Hello everyone, welcome to the 7th Annual H.C. Wainwright Neuro Perspectives Summit. My name is Patrick Trucchio. I'm a Senior Healthcare Analyst at H.C. Wainwright. We have a robust agenda at the conference this year, with more than 25 companies presenting with their sessions available on demand through the conference portal. In addition, we're expecting a full day of panels and fireside chats with world-class KOLs on June 15th for the in-person portion of the conference, with a broad CNS drug development across multiple indications from depression, epilepsy to BBB delivery. With that said, it's my pleasure to welcome Helus Pharma, a clinical-stage pharmaceutical company committed to helping minds heal by developing proprietary NSAs, or novel serotonergic agonists. These are synthetic molecules designed to activate the serotonin pathways that are believed to promote neuroplasticity. From the company, I'm excited to introduce Chief Medical Officer, Amir Inamdar. Welcome to the panel or welcome to the conference. Just for our audience who may be less familiar with Helus, if you could provide an overview of Helus today and your vision for positioning Helus across the interventional psychiatry space. Great. Thank you for inviting me here. Great to be here and chatting with you, Patrick. As you said, we are a biopharmaceutical company that are developing novel serotonergic agonists. These are molecules with agonistic activity at multiple serotonin receptor subtypes, including receptors within the 5-HT1A, 5-HT1, and 5-HT2 families. Activation of these receptors is believed to engage downstream signaling and cellular pathways associated with neuroplasticity, including mechanisms that are involved in synaptic adaptation and neural network remodeling. We believe these neurobiological effects contribute to the therapeutic potential of novel serotonergic agonists. We are a clinical-stage company. We've got two programs in the clinic, HLP003 for major depressive disorder and HLP004 for generalized anxiety disorder. HLP003 has FDA breakthrough therapy designation, and it's in phase III for adjunctive treatment of MDD. Both are deuterated analogs of naturally occurring compounds. Deuteration of these compounds is intended to optimize the physicochemical properties, help with commercial scaling, and create differentiated IP for these molecules. A portfolio includes about 350 patent application, about 100+ granted patents, including U.S. composition of matter. This is coverage for HLP003 as well as HLP004 until at least out to 2041, which gives us the ability to add indications. Our early clinical data is demonstrating that this class has transdiagnostic applicability in psychiatry, which is where we want to be. We want to be at the forefront of helping people with mental health conditions and improving their lives. Right. Terrific. Maybe just moving on to HLP003 in MDD. Maybe walk us through maybe some background on HLP003. As well, maybe you can walk us through the phase III PARADIGM program. Yeah. What distinct question does the program, which includes APPROACH and EMBRACE and EXTEND, what specific questions are these trials answering? Yeah. HLP003 is a deuterated analog of psilocybin. What deuteration does is it's intended to change the physicochemical properties of this naturally occurring novel serotonergic agonist. We've completed phase I and phase II. We did a study in major depressive disorder, with HLP003 as an adjunctive to background antidepressant medication, where we showed effects ranging from 13-14 points with just a single dose of HLP003 at the three-week endpoint. Based on this, we got an FDA BTD designation, subsequently, we designed a phase III program, which is called PARADIGM. As you referred to three studies, APPROACH, EMBRACE, and EXTEND. APPROACH is a two-arm study. It compares two administrations of 16 mg of HLP003 given three weeks apart with two administrations of an inactive placebo. The intention here in this study is to show primarily efficacy in the short term, which is six weeks, which is what the FDA wants, and durability out to a secondary endpoint of 12 weeks. In addition, we will also collect safety data, and having a placebo allows us to compare placebo-controlled safety data. This is one of the two studies that the agency wants as part of a new drug application for this class of drugs. The second study is EMBRACE. It is a three-arm study, again, looking at short and intermediate-term efficacy. Same two doses of 16 mg of HLP003 given three weeks apart. We also have an intermediate dose arm of 8 mg in this study, again, two doses three weeks apart, and an inactive placebo arm, two administrations three weeks apart. Both these are double-blind, controlled studies. The intention with EMBRACE is to try and, of course, replicate the efficacy in APPROACH. You need to show efficacy in two studies, but also attempt to show some sort of a dose response. It's not necessary to show a dose response. What the agency wants us is to attempt at least, and given the methodological challenges in this class of drugs, the lower dose or the intermediate dose of HLP003 acts as its own comparator. Right. [crosstalk] Yeah. No, I was going to say that's really helpful. I was actually, it's good segue because I wanted you to talk a little bit more about the comparator strategy and APPROACH and how we should think about functional unblinding and expectancy effects. Yeah. What we have taken is essentially the FDA guidance on this class of drugs and applied it exactly. As part of our BTD discussions, we've vetted those. In terms of comparators, APPROACH does a very pure active versus placebo comparator. That's the best way of showing a large effect size, but also a placebo- controlled safety. EMBRACE uses an intermediate dose as a dose response, but also its own comparator, and we use an inactive placebo as well. You referred to functional unblinding. When I am asked this question, I always remind people that functional unblinding is inherent in psychiatry or CNS drugs. Good example, sedatives, opioids, antipsychotics, they all cause functional unblinding. With the novel serotonergic agonists, because of the expectancy combined with functional unblinding, it creates some challenges with respect to doing clinical trials. There is a recipe for addressing these challenges, which has been given to us in the FDA guidance. Combination of two studies is one approach. We of course, use remote and independent blinded raters. This is the single most important strategy to address issues related to functional unblinding. We also have some safeguards in place during dosing sessions, which makes sure that the clinical staff do not get unblinded. One other strategy is looking at intermediate term data and the long-term data. 12 weeks endpoint and the long-term data from EXTEND is basically designed to outlast any expectancy bias. Right. That's helpful. The APPROACH top- line data, I believe, is expected in the fourth quarter of 2026. Is that data still on track, and what data should we expect at that readout? Yeah, absolutely. It's still on track. We aim to deliver top- line data by the end of this year. What you should expect to see is data on the primary endpoint, which is the six weeks, and secondary endpoint, which is the 12 weeks, in terms of efficacy, so drug- placebo difference in the MADRS. You'll also get some data on responder remitter rates, as well as key safety data. As time passes, we get closer to it, we'll provide further updates on exactly what will be shared as part of the top- line readout closer to the time. How are you thinking about what constitutes a win for APPROACH? What's the bar on efficacy and durability for both regulatory perspective, as well from a clinical perspective? Yeah. If I see what we saw in phase II, I will be over the moon. That was quite phenomenal. Yes. Like 12- 14 points. We have to be realistic, and we've seen this in clinical trials, having done this for over two and a half decades. I know when you go from small studies to larger studies, you can expect with that scaling some erosion of the effect size. As I said, same results would be excellent, but even if you halve the effect size from phase II, which is generally a rule of thumb, it would still be class leading. To put that into context, of course, most adjunctive treatments, I think we have to remember this is adjunctive as well, where effect size are traditionally quite small, and most adjunctive treatments will deliver only about two to four point separation versus placebo. If I see something that is even half of my phase II data, I will be thrilled. I remain cautiously optimistic. I think one other endpoint that I am curious and keen on is the key secondary endpoint that's out to three months, which will give us intermediate durability data. Right. I think that will be for regulators as well as the payers. That makes sense. Maybe you could talk a little bit about the safety profile, what you've seen so far, and what safety domains matter most in phase III. Should we be looking at things like cardiovascular effects, suicidality, or any other acute anxiety, other DDI, anything that we should be looking for? All safety matters with patients when it comes to clinical trials. Safety has to be the single most important factor. We do want to characterize these drugs accurately so as to be able to provide the prescribers with a very clear picture of what they should expect in the clinic when they administer the drugs. We also need information to educate the patients before they select treatment with this class of drugs. All domains remain important. The FDA and us as well are quite keen on collecting data on abuse liability. This is something we are doing quite closely. We are collecting all adverse events. In the past, there has been some confusion with some players around collecting whether events that are on-target pharmacology, whether they should be reported as adverse events or not. We've had those discussions with the agency, and we are essentially collecting everything, irrespective of whether those are expected effects or not. Typically, what we expect with this class of drugs is a transient physiological effect. Cardiovascular, in that sense, blood pressure, heart rate, we will collect all of those. We are collecting all of those. Psychological adverse events as well, we will collect all of those, things like changes in perception, thought, et cetera. Even though these are on-target effects, expected pharmacology, but we're still collecting those, anxiety, et cetera. You mentioned suicidality, I think, this is kind of a known feature in mental health conditions, including depression. It's part of the illness where people feel lack of optimism for what's going to happen in the future, hopelessness, helplessness. These are features of depression. One would expect to collect this kind of data to make sure patients are safe. With our indication of adjunctive, we also need to be keen on looking at drug-drug interactions. We are collecting those data as adjunctive as well, both pre-clinically as well as in phase III. We'll make those part of our package to the FDA as part of the new drug application. Right. That's interesting. Can you talk about how you're leveraging the breakthrough therapy designation in your FDA interactions, how this impacts things like meeting cadence, alignment on endpoint safety, package durability evidence, or post-approval expectations? Yeah, absolutely. I think we are in a very privileged position with the breakthrough therapy designation, which of course allows us access to guidance from senior FDA staff on a regular basis. Typically, every six months, we are taking full advantage by having regular meetings. What this allows us to do is to continuously update the agency on the progress of our programs. The agency also wants to know we are making full use of the breakthrough therapy designation, we regularly update them. We also work with them to continuously streamline and adapt our clinical program, whether that is through discussing about how to go through a rolling review process or when to submit data, in what timeframe or an expedited timeframe. Based on that, we remain on target to deliver an NDA in 2028. Right. Terrific. How should we think about the two-dose induction period concept versus a single-dose PARADIGM? Yeah. Mechanistically, we believe that the first dose may open a period of increased psychological and neurobiological flexibility, during which participants can then begin to reframe their maladaptive patterns of thought. The second dose, which we give about three weeks apart, is believed to help reinforce, deepen, and consolidate that process. We believe that the robust durability that we have seen may be related to the second dose. The phase II data clearly showed an incremental benefit from a second dose. We also, based on some limited data, saw quite extensive durability out to the 12-month mark. We believe that a single dose may not be sufficient, and the second dose allows us to maximize the benefits of acute dosing. Right. That's interesting. Just HLP003 is being developed as adjunctive treatment for moderate to severe MDD rather than TRD. Can you talk to us a little bit about the differences between these disease areas and depression and your reasoning for positioning in this way, and how we should think about ultimately the label if we're looking very far ahead from a regulatory and commercial perspective? Yeah. Treatment-resistant depression. Depression is a spectrum, and response to treatment is, again, on a spectrum. Some people will respond to the first medication that they receive. Some respond to a second line. Then there is, unfortunately, a group of people who do not benefit from multiple different treatments. These are what we normally refer to as treatment-resistant depression patients. We've, however, chosen to study patients earlier in their treatment journey, and we've also chosen to study patients in an adjunctive indication. We don't require patients to stop their ongoing antidepressant medication. HLP003 is given as an adjunctive. This represents a real-world population where as much as 70% of treated patients who remain on background antidepressant treatment, whether they are SSRIs or SNRIs, they do not respond adequately to treatment. With patients not having to come off their antidepressants, we don't have the risk of inducing what could be a very nasty withdrawal syndrome. It also will reduce friction for prescribers, if approved, if patients don't really need to be titrated off their background antidepressant medication. This MDD space, adjunctive, represents a large addressable patient population compared to treatment-resistant depression. This basically offers us a broader commercial reach, which is why we've chosen to be in this indication. That's helpful. Maybe just one last one on HLP003. If we look further ahead to the future potential commercial launch, what part of SPRAVATO's infrastructure and as well maybe the other psychedelic treatments that may be approved before, what part of that infrastructure do you see as an advantage initially and through later stages of commercialization? We are kind of fortunate that SPRAVATO's done that groundwork for interventional psychiatry. This interventional psychiatry with not just SPRAVATO clinics, esketamine clinics, but also centers that offer REMS, ECT, and other interventional treatments, has grown as a modality of treatment for patients with mental health condition. In U.S. alone, there are over 6,000 certified SPRAVATO or esketamine treatment centers. They help with, of course, the infrastructure. That is established. The healthcare system is established. They potentially establish some reimbursement pathways that could be utilized by therapies like HLP003. They've laid the foundation for a likely REMS program and set up specialty pharma distribution systems which may be leveraged by us. We, of course, may reduce some of the burden with HLP003 on the clinic and the patient with much fewer visits compared to SPRAVATO. I think we are in a great situation right now with this interventional psychiatry framework having been already established by SPRAVATO. Right. Terrific. Maybe moving on to HLP004 and generalized anxiety disorder, or GAD. Yeah. Maybe you could give us some background on HLP004 and what you've seen in the data so far. Yeah. HLP004 is a deuterated dimethyltryptamine. We've been studying this quite extensively over the past few years. We've established a large data body of evidence by conducting almost seven studies between ourselves and what was done formerly at a Small Pharma which we acquired a few years ago. What we've been able to do is understand the route of administration, optimize a great patient experience. HLP004 is administered as an intramuscular injection, with a rapidly acting or rapidly efficacious in terms of pharmacodynamic effects and short lasting duration of effect. In the work we've completed, we've done some work with generic DMT, where we saw in patients with depression, improvements in symptoms of anxiety, which is one of the reasons we selected generalized anxiety as our indication for HLP004. We've conducted a study in GAD with two doses of HLP004. We saw beneficial effects of dosing with HLP004 at two different dose levels. We found also that the magnitude of effect was correlated with subjective effects, we've learned quite a bit to set us up for the next stage of development with HLP004 in GAD. Terrific. Maybe you can just tell us a little bit about the expected development plan for HLP004. How should we think about the regulatory path from here? Yeah. We are finalizing our plans right now, reviewing them with our scientific advisory board. We're going to come and share updates with you and externally as soon as that process is complete. Terrific. Then maybe just as a last question. Maybe you can talk a little bit about the cash runway for the company and which catalysts does that runway get you to, and what do you think investors may be underestimating or misinterpreting about the story at this stage? A three-part question there for the last one, just cash runway, what are the expectations on cash, which catalyst should we be looking for over the course of that runway, and anything that investors are missing? Yeah. Maybe I'm not the best person to talk about money. Well, I think it will be problematic if your Chief Medical Officer starts doing cash runway stuff. I know we've got enough to take us well into our near-term milestones. Most important of which is the top- line data on HLP003. We've got great data coming up hopefully. I think that data will speak for itself. We are doing great on recruitment. We are going to get there before the end of this year. Once those data are out, I think we can have that conversation again. Terrific. Sounds great. Thank you so much to Amir and to Helus Pharma for joining us at the conference. Very exciting time for Helus with just a, I think a paradigm shifting readout coming later this year. Really excited for that. Thank you for everyone else for joining us at the conference. Have a great rest of your day and conference. Thank you, Patrick. Great to be here.