13 patients in the trial described here that are receiving therapy. And so the safety data are continuing to mature. Just to highlight this in cohort 7, these patients have been enrolled over the last month to 6 weeks. And so the safety data definitely is still maturing in that cohort. And so this table then describes for you a critical observation as it provides then our first evidence that using a lower dose and potentially shortening the interval between doses to every two weeks could enhance the antitumor activity by delivering more drug, increasing the dose intensity, but with little to no severe toxicity. There are examples of this kind of approach in the clinic, probably the most relevant here is the taxane paclitaxel in the field of oncology. When paclitaxel is administered in some settings and in every 3-week regimen at a higher dose, it's highly toxic, it's effective. However, when it was moved to an every weekly regimen with a lower dose, the toxicity was minimized and actually enhance the activity. This weekly regimen is used more in the clinic, both are still used. But this is the rationale for these new dose cohorts of every two weeks dosing and is based on the observations in this slide. So if we move on, as I mentioned in the previous slide, the dose response is observed with the severe toxicities and so we're going to characterize those here. These are the adverse events, again, that limit the dosing of doxorubicin. We see a reduction in the grade 1 and 2. These are the events that contribute to more the quality of life versus the severe toxicities noted here. And what's really notable in this slide is the deep reduction that we see and the frequency of these more severe toxicities. Recall that AVA6000, again, can't enter cells. Fiona showed us that data. In the bloodstream or the normal tissues until it is broken apart by FAP in the tumor. So it's only released in the tumor microenvironment, and that's where the doxorubicin comes from. This is why we're not seeing these severe toxicities. This lack of severe toxicity, again, it allows us to explore AVA6000 given more frequently every two weeks. Also important to note that even though doses' level 3 to 7 result in giving higher levels of doxorubicin, we're observing really limited toxicity. The next two slides that we're going to look at are further evidence that AVA6000 is functioning as we designed it in patients. Here, we're going to look at the pharmacokinetics or the PK of the drug. The PK studies allow us to characterize two things about AVA6000 in the patients. First, where does the drug distribute once it's been administered into the body as a whole? And then second, where does that first metabolism step occur? Recall, this is the important part of the mechanism where are we seeing the concentration of doxorubicin, that is where AVA6000 is cleaved such that we generate that doxorubicin active drug. So in this first slide, Slide 15. We're looking at the pharmacokinetics of the drug, specifically in the blood. So we're looking at the concentration of AVA6000 and doxorubicin in the bloodstream. This is plotted on the Y-axis against time on the X axis, where the dose is given at time 0, and we're following the patients in this figure out 12 hours after their first dose is administered. It's important to note here on the Y axis that the concentrations are plotted on a logarithmic scale. And this means that even small changes here are truly substantial changes in concentration given the scale that we're plotting them at. And so in this figure, we're looking at PK data summary curves for only the patients treated at the 160 dose level. You'll recall, this is the first dose level of elevated DOX. It represents almost 1.5x the standard dose of doxorubicin that's being given to the patients. And we do see similar curves for each of the dose levels and are happy to discuss those. But we're going to illustrate this here with the 160 dose level. So let's first look at the yellow and blue curves. The yellow curve here, we're tracking the measurement of AVA6000 in the patients. We measure about 17x after the AVA6000 is dosed. And we're going to follow the blue curve at the same time. Now the blue curve is the measurement of the active drug, doxorubicin, that is released from AVA6000 by FAP cleavage. Both of these patients, both of these values are measured in the patients at this dose level of 160. And this is as we expected, we see a significant difference between the maximum concentration of the Cmax of AVA6000, which they're in yellow is quite high, the peak of the yellow curve, and the maximum concentration of released doxorubicin in blue, which is actually much lower in the blood than AVA6000, exactly the mechanism that we suspected, the active drug at doxorubicin isn't showing up much in the bloodstream. You'll recall, the hypothesis is because active DOX should only be produced in the tumor and not in the bloodstream. And so the DOX that we observe in the bloodstream likely comes from tumor conversion. So essentially, the yellow curve measurement is converted to the blue curve in the tumor by FAP. Now to contextualize this observation of the comparison of the yellow and the blue curve, we're comparing here with the red line, which is the expected curve for standard dose doxorubicin. So this is not AVA6000. This is a model of what standard dose, the 75 milligrams of doxorubicin would look like. It's based on real patient data and a model generated. So if you compare the peak of the red and the peak of the blue, here is real data of patients treated with doxorubicin and patients treated with AVA6000. And you can see a dramatic difference between the percent or the dramatic difference between the peak of the doxorubicin in patients treated with standard dosing and the peak of the doxorubicin in the release AVA6000. This difference is exactly what we expected to see. It fits right into the mechanism of action. It's how AVA6000 was designed. It's what we see in the preclinical data. And it's even more important to note that this concentration time profile is like -- very likely responsible for the limited systemic toxicity seen with AVA6000. So we've answered here the first question, what is the profile in the bloodstream. The second important question is, what do these kinds of kinetics look like in the tumor? So let's go to the next slide. As you'll recall, we're taking tumor biopsies. These are optional, and so we don't get one in every patient. But we're anticipating that we're concentrating doxorubicin in the tumor and seeing the limited DOX in the blood, as we described in the previous slide. In Slide 16 here, we're now looking at the concentration in the tumor and comparing them at the same time, both measures are taken at 24 hours after the first dose with that doxorubicin that's observed in the blood, and we calculate the ratio. This is allowing us to look at this concept of concentrating the doxorubicin in the tumor. And so similar to the safety data, we can characterize the biopsy data as either similar or lower dose doxorubicin. Those are the two lines here in the table. And in this table, we have two key observations. First, we appear to have enough piece of evidence of dose response, namely that as we escalate above that standard dose, we see more doxorubicin produced in the tumor. And we see an even higher concentration, that comparison of doxorubicin in the tumor to the blood. And this is even more important because this is the evidence of the mechanism of action, namely, DOX is highly concentrated in the tumor at these higher dose levels indicated by the increased ratio. And even though at these dose levels, we're giving more doxorubicin, we're seeing less toxicity and more DOX in the tumor. So if AVA6000, as we've seen in the last few slides, is behaving biologically, with behaving exactly in the patients as we designed it to, we should be seeing antitumor effects in the patients. So let's move on to Slide 17. And let's take a look at essentially three different instances of the antitumor effect and take a look at, at some of the specific patients that have been treated in the trial. Although we were on the left-hand side in the red file folder, you'll see this first case to discuss is a young 59-year-old gentleman with a soft tissue sarcoma. This is called an Undifferentiated pleomorphic sarcoma. Based on the evidence in the literature, this subset of sarcoma is anticipated to have high FAP expression and has a limited response to standard dose doxorubicin. What we have seen in this particular patient is a deepening tumor response, whereby the lesions or the tumors in the various organs in this patient have shrunk by 65% from their baseline measure that we do with CAT cans. What's critically important here is not just the deepness of the response. Also the deepening, meaning, over time, the response has continued to increase. We're actually seeing now a duration of the response that is more than 6 months, and this gentleman is now approaching 10 months on the trial. He continues to receive AVA6000 and is doing well. You'll recall, I mentioned at the beginning that standard dose doxorubicin is only administered for 6 cycles or 18 weeks, so 4.5 months. However, given the limited exposure that we've seen in the bloodstream in this patient and others at this dose level of 160, we're going to be able to dose this patient now a further seven additional cycles if his tumor doesn't progress. And this represents about up to another 5 months of therapy, which would bring him to a total of 15 months on AVA6000. This represents almost 3x the length of time that this patient could be treated if he was receiving standard dose doxorubicin. And correlative studies also indicate that this particular tumor biopsy in this patient has high FAP expression. Again, speaking to that mechanism of action and completely recapitulating what Fiona described for us in the preclinical setting that patients with high FAP disease or high FAP expression in their disease would be susceptible to the mechanism of action of AVA6000. Let's look at the second case in dark blue in the middle there. Here, we have a female with a highly progressive tumor type. This is an angiosarcoma. It's a soft tissue sarcoma of a blood vessel that developed in her spleen. This patient has achieved what we call a minor response at the first scan with a minus 14% shrinkage of the metastatic lesions or metastatic tumors. And this deepened at the second scan to a minus 22%, very similar to the prior patient that I described, where we see this deepening so the tumor continues to shrink over time. In parallel, however, this patient at that second scan developed bone metastases, which makes this a mixed response. So the visceral or the organ type tumor lesions continue to shrink, but the tumor was able to escape to the bones, a place that has limited blood supply. And this is a classic pattern of progression in a number of solid tumors, but also including angiosarcoma. But again, what's notable in this type of sarcoma that is highly refractory to therapy, is that although this is not long lived, the deepening tumor shrinkage, so continuing to shrink over time is good evidence of an antitumor effect. In the third series of cases here, we present three cases of a rare sarcoma. This is called Solitary fibrous tumor. It's another type of soft tissue sarcoma that is quite refractory into therapy just given the basic biology of the disease in that as the title described, it's really a quite fibrous tumor. So it includes more stroma almost than tumor cells. And so generally, it's quite refractory and doesn't shrink to cytotoxic therapy. So here, in this particular disease setting, it's important to see the prolonged disease stabilization, and we see this with all three of the patients. And so this prolonged disease control, importantly, with three separate patients here with no progression over 4 to 8 months of therapy. Recall again, doxorubicin can only given for 4.5 months of therapy. And these patients -- 2 of the 3 patients are still on therapy. And so given the favorable PK profile that I know I keep mentioning, but this is really a key aspect of the AVA6000 mechanism and that these patients can receive at least three additional cycles representing a big gain in time that would be allotted with standard dose doxorubicin. So if we bring all of this together, we're seeing deepening tumor shrinkage in those first two patients. And across the board in the trial, we're seeing lower exposure to cleaved doxorubicin, which is allowing us to give more cycles and longer treatment. If we combine that then with a really highly differentiated safety profile, although we didn't discuss the safety profile of the mild to moderate toxicities, these are the adverse events that impact the quality of life for the patients. And so if we think about the GI disease toxicities, the nausea, the vomiting, doxorubicin and many of these cytotoxics create severe mouth sores that we refer to as mucositis. Patients because of all of these have steep decrease in their appetite, weight loss. These are all toxicities that impact patients' lives, and we're seeing a reduction across the Board, which is really what's factoring into patients being able to tolerate these prolonged periods of treatment with AVA6000. So with that, I'm going to hand it back to Alastair to close the formal part of the presentation.

That's correct. Thanks very much, Chris. So I think you'll agree with the data we've presented unequivocally support the statements that we've made in the past few months about the pre|CISION platform. And the key message is on this slide. So the data show that the pre|CISION platform works as intended as designed. So the data from both the preclinical and the Phase I trial show that AVA6000 is specifically releasing active doxorubicin in the tumor microenvironment. That targeting of the active drug to the tumor microenvironment has significantly improved the safety and tolerability of doxorubicin. The preliminary signs of clinical activity that Chris has just taken us through, very encouraging indeed, as Chris has described, but the significant reduction in the severe side effects now allows us to move on in the 2-weekly study to really optimize the schedule and the dose -- the further clinical development. And I should say, just to remind you that we are now, as Chris mentioned, screening patients in the United Sates on the 2-weekly study, and that leaves us on track for beginning the Phase II study in 2024. So I look forward to keeping you updated on progress as we move through next year. And obviously, we're very happy to take some questions now.

That's great. Thank you to you all for your presentation this morning. As I said at the outset, we did receive a number of category questions that have fallen into a number of things. I hope that does address a number of the questions that we received during the live meeting as well, but apologies if we don't read them out specifically, but given the attendance, that would just be inappropriate to do so. So let's start off with the first question, if I may, with reads as follows. Why does modification of a chemotherapy with pre|CISION stop it from entering the cells? What is the mechanism?

Okay. So the whole pre|CISION platform is around know-how, around what makes that specific pre|CISION substrates selected for FAP as we outlined in many parts of the earlier discussion. So the change in the size and the change in the charge, the polarity of the molecule, is what really makes this molecule not enter the cells. So there's a lot of work that's done in the medicinal chemistry, teams to design exactly the sequence of that pre|CISION substrate to make each warhead not to be permeable by cells.

That's great. Turning to the next question around dose levels. Why have you picked these specific dose levels for the fortnightly dose escalation study?

So I'll take that one. To select the starting dose in an initial Phase I trial, we rely on observations in the preclinical setting, essentially, when we started the every three weeks dose escalation, we started just below the standard dose of doxorubicin if you compare our molar equivalents. Now there, we've showed the data that we collected on the every 3-weeks dosing regimen. And that really supports our ability to dose intensify AVA6000 and move to the every two weeks. And so to select the starting dose in a subsequent Phase I trial, such as our every two weeks, we look together at the safety data, the tolerability, so how well the patients tolerate the drug over time. The pharmacokinetics, really understanding where the drug distributes in the body and are we seeing that mechanism of doxorubicin concentrating in the tumor. We can also consider then preliminary efficacy signals at the dose levels in the every three weeks regimen. And so let me describe to you how we settled on the 160 dose level. Recall, this is where we first saw efficacy. So the 160 dose level, this is where we see the patient with our first -- that deepening response in the patient with Undifferentiated pleomorphic sarcoma. It's also the dose level when we go back to that dose response table of severe versus mild toxicities, it's really that dose level where we see the first instance and there was only one but -- of a toxicity that was observed at a grade 3 or 4 dose levels. So a very favorable safety profile at the 160 dose level. And importantly, this is the PK curve that we showed you. We also demonstrate a significant reduction in both the maximal concentration or the Cmax, as well as what we refer to as the exposure or the area under the curve of observed doxorubicin. This is important for a couple of different reasons. The first is that it feeds directly into the safety profile that we're seeing at this particular dose level. This favorable PK signal of both the Cmax and the area under the curve or the AUC being significantly lower than what we would expect with standard dose doxorubicin. It allows us to extend that treatment of the patients from the 4.5 months, which is all that we can give with standard dose doxorubicin to as I mentioned in that one patient over 15 months. And so as we further characterize this dose level and move into the every two weeks, we have favorable safety, the first hints of efficacy and then a very favorable PK profile that's going to allow us to extend that treatment and really create that time on the drug without experiencing severe toxicities. We plan, as you saw in the trial design, we plan in this arm of the trial to use the same dose levels so that we can compare the every three weeks to the every two weeks dosing as we try and identify that recommended Phase II dose.

That's great. Kind of next category of questions, talked around the market size and the value opportunities here. The company has stated that one way of generating value is to make pre|CISION versions of genetic chemos. What is the size of the current market of these drugs Avacta could target? If this is not viewed as the preferred option, can you explain why this is not the optimal value creator?

Yes, sure. So look, I think it's an obvious statement, but fundamentally, the way to maximize shareholder value is to develop most effective anticancer therapy, its possible to using pre|CISION. So those will be the most clinically valuable and therefore the most commercially valuable. Now some of those may involve existing generic chemotherapies. But cytotoxic development has moved on a lot in the last decade, and there are now numerous more potent modern cytotoxics that could never be given as systemic chemotherapies because of the toxicity. So they could be delivered potentially as precision chemotherapies. And we believe it makes a lot more sense to select the most potent and effective cytotoxics than simply go down a list of old generic chemotherapies. But I'm sure it will be a combination of those two approaches that delivers the most precision drugs to patients in the long term.

Great. Just turn to the next question from an investor that read as follows, that the data seemed to show that AVA6000 is considerably safer and better tolerated than doxorubicin. How is the patient experience and quality of life different when treated with AVA6000? I wonder if you could give a bit of color on that?

Sure. I can take that one as well. Let me talk first about the data that we showed, which is the significant reduction in severe toxicities. This has led to an improvement in the patient experience, both from a quality of life standing point, but let's also talk about the length of time that patients are able to be treated. And so I think we can all agree that a safer drug given over a longer duration that is showing activity is the profile that we'd like to deliver. And so the reduction in severe toxicities, we refer to them as grade 3 and 4 in the oncology clinic. This is optimal because we're able to then stabilize the disease for even longer. What we didn't show in the interest of time, but have kind of analyzed is these more mild to moderate toxicities. And these also factor into the patient experience. And so the toxicities that we see in general with cytotoxic therapies, chemotherapies, it's based on cellular damage. And the ones that really are particularly bothersome to patients, I saw this in my practice of oncology is nausea and vomiting. So the turnover in the GI tract, mucositis or the mouth sores that patients experience, the lack of appetite, which then feeds into -- which can be pretty severe weight loss in patients experiencing these. So these factor into really the -- quality of life, being able to eat being -- not having that, mouth pain. Another one that is reduced in AVA6000 is also the pain and muscles and joints. So cells in muscles, cartilage turn over and just treating with cytotoxic can create muscular pain arthralgias or joint pain, and we see a reduction in those due to the reduction in cellular damage. And so we do see everywhere from Grade 1 to Grade 4, a reduction in the toxicities leading to a better experience for the patients as well as that prolonged time on therapy, which allows them to have that disease stabilization for a longer period of time.

Thank you very much indeed. The patient with the 65% tumor reduction, we have a question around that, is that a good result? Would you have expected to see that sort of response in this patient, if treated with doxorubicin?

So it is possible that we would see a response like this with doxorubicin. Doxorubicin is active in Soft tissue sarcoma. Across the board, if we look at the different subsets and then in sarcoma in general, we can see response rates of, I think the lowest I've ever seen is 6.4%. It can get up into the 20s, depending on the particular subtype of sarcoma and whether these are chemo-sensitive or the more chemo-refractory such as, for example, the Soft tissue or the Solitary fibrous tumor, that group of patients that we described. What really differentiates AVA6000 from standard dose doxorubicin is the observed time on treatment. And you saw that in the various patients that we presented. This particular patient with the 65% tumor reduction, this patient has now been treated for -- it's approaching 10 months. And that translates here to a duration of that response of more than 6 months. Recall, it's ongoing. And this individual patient has a very similar safety profile that we've seen with most of the other patients in the trial, meaning that really limited toxicity, really having a great quality of life. And recall, I know I mentioned this a few times, but I'll mention it again, doxorubicin is limited to 6 cycles or 18 weeks, 4.5 months, and that's because of the cumulative toxicity that's based on that AUC. And so the benefit that we have here with AVA6000 is not just that we're shrinking tumors, but those tumors are shrinking and staying in that tumor shrinkage. We're stabilizing the disease for a prolonged period of time that just can't be achieved with doxorubicin. And that's right there with that favorable safety profile. So the patients have strong disease stabilization, responses that last for time and they're not experiencing the really problematic toxicities that are associated with doxorubicin.

Right. Moving on, is the plan still to retain complete ownership of AVA6000? Or might you consider licensing out particular -- to particular cancer types or specific geographical areas?

Yes. The commercial strategy is to retain ownership of AVA6000 for the foreseeable future and take it into Phase II, as Chris described it. We believe it's strategically important that we retain our lead clinical asset and build a clinical pipeline. But it's also important to think about how we accelerate the pace which pre|CISION drugs can get to patients. So I mean we can't do all of that ourselves, but it will be through a combination of in-house development and partnerships licensing deals, who's going to get the pre|CISION platform into other drug developers hands. I mean we're in a fortunate position of having a platform technology. So that's now clearly doing what it's intended to do. So there's the potential and the increasing potential to partner the platform as opposed to partnering our lead assets so that others can develop targeted tumor therapies of their own proprietary cytotoxics. But both of those are very important parts of our commercial strategy.

Alastair, in the pharmacokinetics data, why is Cmax so important?

Let me take that one. So just I stressed several times, the relevance of Cmax in the patients. If we just talk for a minute about what happens to doxorubicin in the body. Doxorubicin broken down to a number of [ new metabolites ], which we also measure in the blood and in the -- actually in the biopsy where we get them. One of this metabolite is called Doxorubicinol and its known to cause whats called a [indiscernible], which actually is one of the main components of the cardiac damage that we see when anthracyclines and doxorubicin are administered to patients. And it's well known that the Cmax of doxorubicin drives that cardiac toxicity. So by reducing the Cmax as we do, I mean, even up to 90% reduction in Cmax is going to have a significant impact while a design mechanism of doxorubicin causing that cardiac toxicity. What we know from preclinical studies is that, that reduction, Cmax does not limit the efficacy of the drug, and that's a really important point to differentiate.

Great. Just continuing along that theme. If you're releasing doxorubicin in the tumor, then why aren't all these patient tumors shrinking?

So back to the baseline characteristics of the patients in the trial, many of these patients with a median of three prior lines of therapy, and as you saw in that slide, multiple cytotoxic mechanisms have been delivered to these patients, a large number of them on the trial can be considered chemotherapy refractory essentially. We have revised the criteria in the update to the protocol. But recall in the every weeks arm, this is still a Phase I trial, and we're still going to be seeing patients with prior lines of therapy. But we have updated in that patients without prior therapy in the metastatic setting can be enrolled in the trial. And so we're looking to update and move forward with that every two weeks regimen.

That's great. Are any patients still receiving AVA6000 from cohorts 4, 5 and 6, so therefore, achieving progression-free survival of 6 months plus?

Yes. And we have 13 patients ongoing in the trial now. You saw the numbers of patients in each of the cohorts there. Four patients have been enrolled in cohort 7. So what you can assume from there in 4, 5 and 6 also enrolling in that there are still nine patients ongoing in each of those. So we are seeing evidence of disease stabilization that we mentioned in the 3 groups of patients of efficacy. And then in the first half of 2024, we do plan an update of these clinical data, and we'll provide more information, especially as we mentioned, we are screening patients for the every two weeks arm right now. So the trial does continue to enroll.

That's great. Thank you very much, indeed. Well, look, as we come up to the hour, I know you have scheduled meetings after today after this meeting. So thank you to everybody for both pre-submitting your questions. And as I say, all your questions here can be reviewed and there's any additional responses, we can make those available. Alastair, I know that feedback from the significant number of attendees you have on today's call will be particularly important to you and to the management team. And I wonder before I redirect investors to give you their feedback, whether I can just ask you for a couple of closing comments.

Absolutely. Thanks, Mark. And just to reiterate that we will do our best to address any of those questions as we can after this call. So well, in summary, I think you'll all agree that there's a huge opportunity that lies ahead and we are just at the beginning of the value curve for Avacta. So there's a lot to look forward to next year 2024, both in the clinic and commercially. And obviously, we'll keep the market updated at each key milestone, and thank you for listening, everybody.

That's great. Alastair, Chris, Fiona, thank you once again for updating attendees today. Could I please ask investors not to close this session, as we'll now automatically redirect you to the opportunity to provide your feedback in order that the company can better understand your views and expectations. This may take a few moments to complete, but I'm sure you've just heard it be greatly valued by the company. On behalf of the management team of Avacta Plc, I would like to thank you for attending today's presentation, and I wish you all a very pleasant morning.