Avacta Group (LSE:AVCT) — Review of the AVA6000 clinical trial’s Phase 1a data

0:01 Good morning, ladies and gentlemen, and welcome to the AVACTA Investor Presentation relating to the review of the AVA6000 Clinical Trials Phase one data. Throughout this recorded presentation, investors will be in listen only mode. 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 pre submitted questions, and the company have reviewed those questions and we'll categorize some responses to those sectors

0:31 in the Q and A session at the end. Questions can be still submitted using the Q and A tab situated on the right hand corner of your screen. Just simply type in your question at any time and press send. The company can review these post today's meeting as well. Before we begin, we'd like to submit the following poll. 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 AVACTA both preclinical and clinical data. And I'm joined by Doctor Fiona McLaughlin, Chief Scientific Officer, and Doctor Chris Cocklin, Oncologist, Immunologist and Consultant to the company.

1:18 So before we get, into the presentation of the data, I just want to set the scene. The overarching takeaway message from the data that we're going to present to you is that precision works as it was designed to do. And what do we mean by it works? Well, we're going to show you data that shows us that a precision chemotherapy cannot get into cells so it circulates in the bloodstream in an inert and relatively safe form. We're going to show you data, that shows the precision platform is absolutely specific to this enzyme FAP so that it releases the drug in the tumor microenvironment and not systemically. And we're going to show you clinical data relating to AVAC6000 that shows a dramatic reduction in the severe toxicities associated doxorubicin and the drug that it delivers. So this redefinition of tumour targeting means that we can optimise the dosing of doxorubicin and chemotherapies more generally and improve the outcomes for patients, as well as improve their quality of life whilst on treatment. I know Chris will take you through our observations, to date. So finally, before we start, realise that many on the call are not scientists. We'll do our very best to make the data digestible, and I'll I'll follow-up this presentation with an interview with Paul Hill on on VOXX Markets as well to make sure that we've got the the key points across. So first,

2:49 you know, what is the problem that we're trying to solve? So the the fact is that traditional cancer therapies don't target the tumour. They don't differentiate between healthy tissue and tumour 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 precision platform that we'll describe in a lot more detail as we go through today. And the precision platform is a method of linking a cleavable peptide. So 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.

3:45 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. And that releases the active chemotherapy in the tumor microenvironment where FAP is predominantly found. So precision modified chemotherapies or precision medicines are designed to reduce the systemic exposure which causes those toxicities to enhance the safety and tolerability and therefore increase the efficacy.

4:25 So a few words on fibroblast activation protein alpha or FAP or FAP because it's fundamental to, obviously, the way precision works and the effectiveness of these precision medicines. So FAP is an enzyme, as I've mentioned, and the 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 that we call precision. FAP identifies that and removes 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 there. The most troublesome actually is usually PrEP, which which other efforts, and Fiona will talk through some some data from the literature that shows that it's it's actually very difficult, and it's it's the proprietary elements of our our IP, the fact that precision is absolutely specific to fat and doesn't get cleaved or chewed up by these other enzymes that are typically found all around the body.

5:42 FAP itself is found on the surface of cells. So it's what we call an extracellular protoenzyme, 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 cell 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.

6:20 So just to illustrate and we'll obviously go through a lot more detail in the body of the presentation, but just to illustrate the PLC mechanism of action of the precision platform using, AVACTA GROUP doxorubicin as the chemotherapy that AVACTA GROUP delivers. So AVACTA is a precision modified form of a generic chemotherapy called doxorubicin. So we have added, chemically added, the peptide that I've been talking about, the precision peptide, to doxorubicin. And what that does and what we'll we'll see from the preclinical data in particular is it prevents the drug 6,000 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 get into cells and it's relatively harmless. In the tumor microenvironment, when the drug gets into the tumor microenvironment through the circulation and then it encounters FAP,

7:22 the enzyme that specifically recognizes the peptide we've added, it removes that peptide and releases doxorubicin. Now doxorubicin will cross cell membranes and get into cells very quickly. So when doxorubicin is released from AVAC6000 by FAP, predominantly in the tumor microenvironment, it very quickly gets into cancer cells, fibroblasts and other cells.

7:47 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 with Chris. Okay. Thank you, Alastair. So the central precision concept is that the parent molecule, in this case, AVACTALAN, is inactive until it reaches the tumor microenvironment where it is selectively cleaved by the enzyme fat that Alastair has just outlined. AVA six thousand is not self permeable, and so it passes through the body inert unless and is not taken up into cells unless fat is present.

8:37 So let me show you the data that supports those 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 AVACTA GROUP and we then measure the amount of both AVACTA and doxorubicin that have been taken up by the cells. Doxorubicin is only detected in cells that overexpress FAP, as shown by the red circles, and not detected in cells without FAP. AVA 6,000, in contrast, is not detected in either cell type, which supports the hypothesis that AVA six thousand is not cell permeable.

9:26 The second important point is that AVACTA six thousand is exquisitely selective for 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 AVACTA GROUP and we

9:48 compare this in the bottom with a modified version of the substrate in which a different peptide sequence is used. As you can see on the top chart, EVA 6,000 is only cleaved by FAP and not other family members, whereas a related peptide, CGP docs, which actually was initially used in most studies looking at FAP activity, is also cleaved by PrEP, which is more widely distributed in the body. On 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 the cells that come from a patient with osteosarcoma. That patient was previously treated with and is now resistant to doxorubicin.

10:36 This model was selected because the tumor was high in FAP at the RNA level. After just four doses of AVACTA thousand, 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 animal study using a pancreatic tumor model called hPAF, On the left hand side of this of this slide, the h path model expresses very low levels of FAP, and there is very little response to AVACTAL, again, shown in blue compared with the control in black.

11:28 However, when we use cell line that overexpresses FAP on the right hand side, what you can see now is a significant reduction in tumor volume when AVACTA administered across a range of doses from six to twelve milligrams per kilogram. It's important to point out here that the high dose of twelve milligrams per kilogram contains four times more doxorubicin equivalent dose than the two milligrams per kilogram dose of DOCS that we use in the red line. And, again, just to make the point that that two milligram dose of doxorubicin is the maximum that we can give to the animal without inducing significant body weight loss as a measure of toxicity. So we are clearly able to administer higher doses of AVACTA six thousand than we can with doxorubicin alone at tolerable doses.

12:21 So taken together, our complete preclinical data package supports the concept that AVAC6000 delivers DOCS directly to the tumor microenvironment, increasing the effectiveness of doxorubicin and further supports the clinical development of AVAC6000. Thanks, Leona. Thanks very much. So there, we've 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, Alistair. So as we look at these clinical GROUP trial data for AVACTA GROUP together, let's focus on the three key aspects of that we see in the preclinical data.

13:07 So first, AVAC6000 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, precision is specifically cleaved by fat, 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.

13:56 We're describing the trial design, and there are a few key aspects of the trial that I want to highlight for us here. Let's start at the top of the slide, the arm one dose escalation. This is the arm that has now completed enrollment, and this is the part of the trial that's using an every three weeks dosing regimen. You'll see the dose levels of AVACTA in each of the boxes there representing the cohorts. Those are in bold. You'll 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 AVAC6000 is a composite molecule it's doxorubicin plus precision. 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.

14:47 For reference, the standard dose of doxorubicin in the clinic is seventy five milligrams per meter squared given every three weeks. And so as you can see there, it's only the first two cohorts of eighty and one hundred twenty mgs of AVAC6000 that are lower or similar to this dose level. Once we've escalated to that third cohort, the 160, we're giving more doxorubicin than is standard, about one and a half times in that first dose level there of one hundred sixty.

15:18 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 one hundred eight, the one hundred thirty five, 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 release today. Next, if you let your eyes wander down the slide, you can see arm two, 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.

16:04 This is with AVACTA GROUP again in the first arm, delivered every three weeks. And looking across these two arms of the phase one trial, so both the every three weeks and the every two weeks, we're going to present finally a comparison of the cumulative dose that would be administered over twelve 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

16:35 levels you can see, let's compare the one hundred sixty dose level. In a twelve week regimen, we're going to give six forty milligrams in the every three weeks, but in the every two weeks, we're going to be able to give a nine sixty 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 two dose from the two arms. And so, this second arm, the every two weeks arm, is currently screening patients in The United States.

17:18 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 Alistair mentioned, there are multiple solid tumors that are known to be positive for fat. 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 six cycles or eighteen weeks at that seventy five milligram per meter squared dose. And this is important because one of the key hypotheses going into this trial was that patients could be treated for longer timeframes, so longer than those eighteen weeks.

18:12 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've treated 40 patients across the dose levels of eighty to three eighty five, and there are 13 patients that are still ongoing. On the left side in the left table here, can see the baseline characteristics. These are pretty standard for oncology phase one 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.

19:06 And then the mismatch of the performance status is actually quite expected and anticipated in such a population of patients with prior treatment.

19:16 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 of both colorectal and pancreatic. And then there's a large number of cancers 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 in the trial thus far, and that most of the patients with these multiple cytotoxic mechanisms you can see there from platinum, topo one, you know, the various

20:21 different cytotoxics, These could be considered chemo refractory. And as we have progressed in the trial, we note here that the range of the number of therapies is as low as zero. 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 fat 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, let's consider all of the toxicities reported in the trial and not break them down yet into the individual events.

21:08 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 one and two 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 three and four.

21:35 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 one and two, 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 three here at one hundred and sixty 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.

22:21 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 threes and fours up to 160. And we're really only seeing the mild to moderate toxicities here, and the grade three and four, the more severe toxicities, are starting to pop up at the higher dose levels. It's also important to note here that cohorts five, six, and seven, 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 seven, these patients have been enrolled over the last month to six weeks. And so the safety data definitely is still maturing in that cohort.

23:16 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 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 is the taxane paclitaxel in the field of oncology. When paclitaxel is administered in some settings in an every three 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 enhanced the activity.

24:03 This weekly regimen is is used more in the clinic. Both are still used. But this

24:08 is the rationale for these new dose cohorts of every two weeks dosing, and it's 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 one and two. 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 in the frequency of these more severe toxicities. Recall that AVACTA six thousand, again, can't enter cells. Fiona showed us that data in the bloodstream or the normal tissues until it is broken apart by fat in the tumor. So it's only released in the tumor microenvironment, and that's where the doxorubicin comes from.

25:05 This is why we're not seeing these severe toxicities. This lack of severe toxicity, again, it allows

25:11 us to explore AVACTA six thousand given more frequently every two weeks. Also important to note that even though doses levels three to seven 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 AVAC6000 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 AVACTA in the patients. First, where does the drug distribute once it's been administered into the body as a whole?

25:55 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 AVAC-six thousand 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 ADA six thousand 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 zero and we're following the patients in this figure out twelve hours after their first dose is administered.

26:46 It's important to note here on the y axis that these 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 one hundred sixty dose level. You'll recall this is the first dose level of elevated DOCS. It represents almost one and a half times 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 one hundred sixty dose level. So, let's first look at the yellow and blue curves.

27:35 The yellow curve here, we're tracking the measurement of AVACTA in the patients. We measure about 17 times after the AVAC6000 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 AVAC6000 by fat cleavage. Both of these patients, both of these values are measured in the patients at this dose level, the one hundred sixty, and this is as we expected. We see a significant difference between the maximum concentration of the Cmax of AVAC6000, which there in yellow is quite the peak of the yellow curve, and the maximum concentration of released doxorubicin in blue, which is actually much lower in the blood than AVACTA six thousand, exactly the mechanism that we suspected.

28:26 The active drug at doxorubicin isn't showing up much in the bloodstream. You'll recall the hypothesis is because active docs should only be produced in the tumor and not in the bloodstream. And so the DOCS 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 Fab. 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 AVA 6,000 This is a model of what standard dose, the seventy five milligrams of doxorubicin would look like.

29:12 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 AVA six thousand, 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 released 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 very likely responsible for the limited systemic toxicity seen with AVA six thousand.

30:05 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 DOCS 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 twenty four 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 as either similar or lower dose doxorubicin.

31:02 Those are the two lines here in the table. And in this table, we have two key observations. First, we appear to have another 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 DOCSIS 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 DOCS in the tumor.

31:53 So, if AVACTA GROUP as we've seen in the last few slides, is behaving biologically, is 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 anti tumor effect, and take a look at some of the specific patients that have been treated in the trial. All the way over 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.

32:49 What we've 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 scans. What's critically important here is not just the deepness of the response, 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 six months, and this gentleman is now approaching ten 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 six cycles or eighteen weeks, so four and a half months.

33:40 However, given the limited exposure that we seen in the bloodstream in this patient and others at this dose level of one hundred sixty, we're going to be able to dose this patient now a further seven additional cycles if his tumor doesn't progress. This represents about up to another five months of therapy, which would bring him to a total of fifteen months on AVA six thousand. This represents, you know, almost three times 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 AVAC6000.

34:47 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 bony metastases, which makes this a mixed response. So the visceral or the organ type tumor lesions, continued 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.

35:55 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 to therapy, just given the basic biology of the disease in that, as the title describes, it's really a quite fibrous tumor, so includes more stroma almost than tumor cells, and so generally is 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.

36:54 And so, this prolonged disease control, importantly, with three separate patients here with no progression over four to eight months of therapy. Recall again, doxorubicin can only be given for four and a half months of therapy. And these patients, two of the three 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 AVAC6000 mechanism, in 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.

37:45 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, you know, the the GI disease toxicities, the nausea, the vomiting, doxorubicin and and many of these cytotoxics create severe mouth sores that that we refer to as as mucositis. Patients, because of all of these, have a steep decrease in their appetite, weight loss.

38:35 These are all toxicities that impact patients' lives, 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 AVAC6000. So with that, I'm going to hand it back to Alistair to close the formal part of the presentation. That's great. Thanks very much, Chris. So I think you'll agree the data we've presented unequivocally support the statements that we've made in the past few months about the Precision platform and the key messages on this slide. So the data show that the Precision platform works as intended, as designed. So the data from both the preclinical and the Phase one trial show that AVAC6000 is specifically releasing active doxorubicin in the tumor microenvironment.

39:31 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 are very encouraging indeed, as Chris has described. But the significant reduction in the severe side effects now allows us to move on in the two weekly study to really optimize the schedule and the dose for further clinical developments. And I should say, just to remind you, that we are now, as Chris mentioned, screening patients in The United States on the two weekly study and that leaves us on track for beginning the Phase II study in 2024.

40:22 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 themes. 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 but let's start off with the first question, if I may, which reads as follows. Why does modification of a chemotherapy with precision stop it from entering the cells? What is the mechanism? Okay. So the whole precision platform is around know how around what makes that specific precision substrate selected for for FAP as we outlined in in many parts of the earlier discussion.

41:19 So the change in the size and the change in the charge, the polarity of the molecule is 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 precision substrate to make each warhead not be permeable by cells. That's great. Thank you. 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 one trial, we rely on observations in the preclinical setting. Essentially, we started the every three weeks dose escalation, we started just below the standard dose of doxorubicin if you compare our molar equivalents.

42:18 Now there we've showed the data that we collected on the every three weeks dosing regimen, and that really supports our ability to dose intensify AVE6000 and move to the every two weeks. And so, to select the starting dose in a subsequent phase one 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.

43:10 And so, let me describe to you how we settled on the one hundred sixty dose level. Recall, this is where we first saw efficacy. So the one hundred sixty 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 three or four dose level, so a very favorable safety profile at the one hundred sixty dose level.

44:00 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, you know, the four and a half months, which is all that we can give with standard dose doxorubicin to, you know, as I mentioned in that one patient, over fifteen months.

45:02 And so as we further characterize this this dose level and and move into the every two weeks, we have favorable safety, the first hints of efficacy, and then a 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 two dose. That's great. Thank you.

45:51 Kind of the next category of questions talks around the market size and the value opportunities here. The company has stated that one way of generating value is to make precision 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? Yeah. Sure. So look, I think it's it's an obvious statement, but fundamentally, the way to maximize shareholder value is to develop the most effective anti cancer therapies possible using precision. So those will be the most clinically valuable and therefore the most commercially valuable. Now some of those may involve existing generic chemotherapies, but, you know, 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.

46:52 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. Thank you. Let's turn to the next question from an investor that read as follows that the data seem to show that AVAC6000 is considerably safer and better tolerated than doxorubicin. How is the patient experience and quality of life different when treated with AVACTA 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.

47:47 This has led to an improvement in the patient experience, both from a quality of life standpoint, 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 three and four 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 analyzed, is these more mild to moderate toxicities, and these also factor into the patient experience.

48:42 And so the toxicities that we see in general with cytotoxic therapies, chemotherapies, is based on cellular damage. The ones that really are particularly bothersome to patients, you know, 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, you know, really the quality of life, being able to eat, being, you know, not having that mouth pain.

49:32 Another one that that is reduced in AVACTA also the pain in in muscles and joints. So cells in in muscles, cartilage turnover, and just treating with with cytotoxic can create muscular pain, arthralgias, or or joint pain, and we see a a reduction in those due to the reduction in cellular damage. And so, we do see everywhere from grade one to grade four a reduction in the toxicities leading to, you know, 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.

50:19 Thank you very much indeed. The patient with the sixty five percent 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. The board, if we look at the different subsets and then in sarcoma in general, we can see response rates of, know, I think the lowest I've ever seen is is six point four percent. It can get up into the twenties depending on the particular subtype of sarcoma and and whether these are chemo sensitive, or the more chemo refractory such as, you know, for example, the soft tissue or the solitary fibrous tumor, that group of patients that we described.

51:18 What really differentiates AVAC6000 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 sixty five percent tumor reduction, This patient has now been treated for, you know, it's approaching ten months, and that translates here to a duration of that response of more than six 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, you know, really limited toxicity, really having a great quality of life.

52:06 And recall, I know I mentioned this a few times, but I'll mention it again, doxorubicin is limited to six cycles or eighteen weeks, four and a half months, and that's because of the cumulative toxicity that's based on that AUC. And so, the benefit that we have here with AVAC6000 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.

53:05 Great. Thank you. Moving on, is the plan still to retain complete ownership of AVAC6000? Or might you consider licensing out particular to particular cancer types or specific geographical areas? Yes. The commercial strategy is to retain ownership of AVACTA the foreseeable future and take it into Phase II, as Chris described. 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 at which precision 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 that's going to get the Precision platform into other drug developers' hands. I mean, we're in a fortunate position of having a platform technology.

54:05 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 chemotherapies of their proprietary cytotoxic. So both of those are very important parts of our commercial strategy. Thanks, Alastair. In the pharmacokinetics data, why is Cmax so important? Okay. Let me take that one. So just as stressed several times, the relevance of Cmax in 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 known metabolites, which we also measure in in the blood and in the actually, in in the biopsy where we get them.

54:56 One of these metabolites is called doxorubicinol, and it's known to cause what's called a free radical formation, which actually is one of the main components of the cardiac damage that we see when anticyclines and doxorubicin are administered to patients. And it's well known that the c max of doxorubicin drives that cardiac toxicity. So by reducing the c max as we do, I mean, even up to, you know, 90% reduction in c max is going to have a significant impact on a defined mechanism of doxidin causing that cardiac toxicity. What we know from preclinical studies is that that reduction c max does not limit the efficacy of the drug, And that's a really important point to differentiate.

55:46 That's great. Thank you. 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, 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 two weeks arm, this is still a phase one 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.

56:55 That's great. Thank you. Are any patients still receiving AVAC6000 from cohorts four, five and six, so therefore achieving progression free survival of six 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 seven, so what you can assume from there in in four, five, and six also enrolling is that there are still nine patients ongoing in each of those. So we are seeing evidence of disease stabilization that we mentioned in the three groups of patients of efficacy.

57:41 And then in the first half of twenty twenty four, we do plan an update of these clinical data and will 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 if 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 could just ask you for a couple of closing comments.

58:32 Yes, absolutely. Thanks, Mark. And just to reiterate that, we will do our best to address if any of those questions as we can after this call. So well, in summary, I think you'll all agree 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. 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're now automatically redirect you to the opportunity to provide your feedback in order that the company can better understand your views and expectations.

59:18 This may take a few moments to complete, but I'm sure as you've just heard, it'd be greatly valued by the company. On behalf of the management team of AVACTA PLC, we'd like to thank you for attending today's presentation, and I wish you all a very pleasant morning.