Theracryf (LSE:TCF) — Research and Development Update

0:00 Good morning, ladies and gentlemen and welcome to the Terra Creeve Capital Markets Day throughout today's presentation attendees online will be in listen only mode. Questions are encouraged they can be submitted at any time using the Q and a tab just situated on the right hand corner of your screen. Please simply type in your questions at any time and press send. The company may not be in a position to answer every question received during the meeting itself. However, the company can review all questions submitted today, and we'll publish those responses on the Investor Me company platform.

0:25 Before we begin, we'd like to submit the following poll. And if you give that your kind attention, I'm sure the company would be most grateful. I'd now like to hand over to CEO, doctor Hugh Jones. Good morning. Good morning, everybody, and a very warm welcome to the first THERACRYF R and D Day. We're going to expose a lot of data. We encourage questions. There'll be several slots for questions during this morning's agenda. With me here in London, Doctor. Glenn Clark, our Chief Medical Officer Doctor. Helen Cullman, our Chief Business Officer and online is Tony Hynonen, our Chief Financial Officer and also our collaborators from the Erasmus Medical Centre in Rotterdam, are leading our academic collaboration on glioblastoma. We're sharing this venue today with a brewery who are announcing their annual results. So I suppose in a funny way, of the things we're trying to do is both add shareholder value through addictions, but in sort of opposite directions.

1:20 So to move forward, we are a public company, as you all know, so the usual disclaimers apply. And I'll start with the mission of THERACRYF, and that is to do what a biotech company can do to build a drug development powerhouse in profitable segments. We understand that we are a small, but agile biotech company, so we identify profitable segments in oncology and in behavioural brain disorders to exploit with novel interventions. That's the mission of the company, which we've exposed a number of times over the last couple of months. So, to today's agenda then, we've kicked off on time. Tony and I will review the full year results and the headlines of the recent acquisition post the headline results period. That's the acquisition of Cronos Therapeutics Limited from Oxford.

2:15 Glenn will take us forward to a pipeline review and then lead with Doctor. Myelin Goertz and Walter Van Bielen from Rotterdam online, and a detailed description of our grant funded programme in glioblastoma. We'll take some questions after that. We'll take a break. And after the break, I'm very pleased to introduce to you Doctor. Fraser Murray, a neuroscientist that we've worked with for some time as a consultant to us, and the discoverer of some of the Cronos therapeutic assets that we've acquired. Helen will then take us through some of the market potential of the markets that we're currently exploited, these profitable segments that represent our mission. And then we'll close with a little bit on the outlook for the company to conclude and take any further questions that may arise either here in the room or online. We'll take them both.

3:12 So, this was our strategic plan, and we call them imperatives rather than just objectives. And this strategic plan is now a couple of years into its execution. Conserve cash in the current environment, of course, the top left hand hexagon, whilst exploring partnering opportunities, and also conserving cash whilst getting external validation of our technology initially via SFX01. We have a lot of incoming requests for use of that agent as the only clinical grade sulforaphane available anywhere in the world. Whilst conserving cash,

3:44 we need to generate preclinical data continuously. And we do that with a group of very good academic collaborators, and also clinical data, which we've also done in the last twelve months. We've validated our enteric coated tablet in a pretty extensive Phase one PKPD study, and the PK part of that is fully complete. The PD part is still undergoing some additional analysis. And the final plank of that strategic plan, the bottom hexagon here, is to look for attractive M and A opportunities. We executed on that imperative in April of this year, with the acquisition of Kronos. So, little bit more about what the two companies that make up THERACRYF are. Many of you know that Evgen was a clinical stage company developing the chemistry of sulforaphane and exploiting the massive biological activity of sulforaphane in a network of targets and in a very carefully selected profitable segments that we can exploit.

4:44 We have extensive IP for this platform, and in glioblastoma, already have orphan drug designation granted by the FDA in The United States. And that confers a number of benefits on exclusivity and IP on size of trials required, and indeed even tax benefits of sales in The US eventually when the product gets to the market.

5:08 Our internal lead program, which our collaborators in Rotterdam will tell you a lot more about, is in glioblastoma the most fatal of the brain cancers, with average five year survival below five percent. So, among the worst of those cancers, and average lifespan about fourteen months from diagnosis. We have an out licensed deal that we're still working on. We're still discussing the dispute that we made public earlier in the year. We're working very amicably with our partner Stellickler on resolving that deal. We've completed our Phase one study on the commercial grade tablet that's scalable, enteric coated, and the top line data from that have been exposed to the market. That is, the enteric coat works, the time scale of release is completely consistent with the release getting past the stomach and into the small intestine where most drugs are absorbed.

6:00 The sulforaphane and the active metabolites released are in the micromolar range, which is unusual for a Phase one study. Normally, these things get released into the blood in the nanomolar range,

6:11 but we have got micromolar concentrations of total thiols, as we call them, which unfortunately is the range of activity we see in the test tube. So, we've got plausibility between the tablet that releases in the intestine through into the bloodstream, and the amount that's required in the test tube to show profound biological activity. So, we're very pleased with that, and we're submitting that for publication. So, we expect our first clinical readout through our colleagues in Rotterdam in the Glioblastoma Internal Programme in 2026, in a window of opportunity study. A lot more about that later. So, to Cronos then on the other side of this slide. Cronos was originally a of the University of Oxford. It raised over their lifetime over 15,000,000 Sterling.

6:58 The key thing for us was that they'd acquired three assets in neuroscience or neuropsychology in 2016 from Shire. The know how came from Shire. Cronos then developed the assets into candidate drugs. Two of those assets were taken forward by Cronos, and they are an Orexin-one antagonist Fraser will tell us a lot more about that system, and why it's important in anxiety, addictive disorders, starting with binge eating disorder. It's a class leading profile currently, and we maintain a close eye on that Orexin market through Helen. And a dopamine uptake inhibitor, an atypical one, which would target fatigue due to any number of conditions central fatigue, that is fatigue emanating from the brain.

7:45 Where do we see that fatigue? Long Covid, for example, is a recent very good place to study Long Fatigue. Eighty percent of MS patients suffer from fatigue, and a large proportion, the majority of those require treatment for it. There is no approved drug on the market for MS fatigue. And also narcolepsy, we have also data that we've reviewed in THERACRYF as part of the acquisition on a model of narcolepsy, which shows potential of that inhibitor in narcolepsy two, which is an orphan condition. There are patents granted, and for example, the Orexin patent in The United States, which was granted last year, runs till 2038. So, a long patent life, which is clearly very, very important. The nature of these patents, they're new chemical entity patents, or novel chemical matter patents.

8:34 Subject to funding, we could get into Phase one clinical study as early as 2026. So, a critical period of clinical data generation both on SFX-one and the early Cronos portfolio. The rationale then for the combination of Evgen and Kronos to create THERACRYF is pretty clear, really. We triple the size of our portfolio. We look at capitalizing massively renewed interest. And by massively renewed interest by big pharma we'll give you some numbers on this shortly there are billion dollar deals plus being done now in neuroscience, having been quiet for the best part of a decade. And we need to capitalise on that in the class leading potential assets that we have as candidate molecules. The neuropsychiatry assets are complementary to what we're doing in worst of the brain cancers.

9:22 We do have the expertise internally to develop and commercialize the combined portfolio. And we've added three times more inflection points, potential value inflection points to the portfolio as a result of that transaction. And we've also brought in some new and high quality investors, the largest of whom participated in our small fundraise in April. So, Tony, I'll hand over to you now online to talk a little bit about the highlights for the year to March 31, and some of the financial details there before getting into the meat of this morning's discussion. Over to you, Tony. Okay, thank you. Good morning, everybody. Thanks you. So highlights in terms of end of March, so previous year, we're going to talk a little bit about the annual results in the next slide as well. So grants are awarded, so we have this project that Marjolein and both are going to talk about, 100,000 project. We have there a grant funded by the Dutch government that we're very thankful for.

10:19 And we also are well, maybe Hugh, if you want to talk a little bit about the media, I can go to the financial maybe a little bit more in the next slide. Would that be okay, Hugh? Grant, you'll hear the start We've of the output from that published a full clinical study report in the period on our Phase one study. That's the regulatory standards, and we're actually preparing it for publication. We know that we're leading the world of clinical evaluation of sulforaphane, and we're going to put it out there as the leader of clinical evaluation of sulforaphane as a publication in an appropriate clinical pharmacology journal. We've found more evidence of SFX-one in other cancer models. We have a collaboration with the University of Michigan in The United States, where we've seen activity in tumour models in that collaboration in colon cancer, somewhere we haven't really been before.

11:10 So, we have this broad spectrum of activity against a number of important cancers. In a rare childhood cancer through a collaboration in Universiti La Sapienza in Rome, we've seen evidence both in test tubes and in animal models of SFX-one working in this rare childhood cancer called rhabdomyosarcoma. That's the most common cancer in the under-10s. Fortunately, it's rare, but it is a cancer that's treated with radiation, typically. And we've seen the combination of SFX-one and radiation in models of rhabdoh that shows that SFX-one can make radiation more powerful, or even perhaps even restore radiation's power against the tumour when radiation resistance has begun to be developed. So, very interesting.

11:56 Where that takes us is actually takes us in a direction that says this is potentially a radio sensitizer. This is something that works on its own, but works better in the presence of radiation in now two different cancer types and several academic centres. We're continuing constructive discussions with Stellickla on our ongoing little dispute, and we'll make that public as soon as we know anything. When we know, you'll know. The board had some retirements during the period, and we want to thank the retired directors, Barry and Susan, and thank very much Sue Foden for stepping up to the chair and Alan Barge stepping up to senior independent non executive director. Richard Molson, our previous CFO, retired in July of last year during the period. And we wish him well with his very extensive travel schedule.

12:43 Back to the numbers then, and you can talk a little bit about the period to the March 31. Okay, thank you, Hugh. Okay, so good morning again, everybody. This is an excerpt from our financial results from past year, which we released two weeks ago. The annual report is available on our website for your download. So in a nutshell, our financial performance was in line with our expectations. We did not have any surprises here, And as you elaborated, can you go back to the previous? Okay, yeah, thanks. As you elaborated, know, imperatives, one of them is being you know, conserving cash and that's what we did. We delivered on that imperative very well here. So post tax loss 900,000 less than in the previous year, in terms of cash outflow 3,400,000, which is 1,500,000 less than in the previous year. At the end of the period, end of March, we had 2,000,000 of cash and the acquisition of Kronos happened in April, so it was a post period event, as well as the fundraise where our full management participated in supporting the fundraise. So with that, we currently have a cash runway until the end of next year, and if you look at that and compare to our peers on the market, European listed biotechs, based on the Rx Securities report, we list in the top third of the European listed biotech companies in terms of length of cash runway, which is almost a year and a half.

14:02 So that puts us in a comfortable position, And with that, I'll hand over to Glenn to talk about the pipeline. Now to the meat of the day, we're going to do a quick change here at the lectern, introducing Doctor Glenn Clack, our Chief Medical Officer, to take us through a quick review of the overall pipeline and deeply into glioblastoma. Over to you, Glenn. Thank you very much.

14:25 Wonderful. Well, you very much for your time. Just to talk you through the pipeline, as we can see at the top here for SFX-one, we still have a line for breast cancer. This is still an indication that we are interested in. However, that would have to be post what are called CDK4six inhibitors and that is an area that is still precipitating as far as the exact nature of that landscape. The other issue with this particular indication is that those experiments that would need to be performed are very large. These are not single arm objective response driven studies. These are large randomized progression free survival driven studies. And we are only a small pharmaceutical company. The neurodevelopmental disorder indication looking at a subpopulation, a selected subpopulation of autism that sits with our industry collaborator Stellickler and I'm not going to touch on that any further.

15:17 Glioblastoma, you've heard that a number of times today. We're going go into a little bit more detail about that next with our academic collaborators, but this is an area where we have already preclinical data. We're refining that and work our way through to the right clinical experiments and Margilaine will talk about some of the issues that we've seen over the last twenty five years in a lack of moving forwards in glioblastoma. And as she has already pointed out, we've also had some data in combination with radiation in rhabdomyosarcoma. Following the break, we'll be talking more about our new molecules, the orexin-one agent and the DAT agent. I'll give a little bit of an introduction to glioblastoma and then I'll hand over to our academic colleagues. As Xu has already pointed out, this is a terrible disease for the patients, incredibly low survival rate and no real move forward since the approval of temozolomide.

16:23 And that only had an incremental impact on efficacy in the treatment of these patients. It's the most common type of malignant brain tumor in adults and is one of the major killers of people 40 in the Western world, obviously. As far as survival is concerned, the average length is twelve to eighteen months and the five year survivor is about five to ten months. So a terrible disease. When I call it a disease, it is a spectrum of diseases. We still tend to use Edwardian terms glioblastoma is a spectrum of diseases and even within one patient different areas of the tumour may have a slightly different type to another tumour.

17:10 So understanding the nature of that disease is important and we know that the nature of the disease can impact upon the survival of the patient. It isn't one disease. As far as the current treatments are concerned, these patients usually have a diagnosis by radiology, by a CT scan or an MRI scan. They then go to theatre, they have as much of the tumour as can be seen, resected and then go on to have radiotherapy and chemotherapy. As Margilaine will reinforce, new treatments are urgently needed in this particular disease. We already have some data with sulforaphane in GBM. Just to remind you, SFX01 is a stabilized form of sulforaphane.

17:57 We are the only people who are able to do that and it's complexed with a sugar called alpha cyclodextrin to produce this inert sugar ring doughnut with the sulforaphane in the middle. The sulforaphane is absorbed, the cyclodextrin remains within the gut. So what have we seen? We've seen effects on cell lines in vitro studies and we've seen a direct effect on those tumour cells, both in simple cell layers, monolayers, but also in more complex three-dimensional spheroids where we're trying to replicate what is going on within the tumour because tumours don't grow as a series of cells on a petri dish. We've also performed studies in mice, in vivo studies, We've done these in the two types of models. One where you inject into the flank, which is probably of the animal, which is less relevant as far as GBM is concerned. But we've also done what are referred to as orthotopic xenograft models, where we're actually injecting into the brain to try and recapitulate what you're actually seeing in the patient.

19:03 And then we've taken cells from patients rather than cells that have just been kept alive in a flask and we've also seen activity on those patient derived cells as well. So we have a good basis for our academic collaborators to move forward with in the collaboration.

19:24 Now as far as GBM is concerned, as I've already alluded to, it is a complex disease. We have SFX-one, it's released to sulforaphane and we have data that shows that sulforaphane will add to the effect of chemotherapy T mesolamide and add to the effect of radiotherapy. But the mechanisms of resistance in GBM are highly complex. I'm not expecting you to go into any detail on this slide, but there are a number of different aspects of the disease which results in recurrence resistance to standards of treatments. As I've already pointed out, sulforaphane kills the tumour cells, but it also has a beneficial effect on the vasculature within the tumour. Making the microenvironment less attractive for the tumour.

20:14 It also has a direct effect on the microenvironment itself to again make that environment less attractive for the tumour cells. And it also has a positive effect on immune cells, therefore improving the body's ability to be able to try and cure those tumour cells themselves. I'm sure that all of you have heard about immune therapy in cancer over the last two or three years. The question is which of these potential opportunities from sulforaphane are the key ones and that is the work that Margilaine and her team are going to be doing as part of the collaboration that we have. So I'll hand over to Margilene. Thank you for the introduction.

21:00 So when looking at those large phase three trials and the successes of them, we then realise that this may not be the way forward for the drug development in the new era. When we're designing new drugs for glioblastoma, we need to realise that we've seen, as Wouter just showed, many failing results of the trials. We saw over 100,000 patients failing in Phase one trials and over 100,000 in Phase three. So with a group of experts in the field, we set up this working group to change the drug development paradigm for glioblastoma research.

21:55 What we think we should do is we need to know whether a drug reaches the tumour and whether it has its biological effect in the tumour as we expect it to have. So before we can move to these large and expensive studies, we need to know what the drug actually does. This means that we have to have a very clear hypothesis, one. And second, we need to know whether the drug does what we hypothesise it to do in the tumour. So what we do in the Erasmus MCA, we have a very strong bench to bedside and back research line, a very translational research line, where we are able to, with very advanced techniques, to assess hypothesis, develop hypothesis and test them.

22:57 So this is a little bit of showing off of what we are able to do in the Erasmus MCA, but on the next slide, you will see how we use these techniques to this specific drug. So now knowing that the way forward for drug development in glioblastoma is not yet another big study, but first, clear hypothesis and a PK and PD analysis in the drug, I wrote a grant together with the team and it was actually granted by the Dutch Cancer Foundation that allows us to test in tubes how the drug could work, how it should work, so that we have a hypothesis to test before we go to the patients.

23:52 After the drug tests in tubes, we will move to the mice and see whether we can validate what's happening in test tubes. And then next step, we will give it to patients in step three in very early studies. What we then do is I think that's shown on the next slide A little bit of how to work. We will give the drug to a patient just before it will undergo its resection of the tumour. So the patient will be on drug a few days, then the tumour will be removed, and then we assess the tumour and see whether the drug reaches the tumour and whether it has the effect that we suppose it should have in the tumour.

24:44 Thank you for that, Margiland. Walter, do you want to take us through some of the early work that you've done, if that's okay? Exactly. So as I already said, my name is Arthur van Bilhoom, a PhD candidate, and I have been working on this project for the last couple of months. And taking you back to the slides of Doctor. Hertz, a couple of months means that we're still mainly working on the cells in the test tube. Because we do want to take the drug to the patients as soon as possible, but to design these early phase clinical trials, we just have to do that smart. And to be able to do it smart, we have to know a couple of things in advance.

25:26 One of these things is how does the drug work, obviously. But other very important aspects to look into is which patients do we expect to respond well to the drug. If we are able to predict which patients are likely to benefit, we can make the trials smaller, but also just make sure that we dose the right patients and don't do any harm, and also filter out any noise of patients that we already knew that would not risk expect. Third thing we need to know is how the drug works together with the current standard of care therapy, because in a lot of these early phase clinical trials, the patients will go on to receive just the regular standard therapy, so radiotherapy and chemotherapy afterwards. So we need to know how these interact. And hopefully we see that this will also indeed make the effect of the regular drugs stronger.

26:18 So that's what we've been focusing on the last couple of months, and I'll take you through some of the results. First, the first question, how does the drug work? And as Doctor. Clegg already explained to you, this is not a straightforward question. There's a couple of different angles that the drug can take on in the treatment of this drug. One of it is the direct effect on the tumour obviously. As affects one influences a couple of different processes in the cell which could influence tumor aggressiveness, how fast it grows, how easy it is to treat. So there is supposedly a direct effect on the tumor cells. On the other hand, there's probably also an influence on the resistance to the standard of care therapy.

27:08 As was said earlier, this is radiotherapy and chemotherapy using temozolomide. And for example, MGMT, you see on the right top corner, is one of the key regulators and resistant to temozolomide. So we hope that we can maybe resensitize the cells that do not respond to temozolomide to the standard of care therapy with our drug. Last but not least is we want to look into the immune system of the tumour. As Doctor Cleck already explained, there's an increasing appreciation for everything that's going on around the tumour cells and what glioblastoma does very well and what makes it so hard to treat is to create its own happy place in the brain where it pushes out or shuts down all the immune cells that try to actually attack it and it just keeps around immune cells that actually protect it from our own body.

27:57 So that's something we want to look into, especially since that three, one of the targets of SFX one is a key regulator in this immune suppression versus immune activation. What we need to investigate our hypothesis is a good model. And we believe that here at the Erasmus MC, we have a very good model to test all these hypotheses in test tubes. We are using patient derived tumor cells. As an academic centre, we have a very good connection to the clinic. So as the patients who are diagnosed with glioblastoma go to their standard of care therapy, which includes surgery, we have access to valuable patient tissue that has been taken out during the surgery. Of course, a big part is needed for the correct diagnosis of the patient, but anything that's left over, we can try to put them in a flask and grow them. So we get a part of the tumour, we process it in very small pieces, we give it the right vitamins, the right nutrients, and then we can grow them in the test tube in a flask actually, plastic flask.

29:02 And that's what you see here on the right side. If you look under microscope, that's how tumor cell looks when it grows into a flask. All these black dots are tumour cells. A very important person in this project is Doctor. Lanfus, who is one of my co promoters who has been doing this for a while. So we have a very big biobank of different of tumor cells from a lot of different patients. And as Doctor. Cleck already said, this is really essential because no glioblastoma is the same. There are big differences between the glioblastoma cells of one patient and another. So now we can compare and look into different patients. What we've been doing with the cell is we grow them in flask, but that's very inconvenient for the experiment. So when we want to do an experiment, we take them out of their flask and we put them in 96 well plates.

29:49 So we have 96 bunches of cells that we can treat with different doses, different conditions to make sure that we find the right results. We also do them a couple of times, the same conditions, the same dose to make sure that we don't make any mistakes so that we get robust results. So what we do in these wells, we give them the SFX01, we give different concentrations of the drugs, and then we put them back in the incubator in a stope for a couple of days to let the drug do its effect, show its effect. And then after five days, we can add a tracer where we can see how many of the cells are still alive. And that gives us these kind of graphs. So on the y axis, you see the cell viability as we call it. So 100% is all the cells are still alive. 0% is all the cells are dead.

30:37 And on the x axis, you see the drug concentration. In this case, the drug concentration of s of x o one or sulforaphane. And what we see is that we increasing concentrations, we can kill an increasing portion of the cells, which is very nice to see.

30:53 And also we have tested SFX01, but also pure sulforaphane, and it's very reassuring to see that while stabilizing it, haven't lost any of the potential of ciforophane. The graphs overlap exactly, so that's very reassuring. What we do to quantify these kinds of graphs is to determine the IC50 value of the inhibitory concentration value that is term drug dose that kills about 50% of the cells. In this case, in this cell line, in this the cell the cells from this patient that is right around 10 micromolar. So with 10 micromolar of the drug, we can kill about 50% of the cells. And we did the same kind of experiments for about 20 different cells from different patients.

31:42 And luckily all across the board we see a pretty robust response. We see that they all have similar IC50 values, also actually similar to previously published results from other collaborators, except for two patients. We see that two patients seem to respond less well to the drug, have a higher IC50, so we need more drug to kill the cells. And honestly, this was to be expected because there's the differences between the tumors are so big that we cannot expect every tumor to respond the same way. And this actually presents us with a very important opportunity to try to see what's different in these cells, different in these patients, which will be invaluable to predict which patients will eventually respond. And so we can try to predict which patients to include in studies or to treat later on.

32:32 Sometimes it's easier to believe something where you can actually see it. So these are the same cells under the microscope, those with different concentrations of the drug. And these images are taken seven days after the treatment. I'll make some of you a little bit bigger for you. On the left side, you see the control cells, which means we have put the cells in the well, but we haven't given them any treatment. And you see that this image is full of cells. There are a lot of cells there and they're actually still all alive. If we give him ten micromolar of the drug, you see that there are way less cells in in the well. There are still some cells that are viable but if you compare to the untreated cells, there is a clear difference. If you go to the right and we give them eighty micromolar of the drug, you see only these very, very small dots. They lose their arms and they're very few.

33:21 These are all cells that are actually completely that. I also have some videos if we follow them the same cells over the day over a couple of days. And the first video is from the control cells. Please go ahead. And we take images every twenty four hours and you see that during this time, these cells grow exponentially. So every day, there are more and more cells. If we treat them with twenty micromolars of the drug, which will be the next video. Yes, thank you, you see that these cells behave completely different. They don't proliferate as well, there is not as many new cells and the cells actually also look different. They make these very long arms to reach other cells to see what's going on.

34:11 So there's a clear difference there if we treat them or we don't treat them. We come back to the slides, thank you. So what we believe is that with the drug we can not only kill the cells, but the cells that actually survive, they behave differently, they seem to grow slower. So that's also a good thing. As I said, another important part of our evaluation is that we have to know how the drug works together with the standard of care therapy. And the first part in this is with radiotherapy. So this image looks pretty similar to you. It looks probably familiar to you as I showed it before, But now we do the same thing, but we add the radiotherapy into the mix.

34:53 And that gives us these kind of bar graphs. So on the y axis, you see the self viability again. And then if we go to the different bars, the first bar is our control group. So obviously 100% of the cells is still alive. If the second bar is SAVXO1 at IC50, so the dose that we expect to kill about 50% of the cells and luckily that's reproducible, that's also what we see. The third bar is radiotherapy alone. And we gave him three grays of radiotherapy. Gray is a way to express a dose of radiotherapy. And we see that seven days after three grays of radiotherapy, 80% of the cells are still alive. Three day, three grey is kind of an intermediate dose. It wasn't our aim to kill all the cells because what we actually want to know is how does these, how do these two work together?

35:44 And this is just one cell line we still have to validate it. So this is just an example. But what we see here is that if we start to combine the drug and the radiotherapy, the effects seem to add up. So if we kill about fifty, forty percent with SFX and we kill about twenty percent with the radiotherapy, combining them kills about sixty, sixty five percent of the cells, which is very nice to see. This is, however, just one of the cell lines we still have to validate, as I said, but it could be a hint to for further experiments. We did actually do the same thing with temozolomide. So this is the main chemotherapy given in standard of care for glioblastoma. So now we instead of just adding SFX01, we added both SFX01 and different concentrations of temozolomide.

36:36 And this gives us again a viability graph. The blue line here is SFX alone. So this is very familiar to the first graph that I've shown you. If we give an increasing dose of SFXO1, we kill an increasing proportion of the cells. The red line is thimazolamide, and you see the concentrates of thimazolamide that we have given at the top x x x axis. But also here you see if we give an increasing dose of the drug, we can kill an increasing proportion of the cell. If we combine the two, you can see that the purple graph is actually lower than the blue graph or the purple graph or the red graph, I'm sorry. So also here in just one cell line, we still have to validate, but we see some hints that in some specific cell lines, these two drugs could work together.

37:33 And that brings us to our preliminary conclusions. And as I said, still a lot of things have to be validated. That's why it's preliminary. But we are very convinced that we can actually kill the tumour cells with the drug. The cells that do survive, they seem to grow slower and at least in a couple of cell lines that we have tested, the SFX01 could add to the effect of the radiotherapy or could add to the effect of the temozolomide. And this will be actually essential when going forward, because we say it's a specific patient derived cell lines from specific patients. We have to try to identify which of these patients are expected to benefit from this drug, because as was said earlier a couple of times, it's such a heterogeneous disease.

38:28 And if we just treat everyone without thinking, we probably will not detect the effects that might be there. The to do list is actually a big, very well, it's very, it's a lot longer than just this part. We still have to validate, we still have to expand on the experiments. But as you see, we kind of have covered the first steps in looking at the direct effect of tumour aggressiveness, the combinations with the other therapies. We still have to look into the tumour immune system, which is probably a very important part going forward. Why we haven't gone there yet? Well, just because one, we didn't have the time yet. Two, we really need to understand what's going on before doing this in the test tubes.

39:17 Because it adds complexity. If we want to add immune cells into the tumours, into the flask, we have experiments with that in our lab, but you have to know what all the things are doing separately, otherwise you cannot detect any effect. But this is something that we look really forward to, to dive into a little bit deeper. And with that, I plan to give the word back to doctor Maja Langheertz to take you to the next steps of the project. Yes. So step one, very busy with it, but I'm getting close to an ending. So next year, well, no, not yet, next year, very soon, I guess, we'll move to the mice and I expect to be able to treat the first patient real quick after finishing the mouse experiments.

40:13 The ultimate aim to build a rationale to proceed with the development of SFX01 to treat glioblastoma patients that are most likely to benefit from it. Thank you. Wonderful. Thank you very much, both of you. Okay, so we are slightly ahead of schedule. We've got some time questions while we've got Marlene and Wotter online. So, I'll start with questions from the room. Mark will be bringing a microphone around. Sean, we'll start with questions from the room. And there are a couple of commercial questions that have come up online that we'll deal with now that we have this time, but we can let Marjolein and Wotard go for that. So questions on the technical piece first, starting with Sean. Thank you very much. Well, mine's sort of a mixture of commercial and technical.

41:02 And if we start the MICE next year, assuming the MICE are a six to nine month process, that implies that, you know, you could be looking at getting it into patients in 2026. Although there might be a regulatory delay in terms of getting the the IND, etcetera. So maybe it'll be patients '27. I mean, what's the what's the timeline on this? Firstly, in getting some proof of concept in a patient population. Well, firstly, in getting into into man, proof of concept in man, and then going forward from there because presumably this is a great out licensing compound. So you'll need data that allows you to out license it. So what's the timeline on that process of getting it into man and then getting getting data? So can you give us some years? Yeah. We've said publicly 2026 is first patient treatment as part of this program. It's very clearly laid out actually in the grant project plan, which of course is confidential to Myelane, Oton and others.

42:06 We've said publicly till 2026, early twenty twenty six. Mayelene, more to comment on that one? I agree. To make it clear, we have a very well running pipeline for this kind of studies, including the regulatory stuff. So we re well experienced and I don expect the regulatory stuff to take a lot of time, especially as we have data in healthy humans and cancer patients. So we can run things in parallel, already busy writing the protocol, etcetera. So I don t expect any delays there. And just to clarify, one of those points that you mentioned IND, Sean. So it won be under an IND, it will be under a CTA, because it will be European through We have already broached this with the European regulators anyway and had some discussions around what a patient study would require from their point of view. And we have received scientific advice from The Netherlands regulatory authorities specifically on this programme. So, we're parallel tracking really, Sean, to get everything lined up so there's no delay from IOLANE treating the first with SFA. Proof of concept by 2829, something like that. Well, I think we haven't speculated any further than let's get this drug into patients in Rotterdam.

43:21 Let's see what it's doing in the tumor and then plan thereafter. I think that's a window actually, proof of drug in tumor, proof of drug interacting with molecular targets in tumour. I think those are very powerful licensing discussions that we'll be having that night. I think it comes back to sort of Marjolein and Wouter's points that you need rationale for the patients that you are treating. So that initial data set will give us the information required to do a broader trial, because as I said, there's no point in treating every patient if they're not going to respond, or they may get worse when they could be trying some other, you know, development agent. So, hopefully, that initial proof of concept, although it's called a something slightly different, will give us that insight into the patient populations that may be responders or most likely to respond. So the work that's going on at the moment is defining what proof of mechanisms we need to define in the clinic.

44:16 This drug has a number of different mechanisms. Some of those will be more important than others. From that proof of mechanism, we can then define what the proof of principle endpoints will be, which is what Marjolaine's study will primarily deliver. And then once we've done that, we can decide whether or not this is an objective response rate or a progression free survival proof of concept experiment. And to be clear, we don't need many patients for this proof of concept. So that will not be a very long lasting study. We do surgeries on, I don't know, 20 glioblastoma patients per month. So if we need 12, that may went a little bit fast. And I mean, we can be really fast in that phase. The could be a start in a year. Oh, yeah, less. Yeah. And you would then have do you think you'd have enough data after a year to out license? We'll test market it at that point, for sure. Great.

45:08 Thanks. Yeah. Wonderful. I think Tim had a question here. Two. Two questions. Excellent. You talked about an IC50 of about ten micromolar in in vitro study you did with Veselz. That would correspond to what sort of oral dose would you have to give to get to a steady state at roundabout ten or twenty micromolar? We're already in the micromolar range from the Phase one study that Glenn supervised last year. So we're there, we're in five easily. If you do total thiols, which is the active metabolites plus the raw sulphurophane together in that phase one study, was a key go no go decision as part of that phase one study. How much do you get in? And is it plausible to get the right amount in that you see effectiveness in the test you're borrowing a whole animal model? And we were there, we're in the micromolar range. Now, what exact range we need and what dose we'll use is again, part of this discussion that's ongoing.

46:12 We have three hundred milligram tablets currently, and we've taken them up to six hundred milligrams a day. We could go higher, but with six hundred milligrams a day, we're micromolar already. Yeah. So you're not going to have to take ten tablets a time. No. And that was a really big finding from that study that Glenn supervised last year. Getting into a laboratory range in an in vivo healthy volunteer study where the blood brain barrier is intact and everything else. Whereas in glioblastoma, the blood brain barrier is broken by the tumor. We know that sulforaphane gets through the blood brain barrier and in an insufficient blood brain barrier, as you see in glioblastoma, we're to get drug in tumor. We're very confident of seeing that in the window of opportunity study that's been designed. Second question. I think you talked about two main mechanisms for how it may be actually exerting its effect, and that was a STAT3 and NRF2.

47:08 Do other drug companies have small molecule STAT3 and NRF2 active molecules which they could use for this indication as well? If so, have they actually tried them in glioblastoma? There's one NRF two activator that made it in a rare disease, into approval range. I'm not sure about STAT3 having There are a couple of programs. Yeah, there are. They're only at very early stages. But if you think about pleomorphic diseases, those drugs which are most successful in pleomorphic diseases tend to be pleomorphic drugs, with different mechanisms of action. We know that this targets STAT3 and SHIP2 because we have our own internal data. We know it targets NRF2 because that's what got people excited about sulforaphane.

48:03 Walter's already alluded to other potential targets. And what the strength, I believe, of sulforaphane is, is not its ability to be able to combine with current standards of care but also future standards of care. It's the fact that it modulates more than one pathway. And in a dirty disease like GBM, that's what you need. And that's where companies like AstraZeneca can fall down with their highly selective molecules because you end up playing whack a mole. So it's an advantage And you need be in detailed generally, but pleomorphic targets equals an opportunity for Sfexo1. We didn't mention NF, NRFK beta, which was on motor slide, which is also known to be affected by sulforaphane or SHIP2, which was also on motor slide, which is also inhibited by sulforaphane. We've got literature data and our internal data through another collaborator here in London, showing that it interferes with SHIP2 as well, which is a phosphatase and ubiquitous phosphatase in many cancers. And so one of the main limitations of single directed agents is that quite often the tumor or the tumor microenvironment overcomes them and and you develop resistance and therefore you get proliferation.

49:08 I think you know we've seen that in breast cancer with CDK four six inhibitors already happening and with some of the other immunological reagents. So as Gwen mentioned it's an advantage to have this sort of networked biology. So hopefully it's more difficult for the tumor to compensate and try and break free of that restrictive environment. And there's reason to believe that it could be active at both of these sites, is there? Others besides, yes. Yeah, and others besides. Yeah, okay. Which we think is an advantage, as you said, Tim. Excellent, thank you. Any more questions from Adam? Yeah, thanks, thanks. Thanks, everyone. Great talk so far. This might be one for the Erasmus medicsacademics. In terms of sort of bringing SFX01 into your laboratoryclinic, what was the sort of selection process? What attracted you towards the asset? Was it a suite of molecules that you were able to choose from?

50:05 Was it one out of 100? This is just the one that really stood out in terms of the preclinical data sets. It's just kind of what was that selection process kind of like from your end? So I take it? Maybe you can comment on This that is a question for you, Marlene. Yeah. If understood well, the question is why we actually selected this drug for our Phase zero pipeline. Is that correct? Yeah, exactly. Yeah. What was that process like? Was the data just so compelling? Did you have a selection process out of maybe another 20 molecules, and this was the one that was your favourite, you know, that kind of stuff? Well, so our main focus is the immunology of glioma and the potential STAT3 inhibiting effect of this drug convincing enough for me to select this drug.

51:00 So as you may know, the glioblastoma are very immune cold as they call it, so they don t react on the standard T cell mediated immunotherapies that we currently have. I hypothesized that this is because there s a lot of myeloid cells in glioblastoma. There s really an abundance of myeloid cells in glioma and they sort of hijack the T cells so that they cannot kill the tumour. And step three has the potential to interact on the interaction between myeloid cells and T cells. So I hypothesized that with this drug, we can make the immune microenvironment of the glioblastoma more active to kill the tumour.

51:57 Thank you. Just a quick follow-up then, I guess, obviously, sort of the world oncologists, everybody knows, is really changing in terms of technologies. You as an oncologist yourself, you obviously still see a place for small molecules, and particularly in this sort of indication as well. And Glyose, just your comments on that as well in terms of the future kind of going forward. Yep. So this is a very heterogeneous drug. And that is the problem, I think, with these small molecules that you never know whether there's this subclone of the tumour that will or will not respond to these small molecules. So that is why as a neuro oncologist, I believe more in this entire drug rather than a targeted treatment. So more an immune system than in the targeted treatment of the drug. Does that answer your question?

52:59 Yeah, no, that's great. Thank you very much. That's all for me. Thank you. Any more from the room? Yes. Yeah, Colin? Yeah, thanks. I may have misunderstood it, but just to try and get a bit more color on exactly how this whole process is going to work through patients. Because I think I heard Wouter saying initially that the plan when it initially went into patients was that you would inject the drug before recession, then undertake recession, and then check what came out basically to confirm that the drug was actually in the tumor in the living patient. Is that all encompassed in what you talked about the 20 patients or so because that doesn't really sound like either a tolerability or an efficacy study in the sense that one might understand. So maybe just to put that in context.

53:44 Yeah so we've done the tolerability work although that will be refined in patients. I can't imagine that there's going to be that much different. Remember these are going to be young fit patients rather than end stage cancer patients. What we will be doing is dosing them in what some people might refer to as a neoadjuvant fashion, so prior to their treatment of the definitive treatments of the surgery, the radiotherapy and the chemotherapy. And to do the two things that the neuro oncologists believe have resulted in the failure of all of the other things that we take into GBM. One is the drug not getting into the tumour. Now we have animal data to suggest that it gets across a healthy blood brain barrier, but understandably our clinical colleagues, academic colleagues are sceptical because of the number of failures that have been seen before. So we will look to see that it does and then we'll see that it modulates the various biomarkers that the work that Walter's doing at the moment and in the near future give us guidance towards. So we can say the drug gets into the GBM itself and it does what it says on the tin.

54:51 We will also get some degree of clinical data, so something more towards that proof of concept, but the initial part of the clinical experiments is to say it gets into the tumour and it does what we expect it to. And that's been referred to as a phase naught study in the literature, although from a regulatory point of view it is not a phase naught study. Well, may be interesting to add that in these conversations about this type of studies in glioblastoma patients, the FDA is really motivated and supportive for this kind of study design. Both terminology is important, think. We don have a therapeutic intent when giving this drug in this phase zero setting. We just want to know, as Glenn just said, whether there s a PK or whether the drug reaches the tumour and does what we expect it to do. But that will help us move quickly to a clinical study in patients of whom we expect it to work. And that is for me the benefit. It will speed up things at the end of the line.

56:06 The other issue that we've got within oncology that many of you may be aware of is something that the FDA talked to Project Optimus. Now it is clear that the FDA and the regulators in general are no longer tolerant of just taking forward one high dose, usually a maximum tolerated dose, and doing the phase two and phase three studies based on that. So their challenge to us is we want you to optimise the dose. So without the work that we're doing, it's going to be difficult to have that conversation with the FDA to be able to choose the two doses that they're likely to want us to randomise against each other in phase two. So this isn't just us doing extra work. This isn't just us doing work to make sure that Margilaine is happy with regards to performing patient studies, we're also building in the conversations that we're going to have to have with the regulators around what are the endpoints, we want them to be as short as possible.

57:07 Unfortunately in this disease they are going to be short. What is going to be the dose or doses more likely that we're going to take into Phase 2b? So this is a bigger piece of work. We're not doing things in series, we're doing them in parallel. We're tick tacking with the regulators as we need to. At some point we will need a collaborative group to help us deliver the phase three programme and Marjolaine has roots in to collaborative groups within Europe to allow us to be able to do that. We're also thinking about who we would need to bring on board in The US to help us to be able to deliver that. So there is a large piece of work that's going on around this and as Margilaine's already said, it's not that we're waiting for the mouse data to deliver before we design the clinical trial. We already have a first draft of a study design concept and we're in the process of refining that.

57:59 I don't know whether that answers your question. It's a lot of the answer, but if I could ask a follow-up. As I understood it, once it gets into patient in the way that we've just described, it's probably a relatively quick test. I'm not sure if that sort of means three months type of thing. But let's say it's short. Is the funding that you currently have, does that take you through to the endpoint of that piece getting it into It takes you through to the end of the phase zero experiment. End of the phase zero experiment. So if we're talking about early twenty twenty six, let's say best possible outcome, middle of twenty twenty six what happens then? While we're delivering that study we would obviously be talking to the individuals who would be helping us deliver the phase twothree programme as well.

58:50 So by the time Margilaine's study has completed, we should have the ducks in a row with regards to where we go next from a finance point of view through Hugh and then through hopefully somebody like BORTC from a clinical delivery point of view. We've said that our cash runway is good to end '25 into '26, currently. Yeah, you're right on time. I think to give some perspective, us, this is I understand that this sounds unfamiliar to you, but for us it s something that is like our daily business. So while we're doing the phase zero, we don't have to do a phase one anymore. I mean, we have this data, so we then would quickly move to a phase two. The phase zero, sorry, the phase, yeah, the phase zero would tell us which patients will benefit. So we just have to change the protocol that we're already writing for the phase two to what are our endpoints and which patients will benefit. So we can move quickly after the phase zero. This is what I call a pipeline for studies.

59:57 We're not gonna sit and wait for the phase zero results. If I just add, because I know we're sorry to cut you off, Marjolein, we're coming to the timing as I'm getting nodding from the session. But just to clarify, I think Colin's point was, if we get some really interesting data, how are we going to take that forward as a business? Because obviously, we've said we will do it at a time then we will need to raise funding to do that. So I mean there are a few options available to us. We have a great collaborative relationship with Marjolein and supporting funders through the Dutch Cancer Foundation. Potentially we could attract a new grant to take that forward into a larger, more precision guided study in collaboration with her and potentially leverage some private funding to match non dilutive funding.

1:00:48 However, if there was really exciting data on the mechanistic side of SFX one in brain cancer, that may enable us to attract a private partnership to also fund that for, you know, take that forward, Still in partnership with Marjolein or out with you know wherever they decide to do that study. And of course if we feel that it's very persuasive data ourselves and we'd be able to attract a higher value valuable partnership by taking it forward, then, of course, we would look to go back and raise further funding to enable that study. And last question then to Marjoleen. I mean, presumably, let's say we get the best possible result and it looks very interesting. You and your funders would presumably be keen to continue to be involved in the ongoing progress of the programme?

1:01:38 From an academic perspective, yes. Thank you. So we've got alignment of objectives. I'm going to draw this session to a close now, because people are waving at me to do so, even though it was a very interesting question. There are two questions online that we will deal with, but not right now while we call for a short break. So I want to say a very grateful thanks to Mayelaine and Walter, and congratulations for generating such meaningful data in such a relatively short period of Thank you very much. It's a pleasure to work with you and good to see that we've got data paying out so early in Moto's PhD progress too. That's an important objective for this. Thank you very much from Rotterdam. Thanks, Chaps. Thank We're now going to call a short break until ten to eleven. Welcome back. I hope you had a cup of tea a bio break. We're now shifting gear away from oncology to our acquired programs, which were acquired only six or seven weeks ago. So, it's all very new to the company and its integration.

1:02:41 Here with us in London, Doctor. Fraser Murray, who I introduced earlier. And Fraser will now take us through the two key candidate molecules that came along with the acquisition of Cronos Therapeutics. Over to you, Fraser. Thanks Hugh, and thanks everyone for the invite to come and talk about the orexin-one antagonist program and the DAT inhibitor program. So starting off with orexin-one antagonist, a mechanism that has a wide variety of applications. We'll talk about anxiety, addiction, and impulse control disorders, all very big markets in their in their own right. So the orexin-one system has been known about and understood for for many, many years.

1:03:26 It's been an attractive target for many years. The problem has been drugging that target and drugging that target selectively where you don't have off target activities that cancel out the value that you get from your your primary pharmacology. So a busy area, Cronos, the Cronos molecule is now the THERACRYF molecule, is we believe the best in class molecule by characteristics, but there are a number of orexin antagonists or orexinone antagonist programs in the clinic and partnered from other companies, which really build on the strong story of orexin-one in anxiety and addiction. So J and J have shown clinically in an experimental medicine trial that you can significantly reduce the effects of a model of panic disorder, which is carbon dioxide inhalation.

1:04:22 AstraZeneca, Indivior, and Cervance all have orexin-one antagonist programs, either in licensed or in house. And this is for a multitude of indications. Addiction is an obvious one. Schizophrenia is one here that Cervance is interested in. Other psychiatric disorders like PTSD are also highly relevant. But one of the things that really sets apart the THERACRYF molecule is its selectivity. It's highly selective, and that means that you don't have this risk of off target side effects. There's some really strong proof of concept data in animal models, which we'll show you. Early toxicology work implies it's clean and safe.

1:05:09 Obviously, the regulatory tox work needs to be done. And importantly, covered by granted composition of matter patents. And subject to funding, it could be clinical in around eighteen months. So the original focus of this programme was binge eating disorder. So it's the most recently recognised eating disorder, only recognised in DSM-five a number of years back. It's a psychiatric condition. It's actually more common than anorexia and bulimia combined. And it's not simply being overweight, and it doesn't respond to anti obesity drugs. So it's one of the few things perhaps that the anti obesity drugs can't do right now.

1:05:55 So it's psychiatric condition, as I say. It's impulsive compulsive eating, usually triggered by anxiety or other life events. It has comorbid substance abuse in a number of patients, about twenty five percent overall. So again, you know, emphasizing this aberrant reward pathway where you're over rewarded for eating, over rewarded for for drugs of abuse. And that has a sex split of about twenty percent women, forty percent men. There is one launch drug for binge eating disorder that's in not in Europe, but in The US and a few other territories, and that support was Shire's, now Takeda's Vyvanse, which is a an amphetamine prodrug. So it's a scheduled drug, so it has multiple issues with prescribing and abuse liabilities, etc.

1:06:46 But it's effective, but it has baggage, and many people are interested in a much cleaner, as effective way of managing, this disorder. Orexin-one antagonism was a really high priority mechanism for Shire, and is viewed as one of the most attractive, targets in binge eating disorder. So no abuse liability. In fact, it's an anti abuse mechanism. No anhedonia. So you see opioid antagonists used, but you basically lose all sense of pleasure when you dampen your opioid system. And that's just as bad as the as the primary disease. So the orexin antagonism mechanism of targeting the aberrant ward, also targeting some of the anxiety driven aspects that drive the disease is viewed as particularly attractive.

1:07:38 So this is a an animal model of binge eating disorder. Believe it or not, you can recreate binge eating disorder in rats. And what you do is you train rats to binge on chocolate. Cadbury's Dairy Milk is the brand of choice for the laboratory rat. And what they do after a period of time, a number of months where you intermittently and unpredictably give them access to chocolate. They learn that when it's there, they have to just eat as much as they can in the shortest period of time as they can. So they they binge and they consume an absolutely enormous number of calories in a in a short period of time. So in the left hand side of this graph, you can see a green bar, and that's just a normal binging animal. That's the chocolate consumption. You can see the food intake is very, very high.

1:08:27 By comparison, on the right hand side is this sort of normal, boring, not very palatable laboratory food that the rats eat. So they eat a very small amount of that, but they eat a load of chocolate. In the blue bars, you can see that there is a significant, highly significant reduction in the amount of binging that the rats do with the orexin one antagonist. And by comparison, Vyvanse in purple, you can see also has a very large reduction. In fact, a larger reduction, which I'll come on to in a second. And then the red bar is Sobutamine, which is a gross anorexia, and it just completely kills appetite. Know, it's it's a drug that was developed but has been withdrawn because of safety issues, but that just stops the animals from eating, drinking, have no motivation to do so. So that's like the absolute sort of bottom of the response you can get.

1:09:22 So to go back to Vyvanse, you know, you can see that it has a greater response than a REX1 antagonist. But if you look on the right hand side at the normal boring food, you'll see that they are consuming none of that. And that's a characteristic of amphetamines. You know, you may have heard or remember, depending on your age, fifties, sixties, amphetamines were, you know, a dietary aid. People took amphetamines to to lose weight. It basically shuts down your appetite. You don't eat normally, and that's an unhealthy way to to treat a disorder like this. If you look at the blue bars for Erection one, there is no effect on normal food consumption. So all it is doing is dampening the excessive levels of reward. So it's not a gross anorexia, and it's not affecting your appetite.

1:10:11 What it's doing is it is stopping your brain from overstimulating when you eat your food of choice. So it's a healthy way to control binge eating disorder. And it's quite unique in with this kind of characteristics. So the the reasons why the THERACRYF molecule is so attractive, it's structurally distinct from competitor molecules, has a much great selectivity. Generation molecules also have the orexin two receptor, and that causes somnolence. So you may eat less, but you're probably asleep, which is is not great for going about your daily life. The selectivity is excellent. Brain penetration is good. Drug like properties are fantastic. We have really detailed target engagement. We know how much gets into the brain, what percentage of receptors are occupied to get that efficacy.

1:11:04 And as I said at the beginning, wide utility in other addict ive disorders or any impulse control disorder. And in anxiety disorders, particularly panic disorder, which is an area with really nothing that can be done. In terms of the development stage, the scale up of the manufacturer, the initial scale up has been done. All looks good. Early seven day talks, completely clean, and composition of matter patents granted, good protection for those molecules. So very exciting program, RX1, with a lot of a lot of activity. And then if we move on to, the dopamine transporter inhibitor for fatigue, and I think an important kind of buzzword to have in your head here is this is an atypical DAT inhibitor, and you will see why we call it atypical as we go through.

1:12:02 So fatigue that we're talking about here is not the kind of fatigue you get if you run up the stairs. It's not being simply out of breath. It's central fatigue, and that's motivation. So subconsciously, every single decision you make to carry out an activity, your brain does an effort versus reward calculation. Whether it's to go to the pub to meet your friends, whether it's to come here today and listen to me, your brain may have miscalculated there in terms of the the reward. But you're making these subconscious decisions. And that's driven by dopamine. And in any disease where there is a dysfunction of dopamine, your effort related choice calculations are skewed.

1:12:48 So you are basically, you know, you don't have the energy to do anything. You don't want to go to work. You don't want to go meet your friends. You insanely don't wanna come here and and listen to me. The big issue we know is that a lot of diseases have an inflammatory component to them, and we now understand that inflammatory mediators in the brain can hamper dopamine synthesis, so you have less tone in that system, and therefore your brain is not making decisions as it should. Multiple sclerosis is one of those diseases where about eighty percent of patients have this central fatigue, this anergia, the lack of, you know, effort related choice to to do day to day activities, and there is nothing that is on the market to be able to treat it.

1:13:39 Now, some drugs cause central fatigue as well. So chemotherapy causes central fatigue. Actually, of the MS drugs, interferons, cause central fatigue, so you address some of the components, but you introduce another element of fatigue. So this mechanism seems to be conserved across a large number of diseases, and it's very common to neurodegenerative disease. And I should say also, you know, long COVID, another inflammatory driven fatigue area. But the MS fatigue field is a big recognised unmet need, and many drugs have been trialled in MS fatigue, but have proved ineffective and are not given a label.

1:14:28 So one of the key drivers is an interleukin, interleukin one beta. We know that that is associated with MS, with MS fatigue. And so these are the sort of ways that we can test, or we did test the the THERACRYF DAT inhibitor. And we have really nice proof of concept data in in animals, which I'll show you. A couple of different types relevant to MS and to depression. And so depression, one of the residual symptoms of depression, which is not addressed, so certain aspects of mood are relatively well catered for with, SSRIs and other classical antidepressants. But one of the real things that keeps depressed patients stuck at home and not getting back out into society and working is this energy or lack of willingness to get out and go meet people and and so on, and that is unaddressed by antidepressants.

1:15:23 So the compound looks great. I'll tell you in the coming slides about the the characteristics. But again, looks clean in early talks. The synthetic route for scale up is worked out, and the composition of matter patents are granted. And again, like REXN1, exactly the same stage, could be clinical in about eighteen months from funding. So if this is so obvious, why haven't other people done it? Why why is this molecule unique? Well, people have tried to address it, but the dopamine transporter has a lot of overlap with the serotonin transporter and the noradrenaline transporter. And even the endogenous neurotransmitters cross, react with with each other. So what has been really difficult is to get a molecule that is selective for the dopamine transporter, but does not hit the serotonin or noradrenaline transporter.

1:16:18 And that is where we have succeeded where, as far as I know, nobody else has. You'll see people talk about broad monoamine modulators. Those are triple reuptake inhibitors, which carry liabilities around the five HT and noradrenaline activities such as weight gain, sexual side effects, suicidality, cardiovascular side effects, and really what everyone has aimed for is this pure dopamine effect. Now what often comes with a dopamine effect is a stimulant profile. So many people think amphetamine is a dopamine transporter inhibitor. Strictly speaking, it's not. It is taken up by the dopamine transporter, but it reverses the transporter and flushes dopamine out of your your neurons and gives you this massive rush that then makes you want to come back and take it again and again and again, allegedly.

1:17:11 So these molecules do not do this. They do not look like this, and I'll show you data to to illustrate that. The other thing that people have struggled with as they've developed these molecules is introducing what's known as Herd channel activity. So a critical potassium channel in the heart, which if you block it, you introduce something called QT prolongation, which is pretty catastrophic and is a real safety flag. So for some reason, the dopamine transporters, the the chemotype is similar to to molecules that block that ion channel. We have completely designed that out of the molecule. So just to illustrate the non amphetamine like nature here, these are quite busy graphs, but you can see that in this left hand graph, have a red trace, and that is the dopamine in the reward center of your brain measured in real time after amphetamine. That's a rat. And so in the rat, you give them amphetamine, you see this massive spike in dopamine, which is that euphoric rush that that happens when you take a stimulant, comes down very quickly, you want to do it again. And in rats, that's also accompanied by a hyper locomotion, which you can see on the right hand graph.

1:18:29 And then if you look at the blue and the green lines, those are the atypical DAT inhibitor. And what you can see is that you get a slow, steady rise that peaks at a fraction of the amphetamine level. Because to induce or to reduce the fatigue, you don't need eight times increase in your dopamine. You just need a doubling or a trebling. And so this nice gentle increase gives you the impetus to make the effort without giving you the rush that says, I'm gonna abuse this drug. So same on the locomotor activity, the animals are not running around in circles like they do if they take amphetamine. So highly, highly differentiated. And the the effect on dopamine is long lived, you know, it's not up and down in a flash like amphetamine.

1:19:20 So really, that's why we call this an atypical DAT inhibitor, to make sure it's very clear this is not a stimulant, it's not like amphetamine. So, again, you can induce this fatigue in animals. And we've got two examples of how you do that here, but the principle is the same. You take rats and you give them a palatable reward. But to get that palatable reward, a sugar tablet basically, they have to press a lever multiple times. And it's called a progressive ratio where as as the test goes on, they might have to press it five times to start, then it's 15, then it's 50, then it's a 100, you know, so they have to make more and more effort to get the reward.

1:20:06 But the reward is is good, so they're willing to make the effort. What you can then induce is this, anergia, the central fatigue, where you can give them interleukin one on the top graph, or tetrabenazine on the bottom graph. Tetrabenazine is a drug that's launched for tardive dyskinesias and Huntington's disease. It's a depleter of dopamine, and one of the side effects is depression, suicidality. It's black boxed. It kinda works, but it's a horrid drug, and it's often used as a model of depression. And this is really classic way to induce this central fatigue. So if you look at the green bars compared to the red bars, top and bottom, you can see that these animals just cannot be bothered to press the the lever for the food reward. They're they're they're effort related choice. They're just saying, it's not worth my time. I'm just gonna sit in the corner and go to sleep.

1:20:58 Now if you give the Erection one sorry, the atypical DAT inhibitor in increasing concentrations, you can see that the lever press numbers get right back up almost to control levels. And this is a spectacular effect in these in these assays, really, really impressive reversal. And this work was carried out by Professor John Salamone, University of Connecticut, who's the basically the world leader in this preclinical area. And really, what this shows us is that when either drug induced fatigue with tetrabenazine or inflammatory induced fatigue with IL-one occurs, you can reverse it with an atypical DAT inhibitor. So really, really nice data.

1:21:45 Then another opportunity for DAT inhibitors is in narcolepsy. So modafinil, which is a launch drug for narcolepsy with, again, with a safety black box warning for a really disturbing rare skin condition, induces wakefulness. So what you can do in, again, in preclinical animals is rig them up to EEG devices, and you can measure their brain activity and their physical activity. You can tell when they're awake, you can tell when they're asleep, and you can tell what type of sleep they're in because of their their brain waves. And so oops. And so what you can see, left hand side is wakefulness, so really important if you're narcoleptic. And then the the two right hand graphs are the are the sleep and the type of sleep non REM and REM.

1:22:35 The white bar is normal sleep levels, normal wakefulness. And then the yellow, orange, and red bars are increasing concentration or doses of the atypical DAT inhibitor. And what you see is that you get a really beautiful dose dependent increase in wakefulness with a decrease in both of the sleep parameters. And you can see in all cases that that outperforms modafinil, which is the standard of care. So a really clear indication as we would have expected that this molecule is affecting wakefulness. Now one of the keys here is amphetamine would do this. Amphetamine would give you wakefulness.

1:23:21 However, with amphetamine, when you wanna go to sleep eight hours later, you ain't getting to sleep because you've taken a stimulant and, you know, your brain is still absolutely firing on all cylinders. With this, again, it's a slow, steady increase in dopamine that is giving you a normalised function without excessive stimulant behaviour. So in summary for the dopamine transporter, highly potent, highly selective, and particularly selective against the other monoamine transporters, completely clean at HERG. Essential is the nonstimulant profile, so it is not amphetamine or an amphetamine like molecule. Highly differentiated from the first generation of DAT inhibitors, which actually had such potent HERG blocking activity that they're now actually one of them is launched as a cardiovascular treatment for people who have a rare QT issue.

1:24:18 So that that activity is is is is sideways. So again, clean and early non GLP talks, seven days. Really potentially the first approved drug with a label for MS fatigue. There is actually not a huge amount of activity in the fatigue space. Most of the activity that there is is these triple reuptake inhibitors, which are kind of just being repurposed into, you know, extensions there, where unfortunately they carry all the side effects that I mentioned. And because this underlying mechanism, why your central fatigue exists, is conserved across a number of diseases, it means that once you get approval here, applicability would be really broad. And those are also, as I said, in non CNS indications where fatigue is a characteristic.

1:25:10 Unlike the EREXIN-one program, composition of matter patents are filed and granted in certain territories. So that was all I was going to say to introduce it. Happy to obviously answer any questions on the Yeah, we do have some time actually for online and in the room questions, because your phrase is fast paced and very clear explanation of the fantastic quality of data and congratulations on leading those programs that we've acquired into THERACRYF. They're excellent programs. We knew that when we did diligence on them. So, we'll take questions from the room now. Mark's doing his usual with the microphone, should you have any. Tim's got a question here. It's rather a trivial question about the animal model with the rats and the chocolate. Yep.

1:26:03 You said they fed them Capri's dairy milk. Yep. Do they also do that when they do this work in The US? Because that isn't available. The only chocolate which is available is Hershey's, which is pretty horrible. Yeah, exactly. Exactly. So it's probably a much worse model. Maybe we're leading the field in The UK with our better quality chocolate. So you can, in all seriousness, so you can use different stimuli. So we used the UK CRO, not located near Cadbury's. But they actually did a significant preliminary set of work. They worked extensively with Shire when Vyvanse was launched. So you can look at high fat, so you can give a sort of suet y type diet, which they love.

1:26:51 Chocolate, we found, was by far the best, and they literally did try different brands, and Cadbury's Dairy Milk was the favoured brand of the discerning rat. Excellent. Okay, thank you. But it's actually so it does actually raise a relevant point because binge eating patients tend not to binge just on any old food. They tend to have a favoured binging food. So, it might be bread, it might be pizza, it might be chocolate, and they tend to be really focused on that particular food type to binge on. So, there's a, you know, there's a, I guess, a selectivity in what triggers our aberrant reward. Got a question here. Yes, sorry, thanks. So just probably on the binge eating disorder, Bridget, I noticed you said obviously the GLP-1s, that's not to treat the disorder. But just in terms of sort of in practice and in the field, how well is that actually understood in terms of binge eating disorder? If I'm a clinician and a patient walks in, does the patient know that they've got it?

1:27:54 What's the diagnosis kind of procedure? Obviously with a lot of neuropsychiatric conditions it's very difficult to diagnose these things. So your ordinary clinician might just be incentivized to say well, know, let's just get my GLP-one and a weight loss drug. And the patient might think well maybe that's probably what I need. Just how well understood is this condition actually in practice? And I'm kind of thinking from a kind of commercial angle, kind of going forward, and maybe that's one for Helen as well, you might come on to that. But maybe if I could pass the Yeah, so I can pick up part, and then you can jump in if you like. So you're absolutely correct. So it is treated and handled by psychiatrists, not someone who, not a primary care physician or someone who specialises in metabolic disorders.

1:28:41 I mean, more and more we understand that obesity results in a systemic inflammation, which will also affect reward pathways in the brain. So there is the potential for this to be more broadly applicable in obesity situations, but the strongest evidence is in binge eating disorder. In terms of diagnosis, so you're correct that there is some risk of going to a primary care physician and just being told, Yeah, take one of GLP-1s, you know, we're giving them away this week, you know. But really the key issue with binge eating disorder is it's cyclical in nature, it is triggered by anxiety, there's enormous feelings of guilt and lack of self worth, and most of the people who present kind of present with the psychiatric indications.

1:29:43 And interestingly, only about seventy percent I think it's seventy percent, don't quote me, but not a hundred percent of binge eaters are obese. So unlike bulimics where they purge, they often do compensatory, you know, excessive exercise, to try and stave off the effects of the binge. And binge eaters tend to have a very different behavioural phenotype. So your average obese patient, you know, will be at work eating a large plate of lunch and, you know, being judged by everyone. But the binge eaters tend to go and sit in the toilet and binge or go and sit in their car because it's, they're so hung up on the guilt aspect of it. So it's very different in that respect.

1:30:30 And it is defined in the psychiatric diagnosis manual, DSM-five was 2015 published, first time binge eating disorder. So the characteristics of this disorder for a psychiatrist to make a definitive diagnosis is laid out in the American, the Bible of psychiatric diseases as it were. Yeah, and just to add to that, I think, you know, when Vyvanse was originally launched or launched for binge eating and not just for ADHD, Shy did a lot of work with the clinician population in education and promotion of that drug and the pathway to treatment. So they've laid a lot of the ground in diagnosis and treatment options for patients. Having something that would be equally as effective but cleaner, I think would be readily taken up. Mainly in The US, so this is a primarily US market. In Europe, we don't tend to treat quite as readily for for things like this.

1:31:21 But are you gonna tell me it's changing? No. No. No. No. You're right. But I think that it's important to caveat the reason for that. And the reason is the only launch drug is Vyvanse, which is a stimulant, and European clinicians do not like to prescribe stimulants. So Shire didn't or Takeda didn't even try to as far as I know, didn't even try to launch Vyvanse in Europe because they knew that actually the uptake would be low. So it's launched as Lvance for ADHD, but they haven't tried to get a label for binge eating disorder in Europe because the uptake on stimulants is low. So I would actually say that's a massive opportunity in Europe because it's a whole market that has no prescribing at the moment. I like our stigma. It's a controlled drug, as we say in The UK, and a scheduled drug, as we say in The US.

1:32:07 So, there are extreme limits on the ability to prescribe it, how long a prescription you can have of it because of its controlled abusable status, whereas the product profile for the orexin-one antagonist is non abusable. So, we don't expect that controlled drug label to be slapped on it during clinical trials, for example. And from a patient perspective, I think compliance is another big advantage. So, you'll find where people are on products like Vyvanse, they don't like the feeling it gives them. So reflecting on the data where you can still enjoy, if you're on an orexin antagonist, hopefully your binge is controlled, but you can still enjoy going out and eating with your family or participating in those kind of social interactions that involve food. If you're on Vyvanse, you don't you don't gain pleasure in eating generally, and patients quite often decide to come off of their own accord, not just on clinician's advice, or come on and off and on and off drug because they don't like the feeling it's giving them.

1:33:10 I think going back to your comment on the Glips, oh, they're really taking the market by storm. They're amazing. However, they aren't burdened by a whole host of side effects. And one of the major issues is this whole nausea, vomiting, actually feeling like you don't want to eat. Ultimately, we can say all we want about kind of metabolic control and reregulation of dysregulated, you know, insulin responses. But ultimately, those patients are losing weight, because they feel sick and they don't want to eat. So it's about fifty four percent of all patients have nausea or vomiting when they're on glyps, and the majority of those come off drug at some point because the side effects aren't worth the effect. So with orexin, it's not just eating, it's control of that aberrant eating.

1:34:02 However, you're going to feel generally well in yourself, hopefully, and be able to enjoy other aspects of your life. That said, if you are that niche patient who requires a GLP-one agonist and an anti binge, there's no reason We haven't done the experiment yet, but there's no reason that the two, an orexin-one antagonist being that specific and selective, could not work together with a GLP-one if you're binging and obese. And if you are obese, the thought process is if you're able to control better your reward seeking behavior, so bingeing behavior, without doing other aspects, your feeding is going to be normalized, and therefore your weight over a longer period of time will be normalized, so in a more healthy fashion than just dropping it very quickly.

1:34:48 I mean, one one last thing that's worth saying about Vyvanse is it's a stimulant. And to go back to what we said in the DAT section, you take it in the morning when you wake up, and it lasts for about eight hours. You can't take it again because if you take it again, you cannot get to sleep. So you're off drug for sixteen hours a day or twelve hours a day, whatever it might be. And if you look on patient forums, one of the complaints is I'm so well controlled in the day. When I'm at work, I'm not going and sitting in my car and eating three pizzas at lunchtime. That's perfect. They get home, and then they associate it with I'm home, and then I've got nothing to do, and I I I often binge. I particularly binge during the night. I wake up, and I go downstairs, and I raid the fridge. And that's because they're off drug, and you can't be on drug because otherwise you'd drop dead of never going to sleep.

1:35:42 So again, it's an advantageous mechanism to have a thing, not to have a stimulant. Okay. Sean? Just a quick one. I'll add that there's lot of overlap between binge eating and obesity but a lot of binge eating is undiagnosed and GLP ones are being looked at for stuff like gambling addiction and sex addiction at the moment. Yes. So they're really pushing limits with side effects that Helen mentioned as well. And I think all those impulse control disorders would be applicable to orexin one. Very common. Absolutely. My question is, it's a bit more nebulous. When drugs go into phase one, the primary point of a phase one trial is to look at safety and tolerability. And these are preclinical assets.

1:36:29 And a preclinical asset is a preclinical asset. But would you say that these two assets, the the the o x one and the data inhibitor, in terms of safety and tolerability, have a better than usual chance of being being safe and tolerant in patients versus a typical preclinical candidate. Would you agree with that point, or is that pushing the envelope too far? Think it's fair. I mean, I honestly don't know what a typical chance is, but I think what I would say is without trying to compare it to something else, the preclinical safety profile looks good and the mechanisms, particularly the type of mechanisms for DAT, let's say, would imply that it has a really good chance of being safe and well tolerated. And you probably have a chance of seeing efficacy readouts in, say, an experimental medicine trial, which is quite unique, I think. But there's reference to a keen this is a keen RX1.

1:37:27 It's a RX1, not an RX1 and an RX2. Correct. So it's infection. That's On that respect, way less. Yeah. Yeah. So that's what the tolerability should be better. We've seen our x one's in the clinic, and it would suggest that this gets into the very least. Yeah, so I think the OX1s that have been in have been two molecules used to explore the mechanism, carry baggage and you see somnolence, sedation, that type of thing. It's fair to say a big part of why we acquired the company was our diligence on the potential safety profile. The fact that the early seven day toxicology was completely clean and unremarkable. That's a big part. So that derisks the future of getting to the clinic period. So, we look carefully at the risk versus the other 130 companies and opportunities we screened at the same time over a period of a couple of years, I suppose.

1:38:20 So, this wasn't an acquisition that was made on a whim. It was an acquisition that was made in context of a long trawl of potential companies and assets that would fit with what we're doing. And it was the best fit in a number of ways, including proof of concept and potential safety going forward. It was a big part of that decision making for our board. I've got one question online, which might be our questioner has been very patient with us. Are there any plans for additional fundraising activities in the near future to support this expanded portfolio that you've heard about? And of course, stated aim currently short term is to pursue non dilutive funding for these programmes. That is looking at grants, which we're currently landscaping and looking carefully at. The addiction space, of course, does have a lot of history of grant awards in it. And we're looking very carefully at that as a management team. So, short term, I think it's about non dilutive funding.

1:39:21 Pretty much all of our business team is looking at non dilutive funding for these very interesting candidate molecules at the moment. So, that's one of the online questions. There's another one just popped up, and I'll deal with the question on nutraceuticals at the end. What are our strategies for protecting our intellectual property? Another part of acquiring these programs is that there was robust composition of matter patents, either granted or about to be granted for both the orexin-one antagonist to 2038, which is about as long as you get these days, and the DAT inhibitor, which was slightly older patent family. So, there was already granted patents for these that are enforced and maintained.

1:40:08 Indeed, as part of the transaction and exclusivity fee, we gave Cronos management some money to maintain that patent family. So, we maintain it very actively the question on the acquired portfolio and composition matter patents are, of course, the strongest type of patent you can get. On SFX-one, we also have composition of matter coverage for the complex and two other patent families in addition to that, covering other aspects of SFX01. So, patents are our lifeblood. They're what creates data and patents are what creates biotech companies. And we're very active. A large chunk of our spend is dedicated to defending them and maintaining them. So, that's a bit about our strategy for protecting our IP.

1:40:54 The spaces we activate are not necessarily too crowded. We avoid crowded spaces where you might not be able to get a patent, or there might be high competition, particularly from big pharma, who can outspend a small biotech. So, this business about profitable niches or profitable segments is key to how we select assets, how we select assets to develop, and indeed what indications or diseases those assets should be directed towards. And some of those indications, as we mentioned earlier, can afford additional protections for you on a commercial basis. So specifically those orphan designations. We have the orphan designation for glioblastoma for SFX01. And with the narcolepsy data we have on the DAT program, we will look to try and get a orphan designation for that program as well. Remember, orphan designation gives you seven years of additional data protection, but that clock doesn't start until you're on the market.

1:41:50 A patent starts when you get the patent, and it's twenty years. That's what you've There are some extensions available. But an orphan drug protection protects your asset from the date it's made available to the general public, not some arbitrary date in the past. So, you've got a relative clock going forward. Currently, it's seven years, and that's what we've got for SFX-one in The United States, in addition to the patent cover that we already have for SFX. And of course, throughout the development, these programs always be looking at any new potential sources of intellectual property that we can protect, and that would enhance the coverage and the commercial protection over a longer period of time. That might be new formulation, new assault forms, I think we were talking about the other day in terms of the production CMC process.

1:42:37 And so, and that's really what we've done for SFX01 as well as that primary composition of matter. We have different forms of SFX01 for the production process, and also optimized process or production for want of saying that word too many times. So you get these additional layers that can help you extend your protection for longer. So that hopefully covers the IP question. It's about looking for data protection strategies and constantly looking at the data we generate from the point of view of, is it patentable? Can we extend? Can we enhance the coverage that we already have? Good. Well, that's probably a good segue then to commercial. Thanks, Fraser, and for the leadership of those programs historically. A very clear exposition of what we've got. I'm going to turn over to Helen now and talk a little bit about why we select these markets, to our business model, to the strategic plan about looking for profitable segments.

1:43:32 Helen will take you through now some of the market sizes and market potential data that she's gathered for all of these programs. So, I'll try and touch on each program in turn and talk a little bit about the indications and the market potential around those indications, and then segue into the competitive environment, especially around the new programmes and why we think what we have is differentiated and therefore attractive from a commercial standpoint. I'll try not to labour too long, because I realise some aspects of what I'm about to say have probably already been covered by other people, so particularly around mechanism or the patient treatment landscape I won't dwell too much on. So starting off with our lead programme, our most clinically advanced programme, which is SFX-one.

1:44:19 As we heard from Marjolein and Glenn and Wouter earlier, we are addressing glioblastoma, the fatal of all brain cancers. The market opportunity here is huge, and I hate using those kind of superfluous words, but it is truly huge, mainly because of all of the failures that have recently happened, and there is not really anything available to patients that are going to change the trajectory of their disease. So they go after diagnosis and get resection, and then go on to a chemotherapy agent called temozolomide. Temozolomide itself is roughly around 30,000 a year, so the expectation that anything that gives a better life extension or quality of life to patients will exceed that pricing envelope considerably.

1:45:11 So there are a number of programs in clinical development at the moment, as well as those failures that have been mentioned. A few have got news articles quite recently, I think there was a sort of vaccine approach and immunotherapy approach. But I hasten to add that although they seem to have got amazing publicity, they're showing results in one patient, and one patient does not on approved therapy make. So all of those products will need to go through, as we stated before, larger trials to prove that they can actually address the broader patient population and give that extension of life that we're all hoping, or a cure, that's what everyone really wants from the therapies that we develop. Although we mentioned this is an orphan disease, so that means it's relatively rare, actually it's been diagnosed more and more readily over the course of the last few years.

1:46:08 It sounds horrible to say, that gives us a great opportunity, commercial opportunity as a business in addressing that population. There's been a lot of market activity, specifically in Asia, particularly with the advances in urbanisation and healthcare in the Asian markets. They've seen rising diagnosis of cancer and other diseases, and in particular, they probably have the highest rising cases in glioblastoma at the moment out with what we see in the Western, I hate to say developed world, because they are developed with the Western medical environment. So that's what's causing the major driver for the market here is this uplift in diagnosis, but also without any therapeutic options, and that unmet need is really providing good supportive environment for the development of new therapies, the FDA with their fast track processes, and the assumption is with relatively short trials, you're going to get a pre approval or an approved with a post marketing commitment from the regulators over there.

1:47:25 So from our perspective, we want to generate good clinical data that will enable partnering, as these companies here have done with Asian large farmers, to enable those larger clinical trials. However, and I must add, if we see amazing data, it's well within the capabilities of the smaller pharma to be able to market in such indications as GBM, so if we had aspiration and funding available to become a fully integrated company at that time, we would potentially be able to address this indication ourselves. However, that is not the case for some of the neuropsychiatry indications that I will come on to in a bit later.

1:48:12 For autism spectrum disorder and the other neurodevelopmental disorders, I won't dwell too much on this because, as we mentioned previously in our other presentations, we have out licensed S of X-one to our partner Stellickler for development in these particular indications. However, I just wanted to highlight, and I covered this when we were talking about the initial partnership, that this is also a rapidly growing field. And again, coming down to a greater awareness of neurodevelopmental disorders more broadly, and education in the clinical environment in the diagnosis, and the management of these disorders. And now when when we talk about autism, we're not talking about those people that see it as a superpower and enables them to do many things. We're talking about a highly disabled portion of this population that can't engage in normal everyday living.

1:49:14 They may be violent, they may be non vocal, they certainly can't live independently. And that is what we and Stellickler are trying to address for the development of SFX-one is to alleviate and support those kinds of patients so they can live a more independent and fulfilling life. So on to addiction, and I think we had a really nice discussion earlier around some of the market opportunities around addiction, and specifically binge eating. But I just wanted to talk a little bit about the more broader impulse control potential indications for the orexin-one antagonist. So a number of companies are developing orexin-one antagonists in a variety of impulse control disorders.

1:50:08 And addiction, as a sort of overarching indication, is the most severe form of the substance use disorder. So this is the most advanced kind of reward seeking behaviour, well, where even though you know it does you harm, you can't help yourself but continue participating in that activity, or eating that food or taking that drug. I'm afraid it can happen to any one of us, all races, genders, all socio economic levels. However, it is more frequent in males and young males, and that may be to do with, as Fraser mentioned before, other CNS effects, other anxiety type disorders feeding into that reward seeking behavior.

1:50:58 There are therapies available for some substance use disorders, but not all, and these generally don't enable the patient to control their addiction particularly well, and as we talked before, they have other side effects that make compliance and adherence to medication a real issue. However, as a treatment market size is growing, and I think our everyday lives somehow feed into our growing anxiety and addictive behaviour and personality and stress all feeds into this. So of these actually, and this was interesting when we did the original primary market research, alcohol use disorder being one of the main market opportunities for an anti addictive therapy.

1:51:56 So for anxiety itself, and we talked about sort of general anxiety and panic disorder, and they're all slightly different facets of an anxious personality. This is also an area where there is growing diagnosis, and I think it's become more and more accepted for people to go and seek help for anxiety and the issues it's causing in their lives. Ironically, being a kind of middle aged, going on to middle aged woman, this is more common in women than in men, and in the area of sort of the menopause and perimenopause, and it's probably some complexity in what's happening here within brain circuitry, not just hormonal, but other aspects as well.

1:52:53 But there are more and more efforts going into finding treatment options for anxiety. And again, referring back to the autism population, there are subpopulations within this that just find it difficult to engage in everyday life, because their anxiety is that burdensome for them, that they can't even get out of the door and go to work. So Fraser mentioned before, the amphetamine like products that are available, and also benzodiazepines can be used for treatment resistant generalized anxiety, so it's important to add that even though there are some options available, they only help in about fifty percent of patients, even if they feel that they can continue taking them with the side effect burden they have. So there is a real opportunity to have drug treatments developed in this area that can give effective relief, but also have lower side effect burden than what's currently available.

1:54:01 So in fatigue, we talked quite in-depth about MS, and MS fatigue as a sort of population is quite large and specifically addressable because of the inflammatory component within MS. But as we mentioned before, fatigue, and as the Americans like to say apathy, is contained within so many indications. There is a good opportunity here for once you get your primary approval to then seek a broadening from your drug by going into additional disorders such as Parkinson's disease, chemotherapy induced fatigue, and also long COVID. And there are studies ongoing trying to address the fatigue that comes with long COVID.

1:54:53 But as with some of these, it's primarily a viral driven and ultimately probably inflammatory driven outcome here. So there's no currently approved products for fatigue, although modafinil is used off label and comes with not very good side effects. Again, the market potential for this is growing at quite a large scale, higher diagnosis, especially occurring after COVID, trying to address some of these conditions really generates a great opportunity for our DAP program here. As we mentioned before, narcolepsy is an orphan designation, so slightly smaller.

1:55:46 However, it's a really great opportunity with a couple of leading players, namely Jazz, that are calling out for a drug which is non abusable and has limited side effects, but still is able to give those patients the alertness that they require throughout the course of the day. So these are you're just sitting at your desk and you're forward dropping off asleep, to cataplexy, which is quite bad, and sleep paralysis with hallucinations, which is really an awful condition to have. So the target product profile you want for your drug is something that creates that alertness during the day, goes away by the time you reach nighttime so that you can have a nice restful sleep, and doesn't give you those horrible side effects.

1:56:42 Mentioning the competitive environment, and I think we talked a lot about orexin, but some orexin antagonists have been taken forward into a variety of different areas. So reflecting on the comment that came earlier about the confidence going into the clinic, there have been a number of orexin-one antagonists taken into the clinic. Some are still progressing. There are a couple that are due to enter phase two at the moment. So although we are a little behind that, we are not very far behind and we have a class leading profile, we believe we could be best in class in this area. So they've been taken forward in substance use disorders like opioid use disorder and smoking cessation, and also other psychiatry fields like schizophrenia.

1:57:33 I just want to note the top one on the left hand side, the Adorsia compound was taken forward in binge eating and actually failed. And that was two years ago. Now we believe and maybe Fraser can comment on this a bit later, that's due to receptor occupancy issues. And we've compared our compound with theirs and the data that they had at that time. And we believe that with our profile, we could still have a good outcome in binge eating, because we're able to achieve over 80% receptor occupancy for these patients in this mechanism. So for narcolepsy, as I said, there are a number going through the clinic, approved yet, but what that is creating is a lot of interest and competitive interest on the commercial side.

1:58:28 So with good data coming from phase two proof of concept study, we would, I believe, readily be able to partner this asset with a major player. I think what it's shown over the past year, and we talked about this when we did our fundraising presentation earlier, is that the field of CNS is really coming back to the fore. Prior to COVID, the focus was on oncology and supporting and bringing through oncology therapeutics. And CNS was, I wouldn't say dying a death, but it wasn't as cool and prioritised in some farmers' pipelines as it now has become. And I think COVID had a lot to do with that, but also that almost development saturation in the oncology space has a lot to do with it. And they have been coming back and seeking opportunities in the field of psychiatry and other CNS indications.

1:59:31 And they've been stating, as J and J said, that it really believes that it's gonna try and focus now on more CNS therapies and build its pipeline around this area when it has not been focused on it in the past couple of years. But where do we see this opportunity with the acquired assets? Well, as I mentioned, there are limited effective solutions out there, especially in the addictive disorders and for fatigue, they're terribly burdened by off target effects. And any future solution needs to be not only effective, give durability in effect, be non abusable, so non scheduled, easy to deliver and have the limited side effects. And we think our programmes can tick all of those boxes.

2:00:24 So they are mechanistically focused, they are assumed to be effective based on our preclinical data and other data we have, that we will have non abusable, or potentially non abusable in the case of DAP products, with limited off target effects. So I think what this does is it gives us a more broad pipeline as a company to generate more deal interest, and long as as we continue to generate positive data through the development pathway, we should be able to attract partners to transact these programs. Or if we have the appetite to take them forward ourselves and deliver even higher value partnerships later on down in that clinical process.

2:01:11 Great, thanks, Helen. So to conclude, we'll talk a little bit about conclusion, do some final Q and A. Hopefully, I can see the questions writing here and take you through finally the last two slides. Thanks for your patience. I hope that we've demonstrated this morning that we've executed against each of these imperatives in our strategic plan. We've got early partnering. We've got external validation of our technology. We generated clinical data in our Phase one with our new tablet. We've continued to generate preclinical data. And some of that for the first time today has been shown to you in our collaboration with Erasmus in those GBM models, both with radiation and with the only other drug that's available for GBM brain cancer, and that's temozolomide.

2:02:03 And SFX-one seems to work together with both of those approaches. Excellent news. We've sought through a two year process attractive M and A opportunities. We've given you a large chunk of the data that we acquired with that company today, thanks to Fraser's very clear explanation of those quite esoteric central nervous system concepts that we're getting across. And we think we've got class leading assets now in both of those areas. So, hopefully, we've ticked each of these boxes. I would encourage more questions and challenges if we haven't. But I'll move a little bit towards the outlook now from the year end and through some of these have been covered through the rest of the year. We're doing regulatory work in parallel to the question that was there earlier, particularly on stability manufacturing, getting SFX-one ready for those first patients in beginning of twenty twenty six.

2:02:58 We are completing the integration of Kronos. This is all about data records. Now, that's the stage that we're at and putting those into our own systems. We're busy looking at the grant landscape so that we can restart the orexin and atypical dopamine active transport programmes. Patents are still being granted on some of these programmes. So, we don't have global patent coverage yet. And the only reason for that is that different patent agencies in different countries process patents at a different speed. But we'll publicize those patent grants as they come. We will be publishing our clinical paper on the SFX-one Phase one study, which is definitive in terms of the behavior of sulforaphane. Nobody else understands it like we do. And that will be submitted for publication. When it's published, we'll let you know. We're still ongoing, analyzing what's called pharmacodynamic data that is, stuff about what the Sulphurovane and the Sulphurothiols did while it was in the volunteers. Remember, these are healthy males.

2:03:57 There's nothing wrong with them. They're screened to have nothing wrong with them. And yet, we have said publicly that some gene changes were observed in that population with sulforaphane, which is really intriguing. We're analyzing that now, and trying to make sense of the entire genome changes in that group of people, and we'll make that public as we go through. So, there were two questions before my computer lost its battery. And I'll make sure that we deal with them now as we move on to Q and A. The first one, based on the acquisition, are you likely to expand the R and D pipeline beyond the current assets and collaborations? Well, we have 200 meetings, 130 evaluations, 65 confidential discussions with companies about their assets or about the company itself.

2:04:45 There are opportunities out there. But I think short term, our job is to make sure now we get these programs restarted with non dilutive funding, show that the newly enlarged company THERACRYF can then get these programs going and show value from them. That's the immediate priority. If something else came to us that was an excellent fit, after we demonstrated that restart, yes, we would look at it. And then there's another question, which was pre submitted. So, thank you for your patience, whoever submitted it. A long term investor who was a big fan of taking Sulphurophane supplements. And the Juvenescence deal, for reasons internal to Juvenescence, didn't proceed. And we got the rights back. Would we look to market our new tablet as an over the counter supplement?

2:05:31 And the short answer to that is no. And I'm going to try and tell you why. It's mainly about the fact that we are developing a drug, a fully synthetic drug made in a factory in the Northeast Of England for brain cancer and other cancers. We're going to explore high doses of this drug in order to try and produce a meaningful modification of the natural history of that disease. We don't want to contaminate that high dose drug with a supplement you combine Holland and Barat for £60. And that's a pricing contamination. That's a contamination of where we're taking this profoundly biologically active molecule. It's already a pretty crowded space. There are supplements out there. The problem with them is you just don't know how much stuff you're getting in the supplement world, because nobody has done what we've done, and that is understand exactly from this patented formulation what sulforaphane is doing, how much you're getting, and what gene expressions is it shifting while it's on board.

2:06:33 So, this is high science, and anti brain cancer and other cancers medicine. So, I don't think we'd be looking for other partnerships in the nutraceutical space for the two contaminations that I outlined, and that's therapeutic and pricing, because at 30,000 plus per year per patient in glioblastoma currently, we'd expect those prices to increase with new interventions. I don't want contamination of pricing. We are developing a drug, essentially. So, that's the end of the formal bit. We're a few minutes ahead of schedule, I'm pleased to say. Any more questions from the room? And of course, online, if they pop up, we'll deal with all of them. One question before that, I just noticed that amongst your high functioning autistics of Steve Jobs and Elon Musk, anxiety is an issue, hence, the cage fighting, etcetera, I imagine.

2:07:28 And therefore, you've actually got with an x one, you've got something to cover both high functioning autotistics and with sulforidex, something to cover the more severe ones. So that's just an observation. But my key question here is, at the moment, the market is valuing your acquired assets at way less than 10% of your total value. Given that, they're relatively low risk, and in fact, they address potentially much bigger markets than so far Floridex, which in its itself is only mostly at phase one with the exception of breast cancer, which, again, takes some time. Why do you think there is that disparity in the valuation? And do you think it's warranted? No, I don't think it's warranted. I think we're undervalued. That's clear with an extended portfolio with a grant funded into patients in brain cancer. You've seen the enthusiasm for that from our collaborators in Rotterdam.

2:08:23 We've got very specific, extremely well developed preclinical assets in neuropsychiatry, but we also have two regional conflicts. We also have a very high interest rate and relatively high fuel prices. And I think we all know that the macro environment is conspiring against investment as a whole in biotech and the realization of real value that biotechs can generate. I think our job is to crack on, to keep going, to continue to unlock the value in this portfolio. And ultimately, we have to believe, and I do fervently believe that value will be unlocked if you're patient. Biotech is a long game. And really the major thing is the sort of exits that Helen has showed us that can happen when you get the data set to the right point.

2:09:09 And they're in the billions. My question was specifically for those in licensed assets, all the current interest as I'm a shareholder or an option holder in THERACRYF because of those assets. Yeah. Indeed. Specifically, there's assets. So, it's macro factors affect everything but specifically, there's assets which at the moment cost you a tiny the market as of users as a tiny bit of the auto value. Yeah. They do. I don't part of today, Sean, was to really explain Yeah. You know, what that market potential is through showing very high quality technical data and very high quality market analysis to solve the visa. We didn't acquire these on a whim, as you know. We acquired these as part of an extensive process, and we looked at what the gains are for ourselves and our shareholders in so doing. And I think they are undervalued, substantially so. And we hope that the market as a result of today and other activities we're doing, including kicking off those programs again, will realize that value that we're so fervent about.

2:10:10 Yes. Question for me basically on the Cronos programs. You've mentioned both as sort of eighteen months development before they could be in clinic. Could you talk a little bit about what the funding requirements for each program would be and what the process would be to get each into clinic and also why you're prioritizing the orexin program over the data inhibitor program? Thank you. Very good question, Colin. The answer is that it's about 5,000,000 to get to the clinic and about another 5,000,000 to get the volunteer study done. Sterling. Sterling. And we made that public per asset. Both those assets we acquired are pretty much exactly the same stage. And then the really interesting stage after that, we're confident we'll get to those stages subject to funding.

2:11:00 These are the phase 1B potential, these experimental medicine studies that Fraser is a leader in that you can actually get in volunteers. You can emulate these neuropsychiatric conditions and show that the drug is interfering with either a carbon dioxide panic attack, which is what happens to the volunteers if they inhale carbon dioxide. And you can reduce that, that's proven with an orexin antagonist. Or with the dopamine antagonist, you can actually infuse the cytokine, the interleukin-one beta into volunteers, and they feel pretty rough. They feel pretty tired. And then you can pre treat with a DAT inhibitor and show with good scales of efficacy that that can be alleviated. So there are good hybrid ways before patients to show proof of pharmacology with these drugs. Non dilutive funding, I think the reason we're pushing orexin first, we're a small team, is because the addiction spaces are hot.

2:11:51 And the grants in the addiction space represent possibly slightly lower barriers currently. We will look at both those assets though. And I'll just add to that prioritization. Obviously, in a world where we have unlimited funds, we take them both forward, because I think with good clinical data, we'd be able to easily partner both of them. However, not just talking about the froth in the addiction space and the grant availability, But if you look at the competitive environment and competitive development environment, just looking at REXN1 antagonists, there are a number of large farmers that are trying to develop their own programs. There are some that have fallen over that we know about, we know why they've fallen over. There is great appetite to feed back in to those pipelines, so I think we would have, I hate to say this because you'll hold me to it later, an easier time of it to partner than we would in the DAT.

2:12:42 Still good data with naval partnering, but I think there's a lot more froth in that potential partnering arena for orexin-one than there is for DAP. Tim? Looking ahead, assuming a golden scenario where we get successful clinicals and successful approvals for autism and for the oncology indications, and assuming it turns out to be the same dose for each, is there going to be a problem with differential pricing for those two? Would you you've got you're probably gonna end up with two companies selling selling each product and they may not agree or NICE or other regulatory body may not think it should be the same price for for each. And might there be an interchange between the two products for the two indications? Yes. So that's something that we debated at great length before we recommended to the board to progress with this partnership and decided that it was a good partnership.

2:13:45 I think we have to also consider that this would be almost done in a companion diagnostic way. The main reason we went with Stellicola was this ability using their proprietary technology to identify patient responders. It So wouldn't just be a drug for all autism patients, in which case, I agree the pricing would be lower. But if we're addressing a subset population with responders, and we can almost guarantee a good outcome, then you can achieve a higher pricing. Also, because of the age of these individuals, we would look to generate, and I think we talked about this at great length before, alternative dosage forms. So that will give us protection and additional pricing and differentiation from what's called that cross selling issue or a compounding pharmacy making it and selling it independently.

2:14:38 So those factors all lead into one, I think we'd probably achieve higher pricing in those particular patients. But also, we'll develop alternative dosage forms and each dose of form will have its own pricing. And we're talking about chronic dosing. So in GBM, we'll cry much higher doses, we're going to really push the dose envelope in autism, probably much lower doses, but much longer time of dosing. And 30,000 per year is achievable in autism as well, actually, because Helen looked at that during, we asked ourselves the very same question. Okay. Well, I want to say thanks very much to everybody online, for your patients online, not easy to listen to three hours, I'm sure. But thanks for your questions and for listening to us, hoping now you understand why we did this thing and where we think the huge opportunity here is. And I'll add those thanks also to everybody in the room and for your very insightful questions. That that brings it to a close and just to say thanks very much, everybody.