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 prospective in nature. In preparing these forward-looking statements, several assumptions were made by Helus, and there are risks and actual results obtained by the company will 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 current and potential investors to certain cautionary 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 discussion and analysis available at sedarplus.ca and on edgar@sec.gov. Forward-looking statements represent the company's expectations as of October 21st, 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 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. HLP003, which is deuterated psilocin, is our lead program and is currently in phase III development for the adjunctive treatment of major depressive disorder.
Our near-term catalyst is the upcoming phase III APPROACH top-line data readout, which remains on track with results expected later this quarter. The EMBRACE study, our second phase III efficacy study, is ongoing, and the EXTEND trial, our long-term extension study, is enrolling eligible patients from both APPROACH and EMBRACE. HLP004, 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 HLP005 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 HLP003 and HLP004. 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 are 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 HLP003 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 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 have generated to date, HLP003 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 HLP003 could represent a very meaningful treatment option for patients. To better understand the opportunity ahead, it is important to first discuss the significant unmet treatment need impacting patients living with depression. I am 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 HLP003 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 HLP003 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 to address. 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.
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. This degree of persistence of the condition contributes to the disability, the impairment in role function, human capital. 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 datasets, 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, 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.
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. The other part about this as well is that even amongst people who do remit, the third that are, if you will, the privileged ones that are benefiting, too often they have lingering problems in day-to-day quality of life and functioning. Now, one option could be to stop the antidepressant, that is the antidepressant that's been inadequate, bringing about remission, and switch to a different monotherapy. The other option is to adjunctively administer a treatment. 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 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. Other reasons, frankly, clinical practice guidelines, published in the United States, around the world, promote adjunctive administration in this context. 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. Each of these five agents that the FDA's approved in the adjunctive paradigm are called atypical antipsychotics that are presented here. 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. 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, 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. 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.
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. If they go with an adjunctive treatment strategy, which is preferred and which is recommended in clinical practice guidelines, we have FDA-approved treatments, these treatments are falling short on efficacy and certainly falling short on tolerability and safety. The frustration is palpable. The next question related is, well, 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. 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. That efficacy needs to be efficacy that can be durable. 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. 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 antipsychotic. 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 HLP003 as a potential adjunctive treatment in MDD. Let me start with what HLP003 is. HLP003 is a deuterated psilocin. At the 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 replace some of the hydrogen atoms from the psilocin molecule with its heavier cousin, deuterium.
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 HLP003 compared with generic psilocybin. In our preclinical studies, we have seen that HLP003 gets into the brain faster and reaches a higher concentration than psilocin from psilocybin. Clinically, when we compare 16 mg of HLP003 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 HLP003 achieves a plasma concentration that's one and a half times higher, and a total exposure that's about two and a half times higher. Published data also show that plasma concentration 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 mg dose of HLP003 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. We tested this in our phase II 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-Åsberg 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 HLP003, which we tested at two dose levels, 12 mg and 16 mg, while remaining on standard of care.
At the primary endpoint of three weeks, a single dose of HLP003 resulted in a rapid and large improvement in symptoms of depression, which was about 13 - 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 HLP003, 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 mg, 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 II 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 III program. Our pivotal phase III program is comprised of two short-term studies, APPROACH and EMBRACE, and a long-term extension, EXTEND. Overall, our phase III study designs are very similar to phase II. However, we have included the second administration in our primary endpoint.
The entry criteria in phase III are also very similar to phase II, though we did increase the MADRS threshold for entry into the study from 21 - 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 this key secondary endpoint at 12 weeks. APPROACH and EMBRACE test a 16 mg dose of HLP003 versus inactive placebo. In EMBRACE, we are also evaluating an intermediate 8 mg dose versus placebo. Participants from both studies are eligible to roll over into EXTEND, 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. 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 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. 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?
Yeah. 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. They 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.
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. Jain. Dr. Koo, same question to you.
Yes, I think Dr. Jain did an amazing job. I would say I see the exact same thing. 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 with the first antidepressant trial. 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. 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. 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 do not respond to the first antidepressant, or they are 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 for years or multiple trials before we are 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 are 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 is a great question, Ken, and nice to do this with Dr. Jain and Dr. Koo, and I certainly echo their comments a moment ago. There are a few factors. The obvious factor, Ken, being if the first, the background antidepressant that are taken is not well tolerated, I think it is self-evident, it is axiomatic, we are just going to stop that antidepressant and switch. But that is not usually what happens. What usually happens is the person is taking the treatment, and as you mentioned, they are having an inadequate outcome. And this is a shared decision. It is influenced by patient preference, but it is also influenced by what is the best available science, and also algorithmically, what is recommended and what is prioritized in clinical practice guidelines.
In 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. Jain and Dr. Koo had mentioned, that being the surplus of hopelessness, the surplus of frustration. But also because patients do not want to go back to day zero, wash out the background antidepressant, 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 are in a position to be a bit more clear as to what are the key therapeutic targets that we are trying to target with our therapeutics. For me at least, it comes down to what is the best available science, what are the clinical practice guidelines, patient preference. But I would say clinical experience would accord with the scientific community's recommendation that in that context, the adjunctive administration is generally recommended for that patient. That is exactly what I do.
Thank you very much, Dr. McIntyre. Dr. Jain, I would love to hear the same answer to that question, but also if you would not mind including, to the end of it, how are patients helping to weigh in on that decision as well?
Right. Look at the numbers. It is 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. What ends up happening, sadly, is clinicians freeze. They do not 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 am defending a cause that is not entirely defensible, which is the side effects can be quite problematic.
What we have seen, we published some of this research ourselves, the majority of people who have suboptimally controlled depression sadly do not get good treatment. They do not get actually any treatment. They do not go see someone like Dr. Koo for interventional psychiatry. 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. We talk about how the FDA has approved five therapeutics in this particular decision point in the algorithm. They are 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 intimidating, understandably so for many people. Rakesh has done some nice work. There has been replication of this, that patients tell their prescribers five times out of six, the majority of the time, they don't want to be on the atypical antipsychotic.
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. 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, that patients have said, look, why can't you find therapeutics that can work much more rapidly? I think that there is 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. Five out of six people have voted they don't want atypicals.
Thank you, Dr. McIntyre.
I will just, sorry, Ken, let me interject, too, because I just need to jump on this bandwagon. This is why being like we are, you see, you feel the desperation for another adjunctive augmenter in the space. I just need to emphasize just two other things that they are saying, but one, 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 potential movement disorders and akathisia, they really aren't happy. I don't know, Roger and Rakesh, what you would say. It's like when you sit with a patient and you are like, we should add an antipsychotic, you should see their faces. You explain, right? We defend them, as Rakesh said.
Like, well, these are evidence-based, and there's efficacy, but they don't want to 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.
Yeah, well put.
Dr. Koo, 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 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 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? 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 SGAs. So I think that we could use much better options.
Thank you, Dr. Koo. Dr. Jain, 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 are 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. Their heart's been broken once, they are leery of having their heart broken twice. Number two, what they really want is something rapid. 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.
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. 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 colleague's 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. Jain. 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. 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. 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. 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, Ken, 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. 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.
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. Both are relevant. That's why I use 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. 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. Jain on this one. Dr. Jain, 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. 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 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 relapses. 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 peer review 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. When I think about transformation, I think about what's happening in psychiatry today with the opportunity for rapid, robust, and durable 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, it become more cancerous, as Rakesh has articulated, but also then through the process of accretion, you start having additional problems start happening. 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 up costs, and obviously diminishing quality of life function and lifespan. I think this is a very, very critical point. We are 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 would like to hear your thoughts on the same question, please.
Sure, Ken. I think they did a wonderful job. The interesting piece I would add is, we were talking before we started, that I was just at the European Conference on Brain Stimulation in Naples, and there is a lot of conversation going on in the interventional psychiatry space about the interplay, between our own treatments and the development of treatment resistance. This is obviously theory, not fact. Roger and Rakesh mentioned very well the facts, which are the longer this illness goes on, the harder it is to treat. The more accumulative issues people develop, and that definitely leads to a treatment resistance. However, there is also a lot of thinking going on and developed more in the VNS space, the vagus nerve stimulation space, around the idea that are we ourselves with our treatments contributing to this treatment resistance.
I do not want to say that strongly, we do not have proof of that, but the idea, it would be hard to separate out just leaving somebody ill, as it has been mentioned, versus our own treatments. But I think the idea of an antibiotic resistance that develops when we keep exposing a bug, bacteria to multiple antibiotics, it learns to not respond to anything, that we have the idea sort of in parallel with depression and perhaps 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 an interventional practice, interventional psychiatry today is anchored by two main treatment modalities, esketamine and TMS. Dr. Koo, how do you see the novel serotonergic agonists fitting into 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 Rakesh, 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. I think the novel serotonergic agonists, 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 in interventional psychiatry training programs. We even have everybody's already organized. We have thousands of TMS centers, ketamine sites, SPRAVATO, esketamine sites where people have the workforces, they have the workflows.
We even now have EHRs like Osmind, which is amazing. It's built-in to integrate the REMS. It's built-in to integrate the workflow. 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, 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 psychiatry, we wait for somebody to be treatment-resistant before we get in and treat them. 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.
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. On top of that, we have an opportunity to introduce these type of interventional programs earlier for patients and in potentially, this will be with the phase III information that comes out, but if on top of that, not only earlier, we have more durable and less burdensome treatments. Coming in for TMS every day, patients do it. 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.
To have an intervention that perhaps is twice over a three-week period and has a durable trajectory, it would be a game changer for interventional psychiatry.
Dr. McIntyre, I would love to hear your thoughts on the same question.
Yeah, it is a great one, Ken. It is something I have thought about a lot, and we have done a lot of interventional psychiatry here at my center for 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 is inadequate, then they engage on this odyssey of one treatment after the other, one treatment after the other, and then once you become very end-stage or very late or palliative, they are referred to people like us who give therapeutics that are esketamine, ketamine, TMS-type treatments.
That portal, so to speak, will not end today or tomorrow, but I envisage a portal system a little different now because what is going to happen is that you are going to have people who are going to immediately go into the interventional psychiatry. They are not going to go through this odyssey forever, and then as an afterthought, let us send you to the interventional psychiatry clinic because all hope is lost. Let us just cross our fingers something works. I think, in fact, what is 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.
I think that is in part because, A, we are going to have these treatments. Second, I think also that the appetite for these treatments is so extraordinary, and people are hearing about them. Psychiatry, Ken, 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? 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. 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.
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 want to go through this odyssey. I want this taken care of now. Can I get access to this treatment now? I think that's going to be a real game changer for the system and the portal of entry.
Thank you, Dr. McIntyre.
Roger and Martha, may I just offer just 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.
Yeah.
is in need of being challenged. It's in need of being called out. 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. I'll just add, 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.
That to me would also be an incredible intervention that we get to treat these people with severe depression who need to be in a 24-hour care system with something quick, right? 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?
Ken, in many ways, it's some of what we discussed. We need treatments that are effective, meaningfully effective, and rapidly effective in GAD. 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 2 dozen treatments that the FDA has approved for the treatment of adults with MDD. We have just over 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.
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. 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. Jain, please, same question.
Yeah. MDD is common in my practice. You know what else is very common in my practice? GAD. 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. GAD is hard to treat. The suffering equals the suffering of patients with MDD. 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. 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. To give something that is 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. Jain. Dr. Koo, Dr. Jain, Dr. McIntyre, thank you very much for being part of this panel. We appreciate your insights, your experience, and your thoughts. 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 will be discussing HLP004, 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. GAD therefore remains a mental health condition with significant unmet need. HLP004 is deuterated DMT that we are developing for treatment of generalized anxiety disorder. DMT as it occurs in nature is not orally bioavailable. 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 I dose ranging 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 HLP004 in an adequately powered study.
Key amongst these studies is the phase I study of intravenous HLP004 and intravenous DMT, which allowed us to establish an optimum duration and dosing regimen for HLP004. 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 004 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-ranging study where we tested doses from 2 mg- 30 mg and observed that intramuscular HLP004 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 II trial where we will evaluate HLP004 at a dose of 30 mg 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 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 mg - 30 mg, we found that 30 mg 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 mg dose, and this was statistically significant versus placebo. The 30 mg dose was also well-tolerated. These and several other considerations, including feedback from industry experts and key opinion leaders, support the selection of 30 mg as the optimum dose for further development. We will evaluate the efficacy of the 30 mg in our upcoming phase II 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 HLP004 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 II 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 at both the screening and baseline visit. 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 : 1 ratio to receive either 30 mg of HLP004 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. HLP004 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 II study in GAD. With a well-characterized profile, an encouraging efficacy signal, and a 30 mg dose that is well-tolerated, an adequately powered phase II 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 Mike.
Thank you, Amir. Before we move to questions, let me briefly reiterate why we are excited about the opportunities ahead. As you have 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 will 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 one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. In fairness to all, we ask that you please limit yourself 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 Cowen. 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 different perspectives. One is what is required to support a regulatory approval, and two, how do you frame what you would need to see from a commercial perspective, what is commercially competitive? And if I could add 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 will try and keep track of them all, and then at the end, I will let Amir speak to top-line readout and in your questions there. I think really critical questions you ask in terms of how to think about both from an approvability/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 and obviously administered on top of standard of care.
From an approvability, and then from the clinician perspective, what we have seen, and you can look to, of course, the precedents that are approved in the antipsychotic space for adjunctive MDD, around three points, certainly approvable, certainly has been viewed as meaningful from the clinician's perspective. Then if we then shift to your question on the commercial profile that we would view as a strong commercial profile, again, it is always in the context of what is the competitive landscape, right? The competitive landscape is, of course, not some of our peers that are working in the psychedelic space. You have people working in monotherapy for MDD. You have people working in monotherapy treatment-resistant depression. We are the only late-stage program in adjunctive major depressive disorder, right? Again, the five approved therapies for adjunctive MDD are the antipsychotics.
If you look at what is best-in-class efficacy for the antipsychotics in the adjunctive setting, that is the four to five points of improvement on the MADRS scale. If we achieved comparable best-in-class type efficacy there, the sour to five points, and then the other critical components, as you are looking at the commercial profile. You mentioned durability. It is absolutely very important. We saw in our phase II study off of the two doses, we saw durability out to a year. To the extent we, again, see that we are going to see how that plays out in not only our phase III pivotal, but then also in the long-term extension studies, but similar long-term durability together, really importantly, with a favorable tolerability profile. Dr. McIntyre walked us through the side effect burden of the antipsychotics and how significant that is.
If we see a similar tolerability as we saw in the phase II, which we would expect to translate into the phase III, and that is mild to moderate adverse events, primarily transitory on date of treatment, and there is only a few days of treatment. When I talk about side effects, just compare them to the list that Dr. McIntyre referenced for the antipsychotics. For us, you are talking about headache, nausea, elevated blood pressure, again, primarily transitory on day of treatment. If we saw those three pieces, that comparable best-in-class efficacy as compared to the antipsychotics 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. That is how I would, from those two perspectives, how I would look at it.
Amir, if you want to talk about the top line readout and what people can expect there, that would be helpful.
Yeah. Happy to, Michael. 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. In terms of efficacy, the primary endpoint, which will be changed from baseline at week six on the MADRS compared with placebo. To your question of durability, that is in the short-term study APPROACH, that is going to be the 12-week key secondary endpoint. We will look at change from baseline again in the MADRS score at 12 weeks, comparing it to placebo. We will 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 EXTEND, which, as you will recall, is a blinded long-term extension up until such point of time that a patient relapses or is requiring any additional treatment.
What EXTEND 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 redosing interval. Finally, how many doses will be required to maintain durability out to a year. Recall also that EXTEND, based on pre-specified criteria, allows up to three additional doses in the long-term extension.
Very helpful. Thank you.
Cheers.
Thank you. 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. 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 suicidality? I'm sorry, my kid next to me. Then secondly, for the doctors actually, obviously, 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. 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 ideation 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, that's background in MDD, what we'd be looking for. 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 suicidality, anything which may affect patient safety. Clearly, APPROACH has completed enrollment.
You can gather from 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. 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 done. Right? Even with the intermittent treatments, the most obvious example, if you like, is esketamine. Even that intermittent treatment is about 30 - 50 administrations in a year. What we know from our data is that in phase II, 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 II data, we need to replicate and further evaluate those in phase III, 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, EXTEND.
Thank you so much.
Thank you. And our next question is going to come from the line of Sumant 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 Doctors Koo, Jain, and McIntyre. First, clearly and unfortunately, the demand exists for novel serotonergic agonist treatment. Do you think the supply side, that is clinical infrastructure, pricing, reimbursement associated variables, are ready to satisfy this demand, or could they limit access to some of the most efficacious treatments? Second, in terms of eventual real-world use of these agents, durability of effect could last several weeks, if not months. 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, Sumant. Unfortunately, the panel members, the Q&A here is just management, Amir and I. I think we can speak to some extent to your questions as well. Maybe, Amir, if you want to speak again to the subsequent dosing piece, and then I can talk in terms of supply infrastructure et cetera.
Yeah. There is no reason why if a patient responds to an initial dose, and whatever the durability, whether that is 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 II studies, then retreatment should also result in a similar sort of response. 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 did not have any room for improvement because how low can you go then? This is something we will study in EXTEND, as I said previously. There is opportunity for up to three additional doses in EXTEND based on predefined criteria. 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. Thanks, Amir. From your question regarding infrastructure availability and supply, you did hear the panel speak to this generally. In particular, Dr. Koo, 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 this space, the excitement for this new class, and the focus on it. Also, in terms of all of our survey work from the clinics, 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, there's really a positive sentiment there and a willingness to meet the increased demand. We're really looking forward to, of course, building patient awareness across the space.
Again, very positive in terms of the clinic's views on these potential therapies.
Thank you. One moment for our next question. Our next question is going to come from the line of Pete Stavropoulos with Cantor Fitzgerald. Your line is open. Please go ahead.
Hi, Michael and Amir. A very informative webinar. Thank you for hosting and thank you for taking our questions. Two from me. For the phase III 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? How do you ensure that these patients are on standard of care, like SSRIs?
Yeah. I can take that one.
Go ahead.
Thank you. Those are the most important questions you flag up. 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 the trial. Firstly, we handpicked all our sites. 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. It starts there, with carefully identified and selected sites. Then moving on to identifying the right patients. 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.
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 MGH CTNI Institute. 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. 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 antidepressant treatment.
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. As per protocol, there is a requirement for patients to be on a stable dose for the past four weeks. All of that is done through standardized tools, and we make sure that the patients that are getting in our trial are the right kind of patients.
Yeah. Pete, it is a very good area of focus, right? Nothing more important than clinical trial execution. 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 Psych Congress that the mean MADRS scores in APPROACH on entry were 33, which is, of course, consistent with the scores that we saw in our phase II 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 II.
Thank you. A follow-up, and thank you for that, how should we be thinking about the placebo effect in APPROACH HLP003 in the adjunctive setting and this class more broadly, and what steps have you taken to minimize it?
Sure. Maybe I will start, Amir, and then you can give your point of view. Pete, this has, of course, been a challenge for depression trials for forever, right? Your general depression trials, placebo response, you have seen something like 10-12 points of placebo response in phase III. It has been a real challenge for drug developers. 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 the recent late-stage trials that have been conducted by our peers, you would see one to five points of placebo response is what we have seen in those late-stage trials. Obviously, in our phase II, we saw approximately three points of placebo response.
Now, we'll have to see how that translates into phase III, but you really like the control over placebo response that we've seen in the psychedelic class to date. Amir, anything you want to add?
Well, I think that's all probably, but just to mention, we also take care to minimize the non-specific 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. We also make sure that only those people at the site level who need to be in contact with the patient or who need to be involved in the assessment, only they are involved. We also firewall the data as much as possible, patient data from the site staff. So, only those 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.
Right. Thank you, all, for taking my questions and looking forward to the data readout.
Thanks, Pete.
Thank you. 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. I wanted to ask about the real-world delivery model. In phase II, obviously, the patients had the EMBARK framework before and after dosing. Could you sort of remind us what the level of preparation, integration was and support, and how we should think about the minimum support that will be required in practice? 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. How should we think about adjunctive versus TRD in terms of step edits and prior therapies, once in the clinic? Thank you.
Sure.
Amir, you want to take the first?
Yeah.
Then I'll talk to payer dynamics.
Yeah. 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. This is exactly the same as we had in our previous study, phase II. We have developed the EMBARK framework, which incorporates evidence-based treatments, empirically supported treatments, and it gives the session monitors the kind of framework and training that is needed to ensure safety of participants 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 benefiting momentum. Post-approval, we do not expect the FDA to dictate what specific pre, post-dose 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-by-patient basis determined by the clinicians.
Thanks, Amir. Eddie, 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. More generally, in terms of the payer dynamics, obviously, it's early days. Once you have your phase III data, et cetera, these conversations progress. 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, so patient compliance, then think about the comorbidities associated with depression. Of course, they're significant.
Putting all that together, and presenting to the payers so they can build their models reflecting those sorts of benefits, I think have the potential to be very productive, constructive discussions with the payers. Again, as an adjunctive therapy, you have already effectively failed on one treatment that is additive as well. Look forward of course, to our phase III results and then having those discussions with all the backdrop that I just outlined.
Thank you. Just one follow-up. When you think of standard of care, is it only generic SSRIs and SNRIs, or is something like Auvelity or something like an antipsychotic that is approved for MDD, are those also considered something that you would expect patients to stay on or be on when taking HLP003?
Yeah. Generally, standard of care would be the SSRIs, the SNRIs, and of course, they are largely generic. In terms of the antipsychotics, I think you heard from the panel today that really is an adjunctive approach versus a monotherapy. Amir, anything additional you want to add from the clinician perspective?
Also from an antipsychotic point of view, those really would be blocking the effects of this class of drugs. So they would in fact be contraindicated when you are administering a patient a psychedelic medication.
Got it. We would assume that any patients that are on adjunctive would go back. Thanks.
Sorry, say again.
I was just saying, we would expect a patient that has already started on an adjunctive Caplyta, 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 antipsychotic, the choice would be whether the switch is to an atypical antipsychotic or instead they could administer an adjunctive like HLP003. So you do not expect patients who are already on an atypical antipsychotic and are responding to potentially come off and take a treatment like HLP003. That would be their choice. But in terms of a treatment 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.
Operator.
Thank you. And our
I think we have time for one more question.
Our last question will come from the line of Patrick Trucchio with H.C. Wainwright & Co. Your line is open. Please go ahead.
Thanks. Good morning, and thanks for squeezing us in. Just a first follow-up on APPROACH. I am curious what placebo-adjusted MADRS difference in variability assumptions underpin APPROACH's statistical power, and is the week 12 endpoint included in the multiplicity-controlled testing hierarchy? As it relates to the commercial preparations, I am wondering what prep work you have done so far and if you can speak to what learnings you would expect as some of these other psychedelic treatments perhaps launch ahead of HLP003, even if they are 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? What would that imply for your field organization and medical education strategy?
Yeah.
A lot to unpack there, Amir. Why don't you start with the clinical questions, and then I will take the infrastructure commercial questions.
Yeah, I'll take the easier one, which is the powering assumptions, and then the MADRS delta. We haven't disclosed in detail the powering assumptions yet. But if you look at other late-stage trials in this space, and you factor in assumptions around 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 BTD discussion, so there's a kind of buy-in there in terms of the powering assumptions. For your secondary endpoint question, yeah, so there will be appropriate adjustments made for multiplicity at the secondary endpoint of 12 weeks.
And then in terms of the infrastructure and the commercial related questions you asked, Patrick, you did point out the peers and to frankly, of course, view them as peers given that 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 at 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. 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 the significant patient benefit here and how everything evolves. But certainly excited to see that process play forward.
Terrific. Thanks so much.
Thank you. 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 III data readout. Thank you everyone for their time today and you may now disconnect.
This concludes today's conference call. Thank you for participating and you may now disconnect. Everyone, have a great day.