Helus Pharma Investor Presentation - HELUS PHARMA INC

Healing is not a moment. It's a process. It starts with a question, a hypothesis, a willingness to look deeper, to follow the data, to test, analyze, and learn, to pursue novel solutions with the discipline of science and the responsibility of care. because healing is a journey that demands more than hope. It demands rigor and tenacity to help people return to themselves. Healing is not a moment. It's our mission. Heal us. Heal this pharma. Welcome to the Helus Pharma Investor presentation. Before we get started, I would like to remind everyone that certain statements in this presentation are forward-looking statements and are perspective in nature. In preparing these forward-looking statements, several assumptions were made by HELIS, and there are risk and actual results obtained by the company while differ materially from these statements. The company cannot guarantee any forward-thinking statements will materialize, and you are cautioned not to place undue reliance on them. We refer current and potential investors to certain customary statements contained in the presentation and to the forward-looking statements and the risk factors section of the company's annual information form and the most recently filed management's discussion and analysis available at cdarplus.ca and on edgar.sec.gov. Forward-looking statements represent the company's expectations as of October 21, 2026. Except as required by securities laws, the company does not undertake any obligation to update any forward-looking statements, whether as a result of new information, future events, or otherwise. I would now like to hand the conference over to Michael Halstead, Chief Executive Officer of Helus Pharma. Good morning, everyone, and thank you for joining us today. Whether you're a longstanding shareholder, a potential new investor, or a member of the analyst community, we appreciate your time and your interest in Helus Pharma. We are developing novel serotonergic agonists for the treatment of several important mental health conditions. Today, we will provide a comprehensive overview of both the science and the strategies that support our development programs and why we have confidence in our potential to positively impact the treatment of mental health. The agenda for today's program is designed to highlight the opportunity for HLP-003 and HLP 004, our clinical strategies, and why мы believe our programs may offer meaningful differentiation from existing therapies. I'll begin with an overview of our pipeline. HLP-003, which is deuterated psilocin, is our lead program and is currently in phase three development for the adjunctive treatment of major depressive disorder. Our near-term catalyst is the upcoming phase three approach top-line data readout, which remains on track with results expected later this quarter. The EMBRACE study, our second phase three efficacy study, is ongoing, and the EXTEND trial, our long-term extension study, is enrolling eligible patients from both APPROACH and EMBREACE. HOP004, which is deuterated DMT, is our Phase III program in generalized anxiety disorder and provides a second clinical opportunity in another large area of significant unmet need. Today, we will share details of our next clinical study in the program, which we expect to initiate in the first quarter of 2027. Beyond these programs, our HLP-005 library of preclinical compounds offers the potential for continued pipeline expansion. We expect to advance the lead candidate from this program in the second half of 2027. All three programs are supported by a broad intellectual property portfolio, which is expected to provide patent protection into the early 2040s across 003 and 004. Our programs are targeting highly prevalent mental health conditions. Here is the scale of the unmet need. There are 22 million adults living with MDD in the U.S. alone, and more than 300 million people have depressive disorders worldwide. There were also about 20 million adults in the U. S. living with GAD, and 15 times that number are affected by anxiety disorders around the world. The scale of these conditions is substantial, but prevalence alone does not define our clinical and commercial strategies. We're focused on indications where the patient need is high, existing therapies have limitations, and the profile of our assets may offer clear differentiation. Let me begin with why we chose to develop 003 for the adjunctive treatment of MDD instead of choosing a development program in monotherapy or treatment-resistant depression. Treating depression with monotherapy is a crowded space with over 25 FDA-approved drugs, nearly all of them generic. While approximately a third of MDD patients respond to their first treatment, two-thirds have an inadequate response and do not reach remission. In order to treat patients having an inadequate response to therapy, clinicians can either switch to a different drug, which requires washing the patient off their existing therapy, a process that can take four to six weeks, or the health care provider often chooses to add a therapy on top of the existing medication and continue the patient's journey towards recovery. The adjunctive therapy approach is a well-established treatment step for patients who have an inadequate response to first-line therapy. However, there are only five currently approved adjunctive MDD treatment options. These are the atypical antipsychotics, and they have significant treatment limitations. We believe this creates a clear opportunity for a differentiated adjunctive therapy that can build on a patient's response to their existing therapy without requiring the clinician to restart the treatment process. In addition, the adjunctive approach has the potential to address the patient's condition before they fail to respond to multiple therapies and become treatment resistant. Thus, we believe adjunctive treatment is the right indication to pursue as it provides access to a significant portion of the MDD patient population earlier in the treatment journey in an area where there are limited approved treatment options. Based on the non-clinical and clinical evidence we've generated to date, O3 has the potential to combine rapid and robust efficacy from a limited number of doses with a favorable safety and tolerability profile. As a result, we believe O3 could represent a very meaningful treatment option for patients. To better understand the opportunity ahead, it's important to first discuss the significant unmet treatment need impacting patients living with depression. I'm very pleased to welcome Dr. Roger McIntyre, a leading expert in mood disorders, who will describe the unmet needs in depression, explain why new treatments are needed, and provide context on how OO3 could fit into the MDD treatment landscape. Following Dr. McInyar's remarks, Dr. Amir Inimdar, our Chief Medical Officer, will provide an overview of our OO2 program. Dr. McIntyre. Thanks, Mike, and good day, everybody. Great to be with you. Roger McInyter, Professor of Psychiatry as well as the Professor of Pharmacology and Toxicology, University of Toronto. What I'd like to do today is just briefly cover two interrelated topics, the disease state of major depression and the treatment landscape. What should emanate, what should surround this concise presentation is that this is a prevalent debilitating condition that has unmet needs that are a national priority for all of us to address, and it really starts off with a description of major depressive disorder. This is a common condition. The estimated prevalence of this condition has been rising across the United States, but also in other parts of the world, and when we step back and look at the longitudinal course of this condition, in other words, the lived experience, it is not the case that most people resolve the illness within a few weeks or a month or two. Most people, in fact, have multiple recurrences. For many, if not most people, it becomes very persistent. And this degree of persistence of the condition contributes to the disability, the impairment and role function, human capital. And we're not surprised When we read results in the United States, around the world, that compared to all medical conditions, depression ranks number two. But within psychiatry, globally, major depressive disorder is the most disabling condition. So along with the suffering and the distress that depression entails, it is not only disabling and impairing role function, but it also is very costly to individuals, to society, and it's lethal. In fact, we know that people with major depressive disorder lose, on average, 10 years of life because of this illness, in part because of the elevated rate of suicide. So the portrait that we sketch of depression today, empirically supported by a confluence of data sets, not just the United States, but globally, provides for us a very clear, unambiguous picture that this is prevalent, it's severe, it is debilitating, and it is clearly very, very costly. Now, with respect to our therapeutics, we've already heard a state of the union, so to speak, of the therapeutics that are extant. They are currently available, ranging from monotherapies to adjunctive therapies. Despite the fact that we've had antidepressants available to us now for many decades, two out of three people who are diagnosed and treated for depression do not remit with the first line antidepressant. So with respect to the inadequacy of our antidegressants, it's been amply documented that two out of three people are just not adequately benefiting. This is in part because the antideressants themselves have relatively small to below medium effect sizes. And the other part about this as well is that even amongst people who do remit, the third that are the, if you will, the privileged ones that are benefiting, too often they have lingering problems and day-to-day quality of life and functioning. Now, one option could be to stop the antidepressant, that is the antinepressant that's been inadequate, bringing about remission, and switch to a different monotherapy. But the other option is to adjunctively administer a treatment. And there are several reasons why the switching option is less preferred than adding an additional agent. One reason just is simply the frequency of this occurrence. Two out of three people who start an antidepressant do not adequately benefit. Secondly, what we do know is, is that when we actually ask prescribers, when we ask clinicians, we ask patients, what is your preference. The preference that they express, and this has been amply replicated, they would prefer to add something on in that context, in part because they don't want to go back to day zero, wash the medication out and start all over again. Secondly, they want to perhaps take advantage of at least some type of therapeutic momentum, albeit inadequate, that may have been triggered by the first antidepressant. And other reasons, frankly, clinical practice guidelines published in the United States, around the world, promote adjunctive administration in this context. Now, as we've heard, the FDA has approved five agents in the adjunctive paradigm, that is, in the person who has had an inadequate benefit with the background antidepressant, which is usually an SSRI or related agent. And each of these five agents that the FDA's approved in the agenda paradigm are called atypical antipsychotics that are presented here. And what we do know is, is that these agents offer some degree of benefit, and for some people that can be meaningful. But for most people, the benefit still leaves the great majority of people inadequately improving from now what is ostensibly a combination, an antidepressant and an atypical antipsychotic. The major limitation, however, of the atypical antipsycotics is the tolerability and safety profile. And you can see here different categories of adverse events and their estimated prevalence of occurrence. This is common, ranging from weight gain, causing metabolic disruption, EPS akathisia, that's a sort of restlessness that people often experience on medications. There's also a very long-term serious side effect called tardive dyskinesia, which is an involuntary movement, sedation, elevation of a hormone called prolactin, which can occur with some of these medications. So we're not then surprised that surveys tell us that clinicians and their patients don't want atypical antipsychotics. In fact, less than one in six people even elect to take one. And of those who do elect to take an atypical antipsychotic, the one in six, three quarters of them are not actually in fact adherent to those treatments over the longer term, in part because they have ongoing symptoms and in part because they don't want, clearly want these types of tolerability and safety concerns. Now in the field of psychiatry, there has been a deliberate effort to try to really become very granular and try to understand at the point of treatment deciding with patients and that shared decision process, what is the mood? What is the tone? What is the vibe out there? No surprise, people are frustrated. They're frustrated with the fact that they're going from one monotherapy after another and they go with an adjunctive treatment strategy which is preferred and which is recommended clinical practice guidelines. We have FDA approved treatments. These treatments are falling short on efficacy and certainly falling short on tolerability and safety. And so the frustration is palpable. And then the next question related is, well, you know, what is the primary source of that frustration? It really is the lack of efficacy that's robust, that's meaningful, and that's durable across time in a way that's acceptable to the patient. We obviously need to have treatments that are effective, that have a short time to peak efficacy, that are durable and are meaningful to the lived experience, but they have to be agreeable to the patient. So what patients and clinicians need now, there's an urgency around this, is we need innovation. We need innovative therapeutics in depression that can work rapidly, that have a robust efficacy, certainly better than we've been used to in the field. And that efficacy needs to be efficacy that can be durable. And the durability of the effect introduces an exciting new paradigm of intermittently dosing these treatments rather than taking them every day. At the same time, it is also in fact essential. We have treatments that are safe and well tolerated. And this is part of really a larger wish that both prescribers and patients have to have alternatives that are adjunctive to the background antidepressant is that that's been the way they've wanted to go, asking for us, can you please provide treatments that are injunctive but are, in fact, more effective and better tolerated than the current treatments, that being the atypical antipsychotic. So it's a very exciting time we're in right now. The stage is very clear. The unmet needs have been very well delineated. I'm now at this point going to pass it over to Amir. Thank you, Dr. McIntyre, for that overview, including what patients and clinicians are looking for. Understanding the burden of depression and the ongoing need for new treatment options provides the foundation for why we are excited about O3 as a potential adjunctive treatment in MDD. Let me start with what O3 is. HLP-O3 is a deuterated psilocin. At the core, it is related to psilocybin, which, as it occurs in nature, is an inactive prodrive. To become the active metabolite psilocin, it needs to be converted in the body through a process called dephosphorylation. What we have done is replace some of the hydrogen atoms from the psilicin molecule with its heavier cousin deuterium, and by deuterating psilucin, we bypass the metabolic step, which we believe increases the efficiency of drug delivery and also decreases the drug load. What that means is that pound for pound, we get higher exposures with HLP-OO3 compared with generic psilocybe. In our preclinical studies, we have seen that OO3 gets into the brain faster and reaches a higher concentration than psilocin from psilocide. Clinically, when we compare 16 mg of HLP-O3 from our studies with a 25 mg dose of psilocybin that has been used in published clinical trials as a therapeutic dose, we find that HLPO3 achieves a plasma concentration that's 1.5 times higher and a total exposure that's about 2.5 times higher. Published data also show that plasma concentrations of psillocin are correlated with intensity of pharmacological effects, which in turn determine a participant's chances of achieving a breakthrough experience. Based on this data, we selected 16 milligram dose of HLP-O3 for our development program as it delivers a high plasma concentration, which is needed for the patient to have a breakthrough experienced and increases the potential to achieve a therapeutic benefit. And we tested this in our phase two efficacy study in patients with major depressive disorder as adjunctive therapy. In this study, we selected participants who were at least moderately depressed as measured by the Montgomery-Asberg Depression Rating Scale or Madras and had a score of greater than or equal to 21. These patients were on a background of standard of care antidepressant medication at a stable dose, but were inadequately responding, though not treatment resistant. Participants were randomized to receive a single dose of either inactive placebo or O3, which we tested at two dose levels, 12 milligrams and 16 milligrams, while remaining on standard of character. At the primary endpoint of three weeks, a single dose of O3 resulted in a rapid and large improvement in symptoms of depression, which was about 13 to 14 points better than placebo and was highly statistically significant. After the three-week assessment for primary endpoint, all participants received an active dose of study medication. For those who had received an Active First dose of O3, a second dose resulted in an additional improvement of about five more points on the mattress. We followed a subset of patients who had participated in the study out to one year, and we found that in the group that had received two administrations of 16 milligram, there was continued improvement at the one-year time point, with 100% of patients being responders, meaning they were showing a 50% or more improvement in symptoms. In addition, about 70% were in remission, meaning they had scores on the madras of 10 or less, consistent with minimal or no symptoms of depression. Based on our phase two data, we were granted breakthrough therapy designation by the FDA, which allows us to access ongoing guidance from FDA leadership and a rolling review, among other things. With feedback from the FDA and input from our key opinion leaders, we have designed our Phase 3 program. Our pivotal Phase 3 problem is comprised of two short-term studies, Approach and Embrace, and a long-term extension, Extend. Overall, our Phase 2 program is a very similar one to our Phase 1 program, Our Phase 3 study designs are very similar to Phase 2. However, we have included the second administration patient in our primary endpoint. The entry criteria in phase 3 are also very similar to phase 2, though we did increase the madras threshold for entry into the study from 21 to 24 points in order to ensure we enroll patients with a sufficiently severe depression at baseline. In both approach and embrace, patients are randomized in a double-blind manner to receive two administrations of either placebo or active drug given three weeks apart. The primary endpoint in both studies is measured at six weeks and the key secondary endpoint at 12 weeks. Approach and embrace test a 16 milligram dose of O3 versus inactive placebo. In embrace, we are also evaluating an intermediate eight milligram dose versus placebo. from both studies are eligible to roll over into Xtend, where based on predefined criteria in the protocol, they have an opportunity to receive up to three additional doses. Xtnd allows us to evaluate long-term durability of the initial doses that patients may have received in either approach or embrace. And for participants that did not respond in either study or who relapsed, Xtand allows us to evaluate benefit of re-dosing as well as frequency of additional dose. In addition to these studies, the team is preparing all the information that is needed to complete a new drug application, including a full non-clinical and clinical pharmacology package and the CMC work needed to manufacture finished product. As Michael mentioned, approach has completed enrollment. and we are on track to report top-line data later this quarter. In this study, we randomized 223 participants across 45 sites in the U.S. At the U-S Psych Congress in September, we presented that the baseline severity, as assessed using the MADRS scale, was approximately 33. This reflects a patient with moderate to severe MDD and is similar to what we saw in our Phase II study. In the top line release, we will share trial design information, including basic disposition and demographic data, as well as baseline characteristics. For efficacy, we Will report changes in the MADRS score at the primary endpoint of six weeks and the key secondary endpoint of 12 weeks, responder and remitter rates, as well as adverse events, including data on any adverse events of suicidality, if that is seen in the trial. Understanding the disease and the science behind a program provides the foundation. Equally important is understanding how key opinion leaders view the unmet need in depression and the potential role an innovative therapy could play in addressing it. To share those perspectives, I'd like to now welcome our expert panel. Moderating the discussion is Dr. Ken Kramer, our Senior Vice President and Head of Medical Affairs. Ken, over to you now. Thank you, Amir. It is an honor to host this esteemed panel. Let me start with introductions. Dr. Rakesh Jain is a clinical professor in the Department of Psychiatry at the Texas Tech University School of Medicine in Midland, Texas. Dr. Martha Koo is Chief Medical Officer of Your Behavioral Health, based in California, a large interventional psychiatry practice. And Dr. Roger McIntyre is Professor of Psychiatry, Pharmacology, and Toxicology at the University of Toronto, who we have all heard from earlier in the presentation. Thank you for joining us for this panel. Let us jump right in. The first question is going to go to Dr. Rakesh Jain. Dr. Jen, major depressive disorder affects how patients feel and how they function across work, relationships, and in daily life. From your clinical experience, how well do patients respond to their first antidepressant, and what does that journey typically look like? Yeah, Dr. Kramer, it's good to be with you and with you, Dr., and Dr. McIntyre. It's a great question because my practice on a daily basis is filled with exactly the kind of patients you talked about. These are the patients who have done first-line treatment, have tried as hard as they can, and what it looks like is a sense of frustration. It looks like a sense of, my goodness, this is the best you can do. And they will report there's clearly something's better. But the whole reason why I came to see you, dear clinician, dear psychiatrist, is for me to get back to where I used to be before this depression arrived in my life like a category firestorm. And I'm not there. So they come in hungry, but also they come in a little bit worried that do I know what I'm doing and can I get them over to the other side? Thank you very much, Dr. Jett. Dr. Koo, same question to you. Yes, I think Dr. Judd did an amazing job. I would say I see the exact same thing. I mean, we know that there are millions of people out there with depression, and we know that the vast majority of them don't get into remission right with the first antidepressant trial. And I think patients don't, we can use words as clinicians like response and remission, but as he very well described, patients, they just want to get back to their baseline, and I think we've had years of psychiatry where, as providers, we got patients partly better, and we were sort of okay with that, and then we left a lot of these walking wounded walking around, and so I think that we're focused a lot more in psychiatry and interventional psychiatry right now on complete remission and really more what we say quality of life. And so we have a huge market of people that don't respond to the first antidepressant or they're not even tolerating the first anti-depressant. Then we have very little choices of what to do besides more polypharmacy, more time, more waiting. As he already described, patients get frustrated, they get demoralized. And then we unfortunately at this stage of the game often wait for years or multiple trials before we're stepping in and doing an intervention that could really bring them back to the quality of life that they really want to have. Thank you, Dr. Koo. Dr. McIntyre, we're going to go to the second question for you. Dr McInyre, for patients who have a partial response to a first-line SSRI or SNRI, but have not yet reached their treatment goals, the guidelines support either switching or augmenting. What factors lead you to augment rather than switch? It's a great question, Ken, and nice to do this with Dr. Jane and Dr. Kuhn. I certainly echoed their comments a moment ago. There's a few factors. The obvious factor, Ken being if the first, the background antidepressant are taken is not well tolerated. I think it's kind of self-evident. It's axiomatic. We're just going to stop that antideressant and switch, but that's not usually what happens. What usually happens is the person's taking the treatment. And as you mentioned, they're having an inadequate outcome. And this is a shared decision. It is influenced by patient preference, but it's also influenced by what is the best available science and also algorithmically what is recommended and what's prioritized in clinical practice guidelines. And my own practice over the years has been in that situation. You just described, Ken, which is very common. Two out of three patients present the way you just described it. My instinct and my practice has been to adjunctively administer, in part because of what Dr. Jane and Dr. Koo had mentioned, that being the surplus of hopelessness, the surplus of frustration, but also because patients don't want to go back to day zero, wash out the background antidepressants start all over again and lose whatever momentum has been started. Now, the momentum may not be adequate, but the momentum nonetheless exists. The other part too, Ken, is that when we have that type of situation present, two out of three patients present this way, we're in a position to be a bit more clear as to what are the key therapeutic targets that we're trying to target with our therapeutics. So for me, at least, it comes down to what's the best available science? What's the clinical practice guidelines, patient preference? But I would say clinical experience would accord with the scientific community's recommendation that in that context, that the adjunctive administration is generally recommended for that patient. That's exactly what I do. Thank you very much, Dr. McIntyre. Dr. Jan, I'd love to hear the same answer to that question, but also if you wouldn't mind including to the end of it, how are patients helping to weigh in on that decision as well? Right. I mean, look, look at the numbers. I means, it's astonishing that three of us who practice in completely different states, different parts of the world are all converging on the same worry that two out of three patients are not getting there. Our antidepressants are getting them only partway there. For the most part, the frustration builds not just for the patient, but also for the clinician. The whole system is suffering. So what ends up happening, sadly, is clinicians freeze. They don't quite know exactly what to do because some of the treatment options that we currently have, they do have efficacy, but not a great deal. But the side effect burden of some of the FDA approved current treatments, particularly the atypicals, who, by the way, I will defend. The trouble is I'm defending a cause that's not entirely defensible, which is the side effects can be quite problematic. So what we have seen, we published some of this research ourselves. The majority of people who have suboptimally controlled depression, sadly don't get good treatment. They don't get actually any treatment. They don'T go see someone like Dr. Koo for interventional psychiatry. So we are in need of serious innovation in the world of adjunctive treatment with major depression. Yeah, I agree with that, Rakesh. And just a comment about that, Ken, you know, we talk about how the FDA has approved five therapeutics in this particular decision point in the algorithm. They're all atypical antipsychotics. In part, Ken, because of public relations, people don't want to be on antipsichotics, but also the side effects are quite intimidating, understandably so for many people. And Rakesh has done some nice work. There's been replication of this that patients tell their prescribers five times out of six, the majority of time, they don't wanna be on the atypic antipschotic. So the only avenue that is supported by adequate, well-controlled studies leading to FDA authorization is an avenue patients are saying five times out of six, I don't want it. So that speaks to the need for obviously acceptable treatments that are very effective. And that efficacy can't come three, four, six weeks later. This is the complacency that we've got ourselves into. The patients have said, look, why can't you find therapeutics that can work much more rapidly? And so I think that there's an appetite for the rapidity, for the robustness, but also something which is clearly not accompanied by the tolerability and safety concerns of what the atypicals come with. So five out of six people have voted they don't want atypicals. Thank you, Dr. McIntyre. Sorry, Candlemeter, too, because I just need to jump on this bandwagon. This is why being like you see, you feel the desperation for another adjunctive, you know, augmenter in the space. And I just needed to emphasize just two other things that they're saying. But one, you know, we don't, it's not just about treating the illness anymore and eradicating symptoms, right? It's about quality of life. And when we add something that even may be efficacious to remove symptoms and then ruins their quality of life because of weight gain and sedation and, you Know, potential movement disorders and akathisia, they really aren't happy. And I don't know, you Now, Roger and Akish, but you would say it's like when you sit with a patient and you're like, we should add an antipsychotic, you should see their faces. it's it's not you know you explain right we defend them as Ricky said like well these are evidence-based and they're there there's efficacy but they don't want to be on an anti-psychotic there's just stigma around that too I would I would say so it's a real dilemma for the the provider who wants to get someone fully better and we have limited choices that really don't improve their quality of life yeah well thank you for that excellent answer I want to go a little bit deeper into what we've just been discussing. We know that the atypical antipsychotics are the most established adjunctive options for MDD. And I think all three of you have done a beautiful job in speaking to a littlebit of where they are benefiting patients, but where they are also falling short in practice. So let me start with you, Dr. Koo. What would a better adjunctive option offer to patients? Oh yeah, so many things. A more rapid response, absence of additional side effects, especially medical side effects. Perhaps something that somebody doesn't have to take every day, right, for the rest of their life and require and maybe add a symptom burden. So obviously we're talking about efficacy, tolerability, and ease of of taking it. I mean, we didn't even mention that the non-adherence issues with the antipsychotics, right? So we're trying hard on our end and the majority of patients, they, you know, when they're honest, you have to ask in a very non-judgmental way, though they just don't adhere to these SCJs. So I think that we could use much better options. Thank you, Dr. Koo. Dr. Jan, I'd like to hear your thoughts on that, especially around the adherence concerns? It's been 40 years since I entered psychiatry, and I thought when I entered that my number one enemy would be psychiatric illnesses, and it's not true. My number one enemy has turned out to be adherence. The adherence for a lot of reasons, but I think side effects, particularly when we're talking about adjunctive agents, is by far my single greatest enemy. So what patients want, and I think I could break it into four components, what they want is something that's efficacious, really efficacious. The heart's been broken once, they are leery of having their heart broken twice. Number two, what they really want is something rapid. And why shouldn't they? Why should they not want something that is a basic right of someone suffering from a horrible disease like major depression? The third thing they want is sustainability. They want it to last. And the fourth thing, and don't let that fool you into believing it's the least important, which is tolerability, meaning weight gain, but also personality changes, also metabolic dysfunction, also movement difficulties. Patients are leery of that. And Roger just quoted the data to you. Five out of six patients have actually, despite suffering from this condition, said, I would much rather continue suffering from major depression than take a treatment you think might only help me a little bit in the majority of cases and potentially cause these side effects. So I hope you're hearing the plight in my voice and my colleagues' voice, which is we're speaking on behalf of our patients. Adjunctive treatment of major depression sadly retains the dubious distinction of wearing the crown of one of the greatest unmet needs in modern day psychiatry. Thank you, Dr. Jan. Dr. McIntyre, would you like to complete this question with your thoughts? It's something I think all of us have marinated, Ken, for such a long time. And when I think about the question of what's more important to the patient the efficacy or the tolerability, it's not a lot different than asking what's more important in a bicycle, the front wheel or the back wheel. They're clearly both critical. And there's no question that patients have said five out of six times, I don't want an evidence-based treatment for my depression because of side effects. So we often say, Ken, that side effects lead to treatment discontinuation. I say that's the second point. The first point is side effects often lead to treatment non-initiation. They don't even start it. But the part I want to get at, Ken, is efficacy. And there's no question that survey after survey has reported this out, no surprise, that the opportunity for rapid acting alleviation of human suffering in a way that is not a small p-value delivered by a statistician, but is meaningful. In other words, it really, really is detectable to the lived experience, their family, their friends, what have you, not only is that desired, but that sets in motion a real possibility, Kim, that is taking this vicious therapeutic cycle, supplanting it with a virtuous cycle of improving aspects of the lived experience that are barriers to quality of life and function. So patients not only have rapid alleviation of symptoms, but it sets in motion a cascade where they can now get back on the usual track. So both are critical, but certainly having that opportunity and to say to a patient, hey, look, you don't need to take this every day. My goodness, that is extremely appealing. Of course, it has to be acceptable. So, both are relevant. That's why it's my bicycle metaphor, clearly, but certainly now we have reasons to believe with innovative therapeutics, we no longer need to live with very low effect size therapeutic outcomes in depression. So we now have positioned ourselves to have that candid conversation with patients. Thank you, Dr. McIntyre. Going to the next question, and we'll start with Dr. Jan on this one. Dr. Jan, one of our implicit treatment goals should be to decrease the number of patients who are adjudicated to be treatment-resistant. In your clinical opinion, based on your experience, could earlier use of more effective, durable, adjunctive treatments help change the course of illness and potentially reduce progression to treatment- resistant depression? Yes, I could give you the short answer, which is a Y-E-S answer. Yes, absolutely. Look, no one ever develops stage four cancer without going to stage three, stage two, stage one. No one ever does that. No One ever becomes a diabetic without going through the stage of impaired glucose tolerance. No one develops treatment-resistant depression without going through Dante's Inferno, metaphorically speaking, of suboptimally treated, inadequately treated major depression. So unquestionably, both the data supports it, my clinical experience supports it. And most importantly, common sense supports what you just said, which is if we are able to intervene at that inflection point in the journey of a patient with major depression, which they have tried a medication, there has been some benefit that's measurable. but it's simply not enough. That is the point where there is real opportunity to change the course, the course back to recovery, the force back to functionality and the course to prevention of future relapses. So that's a longer answer. But the shorter answer was yes, absolutely. Thank you, Dr. McIntyre. I'd love to hear your thoughts on the same question. This is absolutely critical. There are many lines of evidence, Ken, that have been published in the period of literature to show that adequacy of treating depression will, in fact, delay, will forestall, will prevent this sort of cancerous, late cancerous TRD, treatment-resistant depression, endpoint. The other part, Ken, as well, just for this discussion, is that depression rarely exists alone. People have other psychiatric and medical problems. And when I think about transformation, I think of what's happening in psychiatry today with the opportunity for rapid, robust, endurable therapeutics. If I was asked, well, do you have a use case in other areas of medicine? I would say yes. The GLP-1s in obesity. Yes, they are transformative. in the weight loss. There's no question about that. But they also affect the long-term trajectory with lower rates of diabetes and other types of problems. That is a parallel to psychiatry because the longer the depression is inadequately treated, not only does it become more difficult to treat and become more cancerous as recast is articulated, but also then through the process of accretion, you start having additional problems start happening. And so by having a better treatment, we could forestall, prevent TRD itself, but also delay and even prevent the other concurrent or comorbid conditions that are affecting these patients, driving up healthcare service utilization, driving off costs, and obviously diminishing quality of life function and lifespan. So I think this is a very, very critical point. We're not only talking about targeting the here and now, but the view is to try and prevent the there and then in the future. Thank you, Dr. McIntyre. Dr. Koo, I'd like to hear your thoughts on the same question, please. Sure, Ken. I think they did a wonderful job. The interesting piece I'd add is we were talking before we started that I was just at the European Brainstem Conference in Naples, and there's a lot of conversation going on in the interventional psychiatry space about the interplay, right, between our own treatments and the development of treatment resistance. So, this is obviously theory, not fact. Roger and Rakesh mentioned very well the facts, which are the longest illness goes on, the harder it is to treat, you know, the more accumulative issues people develop, and that definitely leads to a treatment resistance, however, there's also a lot of thinking going on it developed more in the vns space the vagus nerve stimulation space um around the idea that that are we ourselves with our treatments right contributing uh to this treatment resistance right so i don't want to say that strongly like we don't have proof of that but the idea you know would be hard to separate out just leaving somebody ill as it's been mentioned versus our own treatments but i think the idea of you know like an antibiotic resistance that develops when we keep exposing a bug, right, a bacteria to multiple antibiotics, it learns, right, to not respond to anything that we have the idea sort of in parallel with depression and perhaps, right not having a fast acting, durable, efficacious, tolerable treatment early in the course of the illness trajectory is really a disservice for the disease itself, not only the patient. Thank you, Dr. Koo. That was a great answer. And I want to continue with you for the next question. Given your work as an interventional psychiatrist in a interventional practice, interventional psychiatry today is anchored by two main treatment modalities, esketamine and TMS. Dr. Koo, how do you see the novel serotonergic agonist fitting in to that landscape, not only the treatment landscape, but into the operational landscape as well? Absolutely. It's a great question. I mean, interventional psychiatry has just been an amazing field. I can't be happier. I tell people all the time that I hit psychiatry when I did, perhaps, right, that we had enough clinical experience, just like Roger and Keish to now and then see this something which I never imagined, you know, in my lifetime, really having access to these treatments. They are not sufficient, though, as we've been speaking about for many reasons. So I think the novel serotonergic agonist, it will be a game changer for interventional psychiatry on multiple levels. I think it's the timing couldn't be better, meaning that we have an incredible workforce of people in interventional psychiatry training programs. We even have the, you know, everybody's already organized. We have thousands of TMS centers, ketamine sites, you know S-bravado, S-ketamine sites where people have the workforces, they have the workflows. We even now have EHRs like Ozmine, which is amazing. It's built in, right, to integrate the REMS. It is built in to integrate The Worst Flow. It built in integrate the tracking of outcomes and safety profiles that REM systems require or that we should be doing for evidence-based practice regardless. The huge game changer for the novel serotonergic agonist that I see is moving interventional psychiatry upstream. And that's why I say it's a game changer. Right now in interventional psychiatrist, we wait for somebody to be treatment resistant before we get in and treat them, right? And with this kind of agent, we would have the opportunity to be doing this much earlier in the patient journey, not wait for them to be treatment resistant. So I guess in summary, I would say it's not only fitting in. I think we have the workforce. We have the operational systems in place. We Have the clinical expertise. We certainly have the patient desire. We've been talking about that. I Think even the programs in Colorado and Oregon, how they burgeoned have given us great evidence about patient preference and scalability. And then on top of that, right, we have an opportunity to introduce these type of interventional programs earlier for patients. And in potentially, I mean, this will be with the phase three information that comes out. But if on topof that, not only earlier, we have more durable and less burdensome treatments, you know, coming in for TMS every day, patients do it. They actually, people always think, oh, that's going to be the biggest part. They will do it because they'd rather do that than be on polypharmacy. But to have an intervention that perhaps is twice, right, over a three-week period and has a durable trajectory, it would be a game changer for interventional psychiatry. Dr. McIntyre, I'd love to hear your thoughts on the same question. Yeah, it's a great one, Ken. It's something I've thought about a lot, and we've done a lot of interventional psychiatry here at my center for many, many years. I think, in fact, that when we step back, Ken, there is going to be a macro effect on the portal of entry for the person with lived experience. Typically, what has happened is we have had people enter the system, they receive a traditional antidepressant, like an SSRI, if that's inadequate, then they engage on this odyssey of one treatment after the other one treatment out for the other and then once you become very end stage or very late or palliative they're referred to people like us who give therapeutics that are you know s-cadamine cadamine tms type treatments that model is not going to in that portal so to speak will not end today or tomorrow but i envisage a a a portal system a little different now because what's going to happen is is that you're going to have people who are going to immediately go into the interventional psychiatry they're not going to go through this odyssey forever forever forever ever and then and then it's an afterthought let's send you to the intervention psychiatry clinic because all hope is lost let's just cross our fingers something works i think in fact what's gonna happen especially now with access to information uh that people are you know using to equip themselves that it would not be an reasonable consideration that many people are just going to go right to the interventional psychiatry clinic rather than doing the therapeutic odyssey for months and years and I think that's in part because a we're going to have these treatments second I think also that the appetite for these treatments is so extraordinary and people are hearing about them and psychiatry can you know this is probably the only subspecialty I know about maybe one exists where we actually have the most effective interventions given last. People are saying, can I have them now? So if you were to go to your care provider and say, I want a treatment for weight loss, and they say, well, we're going to give you the one that works best, GLP-1s last, they're going say, I don't think that's a good idea. And so I think people want those treatments now. And given the way they're being studied, there's going to be good reason to give them now. So interventional psychiatry is going to expand. But I think rather than the late-stage, end-stage palliative-type patient, we're going to see people who are newly diagnosed or who have had relatively briefer durations who've said, look, I've tried an antidepressant. It didn't help me. I don't want to go through this odyssey. I want this taken care of now. Can I get access to this treatment now? So I think that's going to be a real game-changer for the system and the portal of entry. Thank you, Dr. McIntyre. May I just offer a quick comment here because it's got me so excited. I so agree with Roger and Martha that two weeks ago, we tripled our office space. Three weeks ago we hired three extra staff members. Three weeks we hired a new staff member. We now have five different treatment rooms set up specifically for the arrival of the new novel certain educations, because my colleagues are right. The frustration of our patients, the frustration of our clinicians and this old paradigm of we can only offer interventional help to those who have suffered. I wish it was months. It's sometimes years, sadly, sometimes even decades is in need of being challenged. It's in need of being called out. And if we're going to do that, we need to have the infrastructure and people like me across the nation are excited enough, Ken, that we are already preparing. We're already accepting this new model that patients don't have to suffer for long periods of time. If adjunctive treatment is necessary, which two out of three patients are going to need it, why don't we give them efficacious, rapid onset, tolerable, intermittent treatment? If that's doable, then that is how it must be done. That's actually the mantra we're using at our office. Yeah. And I'll just add, you know, we didn't even reference the lack of equipment needed, right? yes, you need a space. But I also have been thinking a lot about this and how even in the TMS evolution, right, we have now accelerated protocols and they were adopted first into the hospitals. So I envision, think about a patient with the severity of depression coming into an inpatient unit and having the opportunity to not being put on a second agent, which is going to take weeks to work and cause a burden of symptoms, being able to give them a treatment. They already have a room there's already staff there they're already safe they're not going home that night I mean that that to me would also be an incredible intervention that we get to treat these people with severe depression who who need to be in a 24-hour care system with something quick right and and and to me easy to operationally add I think it's going to be amazing to watch what happens Thank you for that, Dr. Koo. We are getting to our final question, and I want to thank you all for your fantastic insights on major depressive disorder. We're now going to switch gears a bit and focus on generalized anxiety disorder, GAD, and our HLP004 program. Dr. McIntyre, I would like to start with you on this final question. What do you see as the most pressing unmet needs in GAD currently? You know, Ken, in many ways, it's some of what we discussed. We need treatments that are effective, meaningfully effective, and rapidly effective in G AD. And to keep it brief, when we look at the lifetime prevalence of G AD, the number of people lived experience, it is a lot similar to what it is in major depressive disorder. But unlike major depressive order, it isn't that a little bit even more dire in some respects, Ken. We have over two dozen treatments that the FDA has approved for the treatment of adults with MDD. We have just over just maybe half a dozen treatments for GAD. So this is a condition which, with respect to epidemiology and persistence and the effect on role function, is a lot similar to depression, yet we just haven't had the drop-down menu of options that we've seen developed in MDD, So I think, in fact, all of what we talked about moments ago with respect to MDD would also apply, but I also would say that in the anxious patients, there's no question about it that everything around rapidity and meaningfulness and durability apply, But the opportunity therapeutically in this space is quite limited. And as we talked about the atypicals being encumbered, these are the antipsychotic drugs, by safety and tolerability concerns, the benzodiazepines have been some on label, many off label used here, are limited by not just safety concerns, but also, in fact, long-term tolerability aspects as well. So I think all of that would apply to GAD, and this is a world with much fewer treatment options compared to MDD. Thank you, Dr. McIntyre. Dr. Jan, please, same question. Yeah, MDD is common in my practice. You know what else is very common in our practice? GAD. And I think GAD doesn't get the attention it deserves, and I'm really glad, Ken, that we are having a discussion about it. It's hard to treat, actually. GED is hard to treat. The suffering equals the suffering of patients with MDD. And as Roger said, our treatment options are really limited. Sure, we have benzodiazepines as well, but just think about the tolerability issues, especially with chronic use. Sure,we have SSRIs, but think about what patients are saying. They walk away from it. So, yeah, all I can say is Roger nailed it. We need efficacious. We really do. We really do the effect sizes are embarrassingly low with most of our treatment options, but we need something that can sustain itself and we need something that's tolerable. That same quartet that I had mentioned previously really applies to GAD and with GAD I will accept gladly monotherapy because so many patients I see with GAD actually have either completely abandoned medications or never actually have been treated. So to give something that's highly efficacious for first-line treatment would be just, I hope you can see the excitement on my face and perhaps even in my voice, that would be a complete game changer in my practice. Thank you, Dr. Jan. Dr. Koo, Dr Jan, Dr McIntyre, thank you very much for being part of this panel. We appreciate your insights, your experience and your thoughts. And with that, I will turn the call back over to Amir. Thank you for those insights. We heard why there remains an area of unmet need in depression and anxiety. Now I'll be discussing HLP-004, a Duke-rated DMT program being developed for GAD, and why we believe it has the potential to address an important gap in the treatment landscape. Before we dive into the program itself, let me take a moment to provide some context on GAD and available treatments. Anxiety is a common mental health disorder, and one of the leading causes of disability worldwide. Available treatment options are often inadequate, with about half of patients not responding to initial treatment. With only four approved first-line pharmacological treatments, there has been no real innovation in about two decades. While benzodiazepines may be effective in the short term, long-term use is problematic, given the risk of dependence, misuse, and effects on cognition. GAD, therefore, remains a mental health condition with significant unmet need. HLP-O4 is deuterated DMT that we are developing for treatment of generalized anxiety disorder. Now, DMT, as it occurs in nature, is not orally bioavailable and when administered intravenously is intense, short-lived, and requires complex infusion protocols. Deuterating DMT stabilizes the molecule and extends the duration of effect. The intramuscular formulation that we have developed also smooths the PK curve. In our Phase 1 dose-reining study, we observed acute effects lasting for approximately 90 minutes, with participants being ready for discharge by about 3 hours. This development program is supported by a range of Phase 1 and Phase 2 studies that give us confidence in further evaluation of HLP-004 in an adequately powered study. Key amongst these studies is the Phase 1 study of intravenous HLP 004 and intravenious DMT, which allowed us to establish an optimum duration and dosing regimen for HLP 04. This demonstrated that deuteration extends the duration of pharmacological effects of DMT. In the Phase II signal-finding study, we established preliminary efficacy. Intramuscular administration of OO4 resulted in rapid and robust improvements in symptoms of GAD in an adjunctive setting. This was supported in parallel by a placebo-controlled Phase I dose-arranging study where we tested doses from 2 mg to 30 mg and observed that intramusular HLP-OO4 provides rapid onset of dose-dependent effects. Taken together, data from these studies and additional supportive studies that we have conducted across the development program form the basis of our next phase 2 trial, where we will evaluate HLP-O4 at a dose of 30 milligram in participants with GAD. We identified 30 milligram as the optimum dose for further development based on an extensive body of evidence. Key amongst this is the observation that there is clear correlation between emotional breakthroughs and improvements in symptoms of anxiety. In our signal finding study, we found a statistically significant correlation between the emotional breakthrough inventory scores and change from baseline in the HAM-A scores, meaning that this is a good surrogate for identifying a clinically effective dose. Further, in our dose proportionality study, where we evaluated a range of doses from 2 to 30 milligrams, we found that 30 milligrams resulted in the highest intensity of effect as well as the highest scores on the mystical experience questionnaire and the emotional break-through inventory. In the literature, a score of 60% or more on the MEQ has been shown to correlate with improvements in well-being. The proportion of patients who achieved this threshold on the MEQ was highest with the 30 milligram dose, and this was statistically significant versus placebo. The 30 milligram dosage was also well tolerated. These and several other considerations, including feedback from industry experts and key opinion leaders, support the selection of 30 milligram as the optimum dose for further development. We will evaluate the efficacy of the 30 milligram dose in our upcoming phase 2 study in generalized anxiety disorder, which we expect to initiate in the first quarter of 2027. This will be a randomized double-blind placebo-controlled study in adult patients with generalized anxiety disorder and will compare two intramuscular administrations of HLP-O4 three weeks apart versus inactive placebo. Efficacy will be assessed using the HAM-A as change from baseline in total score at the primary endpoint of six weeks. We will use the same measure for the secondary endpoint at 12 weeks. This trial employs a monotherapy design because we believe monotherapy design maximizes the opportunity to detect a clinical effect. It also allows for efficient patient recruitment compared with an adjunctive treatment design since there are limited FDA approved treatments for GAD. The next slide shows the phase 2 study design in more detail. To be eligible, adult study participants must be diagnosed with generalized anxiety disorder and score at least 20 on the HAMA at both the screening and baseline visits. They must otherwise be healthy. GAD must be the primary focus of treatment. Participants that have a current diagnosis of PTSD, psychosis, bipolar disorder, a personality disorder, substance use disorder, those who are clinically significant risk of suicidality or have recent exposure to psychedelics will be excluded. Approximately 144 participants will be randomized in a one-to-one ratio to receive either 30 milligram of HLP-O4 or inactive placebo. In summary, we recognize that GAD remains an area of significant unmet need, and there has been a lack of innovation in this space for quite some time. HLPO4 is a novel serotonergic agonist, which we have extensively characterized in terms of pharmacokinetics and pharmacodynamics and have identified a dose that we believe will provide robust efficacy and a favorable safety profile. We have already demonstrated a signal of efficacy in our previous phase 2 study in GAD. With a well-characterized profile, an encouraging efficacy signal, and a 30-mig dose that is well-tolerated, An adequately powered phase 2 monotherapy study is a meaningful next step in development to potentially validate this differentiated treatment for GAD. We expect this study to initiate in the first quarter of 2027. Thank you for your attention. Let me now turn the call back over to Michael. Thank you, Amir. Before we move to questions, let me briefly reiterate why we are excited about the opportunities ahead. As you've heard today, we are focused on addressing significant unmet needs with comprehensive development strategies. We believe our programs have the potential to offer important new treatment options for patients and create meaningful value for shareholders. I want to thank you for joining us today. I appreciate the opportunity to share our plans with you, and look forward to keeping you updated as we continue to execute against our objectives. With that, I'll turn the call back to the operator, who will provide instructions for the question and answer session. Thank you. As a reminder, to ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. In fairness, all we ask that you please limit yourselves to one question and one follow-up. Please stand by while we compile our Q&A roster. Our first question is going to come from the line of Ritu Baral with TD Cowan. Your line is open. Please go ahead. Good morning, guys. Thanks for taking the question. Michael, as we get close to the approach data, how do you see where expectations should fall? And maybe I should ask from a couple of different perspectives. One is what's required to support a regulatory approval? And two, how Do you frame what you would need to see on the, from a commercial perspective, What's commercially competitive? And if I could add like another dimension onto the question, as we do our KOL calls, events, and interventional psychiatry visits and consults, we find that things like duration of remission, duration of response is critical to the commercial viability of compounds. what data around durability of remission will we get either with top line or later? Thank you. Great. Thank you, Ritu. A number of questions in there. I'll try and keep track of them all. And then at the end, I'll let Amir speak to top line readout and in your questions there. But really critical questions you ask in terms of how to think about both from an approvability slash clinically meaningful perspective, and then also from the commercial perspective, given the competitive landscape that was outlined earlier in the presentation, which we really believe is the antipsychotics that are indicated for the adjunctive treatment of MDD. Again, all of this needs to be in the context of this is an adjunctive therapy, obviously administered on top of standard of care. So, from an approvability and then from the clinician perspective, what we've seen, and you can look to, of course, the precedents that are approved in the antipsychotic space for adjunctive MDD, you know, around three points, certainly approvable, certainly has been viewed as meaningful from the clinician's perspective. And then if we then shift to your question on the commercial profile that we would view as a strong commercial profile, again, it's always in the context of what's the competitive landscape, right? And the competitive landscape is, of course, not some of our peers that are working in the psychedelic space. You've got people working in monotherapy for MDD. You've Got people working and monotherapy treatment resistant depression. We're the only late stage program in adjunctive major depressive disorder. And again, the five approved therapies for adjunctive MDD are the antipsychotics. And if you look at what is best-in-class efficacy for the antipsychotics in the adjunctive setting, that's the four to five points of improvement on the Madras scale. So if we achieved comparable best- in-class type efficacy there, the four to five points. And then the other critical components, right, as you're looking at the commercial profile, you mentioned durability. It's absolutely very, very important. We saw in our phase two study, off of the two doses, we saw durability out to a year. So, to the extent we, again, we're going to see how that plays out in not only our phase three pivotal, but then also in the long-term extension studies, but similar long- term durability together really importantly with a favorable tolerability profile. And Dr. McIntyre walked us through the side effect burden of the antipsychotics and how significant that is. And so, if we see a similar tolerability as we saw in the phase two, which we would expect to translate into the phase three, and that's mild to moderate adverse events, primarily transitory on date of treatment, and there's only a few days of treatment. And when I talk about side effects, just compare them to the list that Dr. McIntyre referenced for the antipsychotics. For us, you're talking about headache, nausea, elevated blood pressure, again, primarily transitory on day of treatment. So, if we saw those three pieces, that comparable best-in-class efficacy as compared to the antipsichotics that are indicated adjunctively, saw durability, and then that favorable tolerability profile. To us, that represents a very strong commercial proposition to build value and, of course, patient benefit over the near and longer term. So, that's how I would, from those two perspectives, how I, how i would look at it. And then, Amir, if you want to talk about the top line readout and what people can expect there, that'd be helpful. Yeah, happy to, Michael. So as I mentioned earlier in our top line data we will share with you the general information about the trial the standard demographics baseline characteristics but in terms of efficacy the primary endpoint which will be changed from baseline at week six on the madras compared with placebo to your question of durability that's in the short-term study approach that's going to be the 12-week key secondary endpoint. So we'll look at change from baseline again in the Madras score at 12 weeks, comparing it to placebo. We'd also, of course, be sharing some select secondary endpoints with you, including responder and remitter rates. The long-term durability data will eventually come from Xtend, which, as you will recall, is a blinded long-time extension up until such point of time that a patient relapses or is requiring any additional treatment. And what Xtend will tell us is what is the durability of the initial two doses from the short-term studies. It will also, if patients need additional treatment, it will also give information about the re-dosing interval. And finally, how many doses will be required to maintain durability out to a year. And recall also that based on pre-specified criteria allows up to three additional doses in the long-term extension. Very helpful. Thank you. Cheers. Thank you, and our next question is going to come from the line of Andrew Tsai with Jefferies. Your line is open. Please go ahead. Hi, team. Thanks so much for hosting this event. Thanks for my question. So maybe one more on the top line expectation. How should we think about, on the safety side, rates of suicidal ideation? Is it fair to assume at a minimum we can expect zero cases of drug-induced suicidal ideations? I'm sorry, my kids are next to me. And then secondly, and then for the doctors, actually, obviously, you know, ideally a one-and-done dosing paradigm would be most ideal for depression and psychiatry in general. A lot of emphasis on durability. But I'd be curious, at what point does the redosing profile of a psychedelic become unattractive to you? Is it having to redose, for instance, every one or two months, every week? Thanks. Sure. Sure. And Amir, why don't I have you answer those questions? Yeah. So firstly, on suicidality, I always remind people that unfortunately, suicidal ideation behavior are features of MDD. So it is unsurprising if we see any reports of suicidal ideación or behavior in clinical trials. what we will share at top line of course is if there were any events of suicidality that were reported as adverse events those data will be shared with you as i said you know that's that's a background in mdd what we'd be looking for and we have an independent data monitoring committee as you probably already know, which monitors events in the background. It includes also a review of any potential signals around suicidality and has the opportunity or the mandate to stop a trial if it sees a signal, a safety signal, not just suicidally, anything which may affect patient safety. Clearly, approach has completed enrollment. So you can gather from that that the study wasn't stopped for safety reason. But yes, we'll share eventually with you if there were any adverse events of suicidality, those data will be at top line. Your second question was about one and done and durability, Andrew. So, I mean, that's probably, in my view, I think that would be unrealistic to expect from any treatment. There is literally no treatment in medicine that is one and one, right? even with the intermittent treatments, the most obvious example, if you like, is esketamine. Even that intermittent treatment is about 30 to 50 administrations in a year. What we know from our data is that in phase two, we gave two doses, three weeks apart, and we saw reasonably durable effect. We saw durability lasting out to a year. Now, of course, phase two data, we need to replicate and further evaluate those in phase three, which is what we are currently doing. And those data will be available both from our short-term studies approach and embrace, as well as the long-term extension extent. Thank you so much. Thank you. And our next question is going to come from the line of Sumit Kulkarni with Canaccord Genuity. Your line is open. Please go ahead. Good morning. Thanks to Helus for hosting this informative event and for taking our questions. I have a couple of questions for Drs. Koo, Jane, and McIntyre. First, clearly and unfortunately, the demand exists for novel serotonergic agonist treatment, but do you think the supply side, that's clinical infrastructure, pricing, reimbursement-associated variables, are ready to satisfy this demand, or could they limit access to some of the most efficacious treatments? And second, in terms of eventual real-world use of these agents, durability of effect could last several weeks, if not months. But is there any reason to believe that subsequent retreatments might not be as efficacious or durable, not so much from a technical tolerance or tachyphylaxis perspective, but more from a, for lack of a better phrase, familiarity breeding contempt for subsequent sessions. Sure, and thank you, Suman. Unfortunately, the panel members, the Q&A here is just management, Amir and I, but I think we can speak to some extent to your questions as well. And maybe, Amira, if you want to speak again to the subsequent dosing piece, and then I I can talk in terms of supply infrastructure. Yeah. So, I mean, there's no reason why if a patient responds to an initial dose and whatever the durability, whether that's 12 weeks or 24 weeks, retreatment should, if needed, still result in a similar response. In fact, generally in medicine, you see that the biggest or the best predictor of response is prior response. So if somebody has responded to an initial treatment like we saw in the short term phase two studies, then retreatment should also result in a similar sort of response. Now, we did see actually with the second dose, if you recall from the short-term study, that resulted in an incremental benefit. So there is still room for people to respond from additional and repeated dosing. In that study, of course, patients started at a baseline of 33 and they had a large improvement, meaning that they went into remission. so clearly at that point of time they didn't have any room for improvement because how low can you go then but this is something we will study in extent as I said previously there is opportunity for up to three additional doses in extent based on predefined criteria and those data will tell us what the frequency of redosing might be what the need for redosing might be and what the durability of both initial as well as subsequent dosing might be. Sure. And thanks, Amir. And then from your question regarding infrastructure availability and supply, and you did hear the panel speak to this generally. In particular, Dr. Khoo, who runs a number of centers, I thought had some good perspective in terms of the excitement in the interventional psychiatry clinics, given all of the positive data that we've seen across the space, that the excitement for this new class and then all in the focus on it. But then also in terms of all of our survey work from the clinics, That there really is an appetite and a view that to the extent they need to add capacity or in their ability to handle incremental capacity as well, that there's really a positive sentiment there and a willingness to meet the increased demand. And, you know, really looking forward to, of course, building patient awareness, you know, across the space and, again, very positive in terms of the clinic's views on these potential therapies. Thank you. in one moment for our next question. Our next question is going to come from the line of Pete Staropoulos with Cantor Fitzgerald. Your line is open. Please go ahead. Hi, Michael. I'm the mayor of the informative webinar. Thank you for hosting, and thank you for taking our questions. Two for me. For the Phase 3 approach study, what are some of the tools or mechanisms you've put in place to ensure clinical site quality and execution, screening process for enrollment to ensure you're enrolling real MDD patients, and avoiding professional patients, and how do you ensure that these patients are on standard of care like SSRIs? Yeah, I can take that one. Thank you. So, I mean, those are the most important questions you flag up, and we've been thinking about those quite extensively and putting in place measures to ensure the quality of both the patients as well as the conduct and execution of a trial. So firstly, we handpicked all our sites, right? The single most important factor is to get the right sites and the right investigators who have experience in doing this and understand the space. So it starts there with carefully identified and selected sites. Then moving on to identifying the right patients. And unfortunately, investigators don't like us for this, but we have put in place a number of procedures which patients have to go through before they can actually be enrolled. Key amongst those is the MGH Safer interview. And that interview is an extensive evaluation of patients' diagnosis and suitability for the trial, independent of the site. Site has no say in it. It's an independent group of clinical experts run by the MIGH Institute. And And that establishes both the diagnosis independently as well as goes through the inclusion-exclusion criteria to determine suitability in the trial. You talked about professional patients as well. Absolutely. Unfortunately, that is a reality in this space. And we use tools like duplicate patient registries that is quite standard across the industry. And we use those to establish whether there are any duplicate or professional patients being enrolled in the trial. And we as part of the safer interview, the antidepressant treatment response questionnaire or the ATRQ is also administered, which establishes a patient's history with respect to antideressant treatment. it makes sure that or it goes extensively into which standard of care medications were taken by the patient at what doses for what duration partly to establish that these patients are not treatment resistant depression patients it also ensures that we have patients on stable doses of antidepressant medication and as per protocol there's a requirement for patients to be on a stable dose for the past four weeks. So, all of that is done through standardized tools, and we make sure that the patients that are getting in a trial are the right kind of patients. Yeah, and Pete, it's a very good area of focus, right? Nothing more important than clinical trial execution, and I think if you sum it up and look for evidence of this execution, Amir mentioned it in his presentation, but we recently disclosed at site Congress that the mean Madras scores in approach on entry were 33, which is, of course, consistent with the scores that we saw in our phase two as well. So, evidence of that execution, that all of those safeguards and processes that Amir put in place, in fact, translated into the patient population that is consistent with what we saw in the phase two. Thank you. And a follow-up, and thank you for that, is, you know, how should we be thinking about the placebo effect in approach 003 in the adjunctive setting? And this class more broadly, and what steps have you taken to minimize it? Sure, and maybe I'll start, Amir, and then you can give your point of view. And, Pete, this has, of course, been a challenge for depression trials for forever, right? Your general depression trials, placebo response, you've seen something like, you know, 10 to 12 points of placebo response in phase three. It's been a real challenge for drug developers. But in the psychedelic class, actually, placebo response has been managed rather well in the late-stage trials in MDD or treatment-resistant depression. If you look at at the recent late-stage trials that have been conducted by our peers, you'd see one to five points of placebo response is what we've seen in those late-state trials. Obviously, in our phase two, we saw approximately three points of a placebo response. Now, we'll have to see how that translates into phase three, but you really like the control over placebo response that we've seen in the psychedelic class to date. But Amir, anything you want to add? Yeah, well, I think that's all probably, but just to mention, we also take care to minimize the nonspecific measures that may be contributing to placebo response at the site there's of course the issue of functional unblinding which we mitigate using the approach that's prescribed by the regulator which is using a centralized independent blinded rater for the primary endpoint but we also make sure that only those people at the sight level who need to be in contact with the patient or who need to be involved in the assessment only they are involved and we also you know firewall the data as much as possible patient data from from the site staff so only those patient people who need access have access to the information. In an adjunctive setting I think you mentioned that we don't really have a head-to-head comparison between monotherapy versus adjunctive therapy in terms of placebo response. We don't necessarily expect the placebo response in adjunctive trials to be any greater than what you would see in monotherapy in this space. All right. Thank you all for taking my questions and looking forward to the data readout. Thanks, Pete. Thank you. And our next question is going to come from the line of Eddie Hickman with Guggenheim Securities. Your line is open. Please go ahead. Hi, good morning, and thanks for the really helpful event. Just a few questions from me. The panel made a point about moving the interventional psychiatry upstream, and that was interesting. So I wanted to ask about the real-world delivery model. In phase two, obviously, the patients had the EMBARQ framework before and after dosing. So could you sort of remind us what the level of preparation and integration was in support and how we should think about the minimum support that will be required in practice? And then relatedly, as you think about payer conversations, how should we expect it to be positioned at launch? Obviously, the TRD expect a sort of class prior authorization rules. So how should we think about adjunctive versus TRD in terms of like step edits and prior therapies once in the clinic? Thank you. Sure. You want to take the first and then I'll talk to payer dynamics. Yeah. Yeah. So similar to what other drug developers are doing in this space and what is consistent with good medical practice, we provide our clinical trial participants with psychological support. we do this both before and after during the dosing there are clear fda guidance there's a clear guidance as to what is needed and this is exactly the same as we had in our previous study phase two we have developed the embark framework which incorporates evidence-based treatments empirically supported treatments and it gives the session monitors the kind of framework that and training that is needed to ensure safety of participants and the fact that and ability to effectively navigate them through treatment sessions. So what we do pre-dose again consistent with what we would do in good medical practice is discuss with the patients what the expected outcomes are, what the treatment experience will be like. It's an opportunity to build a relationship or a rapport with the clinician. Post-dose would be debriefing around what their experience was like and learning strategies to keep the treatment benefit momentum. Post-approval, we do not expect the FDA to dictate what specific pre-post-dosed psychological support regimens will be required because that is essentially the practice of medicine and the FDA only regulates medicine. So, this will be on a case-by-case, patient-bypatient basis determined by the clinicians. Thanks, Samir. And then, your question in terms of payer dynamics, I think a good place to start is pointing out, of course, this is an adjunctive treatment. So, by definition, the patient is already on standard of care, hasn't received sufficient benefit. So certainly, that factors in. But more generally, in terms of the payer dynamics, and obviously, it's early days, once you have your phase three data, etc., these conversations progress. But in terms of the product profile here, I think that's a great starting point. If you think about durability of effect, the favorable safety and tolerability profile, and so patient compliance, and then think about the comorbidities associated with depression. And of course, they're significant. And so putting all of that together in presenting to the payers so they can build their models, you know, reflecting those sorts of benefits, I think have the potential to be very, very productive, constructive discussions with the payers. And again, as an adjunctive therapy, you've already effectively failed on one treatment that is additive as well. So, look forward, of course, to our phase three results and then having those discussions, you know, with all the backdrop that I just outlined. Thank you. Just one follow-up. When you think of standard of care, do you think is it only sort of generic SSRIs and SNRIs or, you Know, is something like Ovelity or something like an antipsychotic that is approved for MDD, are those also considered something that you'd expect patients to stay on or be on when taking O3? Yeah, so generally standard of care would be the SSRIs, the SNRIs. And of course, they're largely generic. In terms of the anti-psychotics. I think you heard from the panel today that that really is an adjunctive approach versus a monotherapy. Amir, anything additional you want to add from a clinician perspective? And also from an anti-psychotic point of view, those really would be blocking the effects of this class of drug. So, they would, in fact, be contraindicated when you're administering a patient psychedelic medication. So, any patients that are on adjunctive would go back. Thanks. Sorry. Sorry, say again. I was just saying, so we'd expect a patient that has already sort of started on an adjunctive you know, capillite, for instance, would have to go off of that antipsychotic before adding on something like this? I think the way a patient journey would evolve is once they have had the first line, SSRI or SNRI, and they have insufficiently responded, then there will be a choice for the clinician. Typically, when they would switch to an atypical antipsycotic, the choice would be whether the switch is to an atypical antipsychotic or instead they could administer an adjunctive like HLPO3. So you don't expect patients who are already on an attypical antipsychotic and are responding to potentially come off and take a treatment like HLP03. That would be their choice. But in terms of a treatment, you know, evolution in terms of the steps that a patient would go through. It would be that natural step around switching that occurs after they may have failed an initial trial of SSRI or SNRI. Thank you. I think we have time for one more question. Our last question will come from the line of Patrick Trujillo with C.H. Wainwright and Company. Your line is open. Please go ahead. Thanks. Good morning, and thanks for squeezing us in. Just a first follow-up on approach. So I'm curious what placebo-adjusted Madras difference in variability assumptions underpin approaches statistical power, and is the Week 12 endpoint included in the multiplicity-controlled testing hierarchy. And then as it relates to the commercial preparations, I'm wondering what prep work you've done so far. And just if you can speak to what learnings you would expect as some of these other psychedelic treatments perhaps launch ahead of HLP3, even if they're in different indications, what sort of learnings would you expect there? And how do you plan to reach earlier line mdd patients is it primarily through existing interventional psychiatry practices or by building referrals from community psychiatrists and you know sort of what would that imply for your field organization and uh you know medical education strategy yeah so a lot to unpack there amir why why why don't you start with the with the the clinical questions and then i'll take the infrastructure commercial questions? Yeah, I'll take the easier one, which is the powering assumptions and the Madras Delta. So we haven't disclosed in detail the powerings assumptions yet, but if you look at other late stage trials in this space and you factor in assumptions around variability, variability which is pretty standard in this space and a discontinuation rate then we would be adequately powered from that point of view we of course also have discussed or presented the trial to the agency as part of our btt discussion so there's there's a kind of buy-in there in terms of the powering assumptions um for your uh secondary endpoint question um yeah so there will be appropriate uh adjustments made for multiplicity uh at the secondary endpoint of 12x and then in terms of of the the infrastructure and and the commercial related questions you You asked, Patrick, you did you did point out the peers and and to frankly, of course, view them as peers, given given that they're they're operating in different indications if approved. But certainly view it as a positive that peers are going through the approval cycle, the rescheduling process, both the state and the federal level, working through that and making that hopefully as efficient as it can be. But then also building awareness for the class and then also building incremental infrastructure. You know, obviously, J&J through Spravato has done a lot of work over the years, but view it as a positive that the peers are going to continue to expand that infrastructure and then would look to be the fast follower and leverage off that. add incrementally, obviously, in the adjunctive indication. And in terms of the model, obviously, the interventional psychiatry clinics is the current model and would expect that to continue. And then we'll see as, again, this all rolls out and hopefully demonstrate, you know, the significant patient benefit here and how everything evolves. But certainly excited to see that process play forward. Terrific. Thanks so much. Thank you. And I would now like to hand the conference back over to Michael Halstead for closing remarks. Just thank you very much to everyone for joining today. I do want to say how very proud we are of all of the accomplishments of the Helus team to date and really excited about the future of Helus Pharma, the potential that the company has to achieve the mission of really benefiting patients in the mental health space. and look forward to updating you as we proceed and excited about the upcoming phase three data readout. So thank you everyone for their time today and you may now disconnect.