Theracryf Plc (TCF) Earnings Call Transcript & Summary

Good morning, ladies and gentlemen, and welcome to the Theracryf Investor Update regarding the deep dive into the addiction program. [Operator Instructions] Before we begin, I'd like to submit the following poll, and I'm sure that the company will be most grateful for your participation. I'd now like to hand over to your presenters today, Dr. Fraser Murray and Dr. Helen Kuhlman. Good morning, to you guys.

Thank you Mark. And yes, good morning to all of our existing, hopefully new and potentially interested shareholders to Theracryf. This sort of marks a departure in the IMCs we normally give. So instead of just presenting corporate and results-based information, we're going to have a more free-flowing conversation discussion about our orexin program. And hopefully, we can make this interactive if there's anything that you're not clear on, you'd like to get more information on if we're getting 2 [ science ] heavy, please do pop questions into the Q&A box. If we see it at the time we're talking, we're trying to address it. But if not, we will have a review of that at the end 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. Fraser, 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. We have a neuropsychiatry and oncology portfolio. Our strategy is really to develop program to generate compelling data sets, which will enable us to partner for larger clinical phases and ultimately commercialization. So our recent acquisition that we completed last year sort of expanded our portfolio now to 3 defined assets. And these assets include the orexin program that we're going to be talking about today, which is targeting addictive indications, a dopamine inhibitor with an inhibitor of the dopamine reuptake transporter, and that really is involved in fatigue and apathy. And thirdly, our oncology program, SFX-01, our existing investors will probably know a lot about. We're taking forward in glioblastoma, fatal brain disease in collaboration with the Erasmus in Rotterdam and leading into a clinical phase study next year in patients. So the recent fundraises that we did earlier this year has really given us the sort of renewed emphasis around the acquired assets and specifically the orexin assets. And that's going to 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 and value inflection for this program to engage with potential partners and get clearance to go further in clinical development. So as I said, today's discussion will be focusing on Orexin. We'll take you through a bit about the scientific mechanism 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 next 12 to 18 months, what does the program of work we have ongoing looks like where is it going to get us to and what we hope that will achieve. So I'll hand over now 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 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 come and talk to you today. So yes, so just by way of background, I'm Fraser Murray. My background is in basic neuroscience, worked in pharma and biotech industry for 33 years now, 20 of those in big pharma, Merck, AstraZeneca and Shire. And the last 13 in various start-up biotechs, including Aspen. As Chief Scientific officer at Chronos Therapeutics where these programs were previously living. Yes, 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-1 program.

Thanks, Fraser. So when were looking at how we could expand or probably the right word is diversify the risk profile of the company and provide shareholders with further opportunities and inquired programs. There are a few aspects we look at when we're going through that process. And I kind of included this because I was chatting with our new Board member, Ed Wardle, a little while ago when he actually gave me this question.n He was like, why did the Chronos assets reach that bar that you felt you would propose to the Board that we should acquire them. And really, we're looking at sort of 3 different factors. One is the commercial opportunity. So -- we've talked in previous presentations about how neuroscience M&A activity was actually in the doldrums just before COVID and throughout COVID where the focus -- previously, it was oncology and there's still a lot of focus in development activity in oncology and also in that technology and vaccine space. But after COVID there was a real resurgence in M&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-size pharma for commercial stage programs that they're looking to reach out into other jurisdictions. 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 program has sort of small pharma, large pharma partnerships put in place. So this gave us a lot of confidence that -- it was an attractive area for pharma. And ultimately, our goal is obviously to partner with pharma who have the company or the assets acquired. And then we also had really strong opportunity from the patient perspective. So we talk about this thing called unmet patient need. And sometimes, it's quite tight. And as you quite have seen 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. They're not just in the U.S. 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 are some other environmental stresses and factors in life is contributing to that as well. But 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 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. From an asset perspective, the science behind these assets was very strong. The data package with great large pharma standards, all credit to Fraser and Tim, who is also leading the program as we go forward now. And it had a 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 has been applied for in numerous jurisdictions is really important and you want to do deals with pharma that have interest in various countries. And that, that patent coverage extended through a long duration. so you want a long duration of patent coverage, so 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 ultimately the return for the product. So all of those things came together really to identify this asset, particularly is really attractive for M&A. So Fraser, maybe I'll kind of get off why I'm so excited about this and the commercial opportunity really big interacting because we [ don't give out ] orexin. But I don't have as many of our shareholders actually know what that means or what the system is or how it's evolved in addiction. So could you tell me a bit about mechanism itself and why it's implicated in addiction?

Sure. So Orexin is -- was called a neuropeptide. So a peptide in the brain is produced by a certain brain region called the hypothalamus -- actually a subdivision of the hypothalamus and it has a really fundamental role in arousal, motivation and reward. So it acts on 2 different targets on the brain to receptors, orexin-1 receptor, which we are concerned with and the orexin-2 receptor. The orexin-2 receptor, which we won't really talk about much other than liability to be it heavily involved in sleep. So orexin-2 antagonists promote sleep. So you don't want to hit orexin-2 or you'll cause sedation somnolence. Orexin-1 is heavily involved in motivation and reward. And the orexin containing neurons in the brain project to bring regions that are fundamentally driving the reward process. And orexin drives increased dopamine release when we have a pleasurable experience. We get a release of dopamine in the brain and orexin can drive this. And what happens when you have a pleasurable experience, you get a pulse of dopamine and you want to experience that again. Sometimes that can run out of control and you can have too much rewards and that causes you to have 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 done too much reward and that leads to this addictive behavior. And orexin is a key driver of that. So we know that if we can block that orexin-1 receptor, we can restore that balance.

So is this how we've developed our drug to work. Can you maybe talk about -- so from a orexin program and compound, what is this compound doing in [indiscernible]. How is it helping that?

So importantly, 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, and 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-1 receptor how much is blocking it. So it has to get in the brain. It binds to the orexin-1 receptor, then that orexin-1 receptor are no longer has this excess of rewards driving effect. So the important thing is that it normalizes the tone, normalizes the amount of rewards 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 orexin-1. Many other mechanisms have been tried for anti-addictive therapies. But one issue that many of them have is they completely switch off reward altogether, so you no longer feel pleasure in anything. And there's feature called Anhedonia, where you just no longer experience pleasure and doing something that you used to do. So you may be addicted to alcohol, but be a runner and love running. If you take certain mechanisms that blocks the award for alcohol, you don't want to seek that anymore but no longer do you want to go out and run. So you -- people don't want to take it because they experience no pleasure whatsoever.

[indiscernible] Let's talk about this [indiscernible] client patient compliance so they really tags on to that. So it [indiscernible] with your drug to be well tolerated, I guess, is another expression. In this sort of disease, people need to take it on a chronic basis They need to keep taking it on an on going basis. So you don't want to have matters of side effects. You don't want them feeling, they can't function normally or can't get enjoyment of everyday activities because that's when they just stop taking it and you have the lack of compliance. So then they're going to get effect as well, but they're also not taking it.

Exactly. And there's many examples of that where launch drugs, which are quite effective in doing what they're primarily designed to do have poor compliance because they may cause sedation because anhedonia, and that type of anhedonia can lead us to thoughts because you have no pleasure. So drugs can be effective, but they also have to be, obviously, is clean and the orexin-1 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 compliance.

And I it's interesting you bring up some of those other effects. So we'll talk about a couple of other products. So I know people have been really interested in this [indiscernible] and they have been [indiscernible] to suicidal ideation, some other side effects, but we'll kind of park that for now and come back to a bit later. But I would like to sort of go back to the mechanism and what interested the industry and the mechanism and linking that to addiction or substance use disorders reported as well. So it kind of gives me confidence that there are other people interested and other organizations interested not just from a partnering perspective, but sometimes it's very difficult in the pharma industry to blaze a trail and a new mechanism, especially when there's no evidence for translational evidence behind it. So could you maybe talk a bit about who else has identified this particular mechanism interesting and their activity in the space.

Yes, sure. So the target has been known for a long time and its role in reward and particularly exceeding behavior has been known for a long time. It's one of those targets, which in a way, as someone with a drug in hand that is -- has the properties that you would like in a potential medicine. If the target that has been difficult to drug. So difficult to design 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 do have that. So the first generation of orexin-1 research was driven by companies like GSK, and really the main issue that we faced was a lack of selectivity for the orexin-1 receptor. And that was no other unrelated receptors, but it has been able to separate the ability to block orexin-1 without blocking orexin-2. So they had some nice [ tool ] molecules that allow them to show that you could block binge eating behavior with selective orexin-1 receptor blockers. You could not block binge eating behavior with selective orexin-2 blockers but you just get somnolence, and with mixed blockers, you've got blocking of binge eating but also somnolence/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 much more selective molecule than you might normally expect. And that's kind of where the field has evolved to. So now there's the big companies like J&J, like Idorsia, like Indivior, like Cerevance, who have programs on orexin-1 who have improved the selectivity from those first-generation molecules. Selectivity is still an issue for many of those programs, we believe because although they have improved it, we think that probably in long-term studies, you may still see sedation and somnolence.

And that's where we're I guess, excited you just phrased a lot about how we believe we have potentially best-in-class compound. Can you maybe in layman's speak, talk about what best-in-class means and then related to those properties and selectivity that we believe we have for orexin-1 receptor.

Yes, sure. So again, just to maybe rehash something I said earlier, the fundamental things you want with a drug for brain disorders is a tablet that you can easily swallow when you swallow it, it's absorbed by the body. And that is not a given. So not all drugs that you swallow will be absorbed into your bloodstream. 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 doesn't want to get in there. So you have to bypass that barrier. You then need the drug to be free in the brain to interact with the target. And these receptors, these orexin-1 receptors of what are called GPCRs G protein-coupled receptors. And we understand a lot of those, a lot of drugs to 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 in key where you're brain has got lots of locks and the drug is the key and you need to basically shut the key and as many of the locks that 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, but a lack of long-lasting effect. And the differentiation really -- those are all differentiation points from first-generation molecules. So some of them 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. 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 sell it, obviously. But really, the key and probably one of the greatest points of differentiation for our molecules, we have really empirical data that this numbers on this is that we are highly, highly selective. So where you may want for certain targets, 30-fold or 100-fold selectivity, we don't believe that's enough here, and we have thousands of full selectivity, which is really at that sort of top tier of these molecules. And that's one of the things 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 going to have this [indiscernible] effective for orexin-1, even at higher exposure, let's say, to higher levels of drug in the system will not going to affect that [ orexin receptor ].

Yes. And it's important because there are launched approved drugs that block both orexin-1 and orexin-2 and those are sleep drugs, and they work very effectively and making people go to sleep. But even those for sleep medication have certain side effects reported with some of them things like rebound hypersomnia where you just will spontaneously fall sleep the next stage during the day. And so if you think about the disease we're dealing with here, 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-1, but you don't want to introduce sedation, which just gives them another problem to deal with, another way that they cannot go about their normal daily business. So really critical to have selectivity versus that orexin-2 receptor.

Great. And talking about sort of that duration of effect and other sort of potential for off-target effects. There is, as you well know, because it was originally a Shire product, Vyvanse, which is on market in the U.S. with a label for binge eating disorder. But that's an amphetamine prodrug is a stimulant. And so I've heard that patients really struggle with that because having come off with having a 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?

So yes, absolutely. So I mean, as you said at the beginning, binge eating disorder is actually a very large problem, a very large number of patients in both the U.S. and Europe, which are big markets. As you said, Vyvanse and Elvanse as it's called in Europe, is an amphetamine prodrug. 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. 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 a similar story with caffeine. You don't really want to have a double espresso before you go to bed because 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, but it will not cover you through the night. And like 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 don't binge during the day, but I get home. And I just can't control my binge eating during the night, that type of thing. So while it's very effective, it's not perfect. And orexin does not affect sleep. Orexin 1 does not affect sleep. So you could be covered by blocking the target for 24 hours without the adverse effects that stimulants have.

And also reflecting on your sort of lock-in key metaphor before and linking that to the word coverage. So it's really important that you're covering the receptor adequately for that entire 24-hour period. And 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. Can you just refresh my memory, like in terms of the receptor occupancy or how much of the receptors need to occupy all the time to a certain effect.

Yes. So we did very detailed studies with the lead molecule. We developed an experimental process called receptor occupancy where you dose with a radioactive version of orexin-1 blocker, and that will then bind in the brain. And then when you give your drug, it blocks the receptors. You give the radioactive drug and any receptors that are not blocked will be bound by the radioactive drug and 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 molecule showing that we could fully block all of the receptors for a very prolonged period of time. We related that to the effect in animal models of binge eating. And so we could work out when we dropped below a certain threshold. And we -- so we now know that we have to occupy above this threshold. If we don't, we don't get the prolonged effect and we see much less inhibition of binging. So it's critical to have that profile that we have where 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, if you don't have enough in the brain, that is 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 the receptors for a prolonged period of time, we believe. 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.

So maybe going back to this really hot topic, okay, which is [ GLP-1 ]. So I mean, substance use disorder development space, as I sort of reflected on earlier, is a really hot space. It's ramping up a bit like oncology was maybe kind of 10 years ago, right? So there's surge in interest, a lot of development programs, looking at different mechanisms, not just orexin. And actually, a number of my friends have been saying, what about GLP-1s? And should I be on them? And are they going to work for other substance use disorders. It tells you a bit about my friendship group. 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 kind of clearly defined. It's not just as my friend likes to say, I overeat and I overeat all the wrong things, but 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 1- or 2-hour period. You wouldn't just be having your place of dinner, you would be having 10 loaves of bread or 5 large pizzas. And there is a clear preference, food preference for some of these individuals as well, whether it's sort of savory, oily, sweet. 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, they're not necessarily purging. They're not the same as the [indiscernible]. 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. I'm sure I saw a stat recently that said only about 20% of binge eaters were in the obese category. Now that might be a bit more for overweight because now we're going overweight and obese. So products, and I'll probably take the thunder about what you're going to say is you're not necessarily looking at weight control, you're looking more at behavior control. So that's sort of the definition of binge eating and how it may be different than some of the other eating disorders and purely being overweight or not. And then in terms of the ongoing GLP-1 trials, they're very specifically in overweight population. So if you look at those trials that are currently undergoing recruitment, there for binge who are 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 to talk a bit sort of about the differences and the complementarities in terms of mechanism between...

Yes. So I mean, I think the GLP-1 story is probably the hottest story in science for a very long time. As you say, there is some early data implying efficacy of GLP-1 agonists in binge eating. Very small numbers, I think one trial and some preclinical data in other abuse disorders. And I think it's important to state that's preclinical. So we always have a relative healthy skepticism about how those might translate. But I think the GLP-1s and Orexin-1, it's comparing apples and oranges because they do 2 very different things. And you've highlighted, I think, a couple of key areas. So the GLP-1s are really focused on metabolic and satiety pathways. So your brain and the rest of your body sending messages to each other, telling you how much energy you should expend, how much calorific intake you should have. And that's a very finely balanced process and the GLP-1s are clearly very fundamentally involved in that. Orexin 1 is quite different. It's purely that reward pathway, that aberrant reward. It's about the compulsive seeking of that reward and the impulsive behavior. I mean you hit the nail on the head about the behaviors. It's the psychiatric elements of binge eating are huge. And that's actually what many, many people want to get away from. You are correct, whichever one of our stats is correct, not all binge eaters are obese and not all of 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. 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. This is -- it's a similar story. So the psychiatric complications will not be addressed by GLP-1, I do not believe. But the GLP-1 story does make some sense. I think we also have to bear in mind that there is a set of data around GLP-1s making people feel nauseous 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 compound that's well known to cause nausea and vomiting in humans to rats who don't vomit, but they do feel unwell. The binge eat -- 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 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 orexin 1 will address that compulsive behavior. And 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 GLP-1s.

It more harmonization, if you like, because it.

Yes, exactly. It's a slow -- which is a healthy way to lose weight, a slower, steady, back to equilibrium. So you can clearly see the there are apples and oranges. But what I would argue is that it's apples and oranges that you can make a pretty good salad out of because they would work together in combination. So if you want to address the weight loss and there's semaglutide or whatever that you're taking for the obesity, you could take an orexin-1 antagonist in combination with that to address the psychiatric complications of binge, which GLP-1 will not address.

Yes. And it's conversation we've had before for binge eaters, there is a large portion of them that have other substance use that primed to that.

Yes, absolutely. So the comorbidity -- it's a good point. I didn't mention 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 non-binge eating person. So yes, 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 weight gain in a large number of patients.

Yes. And from, I guess, also a commercial perspective, this allows us -- this mechanism allows us to sort of define or get translational evidence of a label of 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's what gives you the approval to give it to a subset of patients and get reimbursed. It allows you to get money for your product. So 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.

Yes, you're absolutely right. I think binge eating has a defined pathway because Vyvanse has gone all the way to market and sells well. So it's logical for a company like Theracryf to think about it that way. But you're right, the optionality is large because there are multiple different addictive disorders. Each will have different labeling, 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 data set. But 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-1 antagonists in anxiety disorders, particularly panic, which is another big unmet need. And I think there's data out there preclinically and even small amounts of clinical data to say that should work.

[indiscernible] Into a Phase I. So...

Yes, exactly.

Could you, maybe, talk a bit high level through that study because it was healthy volunteers, but it was a particular challenge.

Yes. So it's a really interesting area because a lot of psychiatry indications are very complex, very heterogeneous. There's a lot of variability between patients. You can't do much in healthy volunteers 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 simple terms, you can induce panic in healthy volunteers, whether you're chilled out and not remotely anxious. So one of the main studies 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 carbon dioxide than you would normally experience, you start to get this sensation that you're being asphyxiated, you can't breathe even if you know that it's an experiment that you're doing, your body physiologically will panic massive heart rate increases, various other hormones release. So you can test these in healthy volunteers by inducing panic. There's milder versions, things like public speaking test. So you take someone who's not used to speaking publicly, tell them that they're going to have to stand in front of a big crowd and give a talk and they will naturally have some panic-related symptoms. But 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 orexin-1 antagonist preclinically and clinically with very encouraging effects. So again, it's an area that could be explored early. Similarly, maybe slightly less well established, but there are some earlier tests of binge eating that you can do in healthy volunteers, particularly young and healthy males when they're given A, yes, free access to food, you can quantify how much they eat, how fast they eat, you can even quantify chewing behavior that reflects binging. So there are multiple things that can be done in the clinic to derisk before you get to patients.

Okay. So that's kind of a nice segue in how do we get to patients, right? So reflecting on earlier, the fundraise that we've recently done, it's allowed us to reinvigorate and restart this program. And it's come from a great scientific base. So we have data for effect in binge eating in rodent models. We have clean 7-day non-GLP tox. So that's looking at potential toxic effects in rodents, in rats in this case. But we need to move this forward now to get it to -- we banded these sort of [indiscernible] around. So IND and CTA 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 the completely different natures because one is really relevant to the FDA in the U.S., and that's an IND and one is more relevant to European regulatory authorities. And at the moment, we're sort of keeping our options open into where we're going to 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 the sort of work packages we're looking to do now, can you maybe give a bit more flavor on what we're going to try and achieve over the next 12 to 18 months with the Orexin program and sort of what that's going to look like when it all comes together?

Yes, sure. So 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 got over the unpredictable phase. 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 going to take forward. That's largely unpredictable. 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 a well-worn path. It's defined by regulators in each of these territories, but broadly, it's identical. So first of all, you 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 small animal studies here and there. You need to make more of it. So 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. You have to do it in 2 species, rat and then larger species. So it could be dogs, monkeys, mini pigs, it could be some other larger species. So we will do those toxicology studies, they typically run for 28 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, et cetera. You look at other parameters like you take blood samples, make sure none of the blood chemistry changes that's maybe indicative of toxicity in the liver or the kidneys.

[indiscernible] of seeing tox signals should we [indiscernible] understanding what that therapeutics we have. And some of the regulators actually like to see effects at higher dose.

Well, 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 effect. So I talked about how much we have to get in the brain to block the receptor and see the effect on binging. We'll be dosing these animals at maybe 30 or 100-fold higher doses than that. So you're really pushing it as hard as you can. And ideally, if you see a signal, that's great because you know at which point you need to stop. And that's really desirable, believe it or not, 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 blood and in the brain that gives you your beneficial effect and the amount of drug in the blood or the brain that gives you the tox signal that you see. If we don't see anything, it's fine. But if we do see something, it's not panic. So you get through those studies, you write up a very comprehensive document 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 volunteers.

And just reflecting on that, actually, 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 makes it necessary for us to actually generate a lot of material, a lot of API, what's 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. These are quite big mini pigs, right? So [indiscernible] products to reach those top doses.

Yes. you're talking, yes, I mean, a recent program I was involved in. There's a regulatory maximum of dose, which is 1 gram per kilogram of body weight. So for...

[indiscernible] Get 30 kilograms.

Yes, 30, 40. So we had to make 150 kilograms of the drug to dose those for chronic studies. But if you think of that equivalent in, let's say, a 70-kilogram human, that's 70 grams of drug, which is the equivalent of taking 140 paracetamols orally. So that's a lot of drug. So you have to keep that in mind in terms of making enough of the compound and you have to allow the time to make that because going from making hundreds of milligrams or 1 gram or 2 to tens of kilos is actually a significant process to work through.

And this is what -- so our partner, Pharmaron, who are 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, sort of reducing 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 cheaper intermediaries. And this is the process that's going to happen now for the next few weeks. And they will be making starting materials. We're starting materials so we can look at formulation. So we look at conducting this dose range finding in the animals so that we know when we get to that 28-day that we can reach the levels that we need to reach. And after this period, we will then commence that large scale, this 10-kilogram scale, and that actually takes the largest amount of time out of this work program. And it's just an element of time. There is sort of nothing more to it that you go through making these batches 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 10 minutes ago to sort of look at wrapping up. I know we've had a question. Could we get a detailed time line on next stages that's a broad on the website and regular updates? Sure. I think we -- in the presentation that's on the website, we've broken down the time line 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 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 simulating 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 for us on how we can optimize it, whether we've been too science heavy, not science enough heavy, whether it's been too long, too short, you like us to focus on different areas or have more of these in a regular fashion as the comments has 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 going to bring value accretion to the company. And as we move through those next stages of development, we can share updates. We really look forward to providing insights into that. I think sometimes it's the balance of doing this outward-facing activity and sharing. And we're very small company. 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 programs and why they're going to give, hopefully, a good opportunity for shareholders in the future. So yes, it'd be great to have your feedback. And I think that concludes our talk for today. So thanks again, Fraser.

Thank you.

That's great. Helen, Fraser, thank you once again for updating investors. 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 will be greatly valued by the company. On behalf of the presenters, I'd like to thank you for attending today's presentation and wish you all a very good afternoon.