Helus Pharma Inc. (HELP) Earnings Call Transcript

Thank you. hypothesis, a willingness to look deeper, to test, 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.

Welcome to the Helius 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 prospective in nature. In preparing these forward-looking statements, several assumptions. were made by Hewlett's and there are risk and actual results obtained by the company while differ materially from these statements. The company cannot guarantee any forward-looking statements will materialize, and you are cautioned not to place undue reliance on them. We refer certain We refer current and potential investors to certain cautionary statements contained in the presentation and to the forward-looking statements and the risk factor section of the company's annual information form and the most recently filed management's discussion and analysis available at cdarplus.com. 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. 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 long-standing 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 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 HLP003 and HLP004, our clinical strategies, and why we 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 3 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 EMBRACE. HLP-004, which is deuterated DMT, is our phase three 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. 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, by a broad intellectual property portfolio, which is expected to provide patent protection into the early 2040s across O3 and O4. 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 are also about 20 million adults in the U.S. living with GAD, and more than 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 OO3 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 could take four to six weeks, or the healthcare 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 unmet need. 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 depression, explain why new treatments are needed, and provide context on how OO3 could fit into the MDD treatment landscape. Following Dr. McIntyre's remarks, Dr. Amir Inamdar, our Chief Medical Officer, will provide an overview of our OO3 program.

Dr. McIntyre. Thanks, Mike, and good day, everybody. Great to be with you. Roger McIntyre, 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 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 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, conditions, depression ranks number two, but within psychiatry, globally, major depressive disorder is the most disabling condition. But 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 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's debilitating, 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 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 antidepressants, it's been amply documented that two out of three people are just not adequately benefiting. This is in part because the antidepressants 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 getting 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 antidepressant'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 simply the frequency of this occurrence, two out of three people who start an antidepressant do not adequately benefit. 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 again. 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 the in this context. Now, as we've heard, the FDA has approved five agents in the adjunctive paradigm. That is in person who has had an inadequate benefit with the background antidepressant, which is usually an SSRI or related agent. And each of these agents these five agents that the FDA has approved in the Adjunctive Paradigm are called atypical antipsychotics that are presented here. And what we do know 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 antipsychotics 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 will experience on medications. There's also a very long-term serious side effect called tardive dyskinesia, which is an involuntary movement disorder voluntary 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 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 symptoms. 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 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, uh, And if 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 price? source 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, an uh 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 adjunctive, but are in fact more effective and better tolerated than the current treatments, that being the atypical antidepressant. 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. core it is related to psilocybin which as it occurs in nature is an inactive prodrug. To become the active metabolite, psilocin, it needs to be converted in the body through a process called dephosphorylation. What we have done is replaced some of the hydrogen atoms from the psilocin molecule with its heavier cousin deuterium. And by deuterating psilocin, 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 HLPO3 compared with generic psilocybin. In our preclinical studies, we have seen that HLPO3 gets into the brain faster and reaches a higher concentration than psilocin from psilocybe. 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 HLP-O3 achieves a plasma concentration that's 1.5 times higher, and a total exposure that's about 2 and a half times higher. Published data also show that plasma concentrations of psilocin 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 experience 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 MADRS 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 care. 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 MADRS. 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 MADRS 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 three program is comprised of two short-term studies, Approach and Embrace, and a long-term extension, Extend. Overall, our phase three study designs are very similar to phase two. However, we have included the second administration 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 the 16 milligram dose of O3 versus inactive placebo. In EMBRACE, we are also evaluating an intermediate eight milligram dose versus placebo. Participants from both studies are eligible to roll over into X10, where based on predefined criteria in the protocol, they have an opportunity to receive up to three additional doses. Extend 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, extend allows us to evaluate benefit of redosing as well as frequency of addition. 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 US. that the baseline severity as assessed using the Madras scale was approximately 33. This reflects a patient with moderate to severe MDD and is similar to what we saw in our Phase 2 study. In the top line release, we will share trial design information, including basic disposition and demographic data, as well as baseline characteristics for For efficacy, we will report changes in the MADRS score at the primary endpoint of 6 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. Jain, 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?.

Yes, Dr. Kramer, it's good to be with you and with you, Dr. Koo 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 five storm 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. Koot, 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 said, 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 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 medicine. 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 antidepressant. 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, you know, 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. McIntyre, 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 you're taking is not well tolerated, I think it's kind of self-evident. It's axiomatic. We're just going to stop that antidepressant and switch. But that's not you. usually what happens. What usually happens is the person is 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. Jahn, 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 mean, it's astonishing that three of us who practice in completely different states, different parts of the world are 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 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 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. 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.

Yes, 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 antipsychotics, but also the side effects are quite intense. 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 want to be on the atypical antipsychotic. So the only avenue that is supported by adequate, 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. 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 they really aren't happy. And I don't know, you know, Roger and Akish, but you would say, it's like when you sit with a patient and you're like, like we should add an antipsychotic, you should see their faces. It's not, you know, you explain, right? We defend them as Rakeesh said, like, well, these are evidence-based and there's efficacy, but they don't wanna be on an antipsychotic. There's just stigma around that too, I would say. So it's a real dilemma for the provider who wants to get someone fully better, and we have limited choices that really don't improve their quality of life.

Dr. Koo, thank you for that uh excellent uh answer. Uh 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 little bit 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 taking it. We didn't even mention the non-adherence issues with the antipsychotics, right? So we're trying hard on our end, and the majority of patients, when they're honest, you have to ask in a very non-judgmental way. They just don't adhere to these SCJs, SGA's. 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. Okay. And why shouldn't they? Why should they not want something that's 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 is 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, rather continue suffering from major depression, then 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. Jen. 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, 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. Um, they're clearly both critical. Um, 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 by you know 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, Ken, that is taking this vicious therapeutic cycle supplanting 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, 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 which is if we are able to intervene at that inflection point in the journey of a patient with major depression, which is 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 course back to functionality, and the course to prevention of future relapse. So that's a longer answer, but the shorter answer was yes, absolutely.

Thank you. Dr. MacIntyre, 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 peer-reviewed literature to show that adequacy of treating depression will in fact delay, will forestall, will prevent the 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 transplants, transformation. I think about 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 uh uh delay and even prevent the uh other concurrent or comorbid conditions that are affecting these patients, driving up healthcare service utilization, driving up 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 Brain Stimulation 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 treatments. 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, around the idea that are we ourselves with our treatments, right, contributing 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, it 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. 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 that we had enough clinical experience, just like Roger and Keish to now and then see this something, which I never imagined 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 the timing couldn't be better, meaning that we have an incredible workforce of people interventional psychiatry training programs. We even have, um, the, you know, everybody's already organized. We've thousands of TMS centers, ketamine sites, you know, as Spravato as ketamine sites where people have the workforces, they have the workflows, we even now have EHRs like Osmind, which is amazing. It's built in, right, to integrate the REMS. It's built in to integrate the workflows. It's built in to integrate the tracking of outcomes and safety profiles that REMS systems require or that we should be doing for evidence-based practice regardless. The huge game changer for the SG, you know, for the not for the uh 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 psychiatry, 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 interventions interventional programs earlier for patients. And in potentially, I mean, this will be with the phase three information that comes out. But if on top of 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.

Yes, 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. Um, 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 after the other. And then once it become very end stage or very late or palliative, they're referred to people like us who give therapeutics that are S-cadamine, cadamine TMS type treatments. That model's not going to, that portal, so to speak, will not end today or tomorrow, but I envisage a portal system a little different now because what's going to happen 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 it's an afterthought. Let's send you to the interventional psychiatry clinic because all hope is lost. Let's just cross our fingers something works. I think in fact what's going to happen, especially now with access to information that people are using to equip themselves, that it would not be an unreasonable 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, Ken, you know,.

is probably the only subspecialty I know about, maybe one exists, where we actually uh have the most effective interventions given last. Uh 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 to 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, didn't help me, I don't wanna 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.

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 ago, we now have five different treatment rooms set up specifically for the arrival of the new novel serotonergic agents. 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 changed. 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.

Yes, and I'll just add, you know, the, the, 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 in to 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 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 similar to what we discussed. We need treatments that are effective, meaningfully effective, and rapidly effective in GAD. And to keep it brief, when we look at the lifetime prevalence of GAD, the number of people who lived experience, it's a lot similar to what it is in major depressive disorder. But unlike major depressive disorder, it is in fact 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 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 earlier, about the atypicals being encumbered, these are the antipsychotic drugs, by safety and tolerability concerns, uh 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. Jahn, please, same question.

Yes, MTT is common in my practice. You know what else is very common in my practice? GED. 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. 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 the... What patients are saying, they walk away from it. So yes, 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-04, a deuterated 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. GED therefore remains a mental health condition with significant unmet need. HLP-004 is deuterated DMT that we are developing for treatment of generalized anxiety disorder. 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 one dose-reining study, we observed acute effects lasting for approximately 90 minutes. with participants being ready for discharge by about three hours. This development program is supported by a range of Phase I and Phase II studies that give us confidence in further evaluation of HLP-004 in an adequately powered study. Key amongst these studies is the phase one study of intravenous HLP-O4 and intravenous DMT, which allowed us to establish an optimum duration and dosing regimen for HLP-O4. This demonstrated that deuteration extends the duration of pharmacological effects of DMT. In the phase 2 signal finding study, we established preliminary efficacy. Intramuscular administration of O4 resulted in rapid and robust improvements in symptoms of GAD in an adjunctive setting. This was supported in parallel by a placebo-controlled phase 1 dose-ranging study where we tested doses from 2 mg to 30 mg and observed that intramuscular HLP-O4 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, the basis of our next phase two trial where we will evaluate HLP-O4 at a dose of 30 milligram in participants with GAD. We identified 30 mg 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 emotional breakthrough inventory scores and change from baseline in the HAMA 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 breakthrough 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 dose 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 two 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 HAM-A 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 1 is to 1 ratio to receive either 30 mg 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. HLP-O4 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 mg dose that is well-tolerated and An adequately powered phase two monotherapy study is a meaningful next step. 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. I'll turn the call back to the operator, who will provide instructions for the question and answer session.