Definium Therapeutics, Inc. ($DFTX)

All right. Well, first of all, I want to thank everyone for coming and joining us here today. It's an incredibly exciting time for us. It's an exciting time for our field, and it's great to see everyone here. Many of you, we have spent a lot of time with over the last 5 years, and you've watched not only as we as an organization, but as the entire field has unfolded and has really built to this point where now the promise of what we've been talking about for a long time is coming to fruition and the degree of visibility we're seeing for our field is really taking shape. So we couldn't be more excited to be here with you today. And again, I want to appreciate all of you for coming here and spending your morning and afternoon with us. Before we get started, forward-looking statements. We'll be saying things about the future that I refer you to all of our filings and the disclaimers, both here and in our SEC filings. We have a great lineup today and great speakers. I'll talk about in a second. I'll be brief and then turn it over to Dan, our CMO. We'll have a Q&A session, both with our panel a little bit. And at the end of the event, there's a QR code here at the bottom, right, and it will show up later. both for folks who are in the room and online, if you can ask questions via that QR code, you can type them in any time the present, we'll field them and compile them to the end of the presentation. You hear from me, hear from Dan Karlin, our Chief Medical Officer; and Matt Wiley, our Chief Commercial Officer, along with Brandy Robert, our Chief Financial Officer, throughout the day. We're also incredibly excited to have Britty Albright, Andrew Penn and Shannon Sarker here with us today. These folks are directly involved in the research and the delivery of both psychiatric treatments and the research with psychedelics. The ability to get these drugs out into the world is going to be dependent on folks just like this. And hopefully, throughout the day and through the discussion with them, we hope everyone leaves with an understanding of just how feasible this is and how much this can come into being over the next few years. I'm, of course, standing here, but I want to represent and thank everyone who's part of our organization who has had a role in getting us to this point in time. We feel an enormous sense of privilege and responsibility and really excitement for where we are today and where we're going into the future. The need has never been greater for the diseases we're trying to treat. The growth of anxiety and depression has been faster than anyone would like to see, of course. And we're talking about millions of patients whose lives are dramatically altered by these disorders. Some of these things are so prevalent that we don't fully even appreciate how impactful they are because underlying these big numbers that we'll talk about are individuals' lives who are disrupted and who are wrecked by cycles of hope and grief and despair because the drugs we have, because of the treatments we have today don't do a good enough job for them. and we're here to hopefully change that. We, from day 1, have had a very aspirational view of what can be accomplished. If we focus on the right science, if we don't get distracted by exceptionalism and traditions from the past that aren't relevant to modern research, and we really do the right studies. We do the right approach to this research, then we have a chance to actually have a major impact in the world and get these products to the patients who so desperately need them. So what does that mean, right? Patients today show up, they get cycled through medications and most don't get the kind of relief that they're hoping for. We're talking about patients who get a single dose of drug, spend 5 to 8 hours in a clinical setting, can come for months thereafter in many cases in clinical remission in the data we've seen so far. And this could apply broadly to the 50-plus million individuals who are impacted by neurosychiatric disorders. I think it also gets overlooked, I think, very frequently is just what the patient journey is like for these folks. Again, we all know many people who are taking SSRIs who have gone to the doctor, have had a depressive episode, who have anxiety and who get the drugs and stay on these drugs for a very long time. For the patients who we expect to be able to help first. [indiscernible] gets overlooked that patients come in. They have symptoms, they get prescribed the drug, not the path for these patients today. Even when they're getting the drug, they are starting to work, there's a really burdensome adverse event profile for the products we have available today. There's a logistical burden of coming back into the clinic even for daily drugs, for weekly checkups to make sure that you have got the right dose, titrating up the dose, augmenting with other doses. And ultimately is just back to cycles over and over and again through the half dozen to dozen medications that we have approved. For these folks, there has not been anything as promising and as exciting as what we're seeing for the field of psychiatry today and what we're fortunate to be carrying forward. We often get a lot of questions about the drug we're developing, VT120, LSD-ODT, which we're taking forward and having pivotal clinical trials right now. We're coming to the Phase III readouts this year. And while there's often a conversation about, well, this class of psychedelics, don't all the things sort of feel the same. And yet again, I think it misses the underlying reality. And this is the precision and the science we need to be focused on here. This weekend, everyone who followed our field, and I think everyone in biotech saw an executive order that drew attention and gave prominence to the need and the promise of this category of drugs. And it's remarkable to us that I don't think many people may have noticed this, almost 83 years to the day -- the day after that executive order was signed was 83 years after, Albert Hoffman first was exposed to LSD, which ignited research into this entire field. It's not a mistake that we're coming back to this time because we have had these drugs sitting on the shelf for nonscientific reasons. And now the modern science allows us to carry this forward into the world with the highest quality data and the highest scientific rigor. LSD has been the longest study molecule. It's the one that kicked off interest in the field. It's the most potent. We've seen at every level and no matter how we interrogate [indiscernible] 20, its unique profile, we believe, makes it stand out as a potential only development, but among the drugs that are available to patients today. And of course, we have to go out and prove that with our Phase III data, but it's something that we aspire to do, and we'll have data very soon to prove that. And our approach to doing this also is critically focused on providing patients and providers the best support, the best care, hopefully, that they have ever received. We've built -- I couldn't be more proud of the team we've put in place and been able to attract to this effort over the last 5 years who come at this with a clear-eyed view of the right science, the right way to tackle the opportunity in the real world and a strategy to go out and do that. And executing on that today and in the years ahead is what's going to drive not only our success, but success for these patients who desperately need it. Before I turn it over to Dan, I'm going to share a few updates more specific to our program now. All of you know our GAD and MDD programs. We've got 3 pivotal readouts. We're starting our second pivotal study in MDD. And today, we're excited to expand that even further and announce a Phase III study that will be starting in 2027 to study VT-120 in post-traumatic stress disorder. Covering these 3 indications effectively covers the vast, vast majority of all patients who show with neurotic psychiatric disorders. It broadens out the potential both in the scope of the populations and the focus on the symptoms that they present with. And we're incredibly excited to expand this and move forward into a third indication with our lead program. A few other updates. All of you heard recently our outcome from our VOYAGE sample size reestimation in both of our Phase III studies in generalized anxiety disorder, we had a blinded reestimation. We looked halfway through the study to assess whether we had correctly assumed the right standard deviation and the right not valuable rate in the study. So we reported that those numbers were considerably lower than we had planned for in the VOYAGE study. And the same is true even with an excitingly 6% nonviable rate in our PANORAMA study. The quality of the data that we'll be able to present based on that ability to retain patients in the study is just remarkable. And based on these assumptions, based on the results from the sample size reestimation, we're actually able to lower the sample size in PANORAMA to a total enrollment of 200 patients. That study has 99% power. And in both studies, less than a 2.5 point delta would result -- we would expect, assuming all these parameters hold would result in a statistically positive study. So as we approach study designs, if we get to clinical relevance, clinical significance, the statistical significance should follow. This, of course, gives us an incredibly high degree of power going into these readouts to give us decisive answers about whether we can replicate the incredibly exciting findings we had in Phase II. With that, VOYAGE, we're recently happy to pass the milestone that the study enrollment is complete, and we're on track for an early Q3 readout for our first GAD study. And this is, of course, going to follow our first Phase III readout in major depressive disorder, which will happen in late Q2. For PANORAMA, as I said, the target enrollment is now at 200 patients. We have exceeded that enrollment at this point. So screening is now closed in that study. For ethical and practical reasons, patients who are already in the screening process are going to continue through. But we're excited to rapidly be approaching completion of enrollment in that study, which will bring us with great clarity into now 3 readouts across the second and third quarters of this year with PANORAMA coming out in late Q3. Most of you know our Phase II data, but coming to these readouts gives us just an enormous degree of excitement because of the profound impact we were able to demonstrate in Phase II. An effect size that was more than double the standard of care, a magnitude of response that was staggering in the context of current therapies. And the fact that we saw both rapid and durable remission out to 12 weeks, this is a longer endpoint after a single dose than anyone is even seeking to prove. And now we're going to have multiple Phase III readouts across the 2 biggest indications in psychiatry with data out to 12 weeks and even beyond. In Phase II, we saw a roughly 48% clinical remission rate at week 12 and an AE profile that was unremarkable. Patients are in an observed setting. We go to great lengths to make sure we capture adverse events appropriately. So for regulatory and clinical purposes. And what we saw is a relatively benign and favorable adverse event profile that puts us in a great position as we come to these Phase III readouts. We also uniquely were able to demonstrate a dose response across a wide range, down from 25 micrograms up to 200 micrograms, which clearly answered questions around what's driving the drug's effect and what isn't. What we found is that because virtually all patients knew they were on drug regardless of the dose they received, but we still saw a dose response functional unblinding is talked about quite a lot, cannot be the explanatory. It's not the thing that was driving the clinical response. It clearly was a dose dependency based on the activity of the drug in our view. And that, of course, then supports going into our Phase III readouts where we have a head-to-head study and a 3-arm study, giving us complementary designs across 3 studies in GAD and 2 studies in MDD that we hope to take forward to FDA very quickly thereafter. You'll hear from Dan in a second about the overlap between these disorders. I think there's often a degree of familiarity, but a lack of clarity in terms of exactly how we think about the overlap between anxiety and depression. And what we saw and what gives us so much confidence going into our first depression readout, which now is the first of the 3 this year, is the fact that we saw very similar response profile, magnitude and separation on MADS scores on depression symptoms. Now again, Dan will talk about what underlies that. But as we head into this readout, we couldn't be more excited or more confident going into our depression readout. And finally, just talking about the magnitude of impact on patients, right? We all look at means and averages. And of course, that's what drives the statistical proof of whether we're seeing efficacy or not in these studies. For an individual patient, moving patients from what was a starting point of quite severe disease, whether we measure on the HAM-A or the Clinical Global Impressions of severity scale and being able to move patients -- the median patient was at or below remission on anxiety scores in our Phase II. So that level of profound impact. And the way we approached our Phase III design is trying to treat patients who have moderate or worse severity because what we've come to learn through extensive real-world and AOR work is that by bringing patients from moderate or severe impact of the disorder down to mild or remission, we're able to just drive enormous value for the health care system and of course, most importantly, value for these patients and their ability to function in their lives. So the last I'll leave you with is trying to put these results in context. We've shared this before. Whether we look at the absolute magnitude of change, which is an important feature or we look at the placebo-adjusted change, the magnitude of response we were able to demonstrate in Phase II stands out both in anxiety symptoms in the context of approved anxiety therapies. But also when we look at the newest generation of antidepressants and drugs that are indicated to treat depression, whether it be from major depressive disorder, bipolar disorder or others, the magnitude and separation we saw stacks up incredibly well. And as we get into the MDD population and patients in depressive episodes, we're just as excited to look at the Phase III data. Of course, we need to see in this population exactly the kind of response we're able to drive. But of course, anything that comes close to what we're able to see in Phase II gives us enormous excitement for how this could impact patients out in the real world. With that, I'm going to turn it over to Dan and keep going with the program.

The irony of coming up here to talk about anxiety to all of the staff who've been working for the past few months to make this happen, and I can't be really overstated. But let me go into a little bit more about what Rob was talking about here, which is we've said this to many of you before. But when we think about the categories that are GAD and MDD, really, what we're talking about is these 2 clusters of symptoms, which are anxiety and depression. And obviously, from a DSM perspective, from a psychiatry perspective, from a regulatory perspective, we have to draw boxes around a set of symptoms that are severe enough to call a disorder. But the reality is that anxiety and depression symptoms coexist. And the way that we conceive of them coexisting is that anxiety is the background state that people tend to experience starting pretty early in life and that persists through adult and it can fluctuate, of course, because everybody, whether they have a neurotic illness or not, experiences the day-to-day fluctuations of life. But anxiety symptoms tend to be fairly constant even as they fluctuate a little bit around the person's baseline. Whereas when we think about MDD and what that actually is, it's defined by having had a major depressive episode. And each time someone has a major depressive episode, the odds that they have a subsequent one go up and it's very likely that their background anxiety worsens. So when we think about the relationship between these 2 conditions, what we're really talking about is more of a temporal relationship, that most people who have a major depressive episode will have had background anxiety. And when they're between major depressive episodes when they're what we call eutthymic or normal mood, they likely have a high degree of background residual anxiety. So when we think about residual symptoms of depression, those are often anxiety symptoms. And over time, these things, whether treated or not with the treatments we have available, tend to worsen. How do we sort of correlate that with the more sort of specific instruments we use, the more numerical instruments we use. Well, these are the DSM diagnostic criteria for GAD on the left and MDD on the right. And what you see is that there is that tremendous overlap that you can get a GAD diagnosis with only items that are part of the MDD disease definition. But item 1 for both of these is really the definitional and the differentiated symptom of the 2 disorders. One is the anxiety, the other is the anhedonic, the low mood part of depression. And we see that manifest in the scales as well. And this is really pretty dramatic, more dramatic than the diagnostic clusters because what you'll see here is that of the psychic symptoms of anxiety that are measured on the HAM-A, they all correlate to items from the MADRS. And if you do some math with these correlations, what you discover is that you can get to severe on either scale with constructs that come from the other scale. This is the extent of the overlap of the conditions. And between our ability to move the MADRS in Phase II and this construct overlap, we have tremendous confidence in our ability to treat people in a major depressive episode. So let's talk a little bit more about the Phase III program. Rob went over this slide already. Of course, we've now told you our intention to go into PTSD. Really excited about the ability to move that. And when you think about these 3 disorders taken in concert, we just talked about GAD and MDD overlap, PTSD has very much the same set of symptoms as MDD and GAD, but it has an attributable cause. And often, what we find is that the people who having suffered a trauma, of course, not everybody who has trauma goes on to develop PTSD, but that the people who ultimately develop PTSD after a trauma are folks who had this background symptomology regardless whether diagnosed or not. These are people who are often prone to anxiety and low mood. So what gives us this confidence in our Phase III outcome? We obviously have the IIb results that Rob just reviewed with you that I don't think would have been news to anybody. We have our ongoing strong relationships with our sites. So at the end of the day, the research that's conducted at sites depends on the quality of those sites, and we are extraordinarily confident that our relationships with the sites, the time we've spent building those relationships over the past 5 years and the ongoing close management of the sites, our close relationships with them in an ongoing way through the conduct of the study means that the study conduct will be high integrity. We continue to have a dialogue with FDA that we find to be very productive and engaged. We think that we've built confidence in the agency and what we are doing and buy-in for our study plans. The Phase III designs particularly the Part Bs where we keep people in the study and allow them to get open-label treatment if they have moderate or worse symptoms. We anticipated that, that would drive retention. And what you've now seen in the sample size reestimation readouts confirms that those Part Bs kept people in the study regardless of how they were feeling, regardless of their ability or their belief of their first treatment, they stayed in the study because they wanted the opportunity to have ongoing treatment. And ultimately, everything we've done, we get the question sometimes, well, how have you changed your study designs based on the feedback that came from other people's studies and the conversation in the public. We haven't. We led that conversation. We were at the front edge of those conversations and the choices we made at the outset are the choices that everyone else has now come around to do in their studies. And this is just an example of that, right? Here are our Phase III studies, including our newly announced PTSD study. And what you see here is that across indications and across studies, we employ completely compatible and in the case of PANORAMA and ASCEND, slightly complementary designs that ultimately, what we're measuring and in whom across these studies is aligned with the indication, the time points, slightly variable, but we're measuring it essentially at the same times. And all of this is intended to, in concert, allow us to build a body of evidence that says across these indications, across a couple of different control conditions, we are able to reliably see the same drug effect. And that gives us increasing confidence across these indications that the measured drug effect in these studies represents a real drug effect that will translate into the real world, if approved. Who we get into the trials matters as much as anything, right? When you think about what the science of drug development is, it's testing the drug in the indication you're interested in that is in the right people with the right intervention at the right time. So what gives us confidence that we're getting the right people into the studies. And ultimately, it is an eligibility process, right? All of this is about what you do from when the patient shows up to when you enroll them to when you dose them. And we have an eligibility process that plays on our tight site relationships, right, that plays on the desire of the sites to have a successful study, a high integrity study but doesn't depend entirely on that. We have a multi-stakeholder setup where each participant who's enrolled is assessed by the site, but is also assessed by 2 separate sets of blinded remote central raters, one for diagnostic assessment, which is the MGH SAFR program and one for severity, which are the central raters, the same people who ultimately assess the outcomes. And so we get this 3-part verification to ensure that everybody we get into the study is who we want in the study. And our folks, our internal employees are reviewing every set of eligibility outcomes as well. So each thing that is done in the eligibility assessment gets reviewed by internal staff to make sure we're not just doing a box checking exercise, but that everything about the participant makes sense in concert. And so the people that we want to study ultimately are the people who we do study. Another design decision that when we made it was maybe not what everybody else is doing. In fact, it almost certainly was not what everybody else is doing. We decided from the outset in Phase II to assess drug effect in the absence of any sort of diadic psychotherapeutic intervention. If you look around the field today, it's what a lot of people are saying they're doing. When we decided to do this, that wasn't what was happening. And we can assure you, and we will continue to that from our Phase II on, what we are assessing is a drug effect in the absence of any sort of preparatory therapy, in the absence of any therapy in the room during the session and in the absence of therapy after the drug session. We are confident, again, that the measured drug effect is a real drug effect. And so what does that look like in the course of the day? We have moving slides now. We can do that in a room. It's harder to do it when we're putting them on the web. Patient goes into the room, dosing session monitor is there. Patient takes the drug. Because of our oral disintegrating tablet formulation within 15 to 30 minutes, if the patient, in fact, got active drug, they begin to feel that active drug. The ODT formulation brings that in from about an hour for a tablet. Now the upshot there is the time spent in the room where the patient is not experiencing drug isn't time that helps the person get better. So everything about this formulation is intended to maximally make that day efficient for the participant and efficient for the clinical trial staff. From hours 2 to 4, the patient has reached the sort of peak and plateau of the experience. At this point, the effects of the drug are fairly constant. This is where we think the bulk of the therapeutic action of the drug is happening. And then by hours 4 to 6, the effects of the drug start to wane. One of the things that is particularly notable about the 120 experience is that the off-ramp from the experience is smooth that people come back to their normal perception, their normal emotional state, the normal cognitive state in a way that is comfortable for them, that there's not a rapid return or a rapid loss of the symptoms, but instead people sensorium comes back to them in a way that feels comfortable. And then from hours 6 to 8, people hit the point of being back to a place where they're able to leave the clinic and leave a monitoring setting. Of course, in the research, studies, we keep people in for 8 hours. For one reason, that preserves the blind of other study staff. If everyone who -- if people were allowed to leave at, say, hour 5, they're better. maybe half of people would be ready to leave and half wouldn't. That would be another source of potential staff unblinding. So -- but what we've been doing, we'll show you in a slide in a second, is starting at hour 5, we're assessing folks for readiness to leave. So we start to understand the real dynamics at the end of that session and when in the real world, folks will likely be ready to leave. We've spoken to this before, but this is a little more detail on the end of session checklist. Now in Phase II, we kept people in for a fixed minimum of 12 hours. And beginning at hour 8, we used a 23-item scale to assess for any evidence of the acute effects of the drug. Based on the evidence that we were able to accumulate using that scale starting at hour 8, we went to FDA and proposed an 8-hour minimum in Phase III, and we brought FDA a scale that we thought was an appropriate one to assess for safety. That's an 8-item questionnaire that we call the end of session checklist, and we've been administering that starting at hour 5 to really understand what the dynamics at the end of the session look like. What we think this adds up to is the ability to, at the time of labeling and REMS negotiations, talk about a 5- to 8-hour session length, okay? So we've come down from 12 when we started, all the way down to 5 to 8 is what we'll be proposing at the end of this. So all of that adds up to a set of methods that give us and we hope give you confidence that when we bring you Phase III data it's data that represents a real measured drug effect and a measured drug effect that ought to translate into the real world, that we measure the right people, that we use the right comparator, which we continue to maintain that the right statistical comparator is inert placebo that we controlled for functional unblinding, both through the conduct of the Phase II, as Rob explained, that our Phase II dose comparison gives us great confidence that the observed effect isn't due to functional blinding. And in Phase III, 2 studies with a 50-microgram controlled arm, not a comparator arm, give us additional confidence that it's not just knowing the drug that, for some reason, leads to people reporting that they feel better, but it's the actual drug that helps them to feel better. So all of this, we're very confident puts us on an excellent path to bring the data that we get from these Phase III studies and submit an extraordinarily high-quality NDA. So what will we show you when we bring you these Phase III data? These aren't the data. These are just the form of data. It'd be a big surprise if we were to show you data. So we'll show you the demographics, right? We want to assure you that we got the right people. We were measuring the right thing in the right people. We'll, of course, give primary efficacy outcomes. That's the MADRS at week 6. We'll also give additional secondary outcomes at week 6 and week 12. We'll bring you safety data, so full safety table and data on suicidality measured with the CSSRS. We'll talk to you about dosing session dynamics, including what we were able to measure as safe end times per session, so how long people were in and when they were safe to leave based on that end of session checklist. And we'll bring you some data from the extension phase. We didn't talk about it very much today yet, but those Part Bs are incredibly interesting, right? The Part Bs give us a couple of things. They give us a real-world-like treatment dynamic where folks who are moderately ill or worse are able to receive treatment no more frequently than monthly, but up to 4 treatments in that open-label period. But an incredibly interesting additional thing that we get from the Part B is that unlike a traditional open-label extension. So if we were giving daily drug, someone finishes the double-blind period, they enter a traditional open-label extension, the first day they're in it, they're now in that open-label state. Because we are doing triggered treatment, and this is really important. It's a key difference because we're doing triggered treatment unless someone gets open-label treatment and until someone gets open-label treatment, if they do, they remain in that original blinded controlled state for the full year of the study. And we'll give you as much as we're able from the folks who run through that Part B when we do -- when we give you the data. Now obviously, what we won't have is the full set of Part B data. There'll still be folks in that Part B, but we certainly want to tell you what we're able to know based on the people who've been in the Part B and completed the Part B. And we'll give you some preliminary information on retreatment patterns. Obviously, retreatment patterns can emerge over time as more people are in longer, but we'll at least have some early idea of what sort of treatment patterns we're seeing. So as we reach the end of this section of the presentation. We are accountable for numbers, right? What we're accountable to, to regulators, to HCPs, to payers are the sorts of mean change that we can drive in a mean change difference from placebo. What you see here is our study design overlaid with what we were able to show in Part B. We are able to detect a very small change. These studies in certain ways, were overpowered. That's what we discovered in the SRE that some of the assumptions we made about the powering of the study dependent on people's behavioral changes based on the addition of Part B. Those behavioral changes exceeded what we expected. So the studies ended up even more powered than we thought they were. We can detect a change down in the high 1 to low 2 range. Comparative treatments, in sum of studies that look across the different studies of them are generating about 3 to 4-point changes. Our assumption for these studies was a 5-point change. Anything over 4, we're pleased with it. Everything -- anything over 4 puts currently available treatments in a very different light, right? If you think about a treatment where you have to take it every day, accumulate side effects over time and get a 3 to maybe 4-point change versus a treatment that can generate that sort of change with a single dose persist over time without a persistent adverse event. We're talking about a paradigm shift, a best-in-class profile of these drugs. The Phase IIb results stand where they are, right? We're talking 7 and 6.4 point changes over placebo in the Phase II. Anything above 4 best-in-class profile, and we expect that we can do even better. Members only tell a part of the story, right? They're absolutely critical. We're accountable to you. We're accountable to everybody for those members. But behind the numbers, real patient experience, real people's experience, people that you might know, right, the people in all of our lives who suffer from anxiety and depression. And after all of this, after all of the technical details here, we thought it was really important to sort of bring that home. And so what we're about to show you is someone who participated in the Phase II study for GAD and what that was like for them. I think if I press the button one more time, it will start. [Presentation]

Having seen that a couple of times, I still have to sit with it for a second. There's something to be said about -- using a microphone. There's something to be said about someone organically coming to so many of the same conclusions that we have and hearing unprompted much of the language that I'm confident we've used with many of you coming directly from a patient, and it is moving each time. So much of what we are trying to do here with you today is to make this feel as real to you as it feels to us. Rob started by saying what an honor this is. And I think each of us feels both an enormous obligation to the drug we're developing, but also to the patients, as you just saw, the participants in our trial and the patients who, if we're approved, will ultimately benefit and an obligation to the professionals who will be the conduit for this drug into the world and to patients to change lives. And so we wanted today to bring up some folks who are exactly the sorts of clinicians, the sorts of treaters who will ultimately be the folks who interact with our drug and with the patients who can benefit. So I'll let everybody introduce yourselves, starting down here with Brittany, and we'll go from there. And yes, we can ask these around as we need to.

Hi, everyone. First of all, thank you so much for being here. I know you have many other obligations, but the fact that you all care about my patient population speaks volumes. My background is I trained in Boston at Mass General McLean Hospital in psychiatry and just as much in psychotherapy. And then I did an addiction psychiatry fellowship at the Medical University of South Carolina. And about 10 years ago, I felt forced to become an entrepreneur and start my own practice because the way I was seeing psychiatric care delivered in the community and in academic centers was not consistent with my values of holistic care where we're not striving for symptom reduction, we're striving for patient wellness and ideally to work myself out of a job. And so I currently own a large private practice. We have around 30 clinicians and 3 treatment centers. And I've accidentally become an interventional psychiatrist because our traditional therapeutics have failed my patients. And as a result, we do transcranial magnetic stimulation, and we've delivered over 10,000 S-ketamine treatments.

Thanks, Brittany. Hi, everyone. I'm Andrew Penn. I'm trained as a psychiatric nurse practitioner. I trained at UCSF in San Francisco, and we like to joke that UCSF stands for you can stay forever. And so I'm currently a professor there as well as directing nursing operations for a start-up interventional psychiatry company called Salma Health. In my time at UCSF, I've had the good opportunity of being able to not only treat many patients, but also work in research, psychedelic research, working on interventional studies around MDD with psilocybin and worked on the MDMA PTSD study many years ago. So I've got -- I've had a chance to sit in the room with folks as they've gone through these treatments and really get to see firsthand what this looks like, which reflects a lot of what Mary spoke about and also have been in psychiatry long enough to really know the shortcomings of our current treatments, which is one of the reasons why I'm here today.

Hi, everyone. My name is Shannon Sarkar, and I'm a licensed professional counselor in Atlanta, Georgia. I recently got my PhD last year in counselor education. So I'm really passionate about helping support counselors in their journey and becoming better counselors. But I got into the psychedelic field in 2022. I started working with a research facility in Atlanta. And my role has been a dosing monitor -- session monitor. And what I do is I sit with the patients and I hang out with them. And it's been really great being a part of all of the different clinical trials that I've seen. And yes, what I'm really passionate about so.

That's awesome. Why don't you keep that microphone? I start with you... And so clearly, we brought up some folks who maybe aren't necessarily the phenotype that you would ordinarily hear from in an event like this. And we tried to bring folks with different training, different experience, different backgrounds to speak to the perspectives that they have on the world that they occupy today. So I'll start right there with -- we talk about anxiety and depression a lot, and I tried to talk to anxiety and depression in my little section there. But I'd love to hear that from your perspective, when you think about patients with anxiety and depression, how do you think about the impact on their lives? How do you think about making a diagnosis? And then what does that lead to in terms of treatment options and responses to those treatments?

Yes. It's a great question. And I wanted to mention too that I have luckily been a part of all the different phases for the GAD study. So that's been great. So that's definitely...

Aside from enrolling in our trial, which is obviously the best...

But yes, so definitely work -- I'm mostly focused with the anxiety studies, but have worked with a lot of participants who have come in and have been working -- sorry, have had a history of moderate to severe anxiety, had lots of different treatments that have not really worked in the past. And when they get here to this point, there's -- they get here and they're like, wow, this actually has helped. And it makes me wonder about what earlier access and intervention can really do to help support them.

Yes.

That's great. Yes. Andrew, thoughts on.

Yes. So as a clinician, MDD and GAD are really your bread and butter. I mean it's what you see all day. And diagnostically, as you pointed out, Dan, they're really quite similar. The way you end up diagnosing often becomes what somebody's chief complaint is. If somebody comes in and says, I'm anxious all the time, I can't relax, then it becomes GAD. If they come in, they say, I'm sad and I can't sleep well, you say it's MDD. But otherwise, the overlap is the same. And I've been practicing long enough to when we used to give benzodiazepines freely. Typically, people would walk out of my office with a prescription for a benzodiazepine and an SSRI with the goal of taking them off the benzodiazepine after 6 weeks, probably about 50% successful. Now clinicians won't touch benzodiazepines. But the problem is we haven't really given them an alternative. So people end up suffering with anxiety. They get a little bit of help from SSRIs sometimes if they can tolerate the medications. But in general, there's a big gap in what people need in terms of their treatment and what they're getting.

I'm here pleading for change because I'm actually somewhat embarrassed of my field. When you look at the state of major depressive disorder and generalized anxiety disorder, we're no better at treating it today for first episode than we were over 50 years ago. We're stuck in the dark ages. And when you compare our disease states to cancer, to oncology, we are extremely behind. And that's why I'm so excited by the hope and the possibility of new therapeutics. such as this medication that we're discussing today. Even when there are treatments that may work, for example, we do have some new treatments for major depressive disorder and particularly treatment-resistant depression. They don't fully address generalized anxiety disorder. We have not had a new therapeutic for generalized anxiety disorder in what, over a decade, Dan?

Almost 2, yes.

It's shameful.

Really, really helpful and good thoughts on the disorders. When you think about someone coming in, in distress, so patients come to us because they're in some sort of distress or they realize they're in distress, something usually prompts the first visit. What do you have to offer in terms of feeling better quickly?

Psychotherapy is always #1, but psychotherapy lifestyle changes can take weeks, months and having lost several patients to suicide, I can't wait for that. I need rapidly acting treatment. And that's why if you feel my emotions coming out, it's because I'm thinking of all those patients I've lost over the years because I haven't had rapidly acting treatments.

Yes. As a risk of repetition, what we used to do is benzodiazepens because they would work reliably quickly. But since those have become more surveilled and discouraged, we don't do that so much. So a lot of times, really what's happening is patients are leaving our offices with a hope that maybe 3 to 6 weeks from now, this medication will start to work. And there's another challenge with the anxious population, which is tolerability because patients with anxiety often are highly sensitive to the side effects of medication. And so a lot of times, you get these false starts, where they'll take it for 2 or 3 days, feel some maybe GI distress and say, I can't keep doing this. I got to stop. And so you often end up with these sort of false starts where you never really find out if they're going to benefit from the medication. And a lot of those folks sadly give up on treatment because they feel like if this is how it's going to be, I don't want to do it. And so the idea of being able to get somebody better quickly and not have to continue taking medication on a daily basis would be very appealing to a lot of my patients.

Yes. To add on, from what I've seen in my work, people are already anxious because they've been trying to find so many different treatment options. And once they come in and we're able to provide like a prep session with them and kind of educate them about the process and tell them about how it really does work quickly. It really -- that prep session really sets the tone for the treatment outcome. And yes, I really believe that, that rapid onset is very, very important to the treatment process and the momentum and the motivation.

I mean it's excellent thoughts. I was supposed to remind you all, by the way, that QR code, if you put questions in, I will at least be able to pull a couple up for the panel. So if you have questions as this goes on. And if we can't get to questions today, we will certainly find a way to answer them -- so put your questions in if you've got them. I've got a couple for you already. But let's stick with the thread that Andrew, you opened there about side effects. And I'm curious about the experience both of side effects from drugs in these patients, but also long-term drug taking and loss of efficacy and sort of what the -- what those dynamics are like for the patient experience with what we have available from a pharmacology perspective today.

We have a very fancy term for that in our field. We call it poop out. Tachyphylaxis is a technical term for it. But it's another form of disappointment for patients. So I mean, imagine you feel miserable, something helps you for 6 months. And then slowly, as each day goes by, you notice this is working less and less. And then the question becomes for both the patient and the clinician, what do we do next? And a lot of times, what we do is we change it to a different medication. We hope that this will work better, maybe we augment, but we end up doing this again and again and again. And a lot of times, what we find is that people have less response each time we do this. So the idea of really getting people better, not having them have to take a regular medication and then perhaps they come back a couple of times a year or something like that, however long the durability is it's a paradigm shift. And we've done this to some extent with things like esketamine, but those are fairly short intervals. You're coming in every couple of weeks, maybe every 3 weeks. So the idea of somebody getting 4, 5, 6 months of durability from a treatment is really unheard of in pharmacology.

When I give a patient an antidepressant, the data shows that within 6 months, if they have major depressive disorder, they will have discontinued that medication. And their risk of relapse is exceedingly high if they were even in remission to start, but it's at least 40% within the following 6 months. And so often, in my job, my day-to-day job, it's just this never-ending cycle of constant turnover of more and more and more pills and our patients end up on polypharmacy. And like Andrew said, the longer that we wait to get them into remission, the less likely they are to ever achieve remission or to certainly achieve wellness. Depression is toxic to the brain. It truly leaves a scar. And we need to approach depression and anxiety disorders with urgency that we would oncology because these illnesses truly metastasize not just in the brain, but throughout the entire body. Patients with depression and with anxiety disorders have significantly higher rates of cardiovascular disease, of oncological disorders, of substance use disorders. So we're talking massive morbidity and mortality that's unnecessary if we adequately and aggressively treated these illnesses right away.

Yes, that makes a ton of sense. I mean I'm struck by a study I read forever ago now that showed that the predictor of mortality after an MI when you control for the severity of the MI is depression, right? I mean it's the extent to which that this manifests somatically can't be overstated. Shannon, let's go back to you for a second because you have some experience in the specific area. And then I think for Britney and Andrew will talk a little bit about what does it take to give these drugs? What is it -- what do you need? What's the burden to be in the room? And then we'll kind of morph that into what would it take to have a practice that was ready to do it?

Yes. What would it take? I think, again, I talked about more access and timing, better timing is really important. And I I think doing a lot of patient education and helping clinicians to really help support and help the participants feel really safe in the process is critical. I really believe that the prep sessions, again, set the tone for the treatment process, and I really believe that focusing on helping clinicians support them is really important in terms of tolerability and durability and things like that because you're having the clinician in the room with them, you're not doing psychotherapy, but you are supporting them and providing immediacy in that moment. So I think, yes, having well-rounded clinicians that can really create a safe and supportive environment for them to really let go and experience that could be really helpful.

Yes, go ahead. You take it away. What would it take for a practice to be ready to do a thing like this if they're not today?

I sat with a lot of people in these sessions. And despite what people see on TV, they're less remarkable in the room than you might imagine, right? So a lot of times, it's actually very quiet. I actually look forward to these days because they are a less busy day for me. I'm in one place the whole time. And I get to sort of sit with people quietly while they have this experience. And a lot of times, they actually don't need a lot of intervention. Really, it's more about presence and the ability to be with somebody in that state. And then getting to the passroom, making sure they're drinking water. I'm a nurse by training. So this comes very naturally to me, the idea that we're kind of attending a natural unfolding process kind of like we do in childbirth or death that really we're kind of holding that space so that people can do their own inner work and making sure they're safe. But really, it's not a huge lift in terms of actual labor. I mean seeing a full slate of patients is a lot more work in the course of the day, honestly.

I can speak more to the operational perspective. I started my practice when I had a 3-month-old baby and a 2-year-old daughter, and I had $5,000 and a husband who was a car salesman working long, non, I had no business becoming an entrepreneur, but why not? And we've done it -- and it was all me by myself, but fortunately, I've grown a team, and we've done it very slowly, very intentionally. I've never had to borrow any money with the exception of a real estate commercial loan for the office space. And I found that as long as you do it slowly and intentionally, it's feasible. And when I added esketamine to my practice as soon as it got FDA approved in 2019, I was so impressed by the data that in the very conservative south, I knew it would be successful and it has. And it's because the treatment truly helps for treatment-resistant depression, unfortunately, not for generalized anxiety disorder. But I've noticed on those days where I'm practicing and seeing a lot of esketamine patients, my levels of burnout are so much lower because I know I have an effective treatment to offer to patients besides just the same pills over and over and over again.

Yes. And so in your practice, are there -- I talked before about 5- to 8-hour treatment days. Are there treatments that you offer that you think have an analog? I mean, obviously, esketamine has a 2-hour monitoring period. Are there treatments that have sort of an analogous kind of full treatment day kind of timing?

Absolutely. We also offer accelerated transcranial magnetic stimulation, and that can sometimes be up to 10 hours in a day. And we're willing to do it if that's the right thing to do for the patients.

Okay. Yes, that makes a lot of sense. And long day, but if it's the right thing, right? So a question actually came in from the audience that wasn't on our list. So you're ready to think on your feet here. The question was about -- and I just didn't think to ask you this when we were planning, but the provider receptivity. There's -- the question specifically said there's this concern that there may be a bottleneck at the provider level as folks who obviously lead organizations and lead your company and Shannon, your experience just doing the work. What do you think about the sorts of providers who would be amenable to participating in treatments like this? Do you see that receptivity growing? And sort of is there a phenotype of provider who might be more or less interested?

I think these treatments will be implemented first in outpatient private practice psychiatry clinics that focus on interventional treatments like ketamine, esketamine and TMS. Currently, there's around 2,000 SPRAVATO treatment centers in the country. And I imagine most of these treatment centers will be very interested. And Andrew and I are both very involved in psychiatric education on a national level. And this year, we actually launched a private practice psychiatry summit to help to educate and equip and prepare clinicians to be able to offer these treatments as soon as they're FDA approved.

So only about 1% of people who would be eligible for procedural treatments in psychiatry get them. And part of that reason -- there's a lot of reasons for that. I mean some of them are insurance and structural and such, but part of it is also the mindset of our profession. Because we've trained, we've become familiar with this 30-minute return visit, med check, make some small adjustments and them back come back 4 weeks later. So there is a paradigm shift that needs to happen. But I think what's going to happen once the sort of successes of these treatments that -- like the one we're talking about today become more common, clinicians are going to want to be part of that. Because really, if we -- to what you were saying earlier about really being kind of disappointed in our profession that we need to do better. I want to have the same enthusiasm that my oncology colleagues have because when oncology sees a patient, we have all these different options, and we know this is the efficacy data for them. I want to have that level of enthusiasm for treating the things that we treat. And I think as this grows, that will build because the profession is ready for something new.

And just to add on to that, I think that education is really important too, and providing more opportunities for clinicians to learn about this field because you don't really know -- we don't have access to it in our academic settings very rarely and very little continuing education. And so I think just being very mindful and intentional about education and really providing the data, the evidence-based data that's out there, because I honestly feel like a lot of people don't really know what's out there. And so being able to show it, I think, can really help.

Dan, I also just want to add one thing about the psychotherapy aspect because historically, if you're familiar with the psychedelic space, a lot of times the way this was packaged was drug plus psychotherapy. And it was assumed that, that those 2 were essential to go together. And I think what this data is interesting is that it shows that those 2 actually can be disentangled from each other, which creates incredible improvement in ease of operations because when you're trying to combine, say, even 2 -- because a lot of the studies had 2 therapists, 2 therapists for these many hours, for this many repetitions, it's an operational nightmare. So to really be able to make -- I think what you've shown is that you can deliver this safely and effectively with a lighter touch that doesn't require that. That doesn't stop people from going out and seeking their own psychotherapy to sort out what they've learned about themselves in that session. But I think what it shows is that the 2 don't necessarily need to be bundled, which will definitely increase the operational viability of this.

I mean obviously, intentional in that regard and by no means guaranteed to work, but now that it has, we're really happy about that. I think we've one -- probably time for one more audience question. And we've been on the provider side of things. But as people who see patients, and we just all got to see a patient together, but what do you think about patient receptivity? When you think about your environment, your practices and your patient population, is this something that patients are going to be the question was really patients be willing to do this when this is -- if approved, is this something that if you were to offer it, your patients would say, sure, let's try it.

I've actually started discussing these treatments and particularly the one that we're discussing today with my patients already because they're suffering now. And it's my responsibility to embed hope into the conversation. And I find it's all about how you frame treatments. I was the first SPRAVATO clinic in all of South Carolina, and there was a lot of skepticism when that launched, but I explained it from a medical scientific perspective. Again, comparing it to oncology, to chemotherapy, who wants to sign up for a drug that causes you to lose all your hair and vomit, not just for 1 day, but for days on end. It's all about how you frame it. I get to tell my patients instead of having side effects every single day from an oral antidepressant, emotional blunting, sexual side effects, weight gain, you get to choose the day that you have side effects. And you may not have to come back for another treatment for several weeks. And when you frame it in that way, patients are much more receptive. And my plan already is I'm actually building a brand-new office space. We'll have 12 treatment rooms. We'll work on a Saturday that where patients don't even have to take time off of work. And so if our clinicians are busy seeing med management throughout the week, no problem. We'll do these treatments on a Saturday, and we can treat multiple patients at a time. So even if clinicians are not receptive to offering this treatment right away, I am confident my patients will drive from all over the state. They'll drive hours just like I saw with SPRAVATO back 2019, 2020.

It's hard to follow up.

That is hard to follow up. I'm just amazed by your ambition and your entrepreneurial spirit. It's funny when I first heard about this development process, I was talking to some friends who are involved in psychedelics and LSD for anxiety really because sometimes people associate LSD with anxiety. And I think it just speaks to the sort of pluripotent nature of psychedelics is that the same drug in a different context, some of the research work that I'm doing in San Francisco with Robin Car at Harris is looking at the importance of context. And I think what this data shows is that this delivered in that context not only is safe, that the side effects are quite predictable and they're manageable in that particular context and that most importantly, that it works.

Closing thoughts, Shannon?

Yes. Just some closing thoughts. Yes, I think that patient receptivity has a lot to do with Yes. Sorry... Yes. So you're good. Yes. I've seen in my practice that a lot of people -- it goes back to talking about that rapid onset and really wanting something to work faster. And I think that is really what attracts people to this and the patients that I've worked with is that idea that this can work quick because, again, there's been years of trying to find some sort of treatment. And then this rapid onset is attractive, and it makes people feel more motivated and excited and hopeful.

Awesome. All right. Well, please join me in thanking these wonderful folks for coming up here, and they will be around after we finish today. So obviously, happy to answer questions and chat with you. And that is it for me. Now I get to welcome Matt Wiley, who is our wonderful Chief Commercial Officer, and we get to exit the stage.

Well, I'm thrilled that the questions about both physician and patient receptivity to psychedelics came up because we are going to cover that in the commercial section. I am going to spend the next 20 minutes or so talking about commercial readiness and the commercial opportunity. I'll start with this, that we're building out an infrastructure in commercial that is really built for purpose for the introduction of DT-120. There is not a specific playbook for this type of intervention that's coming to market. Certainly, there are surrogates we can learn from, but this is going to have a very unique market entry strategy associated with it. And so we're building out the organization to fit that strategy. I'm going to walk you through the market opportunity. Of course, as I just mentioned, the provider and patient dynamics that do favor the introduction of DT-120 and an evidence-based view of product adoption as well as the commercial infrastructure I just discussed. So there are 4 converging forces that really clear the path to the successful launch of VT120.roider readiness, reimbursement precedent that exists today, patient demand for better treatments and our own operational timing, all are intersecting with the introduction of VT-120 if approved. Providers are primed and ready for this drug coming to market and increasingly so, and we see that in the market research. So physicians have moved from skepticism really to active interest in interventional and psychedelic modalities. And precedents like esketamine have really cleared a path and established reimbursement pathways that we can leverage as we get to market. Patients want better therapeutics, better treatments, and it's now our time to execute and help those patients get to DT120. Now we talk as a company often about the size of this market. We talk about the 50 million-plus patients that suffer with GAD or MDD. Those are prevalence numbers. What we really focus on from a commercial perspective is that patient population that we can access immediately at launch. Sometimes you have markets that need to be built as you go into market. That's not true here. For those patients who have been failed by 2 or more therapies, that number represents over 4 million patients. So this is a large opportunity. We're targeting with our market entry strategy, those patients that are most likely to benefit from the value that DT-120 will bring to the market if approved. This is a significant opportunity, a significant market, and we have the right framework in place and the right conditions for the beachhead strategy that you can see here on the right-hand side that will help establish DP-120 in market. Now that is market entry. As we think about 5 or 10 years post launch, how could this market evolve? And the market can evolve pretty significantly with different levers. So awareness, access and new treatment options should help this market continue to evolve and grow over time. Our forecasts are grounded certainly in the beachhead strategy. But as we help move those patients that are in the community from walking around and undiagnosed to awareness and screening, we believe that we can increase in time the diagnosis rate of GAD and MDD and ultimately, PTSD as well. Increased treatment of mental health disorders, certainly, having drugs like VT-120 in market is going to drive some behaviors. There are a lot of patients out there that are currently diagnosed, and we see this in claims data that are not receiving treatment today. So new treatments as they emerge may bring those patients back in to see a clinician about treatment. And then removing barriers for access. There are certain treatment realities that DT-120 will face as far as the number of therapeutics that are worked through with the payers. And that could change over time. And as they see the value of something like DT-120 in market, we believe that the access barriers could get eroded even further in time. Now psychiatry has been a very unique specialty in the fact that this specialty does adopt innovation quite readily. And so we've seen that this track record of embracing innovation from the SSRIs to the atypical antipsychotics, the TMS to esketamine and certainly downstream the psychedelic class. These are interventions that are precise and very differentiated. And certainly, DT-120 should benefit from the paradigm that exists in this specialty. Now every new major psychiatric class has reached multibillion dollar peak year sales. And so we've seen this with the SSRIs, the SNRIs, the atypicals and the glutamatergics more recently. And peak year sales are reaching anywhere between $9 billion to $3 billion at peak. Obviously, those all the way to the right are still prior to peak year sales. Psychedelics really are positioned to be the next major class of drugs, and DT-120 is positioned to lead that class. Commercial success of each prior class was driven by a combination of unmet need, mechanistic novelty clinician willingness to prescribe. And all 3 factors are present and arguably stronger for DT-120 if approved. Now we use this not necessarily to forecast, but it is a good set of surrogates to gut check our PKR forecast to see even with all of the operational challenges and realities that every single class face coming to market, this gives us good benchmarking data that we can leverage. Now Rob talked about the patient journey. And for both GAD and MDD, this patient journey is long and arduous. It can take years for patients to actually get to the proper diagnosis. Patients will move through their -- the first intervention, which would be either an SSRI or SNRI and then move into augmentation, switching and often years of trial and error. And this leads to frustration and ultimately can lead to patients either dropping out of the system or continuing to seek that treatment without any benefit of remission. So one thing to note here, and I think it is important, it dovetails on something Dr. Albright said about the GAD patients. I mean, these are patients who -- they're highly comorbid with MDD. Oftentimes, those symptoms get left untreated and unresolved as well. And so having a drug that's pursuing both indications can be very helpful. The intersection point for DT120 really is where they're cycling and moving DT-120 up into that treatment paradigm to intercept these patients earlier so they get to remission. The patient journeys for both these conditions should not look like this. in 10 years. And we expect that with the introduction of our drug, we can change this. Now when we talk about unmet need, and we can look at the patient journey quite a bit, but we examine this directly with patients. And so in this particular study, patient preference study, 100 patients in this research. And when asked about their current treatment, their satisfaction rate. And I'm just going to orient you to the top bar here that they were satisfied with how it relieves their symptoms. The #1 reason that they're taking a drug, by the way, is to relieve their symptoms. only 5% were very satisfied. 28% were very dissatisfied with their treatment. So this really does highlight the unmet need and the dissatisfaction in the market. Patients are not getting well, and they certainly need to have something better in the armamentarium. One of the other things that is really important about these therapeutic classes, and I can't overstate this, is that patient persistency is a real issue. So this is a monthly snapshot of branded drugs that are on the market today. And you can see that by month 3, roughly 30% of the patients taking those drugs is eroded. Now this is directly from claims data. So what we see also on a weekly basis, week 8, week 12 are even lower. So we do see that the persistency is a real issue. And this does a disservice to all 3 constituents. The providers are not able to keep patients on the therapeutic long enough to have a real trial. And this doesn't matter whether it's a retail PO drug or whether it's an interventional drug like esketamine. Second are the patients. And so the patients may be dropping off for a myriad of different reasons, whether it's side effects, whether it's out of patient -- out-of-pocket costs, whether it's insurance issues. Certainly, lack of efficacy could be one of those as well. This just leads to their frustration. And then finally, for the payers, they're paying for a drug that never really gets the full opportunity to work in these patients. So the most expensive drug a payer is paying for is the one that the patients quit on, and that happens quite a bit. As we think about physicians in this market and the receptivity let's focus first on the psychedelic class as a whole. More than half of the physicians that we've done market research with are positive -- have a positive view of the psychedelic class that's coming to market. And this has been a pretty durable response over the last 3 waves of this research that we've done, this awareness research. And roughly 36% are neutral category and some are hesitant. We've seen an additional market research how we can move those that are from a neutral category, specifically with DP120 or those that are hesitant into positive on the class. So we do have a plan for that. Now we see that the number on the right actually changed. But this is 58% of HCP surveyed have positive views of DT-120. So this is DT120 specific. And the things that they cite, that's nearly 60%. The things that they cite as important to them, the quick onset of action, the symptom resolution, the durability of response, the unique mechanism of action, those are all things that really resonate with physicians. Additionally, and this is something that we just learned a couple of weeks ago in our last awareness survey is that the awareness of DT120 and formerly MM-120 has grown pretty significantly wave over wave. So Wave 2 was conducted in 2024, and there was an awareness of roughly 27% from those clinicians. And I believe that the medical team has done an outstanding job working with key opinion leaders. Certainly, our data has been presented in multiple formats over the last couple of years, and the MSL activity is bearing fruit, and we're seeing that rise to 64%. So there is a readiness for DT-120 coming to market. Physicians are aware that it is coming and seem to have a pretty positive view on the profile. I'm going to share with you some data about our target market. So the target market, and I'm going to talk a bit about our targeting methodology in a few slides. But these are our decile 7 to 10. So this represents 40% of the opportunity that we see. We've prioritized those physicians based on a number of factors through predictive modeling. And what we found in the research, those decile 7 to 10, not only do they intend to prescribe DT-120 when approved, but they also intend to administer it in their practice. That is a very unique finding. And when we look across to how they're viewing esketamine today and what they actually do with it, 26% of these same prescribers are prescribing esketamine and also administering in the practice. So there is a delta there that we're currently exploring to truly understand this. But one of the hypotheses here is that the prescribers viewing the profile look at this as a single intervention and not a commitment to build out infrastructure to manage that patient every week. And so that may be the difference. And we're excited, though, by the fact that clinicians are this positive and definitely have an appetite to leverage this asset when it's in market. Talk about the appeal to patients. DT-120, for those patients who have been failed by 2 drugs, the expectation or the likelihood to try DT-120 is 40%. And this is from market research that was conducted last year. When we -- when those patients have failed 3 or 4 different treatment options, that jumps to 60%. And then those that have been failed by 5 or more treatments jumps up to 65%. So the longer down the pathway of the patient journey, the more failures that they've had to endure, the more likely this patient population will be raising their hand for DP120 if approved. This is encouraging news because there are a lot of them. When we interact with payers, they also have similar response that we see with physicians. Now this is based on a GAD product profile, but those elements that are important to the payers, rapid onset, efficacy, durability response, all of those things do matter to payers. The first-in-class MOA. So there are a lot of different drugs, obviously, that they can put on formularies and approve, but having differentiated MOA and in this case, is an anxiolytic MOA was very positive for the payers. And then lastly, the onetime oral dosing. So this is very unique for the payers and the fact that they get to pay for the drug and then see how it works over the next 3 months. It also -- and payers get there on their own. We've seen this in payer advisory boards where they immediately understand that taking a drug like DT-120 would reduce any of the compliance or persistency concerns that they see with other therapeutics. So they get there on their own. So -- when asked specifically how they're thinking about covering both the psychedelic class and specifically DT-120, they are anchoring to what they know today, which is esketamine. And so that is the most logical surrogate. They expect the annual price for DT-120 to be in line with that of SPRAVATO. And just to kind of put a fine point on that, the range of pricing for SPRAVATO per label, lowest dose, lowest frequency is about $28,000 a year and the highest dose, highest frequency is about $70,000 a year. So that is the range that they're pegging us to. They indicate that FDA-approved treatments will be covered. They don't see any reason why they shouldn't be, but that they would be managed, and they would be managed very similarly to what they're doing with esketamine today. Typically with step edits prior authorization. Now the chart on the right puts a finer point on this, which is esketamine approvals on prescriptions over the last year, this 2025 data. And you see that whether it's commercial, Medicaid, Medicare, payers are covering esketamine at better than 85%. So this is the type of access we should expect over time. Now this is not going to be immediate, but this gives us a good line of sight into how the payers are thinking and the type of payer coverage we should expect over time. I mentioned I would talk a bit about our targeting model. And our targeting model was very thoughtfully derived. We used a lot of different inputs that we learned in market research or through additional analytics. We start this model based on where the patients are. So there's no logical surrogate for a drug like DT-120. Nothing has really been launched in GAD in almost 20 years. And having a dual indication really forces us into a patient identification model. That's exactly what we've done. We've used patient concentrations, those that have failed through multiple medications, those that are complex patients, those that have had emergency interventions. Those are the type of patients that we know are going to be hand raisers at the very beginning, and they've been prioritized in quantities based on physician target. Now the physician targets are also prioritized by a number of different factors, including adoption behavior. So when we think about the adoption curve, there are innovators and there are early adopters. The innovators, those that are very rapid have a rapid history of adopting new branded therapeutics, they're at the very top of the list with those patients. And then, of course, anyone who is actively doing certain interventions factor into this model as well. So we get the best of all worlds here. This gives us a very nice map to deploy a sales team towards. But that's not the only support mechanism we're going to have for clinicians and patients in the field. So field sales is obvious. We will have reimbursement support as part of the field apparatus and site of care support as well. Our philosophy is that we want high-touch partnership-oriented touch points with our clinicians is very similar to how we conducted our clinical development program. We also intend to launch a hub model. This is a comprehensive model that's designed specifically to remove friction in any of the process. So whether it's REMS management, benefits investigation, prior authorization support, affordability support for patients and, of course, case management and how the drug gets to the clinician. All of that will be handled through a hub service model that is designed specifically to accelerate the process from prescription to drug in patient. Access barriers are known risk. And so we are putting this model in place to ensure that we can neutralize them to the best of our ability. I'm going to end here, and you've seen the chart on the right before. Using the esketamine surrogate, for every 100,000 patients, you're looking at a potential gross revenue of somewhere between $3 billion, almost $3 billion and $7 billion. Now the way I like to look at these things is based on a 4.2 million patient TAM for every share point is roughly $2 billion in gross revenue. This opportunity is not something we take for granted. It's going to be earned through flawless execution as we get ready to market the drug. And so we're working in concert with our Phase III readouts and with the regulatory pathway to ensure that we have the right commercial execution to get us to this launch effectively. And that kind of leads us back to where we started. Execution is key, and we're committed to doing just that. And so with that, I'm going to hand over to Brandi Roberts, our CFO.

Hi, everybody. I'm the shortest of the team. Before we get to Q&A, I wanted to talk about building long-term shareholder value. You've heard a lot today about what we've been focused on over the last 5 years, and we're tremendously proud of the value that we've built to date. You've heard about our scientific rigor, the unmet need that we are trying to address, the significant progress we've made on our clinical trials and how we're building out our commercial strategy. And we really look at this as the tip of the spear. We believe that there is long-term value to be created, and we are excited about what comes next and what we're focused on over the next few years. I did want to take a moment and talk about one of the key drivers of our strategy and building long-term value, and that is really our layered IP strategy. As a new chemical entity, DT-120 is eligible for 5 years of exclusivity, and that would be extended by 30 months if a generic were to try to come and look at one of our patents. And so that is one level of our IP strategy. But we also have a robust patent protection that goes across composition, formulation and methods of use with issued patents that extend into the early to mid-2040s. And we continue to look for ways to expand our patent portfolio as additional insights emerge. And so we're even looking for ways to extend that time period even further into the 2040s. So very excited about what the team has done here to make sure that we are protecting our core asset, and we have done this in a multilayered approach. In terms of takeaways and what I really want people to leave with today, again, we've talked about a lot of the scientific rigor that has been put into our approach to date. We believe that these are significantly large market opportunities. We know that patients need better options, and we have the ability to do this at scale. And starting with GAD, obviously, we've talked about GAD, MDD and now PTSD. But with GAD, we have the ability to have the first drug approval since 2007, and that could be a very, very big change. You've heard from the panel today about how patients with GAD have struggled. And so we believe that we have a significant ability to impact the market and make a significant impact across psychiatry. We're incredibly well positioned for success. We talked about our compelling Phase IIb results, the rigorousness of our Phase III program and how that's been put together, how we think about differentiating ourselves in terms of our strategy and the indications that we've pursued as well as the execution of those clinical trials. And we've developed an experienced incredible team that knows how to get this to the next level. And so when you think about what to watch for over the next 12 to 18 months, we've got multiple anticipated 2026 readouts coming soon. I've been very excited to say IMerge data coming later this quarter, followed with VOYAGE in early Q3 and then PANORAMA in late Q3. So in the next 6 months, 3 very big top line data readouts that will really inform the strategy of this company moving forward. Obviously, we're still very focused on the ASCEND study execution. So more to come there. And then the evolution of the commercial opportunity as we talk more about that as we get to our data readouts. Really, the value of this company is done by looking at 2 key areas. One is the clinical and regulatory execution. And so thinking about our top line data readouts for our 3 studies as the next upcoming events there. But in parallel, also that commercial strategy and making sure that we're taking into consideration all of the items that will make this a tremendous success commercially if we are approved and the data supports that. And so we look forward to continuing that value creation over time, and we look forward to taking some Q&A and making sure that we've addressed everything. I think you guys would say that we developed a very robust schedule today. We've covered a lot of ground, but we want to make sure that we can get to Q&A as well. Before I do move to that, I did want to note that after we're done, there is an on-site dosing room. So we've locked one up so that people can see what that looks like. It's on the other side of the lobby of where people entered. And then we do would love for people to stay for lunch and be able to continue to ask questions. So with that, I will take it to the Q&A that's come over the Internet first, and then we'll also take some in-person questions, but I would like to invite the management team up for Q&A. QR code just in case you want to put them in online as well.

All right. So I wanted to thank everybody for putting in Q&A. A lot of them we did go through as we went through the rest of the information during the prepared remarks, but I did want to get to one that was talking about coordination across multiple agencies as we look to regulatory approval. And the question was, how is Definium engaging at the policy and advocacy level? How do you work with the different industry coalitions, patient advocacy groups and the policymakers in Washington, if we could go through that a bit.

I'll start there. We've spent a lot of time over the last several years building awareness. I think each of us has spent time in state capitals and in D.C. having these conversations. And of course, we saw this past weekend, the highest office in Milan commenting and taking action on that. So we have yet again tried to lead the way in this and be fairly thoughtful, right, not take strategies that would uniquely benefit us at the cost of patient access, but really opening up the field. We have ways of winning. We want to win on our execution. We want to win on the strategy that we're pursuing. We want to win if we have the best drug. At the end of the day, these patients need as many options as we possibly can. And so one of the ways we've been doing that is through cooperation with other organizations to build awareness, to work with patient advocacy groups. We've done a lot of that, of course, ourselves as well. We had a lot of -- again, a lot of success in building those coalitions and building that awareness and having these conversations across the board at every level of government and every branch of government have been really encouraged by where we are today and what that means for the future. Again, I think whether we talked about our organization, the opportunity or about policy and advocacy, the reality is we are just getting started. Sitting here today, I think a lot of folks don't -- can't sort of see around the corner in the future, really appreciate what we believe is the opportunity. And we are going to do everything within our power to make that opportunity maximize and come into the world in a way that when we look back 10 years from now, we're in a better place than we were. These patients are in a much better place, and it's going to require everybody. The fact that -- the fact that there's that widespread recognition that we can go into any office in D.C. and have these conversations. I don't know that 10 years ago, we were there. So this moment has converged in a way that uniquely gives us that opportunity to do this the right way and do this with a really, really ambitious goal.

Great. Another question that came in was related to our expectations for the EMERGE data readout. And the question was, should we expect similar types of data for the GAD readouts as well?

Yes. The primary outcome is 6 weeks on the MADRS for MDD and 12 weeks on the HAM-A for GAD, and that will be the real difference between the 2.

Okay. Kind of following that again, can you talk a little bit about what the NDA strategy would be and what we're thinking about currently?

What I'll say is that we opened our IND in early 2022. We will have our Phase III studies in hand along the time lines we've been talking about today for 2 studies in GAD and 1 in MDD by the end of the third quarter of this year is our expectation. That is moving at a remarkably fast pace in development. 5 years start to finish in the development program is an industry standard that we've heard even Lilly talk about aspiring to. And so for us to be able to execute on that just speaks to how we approach these these problems. When there's an urgency of need and there's a magnitude of need like we face, we don't sit on our hands in anything we do, and we're going to approach our NDA just the same way. We've got an incredible team. We all spend some time with him at lunch, leading that charge, leading the way, who led some of the most important approvals recently in psychiatry, and they're going to hopefully have the opportunity to do that again if we deliver high-quality data later this year.

All right. Next one is related to PTSD. And can you talk a little bit further about the confidence that you have in going into PTSD and how you came to that?

Yes. I mean -- so PTSD is obviously sort of the third leg of the stool of neurotic illness. And we really -- when we think about these illnesses, and I showed you a little bit before about the temporality of them. But often diagnosis isn't just temporality, it's what the patient says about their experience of their life. And so as over time, the just definition of PTSD has expanded in recognition of the fact that us setting very high and arbitrary standards for the amount of trauma it should take for someone to be sick as a result, we've been able to broaden that disease definition. But of course, what happens when you broaden disease definition, you get more overlap between those definitions at the intersections. And it is that overlap that in part gives us such high confidence -- there's obviously a deep historical research with LSD that provided us the confidence to start this project in the first place. But the accumulated evidence that we see -- and I'll say at a somewhat more subtle level, the sort of change that people experience in our studies, and you saw a patient describing that isn't one of a specific symptom got reduced, right? When you treat someone with an SRI or an SGA, a second-generation antipsychotic, the experience is one of suppression. I feel less of X. Now if X symptom was very disturbing to someone feeling less of it, of course, is a good thing. People tend to also feel less of everything. And Brittany talked about emotional blunting before, which is absolutely something we see with suppressive treatments. But it's the description of life feeling different. that gives us such broad transdiagnostic confidence. And that speaks to the why as well, which is that though there is a 50% to 70% overlap between GAD, MDD and PTSD regardless of the source of the trauma, we really thought it was important to get out there and work on true claims in PTSD for those folks who aren't sitting at the intersection or for the folks who understand their PTSD to be the primary source of their distress so that clinicians and patients can have confidence in treating that diagnosis as the primary diagnosis as well if we're able to be approved in the indication.

All right. I'm going to give one to Matt. Can you talk about the SPRAVATO learnings and how that might impact commercial strategy as we progress?

Sure. I mean there's a lot to learn from different surrogates and esketamine is no different. Certainly, having clear road maps for what to expect for clinicians, the reimbursement pathways, et cetera, are really important. Having that hub model in place will be very important at launch to reduce any friction. There's a lot of friction early in the process with esketamine. And so that's a key learning. There's a lot of good that has come out of the surrogate. And so we also are leveraging that the experience that payers have had with esketamine Reimbursement pathways that have emerged give us some confidence. For instance, pursuing a permanent J-code post FDA approval is one of those. J&J received their permanent J-code in January. That's an encouraging development for us as well. And so these are things that clearly, we leverage. We leverage the best of all worlds and ketamine is just one of them. But certainly, we have learned from what they've done extraordinarily well and some things that we believe that we can improve on when we go to market.

I'm going to overlay one other thing, which is more philosophical. But when... A trap that has so often fallen into is being reactive to a world that does exist without realizing the world can and wants to change. And whether you talk to patients or providers or anyone who is involved in actually getting drugs to patients, the need is there, the desire is there, the mechanisms are there to actually make a different future possible. When that is the case, it is a mistake to simply look at the world today and say, we must fit into that box. If that was all we could do, we would be left in the current state, we would never improve. And the philosophical learning, and I think this is where we've seen a correction happen that has put us in this world today where we see all of a sudden a rapid expansion of centers and volume and everything with SPRAVATO is a new world coming into being, right? When SPRAVATO first launched, the number of clinics that exist today didn't that drug was not positioned to be in the market that it is in today. And so while, yes, there are certainly things we will leverage and can leverage, not only from SPRATO, but from the recognition and embrace of the potential for treating psychiatric disorders, the way we approach these problems and the way we approach everything is to not be constrained by what has been, but to see into the future of what we think is possible and what we can invest in to make that happen.

All right. The next question is a little bit more color on the Panorama sample size reestimation. And so looking at the updated end of 200, could you talk a little bit about your thoughts in terms of the nuisance parameters? And if any of them were to worsen a little bit, how you look at the evaluable end for Panorama?

Well, one important feature, and Dan certainly can add some commentary is that while we, of course, in the conduct of studies, there's always a sort of temporal mismatch between when you have learnings and when you can react to those things, right? As I said, the new target is 200. We've already exceeded that target. And so we've stopped screening patients, but have a number of patients already there, too. So we'll even accrue further patients, we would expect as we get to the end of enrollment over the coming weeks. So the numbers we show, of course, will vary almost certainly, right? The things that you learn halfway through a study are never -- or very rarely the exact same. But we've gotten to a point of enough evidence. And why we do the sample reestimations is when we do is that the learnings we've had to that point gives us reasonable confidence that we're in the right area. The other thing is that the way the temporary estimation, of course, is a blended model of all of the patients. And so there will almost certainly be variances have lower distance parameters as well, right? When you unpull the data, you get rid of the variance is explained by the intergroup differences. And while that typically isn't significant, it does tend to drop the individual group and then the unblinded pool variance that you see at the end of the day. And so there will be undoubtedly some degree of wobble, but we feel quite confident. I think the thing that -- again, somewhat philosophically how we approach research, sizing studies and doing studies that are statistically significant but are clinically meaningless is in no one's best interest. It's a bad use of capital. It's a bad use of researchers and everyone's time because really, if we're not going to have something that is meaningfully different that can actually be beneficial, showing that a 1-point separation was statistically positive doesn't mean a whole heck of a lot. And so we've sized these studies and where we are today, where we expect to be in enrollment across all the studies we're conducting give us a high degree of confidence, right, really a lot of comfort that even if we see -- if we just see a clinically meaningful result that it should translate into statistical... I don't know if you want to add.

I think the only -- we're like switching roles today, and you're being philosophical, and I'm going to talk about numbers for a second. The 200 was a protocol-specified edge of what that analysis could lead to. So we didn't -- we're not like cutting to the bone here and risking statistical significance. If there weren't that protocol-specified sort of minimum that we could have gone to, we could have gone quite a bit lower based on those nuisance parameters. So we're very confident that we're preserving not only the power to detect, as Rob says, maybe a clinically less significant result, but we are extraordinarily well powered to detect the clinically meaningful results that we anticipate in that study.

Okay. One more on EMERGE data. Can you expand on some of the secondary outcomes that you would anticipate putting out at top line?

Yes, absolutely. So like I said, other time points and clinical global impression is one of our prespecified secondaries. And so we will absolutely be able to show you multiple time points on both the MADRS and the CGI.

All right. I wanted to open it up for any questions in the audience. Andrew?

Andrew Tai from Jefferies. So in your Phase II paper in the anxiety study, I think we noticed that maybe 75% of your patients on the 100-microgram dose had comorbid depression, which I think justifies why you're pursuing MDD. So when EMERGE data reads out first, will you -- what percentage of those patients will have comorbid GAD for the investor community to have comfort or read across to read across to your Phase III studies?

I wasn't supposed to give it away.

So we will certainly provide you data on comorbid diagnoses. I think the really critical thing to understand about comorbidity in these studies is that we needed to define 2 separate patient populations, right? So that from a regulatory -- everybody knows about the overlap, that's no mystery. From a regulatory perspective, it is really important to have distinctive populations. And historically, for MDD studies, and certainly this is the current standard as well, you're treating people in a current major depressive episode, right? To do an MDD study of people with a history of -- right, once you have a major depressive episode, you have MDD. And so to treat people with historical depressive episodes, not in a current episode wouldn't make a ton of sense. Similarly, in the GAD study, to treat people in a major depressive episode doesn't make sense, right? When someone is actually in a major depressive episode, that becomes the primary diagnosis. So in the major depressive disorder studies, people are definitionally in a current major depressive episode. In the GAD studies, regardless of history, they are not. And we'll provide data on comorbidity. But epidemiologically, based both on the construct of the disorders and just what we know from epidemiological studies of overlap, we expect to find a 50% plus level of comorbidity. All that said, the conversation with the agency, right, these protocols all go to the agency. So they know how we're defining these populations, and we have buy-in on the definitions of the population.

Okay. More questions. Paul if I I was going to say, Paul.

Paul from Stifel. Kind of a question on the same tune of comorbidity. When we've talked to clinicians who use PRAVATO today, they often treat patients who are more complex on average and most of the GAD patients tend to also have depression. So if you get a label for depression, how do you think about that changing the forecast of the drug within that population, given that they're already sort of, I guess, incorporated in the GAD forecast? And then separately, commercially, do you think there's a way you can change the referral pattern to get some of these, I guess, GAD only is more of an oversimplification, but like primary GAD patients that are in a PCP practice or somewhere else to actually get to treat -- get to go to one of these centers?

So as it relates to the comorbid patients as part of our forecast, that's accounted for. We certainly see overlap. The overlap is over 50% per prevalence, but what we see in the actual claims data is somewhere around 35% to 40%. So we do account for that. And as we think about the type of patient that is going to be a hand raiser early, they are the more complex patient. They are likely more comorbid with these 2 conditions. So that's a patient population that we feel will be in our sweet spot initially in our beachhead. As it relates to the referral patterns from PCPs, our targeting model, our beachhead strategy is really focused where the patients are today. And that is a purposefully designed approach. Our top 5 deciles, we're going to get to 50% of the patients. They have been prioritized by, again, those physicians that are most likely to prescribe and those patients that are in the highest volume in those practices that have these comorbidities as you described and also fail through multiple therapeutics. That's where we start. Certainly, downstream, we can examine additional opportunities to drive referral patterns and to help these patients that are struggling in primary care get to a psychiatrist specialist to help them get access to this treatment.

And I might just add that for patients, the sort of, let's say, community patients who never had a major depressive episode, just anxious, we not had a lot to offer them. Talking about Cymbalta is the last time anyone even got a label and Cymbalta was not aggressively marketed for anxiety. And so the last time we're talking almost 20 years, it will be 20 years since we really had a pharmacological intervention to offer these folks. Meanwhile, you can't read about benzodiazepines without reading about their harms in both the context of the overdose epidemic and increasing sort of accumulating evidence for the risks of long-term benzo use. So in essence, nothing new brought to them and being barged with the message that the thing that might make you feel better at least transiently is really bad for you. So while we obviously need to target the launch somewhat narrowly, we can very reasonably expect that for these anxiety patients who've had nothing new in a really long time, there will just be such.

All right. I'm going to go to Gavin.

I'm going to stand up so you guys can see me.

All right. Thanks for putting on the session. This is really great. On the end of session tech list and the discharge period, what do you think you need to demonstrate in the Phase IIIs for the 5- to 8-hour monitoring period to be viable? Like there's probably not a hard cutoff, but hypothetically, if 0% of patients are ready for discharge at 5 hours versus 70% at 5 hours, that could theoretically be a different regulatory scenario. So I'm curious how you guys are thinking about that.

Yes. I think it's exactly the point. There's not necessarily a bright line. When we're talking about drug labels and REMS, which are, of course, an extension of the label are intended to set the minimum conditions for safe and effective use of a drug, requiring physicians and requiring patients to sit around for maybe minutes, but certainly hours after the effects of a drug have resolved is not a thing we have seen happen in drug labeling ever. We have -- we talk about volatile anesthetics, people lose consciousness from life support effectively, cut open tie back together and thin out the door as soon as they can know who they are, where they are and they can ambulate out the door. That sort of framework exists in medicine today. And so while there is not certainly a bright line, we need to build evidence to show the magnitude of patients and what that additional burden would be, right? If a drug label were to say that everyone has to stay in a clinical setting for much hours past when the symptoms are resolved, an undue unnecessary burden being put on both patients, providers and our health care system to pay for people to sit around for no benefit. And so we're, of course, going to be looking at every which way, the number of patients that are cleared at a certain point of time. And if it so happens that no one is clear to go at hour 5 or 6, then we'll tell you that, and that's the world we will live in. And I think what we've seen both from our sites and from providers and all of our research is that there's -- we heard it 10 hours for concentrated TMS. It's not a problem, right? We're going to be able to work with wherever we land with this, particularly in a setting where patients can come from much further because they're not required to come in once a week or once a month, hopefully, right? But at the end of the day, if we see a majority of patients are clear to go at a particular point in time, it's hard to argue that, that isn't a pretty clear compelling set of evidence to say, yes, beyond that, there's going to be some individuals who need more monitoring, but not on average, not for your average patient is going to walk in the door.

That's fair. And are you planning to show this data with the top line results also? Absolutely.

All right. I so apologize. We are at time, but we will be available over lunch for additional questions. And I just wanted to turn it over to Rob for some closing remarks.

Yes. I just want to thank again, everyone, for being here today. And many of you have, as I said at the outset, have both spent your time with us and supported and been a part of this. And no matter who it is and what role we're all playing in this, the ability to actually make a difference is a remarkable responsibility and something we take incredibly seriously in terms of how we operate, what we do and what we aspire to do. So thank you for being here today. Thank you for being a part of this as we go forward. And coming up in a few months here, we'll have some hopefully really exciting data set to be sharing with everybody. Thank you.