Theracryf (LSE:TCF) — Ox-1 – A deep dive into TheraCryf’s addiction programme

0:00 Good morning, ladies and gentlemen, and welcome to the Terra Grieve Investor Update regarding the Deep Dive into the Addiction Program. Throughout today's update, investors online will be in listening only mode. Please submit your questions using the Q and A tab situated on the right hand side of your screen. Just type your questions at any time and press send. Before we begin, I'd like to submit the following poll, and I'm sure that the company would be most grateful for your participation. I'd now like to hand over to your presenters today, doctor Fraser Murray and doctor Helen Coleman. Good good morning to you both. Good morning. Thank you, Mark. And, yeah, good morning to all of our existing, hopefully, new and potentially interested shareholders to THERACRYF. This sort of marks a bit of departure in the, IMCs we normally give.

0:46 So instead of just presenting corporate and results based information, we're gonna have a more free flowing conversation, discussion about our Orexin program.

0:56 And, hopefully, we can make this interactive. If there's anything that you're, not clear on or you'd like a bit more information on, if we're getting two signs heavy, please do pop a question into the q and a box. If we see it at the time we're talking, we'll try and address it. But if not, we will have a review of that at the end and and go through and try and address any that we can. So for those of you new to THERACRYF, I'll give a brief overview of the business, and I'll take you through the sort of schedule of discussion we have today and also allow Fraser to introduce himself who thank you very much for joining us, Fraser. He's got a lot of knowledge on this program and neuropsychiatry development space in general. So THERACRYF, we're a clinical, company focused on brain disease.

1:44 We have a neuropsychiatry and oncology portfolio. Our strategy is really to develop, programs to generate compelling datasets, which will enable us to partner for larger, clinical phases and ultimately commercialization. So our recent acquisition that we completed last year has expanded our portfolio now to three defined assets, and these assets include the orexin program that we're gonna be talking about today, which is targeting, addictive, indications, a dopamine, inhibitor. So it's a inhibitor of the dopamine reuptake transporter, and that really is involved in, fatigue and apathy.

2:31 And, thirdly, our oncology program, s of x o one, who existing investors will, probably know a lot about. We're taking forward in glioblastoma, fatal brain disease in collaboration with the Erasmus in Rotterdam, leading into a clinical phase study next year in in patients. So the recent fundraise that we did, earlier this year has really given us a sort of renewed impetus around the acquired assets and specifically the orexin asset, And that's gonna enable us to complete, the IND package, for this program, and we'll kind of elaborate on what that means a bit later on and get it to clinic readiness. So that's gaining approval to go into people. And this is very important kind of value inflection for this program, to engage with potential partners, and get clearance to go further in clinical development.

3:27 So as I said, today's discussion will be focusing on orexin. We'll, take you through a bit about the scientific mechanism and why it's important in addiction, a bit more, information about why we think we have such a great asset and why it's differentiated. And also taking you through sort of the next twelve to eighteen months, what does the program of work we have, ongoing look like?

3:50 Where is it gonna get us to, and what we hope that will achieve?

3:55 So I'll hand over now to to Fraser so he can give a brief introduction, and then we'll come back. And I can just kind of say a few words about why, you know, we're really excited about taking, this program into the company in the first place. So, Fraser. Thanks, Helen. And thanks for the opportunity to to come and talk to you today. So yeah. So just by way of background, you know, I'm Fraser Murray. My background's in basic neuroscience. I've worked in pharma and biotech industry for thirty three years now. Twenty of those in big pharma, Merck, AstraZeneca, Shire, and the last thirteen in in various startup biotechs, including us then as chief scientific officer at Kronos Therapeutics where the these programs were previously living.

4:43 Yeah, my background really has focused on discovery and early development in both psychiatry and neurodegenerative disorders. And I was part of the original team that initiated this Orexin one program. Thanks, Fraser. So, when we were looking at how we could expand or probably the right word is diversify the risk profile of the company and provide shareholders with few further opportunities, and inquire programs. There are a few aspects we look at when we're going through that process. And, I kind of included this because was chatting with our new board member at Wardle, a little while ago, and he actually gave me this question. He was like, why did, the Kronos assets reach, that bar that you felt, you would propose to the board that we should acquire them?

5:38 And, really, we're looking at sort of three different factors. One is the commercial opportunity. So, we've talked in previous presentations about how, neuroscience m and a activity was actually in the doldrums just before, COVID and throughout COVID where the focus, previously was oncology, and there's still a lot of focus and development activity in oncology, and also in that sort of immunology and vaccine space. But after COVID, there was a real resurgence in m and a activity and not just at the late stage, program level. So you do see a lot of, buying and selling and merging activities between the mid and large sized pharma for commercial stage programs where they're looking to reach out into other jurisdictions.

6:25 But that wasn't just the case. We were seeing programs that were in mid clinical development also having, really attractive deals. And some preclinical discovery type programs, had sort of small pharma, large pharma partnerships, put in place. So this gave us a lot of confidence that it was a attractive area for pharma. And, ultimately, our goal is obviously to partner with pharma or have the company or the asset acquired.

6:56 And that we also had really strong, opportunity from, the patient perspective. So we talk about this thing called unmet patient need, and and sometimes it's quite trite and actually quite sad thing in this area. So in the sort of, neuropsychiatry area and addictive space, we've just seen, rising numbers, and that's across all, locations. So not just in The US or Europe or Asia, but everywhere seeing an increase in mental health disorders and particularly addictive disorders. Now partly that's through increased awareness generally and increasing rates of, diagnosis and support. But I think there's some other environmental stressors and and factors in life that's contributing to that as well.

7:49 But for particularly binge eating disorder, which we have preclinical data on, it's a relatively kind of early known or identified eating disorder and addictive disorder. But actually, in terms of numbers of patients, it's bigger than both anorexia and bulimia combined. So this provides us with a very large market opportunity, ultimately, and and a very high unmet patient need because these patients are really struggling with engaging in everyday life, and Fraser can, talk a bit further about that later on.

8:26 From an asset perspective, the science behind these assets was very strong. The data package, was great large pharma standards,

8:36 you know, all credit to to Fraser and Tim, who's also leading the program as we go forward now. And it had very good IP coverage. So in terms of we talk about this thing, which is NCE or novel chemical entity. So that means it's a new chemistry that was protected by patent coverage. And that patent coverage had been applied for in numerous jurisdictions was really important when you want to do deals with pharma that have interests in various, countries, and that that patent coverage extended, through a long duration. So you want a long duration of patent coverage so that you can get through your development program and have a good time on market that's protected so you can reach those, sales figures that generate the, ultimately, the return for the product. So all of those things, came together really to identify, this asset particularly is really attractive for, m and a.

9:34 So, Fraser, maybe I'll kind of get off why I'm so excited about this and the commercial opportunity and really dig into Orexin because, you know, we bandy about orexin, but I don't know if many of our shareholders actually know what that means or what the system is or how it's involved in addiction. So could you tell me a bit about the mechanism itself and why it's implicated in addiction?

10:00 Sure. So orexin is, what's called a neuropeptide. So a peptide, in the brain, it's produced by a certain brain region called the hypothalamus, actually a a subdivision of the hypothalamus. And it has a really fundamental, rule in arousal, motivation, and reward. So it acts on two different targets on the brain, two receptors, the orexin one receptor, which we're concerned with,

10:31 and the orexin two receptor. The orexin two receptor, which we won't really talk about much other than liability today, is heavily involved in sleep. So orexin two, antagonists promote sleep. So you don't want to hit orexin two or you will cause sedation somnolence. Orexin one is heavily involved in motivation and reward.

10:58 And the orexin containing neurons in the brain project to brain regions that are fundamentally driving the reward process. An orexin drives increased dopamine release when we have a pleasurable experience, we get a release of dopamine in the brain. Anorexin can can drive this. And what happens when you have a pleasurable experience? You get a a pulse of dopamine and and you wanna experience that again. Sometimes that can run out of control and you can have too much reward and that causes you to, have a a an impulsive and compulsive desire to seek out that activity, whether it's gambling, whether it's drugs, whether it's food, whether it's alcohol, you have too much reward and that leads to this addictive behaviour. And orexin is a key driver of that. So we know that if we can block that orexin one receptor, we can,

11:59 you know, restore that balance. So is this, how, you know, we've developed our drug to work? Can you maybe talk about so from

12:09 a orexin program and compound, what is this compound doing in the brain? How is it helping that? So importantly, it's it's what's called a small molecule. So a traditional, pill type drug which you would take orally. It then has to get into the brain, which is not a given. There's a barrier between the blood and the brain we have to design these compounds to make sure they enter the brain to have their action. They have to interact with the receptor. So we have to measure how much of the drug actually binds to that orexin one receptor, how much is blocking it. So it has to get in the brain, it binds to the orexin one receptor, then that orexin one receptor no longer has this excessive reward driving effect.

13:04 So the important thing is that it normalises the tone, normalises the amount of reward in the brain. It doesn't switch off reward and that's actually a really important thing and a really interesting and somewhat unique characteristic of Erexin-one. Many other mechanisms have been tried for anti addictive therapies. But one issue that many of them have is that they completely switch off reward altogether, so you no longer feel pleasure in anything. And there's a feature called anhedonia where you just no longer experience pleasure in doing something that you used to do. You may be addicted to to alcohol, but be a runner and and love running.

13:54 If you take certain mechanisms, it blocks the reward for alcohol. You don't want to seek that anymore, but no longer do you want to to go out and run. So you you you you people don't wanna take it because they experience no pleasure

14:06 whatsoever. Yeah. So this is what I talk about this all flippantly, patient compliance. So this really tags onto that. So Absolutely. Your drug to be well tolerated, I guess, is another expression. So in this sort of disease, people need to take it on a chronic basis. They need to keep taking it on an ongoing basis. So you don't want to have

14:32 masses of side effects. You don't want them feeling like they can't function normally or can't get enjoyment out of everyday activities because that's when they just stop taking it and you have this lack of compliance. Then they don't get effect as well, but they're also not taking it. Exactly. And there's many examples of that where launch drugs, are quite effective in doing what they're primarily designed to do, have poor compliance because they may cause sedation. They may cause anhedonia. And that type of anhedonia can lead to suicidal thoughts because you have no pleasure. So drugs can be effective but they also

15:08 have to be what we see is clean. And the orexin-one mechanism appears to be one of those targets that is not burdened with on target side effects. So side effects that are driven by the actual target you're blocking. So that's a very important part for for compliance. And it's interesting you you bring up some of those other effects. So we'll talk about a couple of other products. I know people have been really interested in the Glipse, and, you know, they have been implicated in suicidal ideation, some other

15:39 side effects. But we'll kind of park that for now and come back to it a bit later. But I would like to sort of go back to the mechanism and what interested the industry and the mechanism and and linking that to addiction or substance use disorders, we call it as well. So it kinda gives me confidence that there are other people interested and other organizations interested, not just from a partnering perspective, but that sometimes it's very difficult in the pharma industry to sort of break blaze a trail in a new mechanism, especially when there's no evidence or translational evidence behind it. So, could you maybe talk a bit about who else has identified this particular mechanism interesting and and their activity in the space? Yeah. Sure. So the the target's been known for for a long time and its role in in reward and particularly feeding behavior has been known for a long time.

16:36 It's one of those targets which in a way as someone with a drug in hand that has the properties that you would like in a potential medicine, it's a target that has been difficult to drug. So difficult to design

16:51 the right chemistry, to design the right molecule that has all the correct properties. And now we're at a stage in the evolution of the biology and the chemistry of the target where we where we do have that. So the first first generation of of orexin one research was driven by companies like GSK. And really, you know, the main issue that they faced was a lack of selectivity for the orexin one receptor. And that was, you know, not other of not other unrelated receptors, but it was being able to separate the ability to block orexin one without blocking orexin two. So they had some nice tool molecules that allowed them to show that you could block binge eating behavior with selective orexin one receptor blockers.

17:45 You could not block binge eating behaviour with selective orexin two blockers, but you did get somnolence. And with mixed blockers, you've got blocking of binge eating but also somnolence of sedation. And with their selective molecules, if you went to a dose that you need to achieve for prolonged activity, so you can do these studies short term and see an effect, but in patients, you need this to work all the time. And when they dosed high enough to keep the receptor blocked for a long period of time, they started to see sedation. And so we knew, at that stage that you needed a much wider separation, a a much more selective molecule than you might normally expect. And that's kind of where the field has evolved to. So now there's come the big companies like J and J, like Idorsia, like Indivior, like Ceravans, who have programs on orexin one who have improved the selectivity from those first generation molecules.

18:47 Selectivity is still

18:50 an issue for many of those programs we believe because although they've improved it, we think that probably in long term studies you may still see sedation in some ways. And that's where we're, I guess, excited. I use this phrase a lot about how we believe we have a potentially best in class compound. Can you maybe, in layman speak, talk about what best in class means and then relate it to those properties and selectivity that we believe we have for the orexin one receptor. Yeah. Sure. So, again, you know, just to to maybe rehash something I said earlier, you know, the fundamental things you want with a drug for for brain disorders is, you know, a tablet that you can easily swallow. When you swallow it, it's absorbed by the body and that is not a given, know, so not all drugs that you swallow will be absorbed into your bloodstream.

19:46 Once it gets into the bloodstream, it needs to distribute to the brain, so it has to get past that barrier that the brain has to keep it safe from various things that it doesn't want to get in there. So you have to bypass that barrier. You then need

20:04 the drug to be free in the brain to interact with the target. And these receptors, these are X1 receptors of what are called GPCRs, G protein coupled receptors, and we understand a lot about those. A lot of drugs target that type of receptor. And we know that you have to block almost all of those receptors to have an effect. So it's like a lock and key where your brain's got lots of locks and the drug is the key and you need to basically shove the key in as many of the locks as you possibly can. If you can, you might get an effect. If you don't block them all, you might get an effect, but it's probably short lived and that's ultimately no use. We'll maybe talk about that later, a lack of long lasting effect. And the the differentiation really, you know, so those are all differentiation points from first generation molecules. So some of them you might have had to give intravenously to get enough in the brain. But we've moved on and our molecule ticks all those boxes. It's got great properties.

21:05 It's also important that you can make it at scale and certain of the molecules that have been developed by competitors past and present are maybe more challenging to make than ours. So that presents a commercial challenge. So you have to be able to make it at scale to to sell it obviously. But really the the the key and and probably one of the greatest points of differentiation for our molecules, And we have really empirical data that you know puts numbers on this, is that we're highly, highly selective. So where you may want for certain targets 30 fold or a 100 fold selectivity, We don't believe that's enough here, and we have thousands of fold selectivity, which is really at that sort of top tier of of these, molecules.

21:53 And that's one of the things we were we were most excited about. So that's like looking at that from a clinical perspective. We are pretty confident that when we get into people, we're not gonna have this sedative effect because Exactly. It's so effective for orexin one even at higher exposures, let's say, so higher levels of drug in the system, we're not gonna affect that orexin receptor. And and it's important because there are launched approved drugs that block both orexin one and orexin two, and they those are sleep drugs. And they work very effectively at making people go to sleep, but even those for sleep medication have certain side effects reported with with some of them. Things like rebound hypersomnia where you just both spontaneously fall asleep, you know, the next day during the day.

22:44 And so if you think about the disease we're dealing with here, know the people have real compromise in their quality of life and how they can go about their daily routine. And so you can take away that aberrant reward with blocking orexin-one but you don't want to introduce sedation which just gives them another problem to deal with and another way that they cannot go about their normal daily business. So really critical to have selectivity versus that orexin two receptor. Great. And

23:19 talking about sort of that duration of effect and other sort of potential for off target effects,

23:28 You know, there is, as you well know, because it was originally a product, Vyvanse, which is on market in The US, with a label, for binge eating disorder. But that's an amphetamine prodrug. It's a stimulant. And so I've heard that patients really struggle with that because, you know, having to come off it, they're having breakthrough. Can you maybe sort of tell us a bit more about that and or maybe how successful it is because it's a successful product. Right? But also Yeah. Yeah. Absolutely. So I mean, as you said at the beginning, binge eating disorder is actually a a very large problem, a very large number of patients in both The US and Europe, which are, big markets. As you said, Vyvanse and Elvance as it's called in Europe is an amphetamine prodrug.

24:19 It's actually very effective at blocking binge eating. It has a differentiated profile from other amphetamine based drugs that were traditionally developed for ADHD. It has a different profile in the blood and the brain, but it's still a stimulant. And if you take a stimulant before bed, you will not sleep. Know, so the dopaminergic component, you increase dopamine in the brain, you're much more alert, and you just can't get to sleep. So it's it's a similar story with caffeine, know. You don't really wanna have a double espresso before you go to bed because the the stimulant, properties prevent you from sleeping. So Vyvanse is formulated as a once a day drug that you take in the morning and you're covered generally for the whole day.

25:12 But it will not cover you through the night. And unlike you, I've read on patient forums, anecdotal stories from a number of binge eating patients who say it's incredible during the day. I I don't binge during the day, but I get home and I just can't control my can't control my my bingeing. You know, eating during the night, you know, that type of thing. So while it's very effective, it's not perfect. Anorexin does not affect sleep. Anorexin one does not affect sleep, so you could be covered by blocking the target for twenty four hours, without the adverse effects that stimulants have. And also reflecting on your sort of lock and key, metaphor before and linking that to the words coverage. So it's really important that you're covering the receptor adequately for that entire twenty four hour period. And Yeah. Some other orexin antagonist maybe don't have the same profile that we have in terms of not only the selectivity for the receptor, but this ability to cover the receptor. So can you just refresh my memory? Like, in terms of the receptor occupancy or how much of the receptors need to be occupied all the time to a certain effect? It's quite Yeah.

26:33 So we we did very detailed studies with with the the lead molecule. We developed an experimental process called receptor occupancy where you dose with a radioactive version of orexin one blocker and that will then bind in the brain. Then when you give your drug, it it it blocks the receptors. You give the radioactive drug and any receptors that are not blocked will be bound by the radioactive drug and then you can see the radioactivity on an image. So where there's radioactivity, you have not blocked the drug. So you want no radioactivity ideally. So we did really detailed studies with the molecule showing that we could fully block all of the receptors for a very prolonged period of time.

27:21 We related that to the effects in animal models of binge eating, and so we could work out when we dropped below a certain threshold. And when we so we now know that we have to occupy above this threshold. If we don't, we we don't get the prolonged effect and we see much less inhibition of bingeing. So it's critical to have that profile that we have where, you know, you dose once a day or maybe even twice a day and maybe you take it before bed as well, which is not a problem with this mechanism. But others, you know, if you don't have enough in the brain, it's one thing. If you have a lot in the brain but it's stuck to the tissue, if it's not free to go and find the receptor, that's another big problem. So certain competitor molecules are less effective at occupying their receptors for a prolonged period of time, we believe.

28:17 But the most important thing is that our molecule has a good profile in occupying, covering that receptor for a prolonged period of time that shouldn't allow the effect to wear off as long as the patient takes it as prescribed. Mhmm. Okay. So maybe going back to this, really hot topic, okay, which is GLP one. So, I mean, substance use disorder development space, as I reflected on earlier, is a really hot space. It's ramping up a bit like oncology was maybe kinda ten years ago. Right? So there's burgeoning interest, a lot of development programs, looking at different mechanisms, not just orexin. And, actually, a number of my friends have been saying, you know, what about GLP ones, and should I be on them? And are they gonna work for other substance use disorders? This tells you a bit about my friendship group.

29:11 But so I'd just like to maybe I can describe a bit more about kind of those trials and sort of the binge eating population, and you can give a bit of insight into why you think there's room for existence of both of these things and why they're slightly different. So binge eating disorder is very kinda clearly defined. It's not just as my friend likes to say, I overeat and I over eat the wrong things, like, generally. You're having defined periods of binge, and these are occurring at least once, if not more times a week. And when you're having a binge, you are eating an abnormally large amount of food in the same defined period of time it would take someone else, let's say, to eat their dinner, so, like, a one or two hour period. You wouldn't just be having your plate of dinner. You would be having 10 loaves of bread or five large pizzas. And and there is a clear preference, food preference for some of these individuals as well, whether it's sort of savory, oily, sweet.

30:16 And then you have a lot of remorse and anxiety, and it turns into a behavior where you're sort of hiding things. You think about it at work. It's affecting your work. It's affecting your, family life. And, interestingly, though, these patients, are not like, let's say, bulimics. They're not necessarily purging. They're not the same as the anorexics. They're not going out always and having long runs. They're not engaging in these compensatory behaviors. And not a lot of them, I would say, you've seen different stats. But I'm sure I saw a stat recently that said only about twenty percent of binge eaters were in the obese category. Now that might be a bit more for for overweight because now we're going overweight and obese.

31:02 So for products and I'll probably take you the thunder about what you're gonna say is you're not necessarily looking at weight controls. You're looking more at behavior control. So that's sort of the definition of binge eating and how it's maybe different than some of the other eating disorders and purely being overweight or not. And then in terms of the ongoing GLP one trials, they're very specifically in overweight population. So if you look at those, trials that are currently undergoing recruitment, therefore, binge eaters who are over obese, actually, obese and overweight. So they're not in that other population. So if I haven't already taken all of those talking points, maybe I'll sort of hand over you to talk a bit sort of about the differences and the complementarities in terms of mechanism between Yeah. So, I mean, I I I think the the g o p one story is is, you know, probably the hottest story in science for a very long time.

32:02 As you see, there is some early data implying efficacy of GLP-one agonists in binge eating. Very small numbers, think one trial and some preclinical data in other abuse disorders. I think it's important to state that's preclinical. So we always have a relative healthy scepticism about how those might translate. But I think the the the GLP ones and and our eczema one, it's it's comparing apples and oranges because they they do two very different things. And you've highlighted, I think, a couple of key areas. So the GLP ones are really focused on metabolic and satiety pathways. So your brain and and the the rest of your body sending messages to each other, telling you how much energy you should expend, how much how much calorific intake you should have. And that's a very finely balanced process, and the GLP ones are clear clearly very fundamentally involved in that.

33:05 The Erexin one is is quite different. It's purely that reward pathway, that aberrant reward. It's about the compulsive seeking of of that reward and the impulsive behavior. I mean, you hit the nail on the head about the the behaviors. Know, it's it the the psychiatric elements of binge eating are huge. Know, that's actually what many, many people want to get away from. You are correct, know, whichever one of our stats is correct, not all binge eaters are obese and not all obese people are binge eaters. So you're not dealing with a straightforward overweightness here. There's a large number of normal weight binge eating patients.

33:51 And they do tend to eat in secret a lot. A lot of us can maybe relate that to stories about alcoholism where people are hiding bottles of vodka in the toilet cistern and shamefully drinking it. Is a similar story. So the psychiatric complications will not be addressed by GLP-one, I do not believe. But the GLP-one story does make some sense. I think we also have to bear in mind that there is a, you know, a set of data around GLP ones making people feel nauseous and and perhaps actually even vomiting, and that will naturally affect binge eating. In fact, we used to use this as a control in the preclinical models. If you give a a compound that's well known to cause nausea and vomiting in in humans to rats who don't vomit but they do feel unwell.

34:49 The binge eating, you can get a false positive in binge eating preclinical studies. So it looks like it works but actually it's because they feel terrible. So, you know, the GLP-1s probably have a place in the binge eating space where patients are only concerned with losing weight, that obese population which is a minority I think. Whereas the Erection one will address that compulsive behaviour. Our view has always been that if you address the excessive reward and therefore you don't binge so much, de facto you will lose weight but you won't lose drastic rapid weight like you do with with GLP ones. It's more of a normalization if you like because it's Yeah. Exactly. It's a slow which is a healthy way to lose weight. A slower, steady, you know, back to equilibrium.

35:39 So you know, you can clearly see there they are apples and oranges, but what I would argue is that it's apples and oranges that you can make a pretty good fruit salad out of because they would work together in combination. So if you wanna address the weight loss and there's cefaglutide or whatever that you're taking for the obesity, you could take an orexin one antagonist in combination with that to address the psychiatric, complications of bench, which GLP one will not address. Yeah. Yeah. And it's reflecting on conversation we've had before for Bingetas, there is a large portion of them that have other substance use. Yes. That's sort of primed to that. Yeah. Absolutely. So the comorbidity it's a good point. I didn't mention it earlier. It's a really good point. So the comorbidity of other substance use is high in binge eaters. And it makes sense because you have an aberrant reward circuit. So your drug seeking or pleasure seeking behavior will be skewed compared to a a a non binge eating person. So, yeah, I I think addressing the compulsion, the impulsivity, the aberrant reward for me has always been the key part of this. I've always thought of it more as a psychiatric rather than a metabolic disease, although, obviously, there's a metabolic component in in weight gain in a large number of of patients.

37:06 Yeah. And from a, I guess, also a commercial perspective, this allows us this mechanism allows us to sort of define or get translational evidence of a label in one indication and then potentially later on down the line or a partner later on down the line to do additional studies to get additional labels. When we say labels, that sort of gives you the approval to give it to a subset of patients and get reimbursed. It allows you to get money Yep. At for for your product. Yeah. So, you know, we're we're going with binge eating because there is the translational evidence because we have the preclinical evidence, but there are other opportunities, aren't there? Yeah. You're absolutely right. And I I think binge eating has a defined pathway because Vyvanse has gone all the way to market and and sells well. So it's logical for a company like THERACRYF to to think about it that way.

38:02 But you're right. The optionality is is large because there are multiple different addictive disorders. Each will have, you know, different labeling, you know, so you would get approval officially to go into different patient subsets. But I would imagine that doctors would prescribe anyway to certain patients with other addictive disorders which would build the dataset. I think it's also worth mentioning, I mean, it's not the focus of today and it shouldn't be because the data is less, but there's also potential for orexin one antagonists in anxiety disorders, particularly panic, which is another big unmet need. And, you know, I think there's there's data out there preclinically and even small amounts of clinical data to say that it should work. Jay took that into a phase one. So for Yeah. Exactly. You maybe talk talk us a bit high level through that study? Because it was healthy volunteers, but it was a chat a particular challenge. So it's it's a really interesting area because a lot of psychiatry indications are very complex, very heterogeneous. You know, there's a lot of variability between patients.

39:19 You can't do much in healthy volunteers to to try it out early. But panic disorder is one, where there's some reasonably robust, experimental medicine trials you can do in humans before you get to patients. So very early on to derisk. And in in simple terms, you you can induce panic in healthy volunteers, you know, whether you're chilled out and not remotely anxious. So one of the main studies, you can do this in animals as well. One of the main ways of doing it is carbon dioxide inhalation. So as you can imagine, if you are exposed to higher percentages of of carbon dioxide than than you would normally experience. You start to get this sensation that you're being asphyxiated, you know, you can't breathe. Sounds blender. Right? Even even if you know that it's a it's an experiment that you're doing, your body physiologically will panic, massive heart rate increases, various other hormones released. So you can test these, in healthy volunteers by inducing panic. There's milder versions, you know, things like public speaking tests.

40:30 So you take someone who's not used to speaking publicly, tell them that they're gonna have to stand in front of a big crowd and give a give a talk and they will naturally have some some panic related symptoms. But the the carbon monoxide carbon dioxide. Sorry. Not trying to kill them. The carbon dioxide test is one that's widely used and people have done that with Eryxin-one antagonists pre clinically and clinically with with very encouraging effects. So again, it's a it's an area that could be explored early. Similarly, you know, maybe slightly less well established, but there are some earlier tests of binge eating that you can do in healthy volunteers, particularly young healthy males, you know, when they're given Of eating.

41:15 Azolubitum. Yeah. Free free access to food. You can you can quantify, how much they eat, how fast they eat. You can even quantify chewing behavior that, you know, reflects bingeing. So there are multiple things that can be done in the clinic to derisk before you get to to patients. K. So that's kind of a nice segue in how do we get to patients. Right? So reflecting on earlier, the the fundraise that we've recently done, it's allowed us to reinvigorate and restart this program. And it's come from a a great scientific base. So we have data for effect in binge eating in rodent models. We have clean, seven day non GLP tox. So that's looking at potential toxic effects in, in rodents, so in rats in this case.

42:07 But we need to move this forward now to, get it to we banded this this sort of around. So IND and CTA is is something that we use, quite often. And, really, what this means is approval to take your compound into a healthy volunteer study. And that's given by a regulatory agency in the jurisdiction that you're, wanting to conduct your study in. And that's why we use completely different because one is really relevant to, the FDA in The US, and that's an IND. And one, is more relevant to European regulatory authorities. And at the moment, we're sort of keeping our our options open into when, you know, where we're gonna conduct these studies. And so really importantly, we need to make sure the quality of our data and the providers we work, with are have been audited by all the regulatory authorities and that we audited them ourselves, so that that gives us freedom to apply, into those, different locations when we have the complete data package. So, Fraser, the the sort of work packages we're looking to do now, can you maybe give a bit more flavor on what we're gonna try and achieve over the next twelve to eighteen months with the Orexin program and and sort of what that's gonna look like when it all comes together?

43:33 Yeah. Sure. So, you know, this route to the clinic is a very standard prescribed process. So what we will do is what everybody else developing a small molecule drug, to go into humans for the first time will be doing. So in a way, we've we've got over the unpredictable phase, know. So the discovery phase where you come up with a target, you design drugs, you test them, you see if they work, and then you decide that that's the candidate you're gonna take forward. That that's largely unpredictable. You know, sometimes you just can't drug it, sometimes it doesn't do what you think. We've got past that stage and the next phase, as you say, that gets us to the clinic is is a well worn path. It's defined by regulators in in each of these territories, but broadly, it's identical.

44:19 So first of all, have to manufacture enough of it to a certain standard to be able to run it in regulatory safety and toxicology studies. So that means you have to take the drug manufacturing process, you have to develop it to be able to make it at scale. So we have been typically making relatively small amounts up until now because we've been doing, you know, small animal studies here and there. You need to make more of it. So that that takes a different chemistry, and we have a very good handle on that. So you have to scale that up. It has to meet certain standards of quality to then be used in the regulatory safety studies. Now those regulatory safety studies and toxicology studies, they extend what we already have. As you said, we've got nonregulatory safety data in rats.

45:11 You have to do it in two species, rat and then one larger species. So it could be dogs, monkeys, mini pigs. You know, it could be some other larger species. So we will do those toxicology studies. You know, they they typically run for twenty eight days dosing to make sure you see no adverse events. So you look at various different organs in the body at the end of the dosing, make sure there's no toxicity observed in any of the major organs. You look for weight loss, etc. You look at other parameters, like you take blood samples, make sure none of the blood chemistry changes that's maybe indicative of of toxicity in the liver or the kidneys. You're Fearful of seeing tox signals, should we be?

45:59 No. So is is open understanding what that therapeutic we have. And that and some of the regulators actually like to see effects at higher dose, don't they? Well, as a as a company, in an ideal world, you want to see some toxicology because you know that something is happening. It might sound weird to say it, but in these toxicology studies, you dose at tens or maybe even hundreds of fold higher than the dose you needed to have your your effect. So, you know, I talked about how much we had to get in the brain to block the receptor and see the effect on binging. We'll be dosing, these animals at, you know, maybe thirty or or a 100 fold higher doses than that. So you're really pushing it as hard as you can. And ideally, you see a a a signal, that's great because you know at which point you need to to stop.

46:52 And that's really desirable, believe it or not, for for human studies because you know what to look for, you know when it should happen, and you stay away from that but you go as high as you can. So we shouldn't be at all worried if we see any minor safety signals. What you want to see is a separation between the amount of drug in the in the blood and in the brain that gives you your your beneficial effect and the amount of drug in the blood or the brain that gives you the the tox signal that you see. If we don't see anything, it's fine. But if we do see something, it's it's not a panic. So you get through those studies. You write up a very comprehensive document on on on all of that, and then you submit it to a regulatory body who reviews it, asks you questions, and then they ultimately will give you permission to go in with a very defined protocol into into volunteers.

47:51 Yeah. Thank you. And and just reflecting on that, actually, you know, what we've seen so far, it's been kind of what we call unremarkable or clean from a tox perspective. And that gives another challenge, right, because the regulators want you to definitely push that envelope, and it it makes it necessary for us to actually generate a lot of material, a lot of API, it was called active pharmaceutical ingredient, to make enough so that we can reach those higher levels. And I'm always surprised when I'm told how big a mini pig actually gets. You know? These these are quite big mini pigs. Right? So Yeah. We need quite willing products to reach those top doses. You're talking yeah. I mean, you know, a a recent program I was involved in, you know, there's a regulatory maximum of of dose, which is one gram per kilogram of body weight. So, you know, for a And then, like, 30 get to 30 kilograms? Yeah.

48:45 Or thirty, forty, you know, so we had to make a 150 kilograms of of the drug to to dose those for chronic studies. But you know, you think of that equivalent in in let's say a 70 kilogram human, that's seventy grams of drug, which is the equivalent of taking a 140 paracetamols orally, you know. So that's a lot of drug. So, you know, you have to you have to to keep that in mind in terms of making enough of the the compound and you have to allow the time to make that because going from making hundreds of milligrams or or a gram or two to tens of kilos is is actually a a significant process to work through. Yeah. And this is what so our partner, Farmer On, who we're working with are really cracking on with this activity now. And so, the first phase is really to explore the chemistry steps, the process chemistry steps, and to look at whether they can be reduced because, obviously, this comes into play into making it sort of more efficient at making, larger amounts of material. But, also, everyone knows COGS. Right? So reducing your your cost of goods at the end of the day. So they're really working hard to, optimize those steps, reduce them down, look at some of the chemical intermediaries, and see if that they can substitute them for for cheaper intermediaries.

50:08 And this is the process that's gonna happen now for the next few weeks. And they will be making starting materials. So starting, materials that we can look at formulation. So we look at conducting this dose range finding in the on animals so that we know when we get to that twenty eight day, that we can reach the the levels that we need to reach. And after this period, we will then commence that large scale, so this 10 kilogram scale. And that actually takes the largest amount of time out of this work program, and it's just a an element of time. There is sort of nothing more to it that you can't do, making these batches in in this process. And we believe that that will be complete by the end of this year, and that's when we'll look to start the dosing of these animals. And then, in the early part of next year, conduct that part of the study so that we can have the data packages that we can put together. So I note that we are kind of getting down now to, only ten minutes to go. So we'll sort of look at wrapping up.

51:10 Kurt, so I know we've had a question. Can we get detailed timeline on next stages? There's a broad one on the website and regular updates. Sure. I think we in the presentation that's off the on the website, we've broken down the timeline into kind of news flow activities. But if anyone wants something a bit more scientific, we can talk about what we can share. Obviously, we want to make it accessible, but bearing in mind that timelines fluctuate because of, things that you encounter in the process. So, you know, we we want people to be aware of how those things can happen as well. So just to say thank you, Fraser, for joining me. It's been a really stimulating conversation. I always enjoy these chats with you, and I hope people have gained more of an insight into the program and why we're so excited about it. And this is a bit of departure, as I said, for us in the format of these presentations. So if it's something that you like or you have any feedback on, for us on how we can optimize it, whether we've been two sites heavy, not sites enough heavy, whether it's been too long, too short, or you'd like us to focus on, different, areas or have more of these in a regular fashion as the comments been maybe shorter, but in a more regular basis, we're happy to take that on board and think about them. So, hopefully, you can take from this why we're really committed to this program. We believe it's gonna bring value accretion to the company.

52:39 And as we move through those next stages of development, you know, we can share, updates. We really look forward to providing insight into that. I think sometimes, you know, it's the balance of doing this outward facing, activity and sharing, and we're very small companies. So in my day to day life, I'm focused on actually pushing this program forward. So it's good. I always like, talking about science and talking about the the programs and why they're gonna give, hopefully, a good opportunity for shareholders, in the future. So, yeah, it'd be great to have your feedback. And I think, that concludes our our talk for today. So thanks again, Fraser. Thank you. That's great. Helen Fraser, thank you once again for updating investors.

53:26 As Helen just said, we'll now redirect you for the opportunity to provide your feedback in order that the company can really better understand your views and expectations. This will only take a couple of moments to complete, but I'm sure it will be greatly valued by the company. Above the presenters, we'd like to thank you for attending today's presentation. Wish you all a very good afternoon.