Steve Gourlay, CEO of Actinogen

[00:00:00] Speaker A: We know there's a lot of interest, both from doctors and patients in a much more convenient option for Alzheimer's. If we are indeed, as the pilot data suggests, five times better than these antibodies, I don't think anybody's going to take the antibody. [00:00:15] Speaker B: Stephen, thank you so much for taking the time to have this conversation today. I'm so looking forward to it. For those who are less familiar with actinogen, maybe we just start with a kind of background of your journey and how you started working on this. [00:00:25] Speaker A: I'm a medical doctor trained as an internal medicine physician. But I and I did a PhD in clinical trials and biostatistics and soon realized that I loved clinical trials and loved doing really good clinical trials. And I did a postdoc at UCSF in San Francisco and went to Genentech for about six years where I really learned how to develop high quality drugs. You know, working with the FDA and that was a really exciting experience. And so many of those drugs are still being used today. So I've had a lot of success there and I stint as an investor and then more recently chief medical officer for a startup called Principia Biopharma that took some autoimmune drugs from pre clinical through to phase two and phase three and was actually bought by Sanofi for several billion dollars a few years ago. So I've got a pretty successful track record. I'm very proud of that. I joke with some of folks here that I haven't missed a clinical trial for more than a decade and I'm not planning to start now. We have a big ongoing Alzheimer's trial. But what attracted me, to answer your question, what attracted me to actinogen was that four years ago when I was asked to look at the company, they'd actually done a negative trial in Alzheimer's patients that was negative, but it was only a very short trial, way too short really to have any hope of showing disease modifying activity. But there were signs of activity in the more severe patients and when we went back later on and looked at biomarker positive patients, there was a really big treatment effect even in a short 12 week period. So the company had some really good data, including on cognition and healthy volunteers and great safety. So I was attracted to the project, to the molecule and to the possibility of showing that you can treat Alzheimer's with a daily pill and having those trials be executed in a few years time. So that's why I joined the company four years ago. So actinogen is all about its lead molecule called Xanami. It's a once a day pill, low dose, very good safety and excellent data both in depression, improving depression and we're slowing the disease progression in Alzheimer's patients. [00:02:27] Speaker B: And we'll get into the kind of applications here in a moment. But I'm just so curious to know. You've seen the insides of large pharma, you've been on the investor side, you've had a successful run in biotech. At this point there must be a hurdle to clear, a burden of proof wise for you to get excited to do something again, talk about how you think about that and like where was that hurdle for you to get here? [00:02:47] Speaker A: Well that's true, that's true. So the circumstances of coming back to Australia, mainly for family reasons because my mother had some early cognitive decline and I wanted to make sure I was closer. Covid hit and Australia had this crazy lockdown, didn't anticipate taking a busy job as a CEO. When I came back to Australia I imagined semi retirement and, and helping companies proceed with their clinical plans and so forth. But the quality of the pharmaceutical we're dealing with, Xanamem, it has no drug interaction potentials, it's very well behaved from a manufacturing point of view. It's super stable. Probably the best looking small molecule I've ever seen in my 30 or 4, 35 years of drug development experience. And they had so much data, including a PET scan data showing high levels of binding of the, of the drug to that it's targeted in the brain, which is essential in CNS drug development. But the data were very clear that the drug was getting into its target at a high level of inhibition, even at super low doses. So the data were very compelling. So I just couldn't help myself and took the job as CEO. And since then I've been building a really amazing team and we've conducted a number of a series of new clinical trials, each of which has been positive. So I'm pleased to say I think I made the right decision and I do believe this drug hopefully in the next few years will be available for patients worldwide. [00:04:07] Speaker B: Yeah, well, let's start on the Alzheimer's side and then we can go to depression. Take me through the, let's call it the scientific journey and kind of where you are today and how you understand it. [00:04:16] Speaker A: Initially when I first looked at the company and its program in Alzheimer's I thought okay, small Australian company, great data, but developing in Alzheimer's is a very capital intensive business. Crazy talk for a small company. However, the science is fantastic. And so the science is all based around the long standing, decades old hypothesis that elevated levels of cortisol in the brain are toxic and related probably to aging in general, but also to the risk of Alzheimer's disease, to the rate of progression in Alzheimer's disease very, very strongly related to severity and incidence of depression as well. So the science of cortisol has been quite compelling. There's probably tens of thousands of papers published over the last two decades linking cortisol levels to these diseases, particularly brain fluid cortisol levels. But nobody ever had a drug that could selectively inhibit cortisol production in brain tissue, leaving your adrenal gland to manufacture cortisol, which is essential for your normal stress response through a different enzymatic pathway. So what this drug does is it targets an enzyme that manufactures cortisol from inert cortisone in tissue, particularly brain, liver, and fat tissue. And in so doing, at low doses, what it does is it reduces to a large extent the tissue levels of cortisol, which is the active steroid hormone that inhibits cortisol receptors as well as changing protein synthesis in the nucleus. And that's highly expressed in areas of the brain essential for memory and cognition, such as the hippocampus and the frontal cortex, unless so in other brain areas. It's also present in the liver and in fat tissue. So basically, by lowering the brain cortisol, and you lower liver and fat cortisol a little bit, too. And that has positive metabolic benefits, but you don't touch the adrenal synthesis of cortisol. So plasma levels of cortisol, which are essential for normal life, remain the same. So it's a really clever way of targeting tissue cortisol and leaving this sort of fright or flight response, if you like, intact. So the science about it is all about reducing brain cortisol and leaving the rest of the body's cortisol largely uninhibited. [00:06:38] Speaker B: And maybe take me a little bit deeper into this cortisol hypothesis, like, what is it about excess cortisol in the brain that we believe leads to the kind of development of Alzheimer's? [00:06:48] Speaker A: I can take you back to a little bit of experimental data to help answer that question. So if you put a pellet of cortisol into a mammalian brain, you will see neuronal dryback around that pellet of cortisol. So cortisol itself, certainly in high concentrations, is directly toxic to neurons. So what we think it seems counterintuitive because high doses of prednisone which is a form of cortisol, high dose are used therapeutically to treat inflammation diseases. For example, like a flare up of rheumatoid arthritis or giant cell arteritis in the brain. You might use a high dose of a cortisol like drug to treat the inflammation, but long term use of those drugs is quite toxic as well. So we know that. So long term use of cortisol or prednisone causes depression, mood swings, you get thinning of your bones, you get high glucose levels, you, you get cognitive impairment from, you know, foggy thinking, from long term steroid use. So we know experimentally in an animal you get dieback of neurons. We know experimentally in humans that therapeutic use of these drugs leads to a whole bunch of these nasty side effects that clearly that's not a placebo effect, that's a real effect of the drug. And then we also know that in patients with depression, you can do a test called a dexamethasone suppression test. So you give basically cortisol and then you see whether or not the pituitary gland will suppress a counter regulatory hormone called acth. It's basically a way of testing the regulation of cortisol. And in a lot of patients with depression, particularly severe depression, that test is blunted. So we know that there's dysregulation of the cortisol system. And so that's the three clear examples of how cortisol is toxic. And that's why we're so excited about the data that we've shown both in depression and Alzheimer's disease already, that if you inhibit tissue cortisol, you can have a clinically meaningful benefit in those diseases. In other words, all of this research that said, hey, cortisol is a bad actor appears to be true because we are the first company to ever have a molecule that got into the brain to do this targeting of brain cortisol. There have been other inhibitors of this enzyme, 11 beta HSD1. However, they were all designed to stay outside the brain as type 2 diabetes drugs. And so we have the first and as far as we can tell, the only brain penetrant molecule that has shown very exciting clinical activity in the brain. [00:09:19] Speaker B: Yeah, so it sounds like this, I guess the pathway for this has been known for a while, but up until this drug has been developed, no one had been able to particularly target it in this way. [00:09:28] Speaker A: Yeah, I mean, the best way to sort of see if a pathway is relevant is to use an antagonist. Right. It's to block the path pathway. And no one's been able to do that safely before. So people did try some corticotropin releasing hormone antagonists in the past for depression, but no one's really done which is a related pathway, but nobody's ever had definitive data. Interestingly, the drug methopristone, which is a glucocorticoid receptor antagonist, so essentially that's a cortisol receptor antagonist. It did, in some small trials show some activity in psychotic depression. And that was also a bit of a clue that targeting cortisol and depression was likely to work. That drug is Also known as RU486, the oral abortion pill, and its toxicity is not suitable for making it a viable antidepressant. So on the other hand, our drug so far in more than 400 people treated, has a really excellent safety profile. So it's looking very promising from the safety side as well. [00:10:24] Speaker B: Now, you mentioned some early clinical trial data that continues to build your confidence. Maybe walk me through what you're seeing on both the Alzheimer's side side and the depression side and how you're thinking about it today. [00:10:35] Speaker A: The series of trials that we've done, I'll sort of step you through each of them, I think, because that's helpful. So we did the standard phase 1 pharmacokinetics in normal people and determined that a relatively low dose was going to be adequate. The next key piece of data was a human PET study imaging the binding of the drug to its target in the brain. And that was very important in showing that doses as low as 10 and maybe even 5 milligrams a day would be adequate. So now you're not showing function there, you're just showing the binding of the occupancy. And we know from animal studies that you only need to inhibit this enzyme sort of 30 to 60% to have full cognitive protection in animal models of cognitive decline. So it's not a target where you need 90%, which is great. So we see 60 to 80% inhibition with a 10 milligram dose in virtually all brain regions of interest. So that was very, very encouraging to me. The second interesting piece was in healthy older volunteers, we saw an improvement in attention of working memory in a placebo controlled trial over 12 weeks. And that was pretty interesting because it's unusual to show cognitive improvement in cognitively normal people. But the drug did appear to show that. And so the question was raised, does this have some mechanism whereby it's causing immediate cognitive enhancement, much like the old drugs for Alzheimer's called acetylcholinesterase Inhibitors. And we've since in patients figured out that maybe it's not such an important aspect of the drug. But in a second trial of 5 and 10 milligrams, we did see some improvement in attention working memory, but not in episodic memory. So there is some evidence that you have a short term, over several weeks improvement in cognition, which may be through a glutamate signaling pathway related to cortisol. But then the most important next piece of data was that we were able to go back to the previous phase 2 study and we had stored plasma samples that we could reanalyze with modern blood biomarkers, which were not available when the trial was done. And so we were lucky enough to reconsent 72 people and reanalyze those. And in patients with mild Alzheimer's who had elevated levels of this protein called P tau in the blood, which indicates both you have amyloid, which is the pathology of Alzheimer's, but also that you have somewhat progressive disease. In patients with elevated P tau, we had a very big treatment effect, about five times better than the modern antibody therapies against amyloid that have just been approved by the fda, such as, such as Leqembi. And so this was very dramatic. And it was over 12 weeks. And so if we replicate this in our current Alzheimer's trial over 36 weeks, yeah, we could be many times better as a simple, safe, once a day pill than these infusions of antibodies to amyloid, which is very exciting. So that was, that was a really big deal and helped us design our current pivotal phase 2b3 study, which is ongoing here in the US and Australia. We also then ran a randomized trial of Xanamin versus placebo in patients with both cognitive impairment and major depressive disorder. Patients could be still taking and were in most cases another antidepressant such as Prozac or Zoloft. And in those patients we saw a clinically significant and at times statistically significant improvement in their depression symptoms, symptoms over just a six week treatment period. So that was really the very, the first prospective big evidence that a 10 milligram dose of Xanamem can have a big clinical effect on something as important as depression itself. Interestingly, the cognition in those patients with cognitive impairment improved markedly in both the placebo and the active group. And there was no real treatment difference between the two. So in other words, there was a very big placebo effect in cognition, essentially teaching us that at least in this trial, when patients depression got better, their cognition improved independent of our drug, but when they're depression. But if you look at placebo versus active, there was a big, there was a fairly big difference between the treated group with patients improving their symptoms more on the drug. So that's where we are clinically. And so now we're in this new clinical trial for Alzheimer's and with such. [00:14:55] Speaker B: Interesting kind of data on both the Alzheimer's and depression side, how do you think about kind of prioritizing your time, prioritizing your resources, given you're still a small company here? [00:15:05] Speaker A: Currently we're a listed company in Australia with 130 million market cap. So we don't have unlimited resources. We do talk to a lot of pharmaceutical companies about partnerships. The bigger pharma companies are keen to see the results of your next trial before they start spending big on a partnership. So these things take time. So we would like to have a suitable partnership up. We're prioritizing the Alzheimer's program ahead of depression, largely because Alzheimer's is basically completely underserved by current treatments. Because in Alzheimer's you have the older drugs like Donepezil, Aricept, Memantine, and they just sort of rev up your neurotransmitters a little bit and don't change the course of the disease. We have the newer infusions of amyloid antibodies that have significant side effects such as brain swelling. You need to go to an infusion center. It only gives you a few months in most patients of preserved cognition. And really the benefit is that much. But really what you want is to take a drug when you notice you've got cognitive impairment and you're diagnosed with Alzheimer's, that will stop progression in its tracks. And our pilot data from those patients with elevated P tau is pretty close to that. And if we get even, if we get close to that in this bigger clinical trial and prove it out, it means that you'll be able to get diagnosed and take a once a day pill and have a major slowing of progression. It's not to say that Alzheimer's might not end up being treated with a combination of medications. Most chronic diseases are. If you think about treating breast cancer in remission, often people are on a cocktail of a couple of different drugs. But yes, because of the unmet medical need, we're focused on Alzheimer's depression's still not very well served. Most patients taking an antidepressant don't like the side effects. And we don't believe we have any of the typical side effects of the common antidepressants, such as Sexual dysfunction or sort of feeling blah. You know, infectious patients on this drug seem to feel better in general. So. But we will focus, for the time being, our resources on Alzheimer's. And if we form the right partnership, we may well proceed forward with depression as well. But the focus is Alzheimer's. [00:17:33] Speaker B: You mentioned you have a incredible track record of successful clinical trials. What do you think that maybe you do differently or how you think you kind of approach this that has given you kind of this edge in your career? [00:17:44] Speaker A: I think I've been lucky. But, you know, I also believe you make you luck. So I'll try and I'll try and answer the question. It's a good question, and I'll try and answer it as humbly as I can. I do follow a fairly strict scientific method when it comes to clinical trials because I do think clinical research should be as disciplined, you know, as any laboratory benchtop research. So, for example, at Principia we were designing for the BTK inhibitor that we were investigating and for autoimmune disease. And so, you know, the method I followed was to, with the team, do that, do our very best with the phase one studies to extend and a phase two study in a different disease to establish the right dose and justify that as much as possible. And then in designing the protocol, we did extensive review of what other people had done in the early stages of itp. We considered how to just sort of stepwise go through that program, how to learn and how to adapt. So in part, so it's kind of an adaptive protocol. But, you know, we put all the best elements of scientific rigor into the design of that trial. And, you know, I think it's also fair to say people were still pretty nervous in the beginning. I sort of reassured people that everything was going to be fine. And that is true, that the drug is about to be approved for ITP in the U.S. yeah. So another part of the element is that where you can use open label studies intelligently, that can be a very important and helpful study design for an early stage clinical trial. Clinical company. For example, we examine Pemphigus at Principia, and that's a disease that doesn't spontaneously remit. So the first studies we did, one was a trial in dogs at UC Davis, and the second trial was in humans in Australia, Greece and other places around the world. And we did that as an open label study. And we were able to show that about 50% of patients in both those studies responded really, really well without high doses of steroids, which was the normal treatment. So again, it's really just really considering the circumstances, the disease, what design you need to use to show an effect. So to bring that back to Alzheimer's disease, Alzheimer's disease is assessed and depression, they're assessed by essentially structured interviews and are scored as diligently and in a standard way as possible. However, there's some subjectivity in those scoring systems and you absolutely need a double blind placebo controlled trial to remove the bias that might come from doing an open label study. A number of companies have boasted about open label data showing that the drug must be working because cognition didn't get worse. But all of them that I know of, when they've actually done a placebo controlled trial, didn't work and they were misled by placebo, by not having a placebo control. So we, you know, so in my career I've always used placebo where it's necessary, but there are times when it doesn't work, when it isn't needed. And for example, our recent depression trial, we examined both cognition and depression. There was a strong scientific rationale, as I've explained, for cortisol and depression, and lo and behold, we were right. But that was all about doing a large enough clinical trial, well conducted, but with a very strong scientific rationale. So, yeah, so a number of different things. I can't claim that it's any one factor. There's no special thoughts. It's just scientific method really. [00:21:17] Speaker B: Earlier you had kind of commented that this work in Alzheimer's and also in depression is famously difficult. I'm sure on clinical studies in, I'm curious, like, I'd love to hear, what do you think makes research in these kinds of, in these indications particularly difficult? And how, how do you think about, you know, intentionally designing your trials around that? [00:21:36] Speaker A: So part of the problem is noise in the endpoints. That comes from sort of the way the endpoints are measured. So standardized interviews that then have to be scored and rated. Maybe the patient who comes in for successive visits has a different rater because it's very hard for clinical sites to keep the same person there for the same patient every month. People have lives and can't necessarily come to work for the same patient. So you have that sort of rate of variability. You have the variability that comes from the patient perhaps having a cold and feeling a little bit off on one visit, which might lower their cognitive abilities temporarily. And that's not really the right assessment. So there's a lot of sources of noise in these trials that use these types of endpoints so it's very different than say the ITP trial I was talking about, where you just measure the levels of platelets in the blood. Right? So that's super easy, right? Super easy. You don't need complicated scoring. So what you have to do in trials in psychiatry and neurology is that these more subjective endpoints, and our primary endpoint for Alzheimer's is called the CDR Summer Boxes Clinical Dementia Rating Scale, Sum of boxes. It's an 18 point scale. So you have to train the raters to standardize them as much as possible to reduce noise. Sometimes you actually use an external party to rate them objectively so that the same rater is doing every visit for the same patient. You try as hard as you can to standardize the assessment, standardize the assessment methods so that when people are doing their testing, they're in a quiet room, they sat down, they're given gentle and clear instructions, they feel less anxious as they possibly can. So all of that. So there's a. In terms of the sort of implementation of these trials, there's actually a huge amount of knowledge that the clinical trial sites and then our company staff who are working with them, that it's. That there's a lot of specialized knowledge in doing these studies. Right? That's part of it. And then part of it is patient selection. So obviously you don't want to choose patients with Alzheimer's who are not going to progress during the 36 weeks of the trial because then you won't see anything. So we can't take patients who are super mild or are not going to progress. On the other hand, if you take people who are too far progressed, it'll be hard to see a treatment effect. So if you, like, you're sort of looking for the patient, the ideal patient in between, who is ideally the right patient to be treated in the future, you know, at the general practitioner as well. And that's patients who've got early symptoms, but those symptoms are going to progress fairly quickly, so they should be treated. And so what we've found is that this P tail blood test is the ideal way to select patients who have the biology of Alzheimer's protein in their, in the end, pathology of Alzheimer's protein in their brain, but also have a progressive disease course. And so this is being used by others. It's not just actinogen, but that's turned out to be an excellent way to help to select patients. For us, that's important. So patient selection is important. How you do the trials is important. Fortunately, in Alzheimer's, the endpoints are reasonably well worked out. So the CDI Summer Boxer score is well accepted by the FDA and the ema and it's been used almost universally in all clinical trials in Alzheimer's in the last five years. So by using that endpoint you can, because it measures both cognition and function. For example, it says, how are you doing on a three point scale on personal hygiene, for example, or something like that, or personal habits. And so it is a very, it's a bit noisy, but it's a good broad measure of how a patient is doing. [00:25:28] Speaker B: Are you seeing benefits accruing to you based on route of administration? I mean, Alzheimer's research is quite competitive, but the kind of delivery mechanism you have here is, let's call it gentler. Are you seeing that kind of play out too? [00:25:42] Speaker A: Yes. So we know already at the sites here in Australia and the US that patients would clearly prefer a once a day pill over an infusion every two or four weeks. That's no contest, as well as the safety being encouraging. So we know there's a lot of interest, both from doctors and patients, in a much more convenient option for Alzheimer's. So, I mean, that will be a big advantage to us. Obviously we need to confirm and prove that we have good clinical efficacy, which we've seen in our pilot data. So that's what we're replicating, hopefully in this new clinical study. And there's no question if we are indeed, as the pilot data suggests, five times better than these antibodies. I don't think anybody's going to take the antibody. I think that would go straight to the drug we're developing instead. So hopefully that's the outcome. [00:26:35] Speaker B: I mean, incredibly exciting outlook. I think you have ahead of yourself. What are you worried about? [00:26:39] Speaker A: The only wild card, but I'm not really worried about it, is that the GLP1 class of drugs, the Ozempic WeGovy Jara class of drugs, did show that in type 2 diabetics in their databases, there was a lower incidence of Alzheimer's in the treated group and they're now doing big randomized trials to look at that. The problem with that class of drugs is of course, the gi, the gastrointestinal side effects, such as nausea and vomiting are pretty major and patients with Alzheimer's typically forget to eat and are losing weight. And so obesity in Alzheimer's doesn't. Obesity is not really a big feature of elderly people with Alzheimer's. It's quite usually the opposite. So even if those trials turn out to be positive I don't think they'll necessarily be suitable for the majority of people with Alzheimer's. And so there'll still be a really important place for our drug potentially as a lead therapy in Alzheimer's. But it's hard to handicap whether the data that they've got on diabetics reads through to efficacy. But those, those GLP1 trials will start to read out at the end of 2025. [00:27:49] Speaker B: Yeah, and I think one thing we've all kind of learned is to not count them out based on how everything seems to be tipping in their favor these days. [00:27:56] Speaker A: You know, there's a lot of competition in the Alzheimer's space. As you, as you said, a lot of small molecules have tried to inhibit amyloid formation and have still been focused on this whole killer pathology concept, which appears to be extremely flawed, because if you can strip out the amyloid protein completely with these modern antibodies, why would reducing its formation have a significant clinical benefit? So I do believe our molecules NM and maybe the GLP1s are the two major classes of interest right now that have a chance of being viable approved therapies in the near future. [00:28:35] Speaker B: So we spent a little bit of, or a lot of this show so far talking about the cortisol hypothesis. Those are maybe like, take a big step back. How do you think about the broader landscape of Alzheimer's research and the other kind of like interesting hypotheses that you're kind of keenly following and kind of like interested to kind of see how they play out? [00:28:54] Speaker A: So there are a few clues in the science. So a lot of people would be aware that the APOE4 gene is the major measurable genetic risk factor for Alzheimer's, with the exception of some special genetic classes where there are clusters of families, I think in Colombia and elsewhere, where there's a particular genetic type where you get Alzheimer's in your 40s and those genes are understood. And unfortunately for those people, we still haven't had any clinical trials that have shown any success whatsoever. But the APOE4 gene codes for the major lipid carrier protein in brain cells neurons. And so why is that gene, you know, if you have twice the copy, as does Chris Hemsworth, for example, he has a 16 times chance of having Alzheimer's and I do believe he had a grandparent or an aunt with Alzheimer's, So he is at a higher risk. So how does that impart risk? Well, it's thought that neuroinflammation and neuronal dropout dieback may be related to inflammation. But may be partly related to metabolic disruption. And there is a bit of a story around insulin sensitivity or insulin resistance being related to neuronal toxicity as well. And that's something that our drug, by reducing cortisol also improves insulin sensitivity. So there's a little clue there. The highest risk for Alzheimer's comes through a lipid carrying protein. So what's that about? Think it's probably about inflammation. But so far attempts to target inflammation haven't shown benefit yet. But there are some trials ongoing in that area with the TNF inhibitor due to readout next quarter, but so far that's not been explored fully. But the feeling is that the causes of Alzheimer's are some mixture of neuroinflammation, neural toxicity and metabolic disruption in the brain, and that it's not. While amyloid itself has been shown to be neurotoxic, there are lots of people who die in their hundreds with lots of amyloid in their brain and it's got nothing to do with. And they're cognitively normal. So there's clearly a different story around why people have symptomatic and clinical Alzheimer's and it's, it's not really about amyloid. So it's probably, yeah, neuroinflammation is definitely a big one that people are looking. [00:31:20] Speaker B: At, you know, with, at least for the last few years, so much attention being put on these plaques. What has it been like competing on a completely different like, hypothesis? Like what has that been like on your end? [00:31:31] Speaker A: The big companies are interesting because we talk to them all the time and we talk to the scientists as well as the business development people. And I would say that the big companies who have amyloid antibodies are somewhat schizophrenic. The scientists know that non amyloid targets are the way to go. And the antibodies to the tau protein haven't been doing very well either. So that's probably not the answer. And the tau protein is laid down later than amyloid, so that doesn't make a lot of sense to me either. But the marketing departments of those companies, very much like you, will talk about nothing but how good amyloid is. And so there is a natural schizophrenia in those organizations, which is a little sad. So. But the other companies that are interested in a potent and effective therapy are very interested in other targets. It's just that the biology of Alzheimer's is not well understood. I mean, we're the first company to really clinically validate the cortisol hypothesis with our depression data, our pilot data for Alzheimer's is very encouraging as well. So we feel like we're a long way down the path of clinical validation for cortisol. So people who take certainly following us very, very closely. And so, you know, a positive confirmatory study with final results next year will be a huge scientific discovery and confirmation of the cortisol hypothesis. So that'll be a very big deal for us, obviously, but also hopefully for patients and for potential pharmaceutical partners who might be able to take this forward faster than we could do it ourselves. So, yeah, so there are believers and non believers and people who choose not to believe. Just simply answer your question. You know, about 80% of all new NIH grants are for non amyloid targets in Alzheimer's. So the, you know, the science, the field is looking away from those proteins and all the new research is really going into different things, such as inflammation, in our case, cortisol. People are looking at. Yeah, a lot of different things. [00:33:30] Speaker B: Yeah. It's interesting to think about the dynamics that might lead one group to try to like, double down and continue marketing like a certain kind of like, pathway versus others who maybe may not have a kind of horse in the race yet and are excited to kind of see how things play out. [00:33:44] Speaker A: Yeah, I mean, look, the bigger deals in Alzheimer's have been done for phase one stage antibodies to amyloid and tau that are allegedly better than their predecessors. And those, those deals, most of them are two or three years old now, so I don't know how many more we're going to see. But companies like Roche continue to develop new, better amyloid targeting. But I think the Eli Lilly drug and the Esai drug successfully remove amyloid quite quickly. And I think that probably shows you the limit of what that approach can do and it's not very impressive. So we'll see. Maybe Roche have got a special idea that I'm not aware of yet, but we will see. But yeah, so I think it's, you know, if you think about the way business development works, it's safe to go with something that's proven, even if it's only modestly effective. It's a lot less safe to go with something new that may have a much bigger upside and much bigger patient value until it's proven out. [00:34:45] Speaker B: Yeah, there's almost like an expected value benefit in the regulatory pathway of something that's already been approved. Talk to me about the kind of path forward. You see, you're kind of in a confirmatory study today. What do the next one, two, three years look like for you? In an ideal world, this Year is. [00:35:00] Speaker A: Very much about regulatory consultations with the FDA and later this year or early next year with the EMA around the design of the packages for approval in Alzheimer's disease and also in major depressive disorder. So lots of regulatory consultation. Finish recruiting the trial. We should have our 100th patient enrolled in the next quarter and second quarter of the year. And we will do an interim analysis roughly six months later. And that interim analysis will just make sure that the safety and the efficacy data are pointing in the right direction so that the trial is not futile. And then about a year later, towards the end of 2026, we will have the final results of the 220 patients. 10 milligrams versus placebo. Those are the really big clinical milestones. We will proceed with a second depression phase two if and when we have the suitable grant or partnership funding. But for the moment we're focusing our resources on the Alzheimer's. We will be designing ancillary Alzheimer's studies. We'll be designing the phase three, doing all of the clinical pharmacology and any of the non clinical studies we need to do for the approval package. So a lot of that work starts soon or it's happening now as well. So you know, we really are doing all of the work that you need to take the stroke all the way to marketing. You know, we're not a big organization that would plan on necessarily on having its own sales force. However, we could develop into a commercial organization in limited geographies. But obviously partnering is going to form a big part of this. And the vision of the company really is to have a larger pharmaceutical company take what is really the holy grail for Alzheimer's disease, if we're right, take it forward quickly in multiple diseases, not just Alzheimer's disease, but also potentially depression, frontotemporal dementia, Lewy body dementia, maybe Parkinson's, maybe ptsd, maybe bipolar. So there's a whole slew of potential applications for this drug. You know, we're not, we'd love a larger pharmaceutical pharma partner to partner with us and help us make all of that happen as quickly as possible. [00:37:05] Speaker B: Yeah, absolutely. What has been the like the regulator response given the, you know, recent, the recent successes, but maybe lukewarm successes thus far. I'm curious, what are you hearing from regulators on this? [00:37:19] Speaker A: Look, clearly the bar is quite low in Alzheimer's disease. The approval for aduhelm, of course, very controversial. Although I did support that approval because there was nothing available for patients. And the evidence, in my view, the evidence was good enough for, for a disease which is the serious as cancer. Anyway, better drugs came along and that one's no longer on the market. But again, the clinical benefit of these antibodies is over 18 months is half a point. On this 18 point CDR, some of the boxer scale, 1 point is regarded as the minimum clinically significant difference. Right. So it's been approved on half the clinically significant difference. Right. So that's a very low bar for approval. So, as I said, our pilot data suggests we're at least five times better than that. So if indeed we were 2.5 points difference, I mean, that would be massive and that would be a very easy discussion with all the regulators about moving forward, particularly since safety looks good as well. Yeah, I don't think that low bar is going to change. I don't think any of the existing antibody therapies or any of them in development are going to do much better than that. You know, it's up to us to prove out what we hope is a much larger effect clinical benefit in our current clinical trial. So. So the big question then is how do you quickly get it to market so that patients. Could you get an accelerated approval? Clearly we can get breakthrough approval if we need to, if we, you know, when we apply for that, which we haven't quite yet, but yes. So could you get an accelerated approval? How could you go forward? Anabex are a company with a drug that, where they've applied in the European Union for an approval on their phase 2b3 study data. Not sure whether the EMA will give that approval, but they have applied for it, the drugs kind of. It's very hard to tell from their published data just what the risk benefit ratio really is, but if they do get approval, that would set the bar even lower. [00:39:13] Speaker B: Well, it sounds like it's full steam ahead for you. You've got your confirmatory study up and running and we're waiting for the interim analysis to kind of land and hopefully by the end of next year we'll have good news to stare at. [00:39:26] Speaker A: Yeah, indeed. And the other thing is, you know, we did raise money in a, in a series of fundraisings last year and we get a huge amount of help from the Australian RD Tax credit. We got $9 million, for example, as a check last November. There's a cash sort of compensation for our R D. So, yeah, we're, we're well funded at the moment through into next year and that means we can focus on the trials and, you know, doing all of the, the good work and the good science that we need to get this drug approved. [00:39:56] Speaker B: In kind of like closing here. I'm curious, as you think, about the kind of landscape and the space and the kind of trials you need to run ahead. If you had a magic wand and you could change anything about how this research is done and the current state and Alzheimer's, what would you change and why? [00:40:11] Speaker A: Well, if I had a magic wand, I would illuminate what the true biologic causes of Alzheimer's were and. And thereby spend way less than the $42 billion they spent on amyloid, getting it right and targeting drugs to the right pathways. So that's magic wand wish number one. Yeah. I think. I wish the big companies would spend more money on alternative targets because that's clearly the right thing to do for patients. So if I had a magic wand. Yeah, I would definitely make that happen, too. [00:40:45] Speaker B: Yeah. Well, if anybody from those companies is listening, it's time to call. Time to call Stephen. He's ready to take that call. [00:40:53] Speaker A: That's fun. [00:40:54] Speaker B: Yeah. Well, Stephen, thank you so much for taking the time today to have this conversation. I've so enjoyed learning from you and hearing about the journey and what you have coming up next. [00:41:01] Speaker A: Thanks, Brandon. It's been great. [00:41:03] Speaker B: Yeah, absolutely.