Crism Therapeutics (LSE:CRTX) — Interim Results

0:00 Good afternoon, and welcome to the CRISM THERAPEUTICS CORPRATION INTERMESTS PRESENTATION. Throughout this quarter presentation, investors will be in listen only mode. Questions are encouraged and they can be submitted at any time by the Q and A tab situated in the right corner of your screen. Just simply type in your questions and press send. The company may not be in a position to answer every question received in the meeting itself. However, the company can view all the questions submitted today and publish responses where it's appropriate to do so. Before we begin, I'd like to split the following poll. I'd now like to hand you to CEO, Andrew Webb. Good afternoon to you, sir. Thanks, Alexandre. Good afternoon. Thank you for taking taking the time to join today's presentation. My name is Andrew Webb. I'm chief executive of CRISM THERAPEUTICS. And, and, today's presentation, we'll be looking to really reflect on the highlights from the interim results that we we we posted yesterday.

0:49 And following that, I really want to take some time to look at the important development for the company, and that's our movement now into commencement of clinical trials. So in order to

1:01 take take that forward, and, I'm not looking so I'm joined today by, professor Garth Kupshank. Professor Kupshank is professor of neurosurgery at the University Hospital in Birmingham. And Vascula Shank, if you could just take perhaps a couple of minutes to to introduce yourself, that'll be that'll be helpful. Hi, Andrew. Thanks very much, and welcome to everybody. Yes. So I I'm Emeritus professor of neurosurgery in Birmingham. I've been involved with the treatment of glioblastoma for well over thirty years or so, and I've been heavily involved in the development of trials, which have really focused in on the very difficult ways of treating these tumors, bearing in mind that they they sit within the brain. Also, working with CRISM's CORPORATION and with CRISM, I've been instrumental in helping design the current trial that's now been approved by the MHRA, and also in particular, how we might actually progress this in terms of sort of practical solution for surgeons to use in the trial.

2:08 That's great. Thank you.

2:10 So if I may start, firstly, I'll run through the the highlights from our interim results. As I mentioned, you that have heard me talk before and getting more of an insight into the company, everything we do is around ChemoSEED. ChemoSEED is the is our key asset. It's the platform drug delivery technology which, which we're developing. And, we're developing it as a platform technology, and the the brain tumor work we're doing at the moment is, is our prime primary indication. There are other, solid tumors which we're looking to address, and, some of those programs have started, which I will highlight shortly.

2:48 As I mentioned briefly in our introduction, we've had an absolute focus on delivering our first treatments in the brain tumor indication. And, the the highlight really is, over the last last few months is that the our application to the MHRA, The UK regulator, to commence our clinical trial has been now being give given given the approval. And, so we were on track for h one to make the submission and, delighted the MHRA at the, end of August, approved us to to go into trial. That removes any regulatory hurdles now, and, we're we're we're free now to to to to set up commence the trial itself. And as professor Gupta Gupta has highlighted, we are starting with the most challenging of the major indications of grade four, which is glioblastoma, which we'll talk about in a little bit more more more detail.

3:39 It's important just to note as part of the the set of an approval for the clinical trial, we also had to seek ethics approval, where we got a very positive feedback on the approach we're taking to to to the trial. Clearly, given the unmet clinical need, this is a sensitive sensitive area. Clearly, of the end of the trial, we need to have a clinical batch of products for the quinoa seeds. And, well, our manufacturing partner has initiated the clinical batch. And, so we'll we'll that's that manufacturing process is under what we call GMP, which is the regulatory standard for human trials and human human met medical purposes. We talked about we've we've announced that we've established the scientific advisory board. And and clearly, because Cushank is our is our lead medical adviser here on the design and setup of the trial, which we'll hear more about shortly.

4:31 I did mention just briefly that we're we're focused this as a platform technology, and I know there's interest to think, you know, what else can we be using the technology for? We we have, building up a portfolio now to extending it into prostate cancer. And, clearly, this is quite a bit of airtime, sadly, for some high profile individuals that, that may have have been diagnosed. This is, now the most prevalent cancer in men, and we have a strategy and the chemotherapy we believe is enviable. So with support from Innovate and on their launch pack launch pack grants, we have actually already initiated that, that program earlier this year. So it's an early stage, but, initial progress has has been good. In order to to move things along, we we did pause and raise some money just in the end of June, July.

5:21 Please say that we raised some 874,000 to cover take us through through to the commencement of the clinical trials. And so we've we've brought in quite a a number of new investors, which was very pleasing. But I'm also grateful to very grateful to our incumbent shareholders who've been with us through this early part of our journey, which was $7,074,000 pounds as part of that offering. So thank you very much for for that. Final comment is our net cash at the end of September was just just over £9,900,000. So just quickly in terms of quinoa seed itself, I think many of you were have been talking to this, so I'll just be very brief. This this technology is the really, this is the brainchild of our chief scientist, professor Chris McConville.

6:12 Garth Kathukusheng has had an early influence as well on this program as you're as you're here when we talk about the the early clinical journey that this that technology has has taken. But, first of CORPORA is, has had this vision to to basically improve. We have a lot of good good cancer drugs that are out there, but often the way they're delivered, in particular indications like the brain tumor where where the blood brain barrier really does a very too good a job at actually keeping the therapies out from the brain. Local delivery, this is something that first CRISM champion personally, really is a we believe it's a significant, opportunity to to to to progress and further further the company. So without further ado, I think it's fully appropriate now. I'll hand over to to Karth Karth, will set the scene for the for Bioblastoma, walk through then the plans and the strategy for our the clinical development key chemo seed treatment.

7:09 First of all, I think Thanks, Andrew. So I thought it would be useful for those who are perhaps not up to speed with the complications of of patients patients with glioblastoma to give you a good feel for what the problem is and how we're we've gone about attacking it. So this this slide shows you a montage of MRI scans using contrast enhancing substances to show up a tumor in a patient over time. Now there are unusual set in the sense that the very first scan actually occurred in this gentleman nine months before he presented with his brain tumor. So we have what you might call a normal scan right at the top.

8:00 And we can then see the focal development of his glioblastoma when he first presents on that second second montage with a tumor in the brain which enhances. And you see its very focal nature, and you can see it what happens over time over those scans. So at the beginning when he first presented, he actually presented with mild headache, and we actually thought he might have had problems related to his previous head injury. But when we did this scan, we found this tumor in in the right side of his head here. Now the appearances on the MRI scan were were fairly diagnostic of that, but it was important to try and understand also, you know, whether we'd missed anything before. So we we we checked on the the previous scans and so on. Now patients who present with glioblastoma don't always present with headache. That's it's relatively an unusual way to present. Most of them usually present with what we call focal symptoms related to the part of the brain in which they actually have their tumor.

9:13 A few will present with seizures. And later on, if the tumor gets larger and starts causing swelling, so they will develop headaches a very particular type of headache that's persistent. But going back to the presentation, which is sort of what you might call focal symptoms, these can often be very difficult to pick up, and GPs and doctors have real problems trying to understand whether a slight discomfort in the hand or a little bit of memory loss or whatever it happens to be is really a symptom or not. So, unfortunately, a number of these patients will present quite late. And that means that the tumors are already of the kind of size that you can see there. And that makes it more of a challenge to deal with.

9:59 Glioblastoma is universally unifocal. You do occasionally get patients who've got multiple sites at the time of presentation, but more often than not, it's really focal. And this means that as a sort of surgical target, it becomes quite possible to think about trying to remove as much of this tumor as possible. So you can see on that third scan down that we've managed to get quite a lot of the, if if not all, of the the the enhancing tumor out. But, unfortunately, these tumors are not discrete. They have a diffuse component and a focal component. And that means that there's an amount of tissue tumor tissue still left in the walls of the area where we've actually operated.

10:47 It doesn't enhance, but it's definitely there. And if you were to do further biopsies in that area, you would probably be able to demonstrate it. Now the current treatment for these patients is good surgery, followed them about four weeks later by radiation treatment and chemotherapy running together. And although that can have an effect, I'll show you some of the results of that, by and large, these patients will recur and then go on to get progression of the tumor. Once you've had recurrence, there's virtually no treatment available for these patients. And perhaps one of the more salutary things to pick up here is that the picture on the right there shows you a postmortem specimen of a patient who had a glioblastoma.

11:35 And although you you can see there that sort of darker brown patch, and you can see the brain being distorted there. And this coronal section highlights the damage that these tumors cause to both function, which can obviously impact on something like physical behavior and physical performance, but much more frightening and awful to

11:55 patients and families is the erosion of mental function and personality making this type of cancer truly awful. So down the bottom right there on the slide, I've shown you that the the median survival is, you know, on or around fifteen months or something like that for these patients, but they all go on and progress. And less than five percent of patients live five years. So it's a truly dreadful cancer in many different ways. Can I have the next slide, please, Andrew? Now this is this is an important slide, and many of you who look at the literature will see this slide. This goes back to 2005. It's from a European ERTC study, and the publication was by Roche Stopp.

12:41 It is probably, and this is sad to say as someone in the business as it were, the last time we saw any real benefit from any particular agent in this disease. It's a survival curve. So on the on the y axis there, you can see the percentage of patients surviving. On the x axis, you can see time in it's in months there. It's in months. And you can see that these curves coming down, and you can see them separating. And this was actually, at the time, quite a remarkable slide in the sense that for the first time, someone had actually shown that something worked in in terms of separating out a

13:23 control group who are having standard therapy with radiotherapy and those who had radiotherapy and a drug called temozolomide. And although they are separating those girls are separating, the downward trajectory of those girls is still fairly disappointing. And indeed, this is an important trial for us to understand because it was a trial which never achieved its intended statistical outcome. That is to demonstrate that you could get a three month improvement in survival. However, this treatment then went on to become the gold standard treatment and still is for this drug in conjunction with radiotherapy for patients with glioblastoma. And if you look at the figures, the reason why it actually went into and became the standard drug was because the two year figures, twenty four months there, showed that it was a rough doubling in terms of patients surviving from about eight or ten percent up to over twenty percent.

14:26 Not remarkable, not fantastic in terms of the the the living five years where I say less than five percent live about five years. But nonetheless, it did show an improvement. Now look. That date there is 2005. And if I'm right in saying that's twenty years ago, and we hardly seen any real improvement since that. Also, less than fifty percent of patients with with glioblastoma get any real benefit from this additional drug, temozolomide. And subsequent research has failed to advance even on this limited benefit despite many trials. So many have failed, I think, because we've not been able to ensure that the tumor is adequately dosed or that with with the new drug or because of poor penetration, as Andrew was saying, into the brain.

15:24 And, also, one of the more problematic areas, of course, is that some of these drugs, there's a limitation on the dose you can give systemically before you get more side effects, making a limitation on the total amount that you can actually give. So this this led me to think about, you know, what other ways could we overcome these problems and particularly to start thinking about whether we could put drugs in proximity with with the tumor and also whether we could do it as early as possible as, for example, during surgery. Can I have the next slide, please, Andrew? So this rather wordy slide describes some information around a phase one trial that I did probably eight to ten years ago. So we know that orenotecan is a topoisomerase inhibitor. It works in a completely different way to temozolomide and calamustine, and it's been shown in had been shown in clinical trials at the time to have an effect on patients with glioblastoma.

16:32 But that you could you almost always had to discontinue the therapy because they had too many side effects. However, those that were able to stay on it seem to get benefit from it, and it quite clearly were were were were showing imaging changes as well, which was which was helpful. We know also that the substrate for ranitikan, the topoisomerase enzyme is not regulated in glioblastoma and is is more potent. And that the product of the enzyme

17:06 creates a a substance called s n thirty eight, which is about a thousand times more toxic than oreniticam. So there were some good biomechanical, chemical reasons why exploring a raniticam seemed a good idea. Not only that, but it seemed to have, in terms of tissue status, relatively little toxicity. So in a phase one study, I had access to some microbeads, about a 100 micron microbeads that we were able to inject in a gel, an alginate gel directly into the tumor margin, in this case, recurrent patients, patients with recurrent disease. And we were able to demonstrate not only that it was safe in the sense that we didn't have anything like the inflammation and wound problems that we had had with carnostine wafers, but also that the patients felt well after it. They were not having to have further chemotherapy because they'd have their chemotherapy put in.

18:09 And not only that, is that with some evidence from the nine patients that we treated that there was an improvement in survival somewhat unexpectedly, bearing in mind that we understood that one of the problems with what we were doing and what we hadn't realized was that it was very rapid out offloading of the drug from these seeds. But it had a sort of silver lining effect in the sense that we were able to work out what dose was released from those seeds at the time, and this gave us a starting point for considering where we might want to go if we could improve the treatment. So that was the time that I started to talk to CRISM THERAPEUTICS CORPORATION about the idea of, well, now isn't it possible for us to put in a much bigger dose of RenegadeCam and control the dosing in a way in which we could get prolonged release in a format, a formulation that would fit for a surgeon to be able to put into a tumor. And I think, Andrew, you're going to summarize briefly what some of the work that Chris has done.

19:19 Yeah. Thank you. So those of you who listened to our presentations before who have maybe been familiar with this slide, this slide was actually pivotal in the proposals to the MHRA to take this proposed treatment forward. So what we show here is that the differences we're comparing this is the first work with with with a chemiseed. This is the the, small cylindrical implant loaded with the drug, Irinotecan. What it means is here we've compared this to the the, standard of care, which is temozolomide, and also irinotecan itself when given intravenously. And as you can see that, you know, we had an exceptional survival on the on the chemosine. So just to put it in context, the this was the study conducted in mice.

20:10 They've been, administered or in in the the brain was actually a human cell line, which is very aggressive. It's it's called a patient derived xenograft. So it's actual human brain tumor that was administered. And then we put in a chemosine to treat it. And you can see that from those images on the right hand side, at the end of the study, this is hundred and forty eight days was the ethical limit of the study. Those those mice that hadn't hadn't died through through through the brain tumor, as has happened in in most cases, were then euthanized, and we imaged the the brains afterwards. So what was remarkable here is that on the those those mice which had the chemo seed showed no sign of recurrence at all. We did lose one mouse early on, and that was really felt that it didn't recover fully from the from the surgery.

20:59 But with, temozolomide, you see on the right hand side, as you'd expect and as Professor Cookshanks just described, it happens to be slightly the the tumor that that does does return, and it does, really, really quite aggressively. So but, you know, to have no no recurrence with QVC really gives us a reason to be, you know, optimistic about the opportunities for for for for the for the program. So with that, I'll hand back to professor Crikshank and who'll talk about now the plans and how we're gonna take the QVC technology through into clinical trials. So when Chris and I discussed this, we we were trying to think of a formulation that would would would enable us to give perhaps a higher concentration of raniticam in such a way that it was released at a a dose rate, which would be CORPORATION satisfactory.

21:51 So CRISM and did a number of in vitro studies looking at what kind of dose we had to achieve to kill tumor cells, and he did a lot of studies during that. And also to look at the way and the the the kinetic behavior of his formulation to enable that dose to be released under the conditions that exist within the tumor bed margin here. And also in a form in which we could actually use this as surgeons to to put into the tissue to allow us to carry out the dosing. The the the the there has been around for a number of years a a drug called calmustine, which is in a wafer form, which you tend to which is approved by NICE for use in this particular situation.

22:43 And the problem with that is that it it it looks a bit like sort of peppermint tablets, sort of like little seed tablets that you just place within the cavity. And the trouble with this is that it just releases drug into the cerebral spinal fluid that bathes this area, and virtually none of it goes into to brain. So built on what I had done on the phase one study, we felt that implantation that is actually putting the drug into tissue and allowing that to, as it were, temporarily heal over it would allow diffusion of the drug within parenchymal tissue to brain tissue directly. And that that that proved to be the case even from some of the the the seeds we used in the the phase one study. But this form of it as little rods so these rods are six millimeters by two millimeters, and they contain about seven to eight milligrams of oroonotecan.

23:41 And the the t the the the matrix that they're in slowly breaks down over time giving us we we estimate somewhere between thirty to sixty days releases the drug, which is an important time period to understand because that's from the time of surgery to well into the time of radiation for these patients. And not only that, it's that you're getting dose into these patients from the moment of their surgery, from the moment you've got the pathological diagnosis, you're getting you're getting treatment running. The other problem that we had to think about here was dosing. Well, we had information from the phase one study, which gave us an understanding about what sudden high doses might happen because of the offloading effect.

24:27 And we were then able to

24:30 calculate how we might do the dosing up to about thirty seeds to generate a reasonable dose for treating these patients. You can see there in that left hand picture, you can see how the seeds arranged into the resection cavity. And then on the right on the cartoon, way you do this is to is to make a small six millimeter hole, a little bit bigger there with a standard brain cannula, and then you put the next seed in. How do you work out the distance between them? Well, we use a sort of raster pattern as I've demonstrated there on the right, and that enables you to cover the area that you want to cover. And indeed, because of the imaging and because of what you know is the surgeon when you go into these, you can avoid risky areas, and you can make sure you try and put it in areas where you think it's more likely that the tumor is going to be so you can get most effective dosing that you can then hope to achieve.

25:34 And this is all obviously based on the idea most important idea that a very high proportion of these glioblastomas will recur locally, implying that that's the area to hit when you're going to retreat these patients. So if we go on to the next slide, Andrew. So in terms of designing our study, we have to build we are obliged to build on the work that we've done already. We're not allowed to just jump off into unknown territory. We have to build on what we've done on the phase one study, take it that bit further, prove safety, and go on from there. So in this study, what we've got we've done is broken into two parts. In part one, we're going to use the same kind of patients as I used in the phase one study, and what we're going to do is to dose escalate.

26:25 Because we know the kind of dose that was released quickly from in the phase one study that I did, we know that that we're unlikely to get to what you might call dose limiting toxicity in the early phase. So the last thing we want to do is to disadvantage these early patients by giving them suboptimal therapy. So the idea is to try and get the dose up as quickly as possible. So what we designed is a novel

26:55 Bayesian approach based on the probabilities of toxicity arising from the first study to rapidly increase the dose so that as many patients get as good a dose as we can give them early on. And it's probably more useful in terms of toxicity to have more patients at a higher dose than to have a lot of patients who are on suboptimal doses. The MHRA were concerned about the rate of dosing versus the numbers of seeds, and we explained in detail that, of course, this will be dependent very much on what the surgeon thinks they can do. I'm very grateful to Victoria Wickes, who's our lead investigator. A lot of discussions on how we might achieve the kind of high doses that we actually want to achieve. And the sheer practicalities of actually doing this towards the end of a period of surgery on these patients. So we plan to treat in the first carter of this part one, twelve patients.

27:53 And from that, we will confirm the dosing and we'll also get a much better idea of any issues and complications to do with the technical procedure and also how patients respond to this. Now the most important thing for us is to optimize the chances of getting a result from this kind of therapy. We need to get ourselves in a position where we can get the best chance of getting these patients to respond. So by selecting patients who are newly diagnosed, who have the smallest amount of tumor left because they just had maximal surgery, And to treat them at the earliest instant, I. E, the moment we've got that diagnosis, at least, for glioblastoma, offers a unique opportunity, I have to say, because I've not seen any studies which have tried to do this in quite this way and quite so early, is to get a high dose of chemotherapy in very early on with the idea of building on the surgery that you've done to get as big a cytoreductive effect as you can. And that will also see patients through the four week period whilst they're recovering from their surgery and then before they start their radiation therapy later.

29:08 So this was this is the plan, and we hope to recruit in the initial phase 60 odd patients and be looking at progression free survival. This is a very common parameter to measure in these sorts of patients. And what we've opted for is to look for a slightly better threshold to obtain this kind of data statistically with the idea that we will get an answer quicker as to whether these patients are getting any kind of response. Not only that, but we've set up the statistics so that if we do get an answer, if we are able to demonstrate statistically significant progression free survival, automatically, we can then consider overall survival, median overall survival as another critical endpoint, the kind of endpoint that NICE and the NHS will need to hear about to be able to take this further.

30:08 So that's that's where we stand at the moment. We've had a lot of discussions with MHRA about the trial, and they're extremely enthusiastic to see how we get on. And this is really breakthrough from the point of view of this kind of cancer in these patients. And I'm very optimistic. Me as a surgeon, I know I've been heavily involved with this, but to be able to offer surgeons something that they could do over and above just surgery alone here and accelerate the therapeutic armamentarium that they've got for these patients is just is it very exciting, but it's also very needed. And given, as I said, for the the outcome for these patients, absolutely needed to try and progress this field further.

30:54 So I think that's that's more or less all I've got to say, Andrew. I think you you've got some other slides there. Yeah. Just the final slide. But thanks very much for what is the exceptional, you know, account of the the story, the backstory, really, to where we are today. And, you know, we certainly I I certainly share your enthusiasm for the the potential that we have, you know, with with our grasp here. So just on a a final summary slide, one that we haven't mentioned, you know, we've talked about the drug in miniticam. You know, this is a well known it's a well understood drug. You know, we can only do miss these programs to to, you know, to to such an extent. The the MHRA were very welcoming. Varenitik can as a as a choice. It's a well understood, well well used drug. It's still used in first line in, in in bowel cancer and also as part of drug combination in pancreatic.

31:46 It's So well known. It's well understood. And it's been described, you know, that it is a mechanism of action which you feel will be complementary to to other the other treatments, out there at this point. Clearly, the the securing to the trial with the MHRA has been a a most significant tipping point. It it's been a significant amount of work. And, you know, and colleagues as well as our COO, Axial, are putting a you know, this has been months of work to get this. And we've but had a great engagement, a very positive engagement, I'm pleased to say, with with m a MHRA. So we're looking forward. Everything now is to is to focus on on the clinical trial setup and treating our first patients, hopefully, early into, 2026.

32:34 The commercial opportunity clearly is is significant, and we've highlighted that that before. You know, we would hope that with our innovation passport, you remember we were awarded as of last year, we are under a regulatory fast track. And they're getting as I've indicated, we are getting very, very good support as on this on on this journey. We do have some service contract work. It it isn't the primary focus. We're reactive, but it it does does certainly brings in some additional revenues to help mitigate the the cash burn. And clearly, that is key. We need to make sure that we manage our cash runway as best as best best we can at this point. But we we know the the the the the journey, this is really this this what we're here in Brightree by doing is opening the door to other other opportunities.

33:20 Please innovate. Saw that in us when they've they've helped to agreed to fund the initiation of our prostate program. So that's, started a little earlier than planned, but, with the with the funding that was available, it gave us the opportunity to get a get a head start there. But, plans also commencing for commercialization as well. And, again, the regulation environment is is supportive of that. So, you know, this has really been quite a remarkable journey. I've been through this with this lived this for seven eight years now, six five, seven years. But, clearly, for for for for this has been a long and exciting journey, and we're actually really quite an inflection point. So but so that really ends the formalities of the presentation.

34:08 And, And, for Scott Gruczak, thank you again for your input there. That'd one or two questions which I'd like to, pick pick on pick up on before before we close. One of which I got partly covered. Beyond glioblastoma, how do you see quemo seed developing as a platform for other cancers? And I think, you know, we've we've touched on the fact that it it it is suitable really for any solid tumor. And we believe we can formulate most drugs into into this in into kibe seed, and that gives us a great opportunity. The just for some parallels, so with pancreatic cancer, sorry, with prostate cancer, which we started on, we're using it again. It's a well known drug, docetaxel. Docetaxel has similar challenges. It's it's it's, it's delivered systemically, but then, it does just have some challenges to temporarily to have its up to have its uptake into the prostate.

35:03 So working with the lead gemologist, we've got some guidance now about implanting these seeds into the into the prostate directly. And that's the program we're running at this point. Pancreatic is something we really, really would like to be doing. It's more more complex, will require more development because we're looking at doing current standard of care is a four drug combination. And we believe we can formulate this, but it will take a little more in terms of development. So we'll ask, can you please give an approximate cost for treating the first 12 patients in the phase two trial and expand on on on how you intend to raise raise the cash? Clearly, this is this is this is this is key. The the the cost of the trial, we will will start in this month. So it's about 250,000 for the for the for the setup.

35:58 It's gonna take probably the to get to a reportable data point, probably around 700,000. Total part one costs will be, we're thinking, somewhere around 1,000,000 in totality. That, is is I hesitate little on that. The reason being is that the rate of recruitment is is gonna be key here. And but as you can understand from professor network, you know, we're working with to to onboard numerous clinical trial sites that will help to to speed up that recruitment. This is really all about so it's a rare disease, so there's only so many patients, but we believe there's, really gonna get a level of interest in whether we can cover this, very, very, very quickly. How the question is, how do you plan to balance advancing clinical pipeline whilst creating value for shareholders in the near term?

36:52 All I can say is the we believe that the commercial opportunity is significant. The the risk the standard of care has has been, eloquently described here, has not changed for twenty years. There's a real appetite for this. We have, the proposed costing, which was being came from a independent health health economic report, done by Page Consulting a couple years ago. That gives us a good figure. Somewhere it was around £1,300 per patient. This sits nicely within the NICE guidelines as we currently understand them. There's always gonna be pressure on the drugs, but one thing the company is very clear about, we do not want to fuel this health inequality we see with, such expensive cancer therapies coming forward. So we're we're trying to fight. We'll obviously find a pathway through that. And, we will likely partner, at some point.

37:45 But, this is something we're we're working on. So the the in terms of the approval, just to be clear on the question, in terms of approval, we we will have these inflection points as first described, where we can issue data through to the MHRA, and we we could get an early approval on the basis of the data. And it's all about the data. And And I I think think the know, it's been just eloquently described. We have a very good preclinical data set and some early clinical experience with the ability care, which gives us the reason to be to be to be optimistic. But our primary market will be the the NHS in the first instance, and that was rolled out through Europe, then leveraging the ILAP program for other markets. And US is very much on our on our on our radar.

38:35 First question, if I may, there's there's a question here for mister Alright. Yeah. You like to take that? Yes. So from your experience of clinical trials, sort challenge do you think team received will have a major significant difference to the life outcomes of patients after trial has been completed? The answer is I don't know. But the the reason why I think it might be work and some evidence to prove that it probably will work is the fact that in a number of patients where we were able to treat super early with temozolomide, for example, in one or two of the trials that I was involved in, there was no doubt that that cohort did better. In other words, indicating that very early treatment of the tumor was small is actually beneficial in a as a general principle of treating this kind of of cancer. So that that that that's very clear. The other thing is that in a few of the patients that I've treated in the phase one study, some of the results are quite remarkable.

39:40 And it was as if if one hit some kind of threshold, maybe you could get an effect. That's why I think that there's a very, very good chance because we're doing something that's not been done before, bearing in mind that previous trials have failed where you've done about conventional adjuvant type treatments. This is what you might call ultra early, and I think that this just stands a really good chance of having an effect. So if one can not only treat early and get the tumor smaller, but you can also expect to see some enhanced effect of the radiation because of the presence of virility down there as well, which we know from our biological work is is probably true, then I I think that the outlook for this is is good.

40:33 So I would be what's the word? Probably about 75% certain that we're going to see some kind of a result here. Is that result going to be big enough to make a real difference in terms of patients now living five or going from, you know, five percent at five years to twenty five percent at five years, I think that's a tall order. But I do think we might see something that's better than the impact of temozolomide was in in terms of those curves for a larger number of patients. And this is really actually economically important because most of the current trials that are going on or most of the current attempts at treatment are involved in looking for molecular pathways and particular molecular signatures within tumors where you can target whatever it is with some kind of id or ab type drug. Now the trouble with that, particularly in glioblastoma, is that so variable is the tumor, so heterogeneous is it, that you will have a relatively few number of patients who are likely to respond.

41:48 So for example, larotrectinib works extremely well on the NTK fusion, but only in one or two percent of cases of glioblastoma where that abnormality is demonstrated. And a lot of the current drug companies are worried that their molecular based approaches are only going to yield relatively few patients who are going to be sensitive. Now our treatment here that we're proposing here seems to have a much more broad effect based on its particular effect on the universal mechanism to do with basic tissue repair and the way in which repair mechanisms were double strand breaks and so on in tumors. So I think it's much more likely that, one, we'll get an effect, and two, we'll be able to do it in many more patients. So that's the best answer I can give you, I'm afraid.

42:40 That's great. So I think that concludes the questions. I don't if we've had any more come in. No. So I'd to take this opportunity to thank everyone very much for taking your time and for your attention during this this presentation. Thanks for moving to Professor Cookshank for that insightful information really about the setting the scene for glioblastoma and how we plan to to address such a challenging disease and one where, clearly, as we've seen, the the unmet need is really is really there with some some we need to address with some urgency. So I look forward to keeping shareholders updated as we as we continue our journey. But thank you again for your commitment, your support. It's it's immensely important to us, and I look forward to updating you again in due course. Thank you very much. That's great. Well, thank you both for updating investors today. Could I please ask investors not to close the session as you now be automatically redirected to provide your feedback, and all the management team can better understand your views and expectations.

43:43 On behalf of the management team of CRISM THERAPEUTICS CORPORATION, we'd like to thank you for attending today's presentation, and good afternoon to you all.