Good morning, welcome to MindMed's Investor Day. I'd like to thank you for joining us. I'm Maxim Jacobs, VP of Investor Relations and Corporate Communications for MindMed, and I'm joined by members of the management team and esteemed key opinion leaders across a number of areas. First, I'd like to remind you that during today's event, we will be making forward-looking statements and refer you to our safe harbor on slide number two of the presentation. Now I'd like to introduce Rob Barrow, CEO of MindMed, for opening remarks. Let's see if this. I think the microphone could work. Are we good? All right. Well, thanks, everyone, for being here today. It's a rare chance to see a bunch of faces we've seen on Zoom for the last several years in person, and hopefully, many others that we're unable to see in person, but they're joining us by the webcast today. We're really honored to have you all here and to be joined by several very important individuals who have been formative to how we think about our programs and can give a unique perspective, I think, on where we are going as a field and where we're going as an organization. All right, the agenda for today, I'll give some brief opening remarks, and I'll turn it over to the stars of the show, Dr. Maria Oquendo, Dr. David Feifel, and then Dr. Michael Kobernick and Chad Shear, who will give us various aspects of the important story, of how we're developing the psychedelic drug class and ultimately how our pipeline fits into the ultimate treatment scheme for patients with brain health disorders. Before we go on, I think it's really important. I like to think about the opportunity we have in front of us in a number of ways, but one that is particularly meaningful is the fact that we are doing something that is quite unique. That uniqueness, though, I think, can at times get blown out of proportion. We have a number of innovative treatments for brain disorders, for psychiatric disorders over the past several years that have gotten significant uptake, and we're leveraging all of those learnings and all of those recent success stories to really shepherd in a whole new modality of treatment for patients with disorders like generalized anxiety disorder, ADHD, and ultimately diseases that have no available treatments like autism spectrum disorder. Today, our focus is on our MM-120, or LSD tartrate program for generalized anxiety disorder, which is our furthest along clinical development program with important data coming out later this year. In addition, we have a clinical readout on our MM-120 program in ADHD, which is a low repeated administration model. One of the things that when we think about the landscape for using this drug class and for, you know, all the applications in brain health disorders, something that's particularly important for us is that we don't constrain to historical assumptions. We're not limited by how these drugs have been used in the past, and we like to think of maximizing the full potential of the psychedelic drug class in a number of use cases that could span both session-based administration models like we're pursuing in GAD, but also more sort of neurobiological use cases. LSD is the most potent serotonin agonist that we've ever invented, that we know of, that we've ever studied, and we're exploring other innovative ways of using the molecule and using its pharmacology in a variety of indications. What gets us so excited about the opportunity here, as a drug developer, particularly as a drug developer working on CNS disorders, often we don't even know if drugs get into the brain. I think we can all safely assume and have enough data to know that a high enough dose of LSD does indeed get into the brain and has some active pharmacology. Historical studies, and there have been dozens and dozens of studies of LSD in the past, including modern studies, but historical studies have shown really three critical things. One is that there's a rapid reduction in clinical response. When we look at diseases like depression and anxiety, we see a clinical response about as early as we can measure it. Of course, there's the on drug, acute pharmacological effects of LSD that are quite perceptible to the individual who's been administered the drug. Also important is the rapid and durable clinical benefit, something that's really going to be important to define. I mentioned some of the more innovative treatments that are being used in psychiatry today, ketamine, SPRAVATO, for instance. While there is a shorter window of sort of on-drug perceptual effects, the window for clinical benefit is much shorter as well. When we start talking about the ultimate use in the real world, I think it's really important to remember that a longer duration of action that translates into a more durable clinical benefit would be a huge win for both providers and for patients. Importantly, in the drug class, of the entire drug class, LSD is the most storied, the most studied molecule out there. We, we hear a lot about a variety of molecules that are in clinical development today. There's certainly been a huge influx of interest in the field and companies over the past several years that have been formed. When we look at the history, even compared to drugs like psilocybin, LSD has been far better characterized, studied much more extensively for a much longer period of time. Ultimately, it was, I think, amazingly born out of Sandoz and research outside of psychiatry entirely. It takes us to where we are today and the backdrop, and I won't steal Dr. Oquendo's thunder here, you know, the landscape in which we are developing our program, developing MM-120, is unfortunately very dire for patients. We've seen no real innovation in anxiety disorders in decades now. We've seen now a growth in both the expenses, but also a growth in the diagnoses. Really over the course of time, when we think about anxiety disorders versus other psychiatric disorders like depression, there's been a significant drift away from anxiety that seems to be coming back into focus. Today, CNS sales are on the rise. It's one of the highest growing therapeutic areas. We also see it's the drug class is dominated by antidepressants, drugs that have been around in many cases for many decades, and even some of the more modern antidepressants, the SSRIs and SNRIs, that have very similar activity to these older drugs. Why is that important? I mean, certainly, it creates a commercial dynamic where a lot of these drugs are genericized, but I think it's also. We can't overlook the fact that the market opportunity may be even more expansive than what we see in the data, simply because we have classes of genericized drugs that are not particularly effective in all the patients, at least. We have a new opportunity to come into that market and bring in treatments that could be more effective, more durable, more rapid acting. It really unlocks the full potential of the drug, but also the full potential of the market and the need for benefit for these patients. We'll certainly listen to Dr. Kobernick talk about how payers think about bringing innovative treatments forward that could have that kind of dynamic. I also think it's really important that with the advent of antidepressants, we know that as Prozac and Zoloft really started to get uptake, there was a fairly substantial diagnostic drift away from anxiety and what we talked about. Historically, decades ago, as the nerves, right, there's a common vernacular around anxiety being this fundamental core feature of psychiatric disorder and neurotic illness. The diagnostic drift to depression really left anxiety by the wayside. We've all seen the commercials in the 1990s and 2000s of, you know, you have a chemical imbalance in your brain, and that's why you have depression, and take Zoloft, and it will cure it. Obviously, antidepressants have benefited many, many people, but in many instances, and we know this from broad long-term studies, that they aren't good enough. They aren't good enough. One of the core features, one of the core characteristics of psychiatric disorders that is less well treated by the antidepressants, is anxiety. We think this is a really unique opportunity to be launching and progressing, and pursuing an indication that has been largely overlooked. In recent times, with the growth of anxiety, and particularly acutely through the pandemic, we saw a massive flood of individuals reporting increased anxiety levels, certainly increased levels of depression. As we went through a global pandemic, this sort of underlying core feature of anxiety came to the front of many people's minds. In the last year, we've seen now the USPSTF recommend anxiety screening for all adults and for adolescents and children eight and above. Now we're entering into a world where the epidemiological data tells us that diagnoses are growing, this is a growing problem, that the focus is shifting towards anxiety, and we have a treatment that has now been studied for decades with extraordinary promise, that we now have a chance to push through, deliver important clinical data later this year, and ultimately seek a label that would, hopefully, you know, if we're successful in our development program, will one day be available to these patients and help what we think of as sort of trajectory altering, perhaps, for these patients. Obviously, in psychiatry, we don't so much talk about disease-modifying as we would in other therapeutic areas, but given the durability for many patients, we think that's a really unique opportunity that we wouldn't just be sort of masking symptoms chronically, but we would rather offer a sort of transformative treatment option that could take patients acutely and long-term into better outcomes. All of these dynamics are also a function of or also play out in the reality that the GAD pipeline is less crowded than the MDD pipeline. Obviously, there's a significant overlap in terms of depression, anxiety, diagnoses. When we look at the diagnostic criteria for anxiety, depression, we internally look at it as something like an 80% overlap in symptomatology. There certainly is crossover in the use of antidepressants that are both approved for MDD and GAD, but also off-label use for other treatments that are used regularly in GAD. We've also seen more and more data that points us into the reality that GAD is an overlooked and underserved treatment indication. Given the relative lack of certainly new treatments, but the relative lack of treatments in general that are approved for generalized anxiety disorder, again, we think our opportunity with MM-120 really represents a sea change that we'll be shepherding in over the next several years. As I mentioned before, LSD, it often gets lost, I think, on the reality of what the incredible opportunity we have in front of us. I don't think many people 10 years ago thought we would have numerous companies developing psychedelics that are getting close to phase III clinical trials and ultimately moving towards approvals. LSD is one of again, the most storied, and in some ways, the more stigmatized of the classic psychedelics. I've had the opportunity to speak and work with several of the leading researchers, and I think one of the things I was always struck by is that the choice of the flood of investigator-initiated trials for psilocybin over the past several years was not so much scientific as it was a political decision. It was a decision that, you know, psilocybin was less well known, and there was easier opportunity to bring it forward. Given what we know about LSD, given its potency, given the opportunity we have to use it again in a clinical setting, and the fact that we're also learning from years and years of compassionate use. We have a strong research collaboration with a group in Switzerland that has been using LSD regularly. They've also been using psilocybin, and in many instances, we hear from these providers that they prefer LSD, that in some cases, patients in their opinion, benefit better from a longer treatment session that gives a greater window of opportunity to have these sort of transformative insights and outcomes in their patients. When we've worked with those researchers over in Switzerland, again, extraordinary insights for why, in practice, in the real world today, in many instances, they're choosing LSD as the drug of choice when they're working with psychedelic treatment options. Where we are today? We announced about a month ago that we had exceeded 50% enrollment in our phase II-B trial. A little bit later on, I'll be sharing much more detail about that trial design and why we've approached the study the way we have. We are coming up on two important data readout study this year, our phase II-B study in generalized anxiety disorder, and our phase II proof-of-concept study of low repeated administration in ADHD, which is ongoing as well. Coming up on a critical period for us, when we look at that long history of LSD's using, I think it's an incredible opportunity, and we are very excited about the data we will be generating later this year, and ultimately bringing LSD back to the front of the pack where we believe it rightfully belongs. Lastly, certainly not least, is our intellectual property strategy and perspective, and apologies for the technical issue on the image here. One of the really important things for us is that as a pharmaceutical company, we have to protect our innovations. We have to have a strategy for how we will block generic entrants, how we will make sure we maintain market exclusivity over a reasonable period of time. There are well-trodden paths to do this. Certainly, we do not have an NCE patent. We don't have a composition of matter patent on LSD. It was discovered in the 1930s. No one could have such a patent. What we have done are make important improvements at every step of the process, we believe. We've made improvements in terms of synthetic pathways, in terms of the stability of the drug, in terms of differentiated drug products that we ultimately would seek to take forward into the pivotal trials and ultimate approval that we believe would have a differentiated profile in humans and will give us a unique opportunity to also block generics and have a longer exclusivity window. Chad, later in the day, will talk much more extensively about IP strategy and considerations. At least to say at the front here, IP is at the core of everything we do. Every R&D decision we make is informed, at least in part, and often as the first part of the conversation, is how can we be thoughtful about protecting our market and make sure that we can responsibly deliver these therapies for years to come. With that, I will turn it over to Dr. Maria Oquendo, who is the Ruth Meltzer Professor and Chairman of the Psychiatry Department at the University of Pennsylvania. She's also the Psychiatrist in Chief at the Hospital of the University of Pennsylvania, past president of the APA. I could go on, but she has an incredibly impressive background. We're very honored to have Dr. Oquendo here today. Thank you so much. Thank you very much. Good morning, everyone. It's a pleasure to be here, and I look forward to sharing some information with you, and happy to chat later or take some questions. Let me just give you a little bit of historical perspective. You just heard a tad about this, but generalized anxiety disorder was coined as a term in 1980. Before that, this syndrome or constellation of symptoms was known as anxiety neurosis. In the 1980s, in fact, when it first arrived on the scene, many clinicians considered that generalized anxiety disorder was simply a precursor to major depression, and that individuals who presented with this condition would go on to develop major depressive disorder. They were kind of right, but not exactly, because we know today that this disorder can persist over many years, and in fact, we also know that it's very often comorbid. The clinicians were observing the co-occurrence of these two disorders and thinking of them as being steps in a trajectory, which is now known not to be the case. It's actually pretty common. About 2.9%, almost 3% of the population will have generalized anxiety disorder in a one-year period. That translates into about... It says 7.5, but really, it's about 11 million people, since we have 360 million people in the country, more or less. If you look at lifetime prevalence, about 6% of the population will have generalized anxiety disorder at some point in their life. In terms of what it is, it's a constellation of symptoms. You have to have three of a set, series of symptoms, including things like insomnia, muscle tension, restlessness, and irritability, very important. One of the things that's critical to making the diagnosis is that you have to have some impairment, either social or in terms of work. Importantly, individuals are oftentimes quite impaired in terms of work, and estimates suggest that between four or five days per month of work are missed by individuals who have generalized anxiety disorder. It has a huge impact, not only on the individual's life, but on the economy and on society in general. The other thing that I would say is that most first-line treatments are with either selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors. One thing that I always find interesting as a pharmacologist is that the FDA has approved a couple of drugs in both of these categories, but clinicians on the ground really extrapolate from that and then will prescribe all sorts of SSRIs and, you know, all of the SNRIs for this indication. The other thing is that about half of individuals who are treated do not respond to that first treatment. I should add that only about 60% of people who have generalized anxiety disorder will ever receive any kind of treatment. There are other choices in addition to SSRIs and SNRIs, and they include things like benzodiazepines and medications that have other serotonergic effects, like buspirone, and also not in this country, because it's not approved, but sort of drugs that are melatonin agonists, such as agomelatine, also can be useful in the treatment of generalized anxiety disorder. Of course, as the illness is more severe, the impairment from the illness is more pronounced. I already mentioned to you that people have significant trouble in terms of work and missed days at work, and that, of course, doesn't even take into account the issue of presenteeism, right? When people show up at work but really are performing suboptimally. It also worsens a multitude of physical conditions, such as cardiovascular conditions, gastrointestinal conditions, migraine, and many other conditions. It has an impact also on the physical health of the individual. I alluded to the fact that it's a diverse condition because you can have a subset of a larger number of symptoms, and so the combinations of those symptoms result in tens of different types of presentation. It's not a one-size-fits-all. That also means that there are different approaches to treatment that may be considered. For example, I also mentioned already that it's comorbid with depression very often. It's also comorbid with post-traumatic stress disorder very often and with substance use disorders, especially alcohol and benzodiazepine use disorder. One of the things that clinicians think about when they're selecting a treatment is what are the other comorbid considerations? If you have a patient who has a risk for substance use disorder, you're definitely going to avoid using benzodiazepines, which are highly addictive, especially in individuals who have high anxiety, or if they have depression, you might select something that also targets the depression. I already mentioned that about 50% of individuals who are treated with a pharmacologic intervention will fail this pharmacologic intervention. All medications have side effects, and SSRIs are relatively well-tolerated, but there are no exceptions, and there are some side effects that really make it difficult for people to stay on them, especially the sexual side effects. There aren't really great treatment guidelines for generalized anxiety disorders, but the first-line treatment in general, as I've already mentioned, are SSRIs and SNRIs, serotonin and norepinephrine reuptake inhibitors. Again, it makes sense to choose these types of drugs because they're also very effective for major depression. It is sometimes the case that individual clinicians will add a benzodiazepine early on to SSRI treatment. Individuals who have anxiety oftentimes have an initial increase in agitation and anxiety when first exposed to the SSRI, and the medications are typically started at very low doses with a slow titration up to improve the chances that the person will be able to tolerate taking the medication. As you can imagine, if the patient experiences an increase in anxiety at the beginning of the treatment, that does not predispose them kindly to staying on the treatment. In terms of second line, if a patient does not respond to the first medication, oftentimes clinicians will switch to a different SSRI or a different SNRI or switch between the two. Pregabalin is another option, marketed as Lyrica. It is a calcium channel blocker that can be effective against generalized anxiety disorder but also has some significant side effects, also in terms of agitation and initial somnolence. In terms of third-line treatments, buspirone, which I mentioned earlier, a serotonin 1A agonist, can be very useful for generalized anxiety disorder. Most individual clinicians will not prescribe benzodiazepine as a standing medication because of the propensity for addiction in individuals with anxiety. Antipsychotic medications have been used. Perhaps the most commonly used one is ziprasidone. These medications have significant side effects that make them difficult to use, especially metabolic syndrome, which you may know includes increase in weight, very significant increase in weight. It's not unlikely, uncommon for individuals to gain between 20 and 40 pounds on these medications. Also increased cholesterol and increased waist girth. Very difficult. Although the bullet says that patients would be considered treatment-resistant after four failures, I would say that most clinicians consider two failures an indication that this is a treatment-resistant individual. This is just a bit of a summary. I already mentioned that these, the SSRIs and SNRIs are the most commonly used, and their... The approvals for generalized anxiety disorders include paroxetine and escitalopram, as well as duloxetine and venlafaxine- ved for treatment, and it does take quite a while to take effect, as do the antidepressants, the SSRIs and the SNRIs, and tends not to be a go-to drug for this condition. Most individuals, clinicians will not select a tricyclic antidepressant. They also have very significant side effects, including cardiac arrhythmias, and importantly, if taken in overdose, can be lethal. I would say that it would be exceedingly rare for a clinician to use a monoamine oxidase inhibitor for this condition. Also, very dangerous in overdose, lots of interactions with other drugs and with food, which can be fatal. I mentioned already the GABAergic drugs such as pregabalin, which is a calcium channel blocker and has downstream effects on both GABA and glutamate. The antipsychotics are kind of a last resort because of their significant side effects. I didn't mention tardive dyskinesia and other movement disorders that can occur with their long-term use. We definitely have some opportunities in this space in terms of finding other medications that can be useful. Some of the early data suggests that there can be rapid and pretty durable effects of psychedelics. Because they don't have to be taken on an ongoing basis, necessarily, the concern for safety issues is diminished by that. Also, one of the most difficult things about treating any condition, if you're a clinician, you know, is getting the patient to take the medication. The fact that these are often taken, not frequently and also under supervision, increases the likelihood of compliance. With that, I'll stop, and if people have questions, happy to answer any. I don't know if we have time. We probably don't have time. Okay, thank you. Thank you, Dr. Oquendo. Just to let everyone know, after the next speaker, we will have a Q&A session for you to be able to get in some questions. Our next speaker is going to be Dr. David Feifel from the Kadima Neuropsychiatry Institute, and he'll talk about some of the practical aspects of modern therapies. He'll be joining us remotely from the West Coast at a very early time. Good morning, everybody. I hope everyone can hear me. Sorry I couldn't be there in person with you. I'm glad to be able to participate in this exciting event today and tell you a little bit about the practical aspects of incorporating innovative treatments like psychedelics into the armamentarium of a typical psychiatrist. A little bit about me. Rob Barrow wanted me to share a little bit about my journey. I started my career as an academic psychiatrist at the University of California, San Diego. My biggest focus really was trying to develop innovative treatments. You know, I decided to become a psychiatrist because I really felt that during my career-[audio distortion] While Dr. Feifel is getting set up here, I'll sit down as soon as he's... Hello, can you guys hear me? There we are. Can everyone hear me? I'm not sure, because I had started, and Rob, it sounded like maybe I wasn't coming through. Alyssa, if you could let me know if I'm coming through now. Okay, great. All right. Well, I'm just gonna start all over. Hello, everybody. I'm Dr. David Feifel. Sorry, I couldn't be there in person with you. I'm over on the left coast here in San Diego, California. I wanted to talk to you today about some of the practical aspects of incorporating an innovative treatment like... I guess my video isn't on. Let me see. It says, You cannot start your video because the host has stopped it. I don't know if that, if that makes a difference or not, but if anyone can permit my video. Anyway, I wanted to just tell you a little bit about the sort of practical aspects of incorporating novel innovative treatments like psychedelics into the sort of armamentarium of the typical psychiatrist. Rob Barrow wanted me to share some of my... It says, "Please open your camera." Well, I'm trying to, by the way, Alyssa, I'm getting a little chat, says, "You cannot start your video because the host has stopped it." That's on you guys. Haha. I'll keep going until I get a little message that I've been enabled to start my video. In any case, Rob Barrow wanted me to share a little bit about my journey. I just wanted to say that I went into the field of psychiatry largely because I really felt that it was going to be a golden era during my career, that because in neuroscience, advances were accelerating in such an amazing way. We were, you know, we were developing, you know, ways to image the brain non-invasively, and just really it heralded, you know, was very auspicious for new treatments. I thought, this is going to be... Psychiatry is going to have a golden era, you know, much like some of the other fields like, you know, thoracic and cardiovascular surgery in the sixties, when they had heart transplants. I just wanted to be part of that. I was really interested in research and also in clinical work. I came out to UC San Diego, do my residency and began an academic career, ran a research lab, where I was looking at animal models of psychiatric illnesses and also trying to, you know, do research in humans to develop novel treatments. About midway through my career, I really had this terrible sinking feeling, that maybe I was wrong about the golden era in psychiatry, because essentially I was still using the same treatments, some of which the previous speaker had mentioned, same treatments that were developed, you know, in the 1960s, and the original antidepressants and anti-anxiety patient medications. It was very disheartening because, while they do help some people, they really fall short for very many people. As everyone, I'm sure knows, mental illness is just an incredible scourge on society, and the prevalence is doing nothing but growing. Certainly recently, COVID has definitely sort of add gasoline to that fire. You know, there I was, mid-career, thinking, well, you know, I might have missed the boat on this because really nothing is coming down the road. In fact, I just want to tell you that about almost a decade ago, in 2013, there was a very well-known op-ed, at least well known in our field, in the New York Times by a prominent psychiatrist by named Richard Friedman. In August 19, 2013, he wrote an op-ed that was titled A Dry Pipeline for Psychiatric Drugs. He starts off by saying, "Fully one in five Americans take at least one psychiatric medication. Yet when it comes to mental health, we are facing a crisis in drug innovation." He goes on to say that essentially all the drugs that we're using today are really me-too versions of the drugs that were developed, you know, you know, decades ago, at the beginning of the psychopharmacological revolution. I remember that op-ed and the gloominess of that era very well. I remember sort of the alarmist kind of talk at conferences, because actually, pharmaceutical companies... There I am. Pharmaceutical companies actually were pulling out of CNS R&D because they just could not develop anything innovative. It felt like we were on a ship in the middle of the Atlantic, no tailwind at all. We were just stuck. It's interesting how things have changed. I'm going to talk a little bit about that. You know, I started to see some things, exciting things happening around 2006, 2008, when some papers, small papers came out, describing incredible effects of an old drug called ketamine, which was developed in the late sixties and early seventies as an anesthetic, being repurposed for depression. The results were just amazing. You know, occasions of ketamine were producing rapid and robust improvements in major depression. Since then, you know, it's been extended to other things like anxiety and so forth. There was also an approval of a very innovative treatment called transcranial magnetic stimulation, which really a lot of people didn't think was gonna pan out to be much, but I thought that this could really be revolutionary since it's a non-invasive way of stimulating the brain and treating things like major depression. Next slide, please. In any case, I left UCSD in around six years ago because I felt that these treatments were so exciting, and the reality was being an academic environment was very limiting in terms of, you know, trying to be, you know, nimble and, you know, highly innovative, which might come as a surprise to some people. You know, I was, I had, I founded the very first ketamine infusion program in the real world, you know, taking those the research that had been done in a few centers. I was seeing remarkable results. Then was one of the first in the country to start providing TMS therapy. I felt that I needed to leave academia to be able to really kind of fully take advantage of what I felt finally, at long last, was possibly a revolution in psychiatry. Another big motivation was watching the landscape with psychedelics coming down the road, being, you know, starting to be sort of rejuvenated or resurrected from their sort of their relegation to kind of Schedule I taboo. I felt that this was really going to be the tsunami that finally was going to push psychiatry, you know, over the top into sort of this modern era where we had really effective treatment. In 2017, I left, and I started a private institute called Kadima Neuropsychiatry, where we provide ketamine treatments. We do transcranial magnetic stimulation. We participate in a lot of research with collaborators trying to develop these treatments, improve them, but also develop new ones in the pipeline, like the LSD compound we're talking about today, and psilocybin formulations, et cetera. Next slide, please. I wanted to tell you a little bit about sort of how we run our ketamine program, because I think, doing this over the last 15 years has helped me really kind of develop a kind of highly efficient, high throughput protocol for doing this. All our patients start with an initial consultation, which is usually done by me to see if they're appropriate and for which treatment they might best fit. We're going to talk about TMS a little bit. We have really good coverage for insurance coverage for TMS. ketamine remains an out-of-pocket cash treatment, unfortunately, because it's not FDA approved for the indication of any psychiatric indication. Insurance companies tend not to want to pay for things that don't have the imprimatur of the FDA. After a consultation, if the patient is appropriate for ketamine, we start them off with a series of six treatments over three weeks. Then, adjust the dose, gauge their response, and eventually we will, if they're doing well, we'll move from this induction phase to the, we call maintenance phase, where they're needing to come in every several weeks, typically for booster shots to maintain the benefit. That is probably the biggest limitation of ketamine, is that it's its durability. The fact that it, its efficacy can be quite good, but its durability is quite limited, and oftentimes it only lasts a matter of days or a few weeks for patients. If they want to continue their benefit, they need to come in, again and again, because again, it's, not covered by insurance. This is probably the biggest single limitation for reaching the large percentage of the population that really could benefit from ketamine. Nevertheless, next slide, please. Nevertheless, we are providing about 75 ketamine treatments a day. I wanted to show you this picture. This is sort of our setup. It's a little bit dated. Our decor is better now, but this is basically the setup. We have five treatment rooms, sort of in a semicircle. The patients are monitored by through CCTV, and we have wireless blood pressure devices that give us allow us to monitor the patient's vitals without intruding on them, because, you know, they really don't like to be disturbed. They're experiencing this psychedelic-like experience. Ketamine, although you might not have heard of it as a psychedelic, or if you've heard of it, you've heard of it as an anesthetic. At the sub-anesthetic doses, it does produce a psychedelic experience. These patients are having psychedelic experiences, often referred to as dissociative experience, because ketamine tends to kind of dissociate people's thoughts from the feeling of being in a body. Nevertheless, we typically have five simultaneous treatments going on with nurses and a doctor ready and available to intervene. Doing it this way, we're able to treat about 70 - 80 patients a week. Treatments are relatively short, I think, as Rob alluded to. The trip, for lack of a better term, the duration is about anywhere from 45 minutes to an hour and a half. Next slide, please. Now, I wanted to give you a couple examples of innovative treatments over the last few years that have been widely adopted in psychiatry. I know a lot of you are probably thinking, you know, if psychedelics are such a different type of treatment than traditional treatments in medicine and psychiatry specifically, you know, how, you know, how, you know, how is this going to kind of, you know, be applied in the real world? Trying to take advantage of this ketamine revolution, in 2019, Janssen was able to get a ketamine-like treatment called SPRAVATO approved by the FDA. It is actually S-ketamine. It's the enantiomer of one of the enantiomers, or one of the components of ketamine, but administered in a nasal spray. The two features, the S-ketamine versus ketamine, and the nasal spray versus IV infusion or intramuscular injection, which is the typical way ketamine is delivered, allowed I think some innovation that allowed us the approval of a patent for SPRAVATO. Because of that, Janssen felt that they could from a business point of view, go ahead and develop this drug. Got it approved in 2019, initially it fell flat because there really wasn't the appropriate codes for billing this nasal spray that patients actually self-administer. I mean, they don't actually get to be in possession of the spray. They need to come into our clinic, but where they are given the spray, they're monitored as they administer it nasally. They take, you know, they put it in their nose and take puffs. They're required to be monitored for two hours according to the FDA regulations, before being discharged, and they can't drive. Initially, this was very kind of unprecedented, you know, a nasal spray that needed to be done in the presence of a monitored environment, and then watching the patient for two hours. It was very unusual. Within a short time, because there was such a need for treatments like this, especially something that was covered by insurance, unlike ketamine, within a short period of time, codes were developed and insurance companies put out rates for these codes. Today there's a very robust business of SPRAVATO, I would say. It probably accounts for close to a third of all of our all of those treatments that I mentioned, that we administer in a week. That's a good example of something that really had no precedent in the field before, but now has become quite routine, increasingly routine. I should also mention, because I think it's an interesting model for psychedelics, I should also mention that the... In order to administer SPRAVATO, sites have to be certified and trained by Janssen. you know, I think this is probably going to be the model for psychedelics, at least initially, because they require distinct and somewhat specialized skill sets and trained personnel. whereas when I started doing SPRAVATO, it was one of maybe one or two providers, you know, in the San Diego, metropolitan San Diego area. The number of providers has grown, but also the number of patients seeking this out has grown as well, as sort of, the, you know, knowledge about this ketamine-like treatment that's covered by insurance has grown. I think that's a very useful sort of example. There's another example I want to tell you about. Next slide, please. Well, there's some data on sort of the evolution of SPRAVATO in 2019 today in terms of sales and so forth. It's been really a very remarkable and quick uptake. Once they figured out some required stumbling blocks, like those codes for this very unique treatment. Next slide, please. The other innovative treatment that entered psychiatry quite successfully was TMS, which stands for transcranial magnetic stimulation, and I have already mentioned it. It was approved in 2008. It's obviously a medical device. You can see a picture of our TMS device here. You see three helmets there. The middle helmet was approved initially by the FDA for treating depression. It is sort of a second generation TMS device. It was actually approved in 2013. It's called Deep TMS. It goes a little bit deeper than the original version of TMS. You can see now that there are two other helmets, and those helmets target different areas than the original helmet, or coil, as we refer to it. The yellow one on the right side is been FDA approved for OCD, and the one on the left targets yet a different area that's involved in addictions and is approved for smoking cessation, and we think will be approved for other addictions over time. Because it targets the same underlying circuits for addiction. Now, this is a very, very different type of treatment than historically the top therapies or the medications, or even the ketamine and SPRAVATO, because at least those are medications. This is a non-invasive device that stimulates parts of the brain, and then slowly, over time, will strengthen those areas. The practical logistics of TMS are very unique because patients come in every single day, at least Monday to Friday, for six weeks, and then there's a less frequent period of tapering down over three weeks. They actually come into the office. It doesn't actually require a physician to be present during the treatment, just available. That was kind of unique for those of us in the field, allowing us to do treatments and to actually be able to bill for treatments while not necessarily being, you know, physically face-to-face with the patient. I can tell you that in 2009, I think it was 2009, when I started doing this, even though it was FDA approved, there was no insurance that was covering this. It was quite expensive. You're coming into the office every day, and it was only out-of-pocket. It didn't take long till insurance companies started to write policies for that. Today, TMS is widely and extensively covered by both public and commercial insurance policies. In fact, insurance, you know, has made it easier and easier over the years to get this approved, I think, because they see that, you know, it's something that can help patients who fail to benefit from medications. It was hard to imagine, you know, when this device was first approved. In fact, when I went to my chair, chairman at UCSD, really pushing hard that we should get one of these new devices in 2008, that had just been approved, he scoffed at me. He thought, how can that, you know, how can this device that emits sort of magnets, you know, help anybody? It was just kind of the, it was hard to envision that this could be an important new treatment. I can say today that TMS is part of the consciousness of every psychiatrist, whether they actually do it themselves or just, you know, refer patients to psychiatrists like me, who provide it. It's an interesting model of something that sort of came out of left field, was totally not in line with the way we had been doing, you know, treatments up to that point, but in not too much time is, you know, widely accepted in the field, it's in all the guidelines, as even a potential first-line treatment, and has wide insurance coverage, and is actually very, you know, very profitable, or at least from the provider point of view. I think that the important message here is that while psychedelics may seem like they are very different than traditional medication treatments because of the, you know, the subjective effects. Next slide, please. Because of the subjective effects that they produce, the trip, because of the need to kind of monitor patients, have providers, you know, present, to be in, to be physically in a safe environment that's monitored for many, many hours. It seems like it's really, doesn't, you know, it's a square peg in a round hole. I can tell you that there are precedents in our field for very different treatments integrating very well. I think, the important thing is that there is such a strong unmet need, even with ketamine and TMS, because of their limitations, for something that can really make a dent in this scourge of mental illness. That, when there is a good treatment, that has been demonstrated to be efficacious and safe, the field accommodates because we need it. There's no way we can ignore a safe and efficacious treatment. By all accounts, psychedelics are going to, you know, gonna be the leader, in terms of, treatments that really, you know, make an impact, on patients. One of the things that we're looking forward to with psychedelics is being able to produce that dramatic ketamine-like improvement that's very quick, but with a much longer durability, because the initial data suggests that the durability of the therapeutic effect is much longer than ketamine, and that which is, of course, the limitation that I had alluded to before, main limitation with ketamine, making it otherwise be the really game changer for the field that it would otherwise probably be. With that, I will, I'll end my presentation. I think there might be a Q&A period opening up next. Thank you, everybody. Thank you, Dr. Feifel. We'll now begin a Q&A session. Please wait for a microphone before asking your question. Brian? Hi, thanks so much for the great presentations. Brian Abrahams from RBC Capital Markets. Maybe for Dr. Feifel, but maybe also for Dr. Oquendo as well. I'm curious if you could talk a little bit more about how you expect some of the practical considerations to be, I guess, both similar and different for a therapy that would have a longer duration of both monitoring in office time, but also of ultimate effect size? Just sort of wondering both in terms of staffing, as well as access and reimbursement, what the differences might be if, you know, with the centers geared up for treatment of multiple sessions in a short period of time, multiple short sessions versus pivoting to longer sessions, but less frequent delivery. Well, I'll jump in and say that, I mean, a lot of the patients that we see, weekly with ketamine, for example, are patients that are coming in for maintenance. At any given day, we have a mix of patients that are still in their initial phase, ramping up to get that optimal effect. Then also patients that have already had the effect established, but are coming in for, you know, for their boosters. Now, we anticipate that psychedelics require a lot less frequent boosters. You know, if we were to take a site like Kadima, what we would expect is those rooms would be sort of disproportionately utilized for new patients because patients would be returning a lot less frequently, needing that. I don't know if that sort of is addressing the question you were asking, but I think that's going to be. I think it's going to be very, very applicable, a setup like this. You might be thinking, well, you know, you're talking about now, you know, 8-12 hour sessions versus, you know, a one-hour session, how, you know, how is that going to be accommodated? Again, I think the big difference is that because patients aren't going to be needing that repeated dosing, and certainly not as frequently as right now with ketamine, that I think it's gonna be a relatively easy adjustment. Got it. Got it. No, that's really helpful. Maybe just one quick follow-up. Can you give us a sense of scale? How many centers are there out there that have this type of throughput, at least in the United States, and how quickly do you think your center and others could potentially pivot towards administration of a different therapy like LSD? I know, I, it's remarkable how many ketamine clinics, and you're probably aware of this, have sprung up. I think that, you know, a large proportion of them, you know, have the capability, if not of doing, you know, five simultaneous, certainly, you know, more than one patient at a time. I think that probably the biggest lack in terms of adopting psychedelics would be staff trained to monitor. You know, it's gonna, it's really gonna. We need to see exactly what the FDA, you know, REMS are going to be, because I think there's already a push towards, you know, minimizing that monitoring. We've seen some initial phase II studies going from two people in the room to one person in a room. We've seen a sort of a downgrade from two fully licensed therapists to one licensed therapist and one assistant who has a bachelor's degree with some experience in a mental health setting. As is the case, you know, with my MMED008 GAD study. The FDA is agreeable to this, it seems to me, as the safety is demonstrated at each phase to kind of lowering it. I think there's gonna be a... You asked about speed, I think initially, this is going to be a bit of a of a adjustment for a lot of the clinics, you know, getting people that especially at the licensed clinicians who have to go through the training associated to get them, kind of, hire them or get them, you know, affiliated with their sites. That might affect the initial ability of some of these sites to kind of adapt these this treatment and treatments like it. I think, over time, more and more of those sites will establish that, you know, that staffing ability, and also the requirements will continue to come down until we find that, like, that margin where this is adequate to keep people safe, but isn't sort of excessive. Great. Jonathan Aschoff? Thanks. Dr. Feifel, I want to ask you the median time that you typically have patients on ketamine, and what do you think you could improve with 120 for, you know, the median time until they drop the therapy for lack of efficacy? Median time before they drop the treatment because it doesn't work? Right. Well, I think that right now for ketamine. It's an interesting question. Right now for ketamine, you know, there's a sort of the de rigueur, you know, 6-eight treatments over, you know, 2-3 weeks. You know, at almost all the sites, there's an induction phase. You know, we, unless patients are having just a horrible sort of reaction to it and just don't want to continue, we at least, you know, we'll finish the six treatments before passing judgment. There is evidence that with ketamine, there's a cumulative efficacy, that multiple treatments stacked over a short period of time will convert more and more patients from non-responders to responders. I would say that everyone does six treatments, and at that point, if they don't have much efficacy, you know, we'll either recommend that they stop, or if they have a little bit of efficacy, we have some strategies that might convert them if they're willing to pursue that. Again, cost usually kind of plays a factor there. I think with these medications, with like, the psychedelics, it's a little bit harder to know because they probably, you know, there's individual variability. Depending on how the initial approval is, you know, if it's gonna be one administration, are there gonna be options for, you know, doing a second administration at a higher dose? Also what we do is adjust dose as during those six treatments, if patients aren't showing evidence of a benefit and they're tolerating it well. I think there will be. The median time probably will be lower because we expect, you know, I think, a more robust efficacy from these treatments. It's hard to know because we won't have the same flexibility like we do with off-label ketamine right now, to just, you know, bring them back very quickly, adjust the dose. That's a hard one for me to answer because I don't know the limitations I'm gonna be handed with the REMS, the restrictions given by the FDA. For example, with SPRAVATO, there's a set protocol. They need to come in two times a week for four weeks. After that, it drops down to one time a week or less. At that end of those four weeks, if patients haven't really had a good response, they're probably not gonna want to continue. We do go for those eight treatments because we do know that a lot of times it takes those eight treatments, and sometimes longer, but it takes those eight treatments for a lot of people to kind of experience the benefits, for the benefits to emerge. That's the protocol. We can't deviate from that. That's part of the label. I don't know what kind of label we're gonna get, but, you know, we expect to see greater rates of efficacy, and also we'll probably see less people dropping out because of a just untenable short duration, which we see with ketamine. They get great effects, but it's, gosh, it's, you know, it's only lasting me, you know, five days, and I can't come in every five days. Even if I could afford it, I can't really do this every five days. I'm sorry, that's a little trickier for me to predict. Okay, great. Thanks. Frank? Yep. Hey, Frank Brisebois with Oppenheimer. Thanks for the questions. I was just wondering, we talked about first line, second line, third line, fourth line therapy, and then, you know, treatment resistant. It seems like physicians kind of agree it might be after two lines. I'm just wondering, in the grand scheme of things, you're seeing developments with ketamine, you know, if LSD and psychedelics come to market, where would you kind of see it? Is it dependent on the patient? You know, any thoughts on the duration of treatment relationship to durability of effect? Thank you. Well, you know, I think that, you know, the, the label is gonna dictate where, you know, where these psychedelics start. You know, like for example, with TMS, you know, they have to fail. By the FDA label, actually, they only have to fail one antidepressant. Insurance companies initially put the bar at four because they were, you know, hesitant to be paying for this expensive multi-week treatment of those patients. They put the bar at four. Interestingly enough, they've lowered it, most of them to two now. Ketamine, of course, was limited to patients who had failed multiple medications, mostly because of its controversial nature. You know, we felt that, you know, to justify providing this drug that a lot of people, you know, were worried about would cause addiction and so forth, we had to be able to justify very few options being open to the patient. I can tell you that because these drugs are. You know, usually in medicine, if you're going to a more powerful treatment, there's a commensurate increase in the side effects and safety issues. I think with psychedelics, as with the case with TMS and ketamine, we see less side effects even though we're getting higher efficacy. What I'm seeing over time is that more and more patients coming in with fewer failed trials, and even no failed trials. Now, with TMS, it's a little harder because patients want insurance coverage. Insurance won't approve that. With ketamine, I'm seeing patients coming in saying, "I just don't want to do the SSRIs. I've done the research. I've had family members or friends on them, and, you know, I don't think they're great treatments." Because there's no insurance, you know, barrier in the way, there, and patients know they're paying out of pocket, you know, they can make that decision. I tell a lot of patients, "Look, five years ago, I probably wouldn't have done this because it was still so controversial. Now, as it's been more accepted and we see it's safe, as long as you know that, you know, the guidelines in the field would still be sort of that you should try one, two, three antidepressants before doing ketamine. As long as you understand that there are other options to try, but you knowingly want to forgo that, I'm okay with that. I probably would do the same thing if I were in your shoes. So I think initially, they're gonna come out as a, you know, not first line, but from a clinical point of view, here's my prediction. I have a talk that I give, and the title of the talk is, Adios, Prozac! Psychedelics are Revolutionizing the Treatment of Mental Illness. I really believe that it won't be long before the conventional medications, the SSRIs and the SNRIs that we've been using for 50 years, are just, you know, no longer utilized. They're just, you know, I think it'll be kind of a kind of a silly waste to try patients on these medications when you've got these treatments that, you know, one session could potentially vaporize these symptoms and are durable. That's my prediction for the future of psychiatry. Maybe a little bit extreme, but I sincerely believe that the days of the SSRIs and the like are limited. Great. thanks, Dr. Feifel. We have time for one more question. Oh, sorry, two more questions. Sumant Kulkarni from Canaccord Genuity. Thanks for taking my questions, and thanks to the company for hosting this event. For Dr. Feifel, how do you expect the potential availability of episodic treatments like zuranolone in the MDD context, to impact the potential for use of psychedelics, given that one is not a psychedelic, the others are? I think that there's still, you know, initiatives to develop, you know, novel, non-psychedelic drugs. I think that I'm not impressed that they're gonna that they're going to make a large impact. We've, you know, in our site, we've, we run a number of clinical trials, and some of the novel mechanism drugs that we've been participating in as a site have closed because of lack of efficacy. Aptinyx, you know, had a novel treatment for PTSD. Just, you know, some data from other studies came back, and they were disappointing, and recruitment was kind of poor, and they were difficult to recruit and administer. I'm not seeing the landscape being nearly as exciting as it is with the psychedelics. Maybe I'll be wrong, maybe something will come out. You know, these I think this is sort of continuation of the field, of the situation where a lot of the companies were pulling out because they just, they couldn't get novel mechanisms to really show robust efficacies. Zuranolone, I think is, you know, it's an interesting and it is a novel mechanism. I just don't think it's going to be revolutionary, you know, and take a real chunk out of the treatment-resistant patient population that we really need. As far as I can see, really there's nothing that comes close on the landscape in the pipeline to the, you know, to the psychedelic drugs and the treatment approach involved with those. Great, just one more question. Thanks. Patrick Trucchio with H.C. Wainwright. I'm wondering if you can talk a little bit more about the regulatory dynamics, specifically around the approval pathway for psychedelic or psychoactive agents. Would there be any special considerations from the FDA as far as pivotal program, anything on the side effect profile? Secondly, can you talk a little bit more about the necessity or potential need for therapy or psychological support with some of these next emerging psychoactive agents or psychedelics like LSD? I can address the second question first, and then I'm gonna ask you to repeat the first one because I wasn't sure I understood it. Right now, there's a lot of controversy, or let's just say there's a lot of unknowns about the need for psychotherapy with these drugs. I think that from what I'm seeing, I think that there's a trend towards moving away from the need for very specialized psychotherapy, we talk about something called psychedelic-assisted psychotherapy, and ketamine, we call it ketamine-assisted psychotherapy, but it's the same kind of concept. You know, there really isn't even an established standard of what, you know, what approach should be used. There's family systems and other kinds of approaches that are being applied to this. There really is almost no data that supports the that adding very, very deliberate, highly skilled psychotherapy adds to just sort of support and set and setting considerations. In fact, in the phase II, large phase II COMPASS trial with psilocybin, we presented secondary analysis that showed that sort of the rapport or the therapeutic alliance between the patient and the therapist really had no impact on the outcome. That was very disturbing for a lot of, I think, people who really want this to be a drug that facilitates therapy rather than the other way around. I definitely see this as the other way around. I do think the adjunctive therapeutic aspect is going to shrink over time to something much more kind of minimalistic, because studies are gonna show that there. It isn't really the therapy that occurs, you know, afterwards, the integration, the specific nature of it, that is really making the difference here. That, not to say that that's not going to be important, but I think it's gonna be much less, you know, there's gonna be much less emphasis on, you know, the training and the skill of that. There are companies that sprung up certifying a therapist for psychedelic-assisted, and they have hours and hours of training, and I think it's a great business model, but I've not seen any data, and my sense is that it doesn't really make that much of a difference how well-trained above a certain minimal level it is. This study, this phase II MindMed study, is, I think, very interesting because the support isn't distinct therapy. It is mostly support, and I think it's, I think what this is gonna demonstrate that the need for that specialized, super specific kind of training is not gonna be required. In terms of your first question, if you could repeat it. Yeah. Um. Just is there any difference in the way that the FDA would be viewing more kind of traditional anxiety medications relative to psychedelics? Is there any difference in the approval pathway? Would there be additional, you know, evaluation of safety or other variables? Well, I think because this is the... You know, there's probably gonna be political pressure on the FDA. These are drugs that are associated with, you know, with bad things. They've been Schedule I. The FDA is gonna be super cautious at first. It's remarkable in my mind, I still find it hard to believe that drugs like LSD and MDMA are, you know, fast-tracked and accepted by the FDA in terms of these register studies, and they're actually, you know, facilitating that. They want to come. I think it speaks to the incredible need, the unmet need that's pushing the FDA to say, "Look, we cannot, you know, stand in the way of potential, you know, game changers." I'm always surprised to hear from colleagues, you know, on the industry side when they're talking about how the FDA is actually being very, very user-friendly with these, with these medications. There are obviously gonna be restrictions because they don't want anything bad to happen, and they're gonna start off with very specific, you know, REMS and requirements. I also think the companies themselves, they're going to really be very, very vigilant and be selective initially, you know, in who gets to do these treatments, and who they certify. They want this to be done right at the beginning, because that's when something, you know, untoward could really have a bad impact on the whole field. As I think the familiarity with these drugs and the safety becomes more and more apparent, I envision that the restrictions are going to be decreased. Specifically, to answer your question, I think the approval is essentially the same. I think what the FDA is requiring for in other words, they approve, they're gonna approve what the studies have done. The way the studies have done it, that's the way they're gonna approve it. They're still gonna require two placebo-controlled phase III studies. All the same requirements are gonna be there. I think that they're requiring more from the studies in terms of built-in safety, like the monitoring and so forth. You know, there's probably going to be a period of post-marketing, very, very close vigilance, where like with SPRAVATO, where we have to fill out a form after every treatment, which we send to Janssen, as part of probably their obligation to collect data on how are patients able to be discharged typically after two-hour mark, or do they have to be retained longer? You know, have there been any kind of, untoward effects, you know, from the treatment? I think there's a little bit more concern, so it'll be a little more meticulous, but I don't see it's fundamentally different from the way the FDA works, with any anxiety, or any medication at all. Thank you so much, Dr. Feifel, for answering all those questions. Next, we have Dr. Michael Kobernick. He is a senior medical director at Blue Cross Blue Shield, and he will discuss the, you know, the payer landscape. Great. Thank you. Well, I think we're pretty clear on the unmet need. Just give you a little bit about my background, a little personal note, highlight from the payer perspective, what we're thinking about. Pretty much I've heard it all. I have a couple of comments that relate to the questions that you had. I spent the first 30 years of my career as an emergency physician. Oh, as a, sorry, as an emergency physician and saw all of these patients in the emergency department suffering from generalized anxiety disorder, depression, PTSD, and I saw it in a lot of my colleagues, and I wouldn't underestimate the, these conditions in high-stress professions. I expect you see it in some of your colleagues. A piece of the unmet need is to support individuals that are really in high-stress positions, that experience generalized anxiety, and it limits their work. My role, I teach population health at Jefferson. I lead the population health strategy for Blue Cross of Michigan, and my primary role there is advising employers on strategies to manage healthcare benefits, which I've been doing the last five years. I focus on both outcome and cost as a basic economic principle and was very active in Ascension, a health system that had many administrative positions there. I bring a variety of perspectives to this discussion. The employers really feel behavioral health is a crucial effect to support their members on. You can see here when we talk about claims and where they're spending their money, behavioral health shows up fourth or fifth, and that includes both the stresses of daily living at one extreme and then the acute psychiatric illness, which we're hearing about today, generalized anxiety disorder, ADHD, and so on. I'd like to point out on musculoskeletal that relates to this question. five years ago, when we looked at, when we broke out the claims on musculoskeletal, 90% of the surgeries, joints and hips, were done inpatient. Today's question was: Can we scale the treatment centers that were, was so elegantly described? Now 5% of orthopedic procedures are done in the inpatient. 95% are done in outpatient. We've seen the development of orthopedic surgery centers across the country as the standard of care. I think scalability, the market will drive scalability. I think that's a really good example in orthopedics of how that's developed, and that's been a win for everybody. It's been a win for the patients, for the health plans, and it's something to keep in mind as you think about scalability of treatment centers. Five years ago, we was talking to employers, and we're like: "Yeah, we're gonna move all your knee replacements to the outpatient setting." They were like: "We're kidding." Results are better, outcomes are better, and fewer infections. People are back to work sooner. Employers are concerned about. We heard a nice study today about absenteeism, presenteeism. They're concerned about it. They don't think it's a cost savings. It's soft savings. They don't really believe that they're gonna save anything, but they think people are gonna do a better job. They have a philosophy, they're gonna give benefits to people and or share the cost of benefits with people, and they wanna make sure there's an effectiveness there. Behavioral health issues drive cost. I think we have to also be aware of the data that is showing us that individuals with chronic disease and multiple comorbidities have depression, anxiety disorders, and there's really good literature on if you don't treat the behavioral health components of chronic disease, the costs and outcomes, costs are higher, outcomes are worse. This slide gives you some sense of where this fits in the total, the total scheme of cost. My point is that what we've heard about the unmet need of behavioral health disorders is clear. High priority for employers. I think that as you think about the development of the behavioral health space, all employers are interested in it. I can't say that enough. The, we talk about in population health, social determinants of health. Depression, mental illness is a core social determinant of health, and we know that I know that you can't get to the correct outcome and the best outcome without addressing social determinants of health, like behavioral health. All of these are, lay the groundwork for the unmet need for innovative treatment. New innovative ways are developing, virtual care models, co-care models. We're seeing that developing where you have a primary care physician and a psychiatrist working together in the same setting. Compensation models are developing to support that. As we've heard today, and I can't add anything to, on the interest in ketamine and psychedelics. Here is a series of questions that I think, I'm here to tell you about. What goes into that prior authorization and payer coverage that we've heard so much about today? Clearly, it's FDA approval. The FDA approval is going to be based on the study population and the protocols that were followed. Peer-reviewed journals that show clinical efficacy, we also look at that. Things that I call informative, but not decisive, are specialty guidelines and subject matter expert opinions. Health plans and PBMs who make prior authorization policy, much to the chagrin of our psychiatrists, don't really, we really focus on the FDA approval and the journal reviews, and they're objective. The health plans, I know we take very seriously the prior authorization criteria because it's a means for protecting the public and making sure that we have that. He described very well the prior authorization development for TMS. I was on the P&T committees when we developed it. Very conservative approach. We were part of the group that were saying, "Really? Magnetics?" We had a whole committee of physicians, but the data drove the approvals, and it really is crucial to understand that the data drives it, even when we're looking at new therapies. Monitoring and administrative coverage, we've heard a lot about that. We have precedent for that. We have observation coverage, psychological evaluation coverage, E&M codes for that, and precedents include SPRAVATO. Sleep study is another good example. Sleep studies are another good example of continuous observation that have coverage criteria. Really, a couple more comments. There is an unmet need. It's going to get covered once it's FDA approved. I think that the model that we saw will be a predominant model for this. A couple other points I wanted to make. We wouldn't have expected that adios Prozac caught my attention. We wouldn't have expected to be saying goodbye to metformin in diabetes. Those of you who have been following the Ozempic, Mounjaro treatment of diabetes as well as weight loss, that we wouldn't have expected that. We're going to see that move forward in addiction. I'm not so surprised about there. The other point I wanted to make is indications start narrow. He made that point, and then we see them broaden. I think that you'll see the PA that will be based on the studies, probably failure of an SSRI and you're only going to get to the psychiatrist if you have failed and are referred there, and then are going to be treated for generalized anxiety disorder. Thanks for listening. Thanks for having me today. We actually have time for a couple questions. Oh, questions! Good. Questions? Yeah, good. Sumant from Canaccord Genuity. From a payer perspective, what do you think the sweet spot is for durability and duration of treatment, or is that not a consideration at all? I don't think we're going to rule on that. I think there'll be a lot of questions from the payer on durability, but I don't think, as long as it's FDA approved, I can't underestimate the value of FDA approval in a coverage determination. The only place that might come up is in a reauthorization. That will set how long it's approved for, and if there's a reauthorization. Sometimes you'll see a six-month reauthorization or after a durable time, where the documentation required is evidence of improvement. I think if they have improvement, and then after three months, it needs a retreatment, we may or may not prior authorize it, but if we do, it'll just be to attest to evidence of improvement. Do you see the prior auth as the key impediment to someone being able to use this product or use a product like this, a psychedelic? No, I don't see it really as an impediment. It's a validation. What you heard was about TMS. What you heard from him is that established lines of treatment approval, same thing with SPRAVATO, established lines of treatment approval. It really isn't an impediment. Some people see, you know, clinicians, because it's a paper process or electronic process, see it as an impediment, from a health plan perspective, we just see it as validating that the care is necessary in the right setting by the right individuals. We see that, and the PBMs will tell you the same thing. We see that as our responsibility to the employer and the member. Yeah. Hi, Frank with Oppenheimer. Just a quick question. What do you think the biggest obstacle for this class will be on the payer coverage? Could reimbursement happen quicker now that we've learned from TMS and we've learned from SPRAVATO? Yeah, I think that once... The biggest impediment is FDA approval. I think that, there's always a lag time between approval, release, and policy, but I would expect there'll be a pretty strong request, both from the member and the provider community, to get policy done on this committee. Most health plans that I'm associated with or have been associated with, pride ourselves on having policy ready at release. Yes? Brian Abrahams, RBC Capital Markets. Any framework for what sort of price would be supportable in terms of the cost of both the, a drug like this, and the administration around it? Yeah. Any framework based on precedent? I couldn't give you any numbers specifically. I'm sure you guys have actuaries and teams of finance people. I would say that the same price that applies to SPRAVATO and other observation services will be appropriate for the treatment. I don't have any concerns about that. The price of the drug will really be left to what the manufacturer brings out. Can you maybe give us a little bit more color around what the steps would be post the potential FDA approval between the approval and establishment of access? What needs to happen at a typical plan level? Yeah ... for this to become broadly available? So- How long does it typically take? Typically, we try to work to have these available at the time of release. Typically, during that six-month period prior to the anticipated release, and sometimes up to a year, the manufacturers reach out to the wholesalers. They reach out to the biggest plans and PBMs. A lot of our plans are dealing with PBMs now that are taking recommendations from PBM. There is a very robust payer access team and approach that every manufacturer has, and they're aggressively marketing the plans. I would expect that to occur here, probably starting in some priority fashion with your biggest PBMs and health plans. Yeah. Maybe one more last quick one, if I could squeeze it in. What are the key factors that influence how you think about where a drug like this or therapy like this would be tiered from a prior authorization standpoint? Is it just the robustness of efficacy? Is it safety profile, durability, how it's administered? Like, what are all the things that you consider, and what are the most important elements? Right. Tiering, your tiering question really is about where will it fit in the form, where in our, you know, what copay will be attached to it? Right. What out-of-pocket expense? The oral agents usually come in. Employers have, in commercial, mostly 3-5 tier plans. A 3-tier plan is, you know, generic, preferred brand, non-preferred brand, specialty, and preferred, non-preferred. I would say this would be a preferred specialty, or preferred brand, non-specialty, and that's where I think it would land because we don't want to disadvantage the member, and employers are not gonna want to disadvantage the member with an overly high out-of-pocket expense. You gotta remember, the behavioral health medications are protected by employers and PBMs. That is, that they're not the areas of highest management. It's not like the branding we're seeing in diabetes or other areas. Behavioral health and oncology are two protected areas. We don't put a lot of management in there. There will be some negotiation around rebating, I'm certain, but that's. All the health plans and PBMs have non-clinical negotiating teams that manage this, and for good reason. That's how I see the landscape playing out, preferred brand. Okay. I don't think you'll have a lot of access limitations. I don't even think your PAL say, administered by a psychiatrist, because nobody else is gonna administer it anyway. Thank you. Mm-hmm. Any more questions? Patrick. Yeah. Yeah, I'm just wondering, under what scenario, could there be a case where MM-120 would be administered as a frontline treatment? Would there be something in the data that they could generate? We see that evolution, and as when I said that things start out narrow and evolve, we always That will evolve that way. There will be patients who have generalized anxiety disorder. PTSD is probably the place you're gonna see it the most. Most often, people aren't getting to the psychiatrist without seeing a primary care physician who might start an SSRI anyway. I think as there are certain case parameters, and we heard from two experts today, and they really know, will know the patients that will benefit from first-line therapy of these medications. Since it's gonna be in a controlled setting, I honestly don't think that'll be a major barrier to the advancement of and use of the medication. Can you also talk about the relative benefit, or how beneficial is it to have more indications? You know, as maybe there were two, three, four indications, does that help get the drug more into that frontline setting? We look at it. Great question, too. We look at each indication independently. As you look at subsequent indications, you're more familiar with the drug at the committee level. It gives you a little more information. You spend less time worrying about safety, more time worrying about the evidence of the indication. Of course, the indications are the key. Again, everything, when you're looking at this, it's really, what does the evidence say? That's what we say. Thank you. Mm-hmm. Great. Okay, thank you. Great, I'd like to introduce Chad Shear, who will be talking about the IP landscape. Good morning. I don't know. Good news, bad news, maybe I'm the only lawyer that they let have the mic, they put me on a clock, I won't be up here too long. My name's Chad Shear. For the last, I don't know, 20, 25 years, I've been helping innovative drug companies maintain, or rather analyze their market position, their exclusivity position, then ultimately try the cases and try to maintain that position. The focus of really what I'm gonna talk about today is the main question I'm sure at some point all of you will be asking, which is loss of exclusivity. How long will any drug, whether it's the drugs we're talking about today or any other drug, how long can it possibly maintain its position in the market before there's generic competition? The goal here will be to walk through sort of where those exclusivities come from, the different types of patents that you can get, and then, sort of their overall play in the landscape. Quick sort of patent background. Under current law, a U.S. patent is good for 20 years from when it's filed. There are a couple of different ways that that date gets extended, and the goal here is to talk about the two different sources of exclusivities. There's patent exclusivities, there's regulatory exclusivities, and they both interrelate. Patent's good for 20 years. There are three ways that it gets extended. Two of them are unique to drugs. The one that's not unique to drugs is what we call PTA, Patent Term Adjustment. That is basically when the patent office isn't super diligent in how quickly they move things through the office, you can actually get some of that time back. It gets added on to your 20-year period. That's the first one. The second one is unique to drugs, PTE, Patent Term Extension. The idea there is, if you're gonna spend a lot of time with FDA going back and forth to get your drug approved, you shouldn't be essentially penalized from a patent perspective because you have to go through this regulated market. The PTE, it can be a max of five years. There's a I'm gonna call it complicated only because it's kind of a nuisance, but there's a formula that you use that's available on the Patent Office's website, where you put in the dates that you spend in clinic, the dates the FDA takes to review, you divide it in half, and you end up with a timeframe. And that can be anywhere from a couple of years up to five is the max. You'll see on the slide it says 14 years from approval. If by happenstance, just the way things work out, you're allowed to get Patent Term Extension on one patent. If because of the way things work out, you would essentially be adding that time to a patent that already has 14 years of life when your patent issue... When your drug is approved, you don't get PTE. That's the sort of the 14-year caveat. You can add up to five years, but they're not gonna let you have more than 14 years of sort of your drug being on the market. That's the sort of the patent side of the exclusivity. The easiest way to do this, of course, is to look in the Orange Book when the drug gets approved, because drug companies have to list when their patents expire. You can literally just look at the grid and sort of map out the timeframe and then try to figure it out from an exclusivity point of view. The last little, tiny thing in there is pediatric exclusivity. That's unique to drugs as well. If the FDA invites you to do studies for a pediatric indication, whether that's successful or not, that it's not always successful, because the FDA has asked you to spend those additional resources on that study, you get six more months. It's six more months of patent effect, but not patent life. Let me explain what that means, 'cause it sounds really stupid. Your patent actually isn't in force for six more months. Your patent expires when it expires, but the FDA will give you a six-month period of an additional regulatory exclusivity that gets added on to the end of your patent life. Most people just sort of confusingly think, "My patent's gonna be around for six months longer." Not exactly true. Most times it doesn't really matter in the big scheme of things, but for the time that it does, there's the distinction. Okay, this slide might be a little more confusing than it needs to be. Let me break it down a little bit. There are two main kinds of exclusivities that you get from FDA. There's what we call NCE exclusivity, New Chemical Entity. If it's the first time that a drug has ever been approved, you get five years of NCE data exclusivity. That means no one is allowed to rely on your data for five years. Generics can actually rely on it a year earlier in file, but nobody actually gets approval in those five years. That's important because new chemical entity means never approved before. It doesn't mean that the chemical entity itself has never existed. Like, in the context of LSD has been around a long time, but it's never been approved by FDA. That's new, that's NCE exclusivity, and that is the strongest of the exclusivities. The next kind of exclusivity is what we call a commercial exclusivity, and it's a three-year market exclusivity. Now, why does that matter? It matters if you've seen drugs. I'll give you an example. Diclofenac has been around forever and has been sold by dozens of companies. If you go out and you come up with a new formulation for diclofenac. Is it Vivlodex is coming to mind as one of the drugs. If you come out with a new formulation, you can get a commercial exclusivity for three years of your formulation, but you don't get the NCE exclusivity because diclofenac has been around, been around forever. The pediatric exclusivity, we talked a little bit about here. The key interplay for all of this is this: the FDA exclusivities sit on top of the patent exclusivities. They are different things. The FDA exclusivities exist whether you have patents or not. If you get an NCE exclusivity, you get five years. Now, there is a bonus if you have a patent. If you have an NCE exclusivity, that's five years, and you have a patent, you end up with a period of time of 30 months being added to the end of your five-year exclusivity. If a generic, just to sort of break this out a little bit. You have a five-year NCE exclusivity, a generic drug company files an application, they want to launch a generic version of your product. They can do that a year before your five-year exclusivity expires, but the FDA will be statutorily prohibited from granting them final approval until 30 months after your five-year window ends, or 7.5 years. That NCE exclusivity, if you have one patent in the Orange Book, that NCE exclusivity turns into 7.5 years. That's the exclusivities. We're going to talk a little bit more. That's a lot of information in a very brief period of time. I'll give some examples in one second, you can sort of figure out how some of this works and how it actually has a financial impact. Before we do that, let's talk a little bit about the kinds of things that can be patented. New compounds, that's the NCE I was just talking about. There is a common misperception. I cannot tell you how many times I have seen products priced by the market as if the new compound patent is the only one that matters, I'm going to give you some specific examples of that in one minute, it ends up being, from a financial point of view, a big deal. You can patent the new compound. As soon as you discover the molecule, forever ago, the chemists figure it out, they make it, they patent it, you get your patent. The problem is, you still have years and years and years of clinical research ahead of you, which also often corresponds to years and years and years of innovation, and you're allowed to patent those years of innovation that follow the discovery of the compound. Everything else that you see that follows really tracks those innovative steps, whether that's drug formulation. You know, how do you actually get this thing into a pill or in something you can inject or in something that can actually survive the GI tract and be absorbed by the body? The way you make it, obviously, is a big deal. Its use. You discover that a drug can be used for a certain disease state that nobody anticipated. You can get a patent on that. Drug delivery systems are a super big deal for certain molecules, especially those that you can't take orally. If you have to inject them, if they have to be used on a patch, if they have to be a fast-acting absorption mechanism under your tongue, whatever it might be, all of those steps along the way are open for patenting. Finally, sort of the risk factors, the REMS, you can actually patent those processes as well. To give you some examples of why this matters and why I started this by saying that a common misunderstanding is that the only one that matters is new compounds. I did a case years ago. I'll just tell you a couple of examples. I did a case years ago where the underlying drug had been discovered, I think, 20 years earlier, and nobody could figure out how to make it work. They saw incredible results in a lab, in animals, but they could never figure out how to make it work in a human population. 64 clinical trials later, they ultimately figured out it was a formulation trick to get it to work and stay in the body long enough to have activity. By the time that the generics challenged the patents, the compound patent had expired. The compound was, quote, unquote, "old." We ended up going to trial on formulation patents. The compound patent expired, I want to say, 2011. The drug was open for challenge by generic drug companies, 2010. The company maintained the market until 2019, all because of some formulation patents. The formulation patents in that context gave the company eight additional years of exclusivity on the market. Another example, did a case in the mental health space where the compound patent expired or was set to expire. We had a patent on side effects or a lack of a specific side effect. The market had priced that drug based solely on the compound patent. Thought the market was going to completely lose exclusivity as of the expiration of that patent. Long story made short, case settled the night before trial. When the settlement date was announced, the stock jumped 19%, and stayed there for a matter of two years. These other patents, separate apart from the NCE patents, can be incredibly valuable. Literally, I don't get hired for cases involving new compounds. I wish I did. Those are easy cases. I get hired for the cases where the patents are all of the other ones. I could sit here for the next 45 minutes, this is why they put me on a clock, I could sit here for the next 45 minutes and just tell stories about the number of times where we've seen products, and products protected by these patents that we call secondary, tertiary patents, that the market has not priced into the value. Then you see the jump when the dates come out. When you're trying to figure out, looking at all the patents that some company might have in the Orange Book, just some really, really basics here on patent law, there are basically three requirements. Whatever the invention is, has to be novel. Just think about it. It has to be new. Kind of obvious, right? You can't invent something that's old, that somebody else has already come up with. It also has to be what we call non-obvious. From a scientist's perspective, and this is the key, it's a scientist that's looking at this, it's not, thankfully, me, it has to be non-obvious. It can't have been obvious to a person of skill, just sort of looking at it. In, in Europe, they call it inventive step. That's the analysis they do, is whatever the patent they're looking at, is it an inventive step over that which came before? Finally, it has to be useful. Sort of a basic idea, right? If the government's gonna give you a monopoly on something, you actually have to be contributing something useful to the space. Finally, this all plays out in the context of the Hatch-Waxman Act. There are incredible resources available to you for free to help you figure all of this stuff out. I mentioned the Orange Book. I assume most people are familiar with it, but if you're not, it's on the FDA's website. Literally, just Google FDA Orange Book. You'll get the Orange Book. It used to be orange. It used to actually be a book that was published. They haven't published it in a decade, I think. But it's an online database. Type in the drug's name. Instantly it'll come up, it'll give you everything you need to know about the drug. There will be a little button on the bottom that you tap that says, "Patents and Exclusivities." It'll take you to a new page that lists all of the patents, lists when they expire. For some of them, it'll even give you a use code as to what it is that the patent is related to. On the bottom, it'll give you all of the exclusivities. There's other kinds of exclusivities that I didn't talk about today, but it'll give you all of them across the bottom. When you're trying to analyze any drug, it's an incredibly valuable tool. The last piece, then I can shut it down. The last piece of all of this that's unique to the Act, that's important, is what we call the 30-month stay. Regardless of what kind of exclusivity that you have, whether it's an NCE exclusivity that goes for five years or the commercial exclusivity that goes for three, when a generic drug company challenges your patents, the FDA puts a stay in place automatically for 30 months. They will not give final approval to the generic drug company for 30 months. The whole point of that is to allow the court system to work out the patents, the validity, the infringement of the patents, without fear of there being a change in the marketplace. That's it in a nutshell. Max, I don't know if you want me to take a couple of high-level questions. I can take a couple of high-level questions. Sumant from Canaccord Genuity. I can't think of another drug class that has so much anecdotal evidence of potential efficacy as the psychedelics. How do you think that is going to impact the landscape for patentability from a method of use perspective, or are we gonna see inter partes review every day forever? I think it's actually really challenging because whenever you're trying. I'll sort of speak in generalities as to specifics. Generally speaking, when you're talking about method of use, and you're talking about efficacy, and you're talking about patentability, you're not just talking about efficacy, you also have to talk about what I would call the evidence of teaching away, so all of the evidence of things not working. That's never just. You say efficacy, right? It's never just about one thing. I'm just gonna give you an example. The case that I've mentioned, where the drug that jumped 19%, that claim was to a drug used for a certain dose, once a day, without a side effect, and what made that patent patentable was the absence of the side effect. When you're talking about patenting a method of use, what examiners at the patent office will look at is all of the criteria that are in the claim, as opposed to, you know, one piece of efficacy. Anecdotal evidence, just to your last point, anecdotal evidence is very difficult for the patent office to consider because it's anecdotal. There's typically not actual, real evidence to support it. Oftentimes, anecdotal evidence, if it's a lot of times it's not even admissible in court, because think about how is it, you know, how is it you're gonna get it into evidence? In the end of the day, I wouldn't put a lot of stock in anecdotal evidence and instead, track, you know, what's been written in journals, what's been presented in conferences. You know, those are the things that really in the, from an efficacy perspective, really matter. This might be a high-quality problem for eventual, like, developers of psychedelic medicines to have, but do you think that psychedelic medicines could be subject to generic label carve-outs, or is the nature of the compound too complex to do such a thing? Carve-outs is a really trippy, really sort of complicated topic just for the group. There's a portion of the Hatch-Waxman Section statute that we call Section viii, that allows generics to carve pieces of the label off of the drug for the hope of being able to get to market sooner. The easiest example for everyone to understand is Paxil. Paxil, of course, was approved as an antidepressant. Later, it got an indication for PTSD, and the patents on PTSD went way longer than the patent on depression. The generics used the section of that he's talking about to carve PTSD off of the label so that they could get on the market for, as an antidepressant, because those patents had expired. The really, the crux of your question goes to what is going to be on the label, and what are going to be the different terms of the patents that cover the various indications? It really just depends. It's kind of a question that I can't answer without actually knowing the approved label, because you have to look at first the indications, and if you have one, two, three, if you have multiple indications for more than one, then you have to look at it. I think the interesting area for psychedelics is going to be when you start carving things off the label. The FDA will sometimes let you carve indications off the label, but they're far more cautious when it comes to carving safety data off of the label. This, to me, seems to be a space where the FDA might sort of scrupulously guard the safety data that's on the label, and if the safety data finds its way into patents because of the clinical trial results, I think it could... You might find yourself in a situation where it's hard to carve off that stuff. Just a quick one, Frank Brisebois with Oppenheimer. You talked about the non-obvious bar, does that non-obvious bar move a lot depending on the country that you're in? Just anecdotally, have you seen experiences where as much as you would think something's not obvious, some scientists might think it's extremely obvious, just the movement there? Well, so I can tell you this. In every case that I've tried, there will be an expert on the other side who says it's obvious, right? I mean, that's the nature of the beast. The answer to your question is sort of at a high level, yes. In the U.S., in Europe, Canada, Australia, in those markets, obviousness is really looked at the same way. The rest of the world, it just depends. Just to give you anecdotally, some color, I had a case, it's over now, involving a patent on what many in this room would probably consider one of the most biggest medical breakthroughs of probably our lifetime. Have patents in Europe, have patents in the U.S., have patents everywhere. To this day, we still can't get a patent in China because they say it's obvious. It just depends on the market and it depends on. Now, there are a lot of ways to strategically work your way around some of those situations, for the most part, the major markets, the major places where you're going to generate revenue, apply the same standard or close enough that you wouldn't really be able to tell the difference. Great. Great. Thank you all very much. I appreciate it. Okay, great. Now just our concluding speaker, Rob Barrow, CEO of MindMed. Thanks. Turn this down. Well, I want to thank everyone again for coming here today and for all of our presenters for joining us and taking time out of their busy schedules. You know, when I look at where we are as a business and all of the progress we've seen over the last several years, the extraordinary talent we've been able to build in the organization, Then we look at what's ahead, coming up on clinical data later this year, I hope everyone leaves today with an understanding of several things. Hopefully, you've learned a lot, but at a minimum, what I want to make sure you come away with is the reality of the backdrop. The fact that we are working in an environment where the diagnoses that we're targeting are on the rise, or we're coming up in a critical time with very important data that really takes us back and for the first time with modern, high-quality evidence, we hope will generate, you know, solid clinical evidence that we are seeing a rapid and durable effect in these disorders. Second is that, as we heard from Dr. Feifel, while psychedelics are unique phenomenologically, while they're certainly something different than many of the drugs we have approved today, it's not all that unique in the sense of how this could be rolled out in clinical practice. We've seen, and I've had the good fortune of going to Dr. Feifel's site and to a number of other treatment centers, both academic and commercial for private treatment centers. What we hear over and over again is this desire by providers to have new tools, and that if they have those tools, the infrastructure either already exists or is going to be easily adaptable to create a delivery network. Over the past couple of years, again, I want to highlight, we've been incredibly fortunate to build out an extraordinary team. We've, from day one, taken a very rigorous approach. Bringing in experts who have gotten CNS drugs approved in the past, who know the landscape, who have worked on, and many intersect with some of the cases that Chad was mentioning before, and have the experience to leverage market exclusivity. Ultimately, as we saw it out, and as I said before, you know, IP is at the core of everything we do. As part of that, one of the reasons why, very early on, we've brought in such talent and skill in terms of intellectual property strategy, is because the label is critically important. The technologies we develop, all that goes into our label and our strategy, impacts reimbursement, and affects the ability for providers to ultimately dole out these therapies, and ultimately affects our commercial exclusivity, which is one of the reasons we've been so intentional from day 1 about how we've approached our entire development strategy, our entire delivery paradigm. While we are talking today about generalized anxiety disorder, we also have important data coming out on MM-120, and ADHD, which will also be reported by late 2023. We're moving into the clinic with our second lead program, lead product candidate, which is our MM-402 program, or R(-)-MDMA, which is developing in autism spectrum disorder, and have a number of other programs through collaborations and earlier in development, that we're actively progressing into the clinic, and with other important readouts over this year. We didn't talk a lot about mechanistically, how LSD works. I think many of us have heard this story with the psychedelic drug class. These are serotonin agonists. The perceptual effects are driven by agonism at the 5-HT2A receptor. One of the most studied, storied, targets in all of psychiatry, but one with LSD, with MM-120, the most potent agonist that we have seen to date on serotonin 2A. It also doesn't stop there. Again, we think of multiple modalities how we could use these drugs. A session-based delivery setting, like in GAD, but also, either subanesthetic, synergistic dosing or innovative dosing paradigms and dosage forms that could be leveraged into the future, and other creative ways of getting the pharmacological kind of activity that we see with LSD, and ultimately having other innovative treatment opportunities. Going back to some of those, what we think of as old, quasi-anecdotal evidence, Prior to the Controlled Substances Act really coming into force, we had dozens of studies, hundreds of patients, where we saw consistent strong response in anxiety, depression, and neurotic illness. More recently, this has played out with clinical results in anxiety and terminal illness, clinical results in other anxiety disorders, such as our colleagues from University Hospital, Basel, who last year reported out results where two treatment sessions of 200 micrograms of LSD resulted in rapid, and 6-12 months durable effects. We heard from Dr. Feifel, and we heard from Dr. Kobernick, the importance of showing that durability. When we stack that up against the other available therapies, I think it can't be lost on us that treatments like TMS and ketamine or SPRAVATO, require repeated administration many times over the course of weeks. I know in talking to Dr. David Feifel about some of the patients he sees, we have patients that drive over half an hour to get to the treatment site for a five-minute, 10-minute TMS session. They do this over and over, and over, and over again, over the course of weeks because the need is so significant. If we have a new treatment where we can show, even a three-month durable effect, as we'll ultimately be able to report from our phase II-B study, that would be a major advancement for these patients and for clinical settings that are seeing a massive demand, but in many cases, throughput is going to be critically important, and making sure that they're able to get patients in, treat them, and show that durable response, is what really sets this drug class, and sets our asset apart. More recently, as we heard as well, results in other diagnoses, such as depression, open up new markets, open up new revenue sources, new sources of profitability. We also think of it as this sort of trifecta of psychiatric disorders, with anxiety, depression, and use disorders being highly comorbid and highly consistent in terms of sort of the underlying causes. As we've seen historical evidence and more modern evidence that we reported out this year, again, through our collaboration, where we see strong treatment effects in major depressive disorder symptoms after two administrations of LSD. We again think this is an extraordinary opportunity to think more broadly about where we might be able to take the ultimate label and the ultimate indications we're able to pursue, and as we progress our lead program and get into pivotal studies following into phase II, and following the successful eventual readout of our phase II-B study, we really believe that there's much more that could be brought into the pipeline in the future. Talking about our ongoing study. phase II-B study, many of you are familiar with, 200 patients across five treatment arms. This, in the drug class, to our knowledge, is the most robust exploration of dose response ever conducted, particularly in a patient population. Now, we've seen many studies looking at healthy volunteers, where we look at pharmacodynamic effects. There's a degree of correlation, between the magnitude of the perceptual effects and the ultimate clinical response, but that correlation is not necessarily causative. We've also seen more, more recent research suggesting that the duration of a perceptual effect, opens up things like social learning windows that could be correlated. Just because of its potency, but also because of its duration of action, LSD could have an opportunity to stand apart from the rest of the field and really represent a, a differentiated treatment profile when you look at some of the other drugs in this class as well. The other thing that's really important, and we talked about, you know, Dr. Feifel talked about the considerations around- making sure we don't overemphasize psychotherapy. This is something that we have baked into our program from day one, that we feel very convicted about, that we do not from day one, when we designed our phase II study, we went in with this concept in mind, that we need to make sure we're developing a drug that can ultimately get to patients, that can be marketed at scale, that can be accessed by patients at scale, and providers can deliver it. It also can't be lost on us that things like generalized anxiety disorder and depression and use disorders are not isolated to high population metropolitan areas with good academic centers. Our view from again, from day one has been that the labeling and our development approach needs to be aligned with a treatment that could actually get prescribed, could be delivered, and is not necessarily gonna require the same degree of intensive oversight that we are required to do in clinical development. We see this over and over again with other drugs in development. A great example being VIVITROL, where in development there's a very confined, very contained delivery modality and delivery paradigm that is FDA mandates in research for us. That's a good thing. That ensures that we have high-quality data, ensures that we have robust monitoring and patient safety in clinical development. We are ultimately getting to a label and a REMS, if one is ultimately used for these drugs, that we have to be thinking about all of the patients who could access these, all of the geographies where those patients live. That's been our intent from day one and how we've approached this clinical study. Our view is that it also gives us important insights in terms of the effect size and the treatment response, that we can then leverage into a phase three study. When we've seen the field really move in the direction of walking back the psychotherapeutic intervention. From day one, we've been talking about non-interventional psychosocial support, and our view is that our phase two results will then be much more translatable in terms of predicting the effect size that we can ultimately expect in phase three pivotal studies. Again, we recently, a little over a month ago now, announced that we have exceeded over 50% of the study enrolled in dose. We do anticipate providing further update at our next earnings call, which will be in August, and are very excited as we come up to the end of the year. You know, I think we can't lose sight of the fact that while a lot of this research has been ongoing for several years, you know, other programs that have been of similar size have taken years to complete studies. Our program, we dosed our first patient in August, excuse me, in August of 2022, and we really had all of our sites fully activated, enrolling only at the beginning of this year. The ability to execute a study of this size, in such a rapid progression, I think, stands out in the field and also speaks to the kind of organization, the kind of way that we operate, and the way we're able to execute these studies. As we look to phase III pivotal studies, as we think about the kind of treatment effect sizes we've seen in historical literature, if we're ultimately able to replicate those, of course, we are optimistic about going into [data readout], and we're not arguing about studies of 5,000 patients either. I think it's really important to note that the study size that we are already executing and have been able to do very efficiently is not that out of line where we expect pivotal studies to be in terms of the magnitude and the scope of those programs. It gives us a really unique insight in terms of how we can be most effective in executing pivotal studies, how we can be really efficient in progressing from the end of a phase two program, getting into phase three as quickly as possible, and then running those studies as quickly as possible. We have such a degree of optimism in our clinical program and in our development strategy, we wanna make sure we are pushing the envelope. It's also, in some ways, a benefit to be, where we are positioned in the industry, coming out to an important readout this year, where we have, you know, obviously peer companies, competitors, who are embarking on phase three programs, who are in many ways going to be supporting and laying some of that infrastructure and help, we hope, minimize the timeline and maximize the efficiency for getting things like policy in place and getting reimbursement, and laying that infrastructure out, that when we get our drugs to market, they'll ultimately be able to be rolled out and uptaken into the treatment setting as quickly as possible. I did speak about this briefly a second ago, but again, our view of the clinical care model is one that does not rely on psychotherapy. It's not because... You know, I think it's, we believe that psychotherapy has a place. We also believe that many of the patients that are going to be coming into these studies and that ultimately will be treated, likely are already receiving some form of psychotherapy. Here in this country, that tends not to be from psychiatrists, it tends to be from lower-degreed individuals. Our view from day one in our clinical trials and where we ultimately see this fitting in the real-world use case, is that we need to have a label and a REMS and a development strategy that prescribing and oversight certainly has to rely, be put in the hands of clinicians and physicians. Ultimately, the observation and the oversight of delivery of these therapies could be done by other individuals who aren't necessarily MDs, who don't have necessarily even doctoral-level training. We see a number of treatment centers that are set up this way, where licensed clinical social workers are giving psychotherapy, who are coordinated or partnered with overseeing prescribers. Ultimately, there's a kind of collaborative care model that can be rolled out, where patients can be seen, be prescribed a therapy, and ultimately be delivered that therapy by someone else. In a post-treatment setting, episodic care is something that's a little bit different. This isn't the same as an SRI, where you give a prescription and say, "Take this forever, and, you know, come see me at some point in the future. We're being very intentional about patient follow-up and making sure we can track the durability, but we don't view that this would be the same durability profile for every single patient. It could vary by severity, it could vary by years in treatment and treatment resistance, for instance. We are developing tools and ways of monitoring patients and trying to ensure that patients who ultimately do see some benefit, but at some time in the future, return to have a relapse of their symptoms, are able to come back in, be tracked, and be helped again. That's also where our digital programs come in. Digital medicine programs, one of the things that really is important to us, both from an intellectual property standpoint, but also how we can try to maximize uptake. We heard from Dr. Feifel, that they use technology in their clinic to deliver multiple, over 70 deliveries of ketamine and SPRAVATO per week. That's a fairly impressive throughput, and we think of the administrative overhead for doing that versus delivering perhaps one treatment session per room per day. We wanna make sure that all the clinics that could ultimately be delivering these, have those tools available. Our digital medicine programs are very much aligned with facilitating adoption of these drug therapies that we're developing, particularly our session-based delivery of MM-120. As we progress in our clinical programs, we're also starting to integrate the research of our digital medicine tools into our clinical development for our MM-120 program in GAD. This could be useful in every phase of treatment delivery. When we think about pretreatment, we still anticipate that as with SPRAVATO, there's gonna be some prior-to-treatment education. We think about medication guides, about making sure that physicians and patients are educated on what to expect and have the kind of information that they would need to... before going into a treatment session. During a treatment session, we also want to make sure that physicians have tools to monitor patients effectively, that we can try to minimize the duration that patients can also be held into a clinic. A fixed interval observation window, such as two hours for SPRAVATO, is somewhat limiting because some of those patients may not need to be in the clinic for a full two hours. We are developing tools that we would seek to try to make it on an individualized basis, the duration that patients could be held into a clinical setting. If we can do that, one patient may be held for a shorter period of time based on when they would ultimately be able to leave safely and return out back to their home or back with oversight and released from the clinical setting. Then again, in a post-treatment setting, how can we monitor patients and make sure that as we see the return of symptoms, if we see the return of symptoms, that they can be intervened with and brought back into a clinical setting for perhaps a retreatment. We can have data to support why that treatment worked in the first place, and ultimately, why they should be given authorization to be treated again. At the end of the day, you know, our path to commercial success, and I hope you leave here today understanding that providers, at least all the providers that we speak to, who are engaged and knowledgeable about the developments in our area and in our program with MM-120, we see this consistent pull, a desire, that they will adapt their clinical settings. They will be adaptive and lay down that infrastructure so they can deliver these drugs if we ultimately get them approved. That, of course, requires getting an FDA approval first. It also requires getting rescheduling, which occurs both at a federal and state level, and something that we are already actively involved in laying the groundwork to make sure, again, we minimize any sort of lag from FDA approval to getting a controlled substance rescheduling, so that these drugs can be marketed and given to patients. Then getting through payers and having these negotiations. I think we're already seeing in psychiatry, there's been so little meaningful innovation over the years. We're already seeing the kind of innovation where we're seeing the kind of engagement, where payers are knowledgeable about what's happening. There's a desire to facilitate the rollout of these therapies if they ultimately are approved. Finally, again, developing real-world data. developing care models and tools that can facilitate the adoption broader than just in major metropolitan areas, at academic tertiary care kind of facilities. That has been core to our development strategy, core to our mission from day one, and something that, you know, we feel very optimistic about the ability to get these drugs to patients that need them at scale. Finally, I see lunch is coming in for all of those of us who are here in person. I'll pause there. Again, we appreciate you all taking the time to be here. We're coming up on a really exciting period and certainly happy to take any questions before we close out here. Brian? Can you talk a little bit more about how the GAD study is going? It sounds like enrollment's on track. What are some of the learnings and the takeaways that you have, I guess, both the good and the bad that you've found that you can apply to your phase III study and then ultimately to your commercial strategy? I guess, maybe along those lines, how quickly do you think you'd be able to roll into a phase III study? What are some of the gating factors there? Presumably, you'd need an end of phase II meeting with the FDA. How quickly could all those steps take place, given that the size and scope of the study would be relatively, or the study or studies sound like they'd be relatively similar to what you're already doing with the phase II? Yeah, absolutely. Dan, if you want to come up too, we can certainly tag-team Q&A, but I'll start by... You know, some of the learnings. Why don't we sit down? Some of the learnings we've had, of course, this is a blinded clinical trial, so we can only learn so much and only say so much until we get data. In terms of conduct, of course, not. Yeah, absolutely. You know, I, one of our clinical sites, the Cleveland Clinic, you know, in Ohio, I think. I was there several weeks ago, and we don't know what any of these patients receive in terms of treatment. They didn't know that one of the study participants really commented on how much they appreciated not having the, what we call dosing session monitors in their physical space. We have heard this from multiple sites as well, that the ability to have a patient in the room undergoing a treatment session or a dosing session, and then for the providers, for the dosing session monitors, to be able to effectively, one said, "You know, I sat in the corner and read a book for the day." We are not seeing any kind of concerns around how our approach in delivering this, which compared to what some of the other approaches in the field, we think will be much easier to adopt. The fact that that actually, not only is that facilitating easier administration, but we're actually hearing that, you know, there's an appreciation by providers and by study participants that, you know, they're effectively left alone to do their own work. We hear this with SPRAVATO, we hear this with ketamine as well, as we heard from Dr. Feifel earlier. It's one of those kind of funny oddities, where in our drug class and with the psychedelics, there's this legacy of how things have been done. I think in the early days and just a few years ago, really, there was an assumption that because this is how things have been done, this is how they should be done, and in the absence of evidence, that really is hard to justify for us. I think we've seen a really regulatory embrace, a practical embrace of the way we've been approaching this, which we, you know, are... Obviously, when you go into these things, and you have a conviction about something, it is somewhat of an uncertainty because you don't know if the world's gonna come back your way or stay the way it is. We feel really justified in our approach and now the evidence is more and more supporting that. In terms of the timeline to getting into pivotal studies and the gates there. Certainly moving to an end of phase II meeting is an important step in the process. We have had very positive regulatory engagement along the way, and I think, you know, as we think of our phase II design, when we designed this study, oh, gosh, almost a little over two years ago now. You know, when we first set out on this approach, it started with thinking about the ultimate label and commercialization. You know, our phase II-B study, while it's five arms, and we don't expect to be doing five arms in phase III, almost everything else about the study design was set up to be like a phase three study. Where you know, we, I don't think we anticipate any sort of massive changes in terms of our delivery protocols, in terms of, you know, how we assess clinical outcome measures or primary endpoint, things such as this. Certainly, there'll be some differences as you go into a phase three, in terms of the number of sites, perhaps, the number of subjects, and it's gonna be data-driven. Overall, I think we believe we'll have a high degree of consistency with what we're already doing, and so we'll be able to leverage this very quickly. I mean, I think of it as almost a, you know, we'll be able to copy, paste, and go with a more streamlined design, but one that will be very much leveraging all of our learnings and our conduct in the phase II program. Hi, Jonathan Aschoff at ROTH MKM. I'm curious to what extent you're aware of, in geographies where there's been broad decriminalization of, let's call them recreational drugs, to what extent is MDMA and LSD being used in these indications by docs there? Do you know anything about that? In terms of, outside of the clinical setting and anecdotally? The docs, these are patients, they have- Yeah ... diseases, so it is a clinical setting. You know, I guess what comes to mind is like Portugal. You know, something that might embrace Western medicine, also have, you know, have dropped these boundaries that we still have here. Yeah, you know, I think Dan, feel free to comment, of course, but where we often look to is Switzerland, and we have, you know, strong ties in Switzerland. There's also, you know, this doesn't get talked about all that much, but there are dozens of psychiatrists in Switzerland who have a license, a right to use psychedelics in a compassionate use setting. They do regularly. I mean, there are dozens or even hundreds over years of treatment sessions that are administered with LSD, with MDMA, with psilocybin, in some cases. We've had a lot of learnings, having those discussions and reaching out to those networks, and, you know, it has informed our development approach, has informed how we think about delivery models. We also, again, looking at those use cases, they're anecdotal. They're not high-quality clinical research, but I do think we can learn a lot. Over and over again, we hear about the importance and really in many cases, the preference. I think the field has, in some ways, taken a view that the duration of activity or the phenomenology of these different drugs is irrelevant, and that the shorter is better. That's not something we've seen supported in data. It's also not something that we've heard from practitioners. When we had these discussions and interviews with the Swiss psychiatrists. In many cases, they say, we choose LSD because either because of the duration or the reliability of getting to some sort of desired acute effect that they believe translates into this meaning, meaningful clinical benefit. We really don't look to sort of anecdotal out of clinical setting use, but there's enough evidence being generated in compassionate use settings in Switzerland and other areas that we've had a lot of important learnings. Hi, this is Elaine on for Charles Duncan at Cantor. Just wanted to ask a question on your, what you expect the phase III design to be, given the known robust activity of LSD and its high durability. How do you plan on tracking a long-term clinical outcome, and like a certain ongoing phase III trial design with the psilocybin, will you be looking at redosing? I have a quick follow-up. The exact design is something I think we'll certainly save for, once we have that alignment with FDA and have an end of phase II meeting before we commit to exactly what that program would be. You know, our expectation is that we, you know, we intentionally embarked on a phase II-B study. That is the most extensive exploration of dose response in a clinical setting ever conducted, to our knowledge, in the entire drug class, but certainly with LSD, and that was to generate solid clinical evidence and select a dose to take forward into phase III study. Our expectation is that we would have a very much streamlined design in terms of the number of groups, that ideally, we'd be looking at a placebo-controlled study of one or at most two doses, depending on what we learn from the phase II-B study in terms of clinical response and how that may vary by patient or severity or past history of treatment. In terms of the other kind of considerations, and there's this interesting interplay, and we've heard FDA now on multiple occasions, very publicly at conferences, you know, talking about the considerations that we as a field, need to be thinking about and generating evidence around. Things like durability of response. There's many ways to tackle this, right? I think we all want to make sure that we have an understanding that if a patient sees benefit and then ultimately relapses, that we know what happens next, right? I think a sort of odd but relevant analog would be anesthetics. If you took an anesthetic and got surgery the first time and it worked great, you know, but the second time you came in and you didn't get any anesthetic effect, that would be a big problem. We want to be thinking about that and characterize either such a long durability that we reasonably believe that on average, patients can have many months of benefit, or more likely, that we're going to be able to retreat patients and characterize what that response has been. I think the thing that gets us excited is that, at least all of the evidence we have available to us today suggests that those subsequent treatments, again, this is preliminary evidence, but those subsequent treatments would be additive, not blunted. When we talk to the Swiss psychiatrists who use these drugs, they continually kind of represent that, you know, first treatment, second treatment that they do with patients are meaningful improvements, but as they get out to treatments beyond that, they become less frequent, and in many cases, they stop being needed altogether after several months or years. We see enormous excitement around the ability to retreat patients, both because it will generate the evidence for an approval, but also because it could generate even more meaningful long-term kind of clinical response. It would be important for the patients, important for the value proposition of these drugs as well. That's really helpful. Thank you. The quick follow-up. We believe that the 200 microgram dose will probably be the most robust and perhaps the most therapeutic. Of course, we need the top-line data, but for example, what if the 100 microgram dose shows a modicum or a measured therapeutic response as well, with a reduced safety profile or side effect profile? Do you plan on taking that forward as well as part of the labeling for perhaps patients with CV risk, or what are your plans? Yeah, it's a bit premature. I mean, I think the reality is we're going to have to... We will see the data, and certainly, you know, we have a multitude of scenarios in mind for what we will do in X, Y, Z scenario. You know, the reality is we want to obviously choose a dose that has a meaningful clinical response, meaningful efficacy. We also have to be very mindful of safety, and the data we will generate later this year will be so important because it may not be limited to one or the other. It may very well be that a dose can be selected in a particular use case, and that another dose might open up an entirely new way of using the drugs. Really, you know, part of our view of why we wanted to conduct the study we're conducting now is because so little is actually known about dose-response relationship, you know, whether it speaks to the acute magnitude of treatment effect, whether it speaks to the durability. There's certainly a scenario in which a lower dose, say, a 50 or 100 microgram dose of LSD, results in a similar magnitude of acute effect, but over time, a higher dose is more durable. These scenarios are really important when we think about the value proposition and also, you know, the interplay for which patient populations we should be targeting with which doses. We're not sort of constraining our thinking quite yet. We're just going to be waiting for the data and ultimately make some decisions based on the safety and efficacy response that we see in the phase II 70. Sumant? Thanks. Patrick Trucchio at H.C. Wainwright. Just a few follow-up questions. First one is just, you know, show the slide on the digital strategy. Just curious, how will your digital strategy potentially expand access to MM-120? Then secondly, just as it relates to your target product profile, clearly a lot of work has gone into designing this phase II trial with a view toward the phase III and eventual potential approval. I'm wondering, will your target product profile, this enable you to kind of slide in with that SPRAVATO infrastructure? What would that look like? Then just finally, you know, earlier you mentioned, you know, approximately 76% of GAD is moderate to severe. What proportion of that group is going to be or could be appropriate for MM-120? Yeah, I can speak to digital. So really, when we consider the impact of digital, what we're looking at is reducing the friction, right? So in order for providers to prescribe the drug, they have to feel that they can prescribe it safely to appropriate patients. So if we can provide tools to help ensure that that's the case, we'll see more prescription. Then a lot of this will be at the point of delivery. This relates to your second question, which is, who's actually going to be sitting with people while they're having the drug experience? That's a place where we think that digital tools can be particularly enabling by giving folks the ability to believe that they can, one, conduct a safe session, that they can document appropriately, that they can be adherent to any REMS and label requirements, and that they can be assured of reimbursement. If we're able to do that and to increase provider confidence in safe, effective, and compensated delivery, we think that will drive increased prescribing and increased use. It expands to your second point, the environments in which the drug can be administered. There's the sort of ketamine-like infrastructure, where you think of a specialist clinic that does session-based therapies, but we think we can drive uptake in more routine psychotherapeutic environments. The kind of places where psychotherapy is delivered today by the folks who are doing that psychotherapy today. I don't... I'll just make one other comment on digital, which is that, you know, when we talk about things like REMS and technology and its ability to reduce those frictions, many times, and we've seen this recently with SPRAVATO in some sense, the REMS and the sort of procedural barriers that were put in place really were, you know, a challenge for adoption. That, in some instances, it's certainly a negotiation that happens with FDA and late in development. We have a number of learnings from the SPRAVATO case, but also things like, you know, with Celgene, for instance. The Celgene REMS for things like REVLIMID, was actually a great use case in the other way, where it was particularly beneficial in driving patient adoption and getting documentation in place and making a very streamlined approach so that providers and patients could use the drugs. Where this intersection is in terms of where the drug can be used, how we can get good documentation, and how we can develop tools, where you launch is where is what you live with for at least a very important period of time when you're rolling out a drug. Having the ability to be very thoughtful and coordinated early in development so that we can ultimately get a drug approved, but then reduce those frictions and get it out to patients, is where our entire digital strategy has resided. Just something to address your question, Patrick, about the percentage of patients that will be eligible to MM-120. The first thing is that because no drug has been approved for GAD for the last 12, 14 years, you have very limited data on the market. The sizing of this market, there's different segments there. When you do primarily market research and you ask the provider of the HCPs about patients with schizophrenia, bipolar disorders, suicide ideation, substance use disorders, you tell them that those patients might not be, based on the initial label, eligible for the drug. Usually, the numbers that you get is like 20%, 30%. To be on the safe side, they will say, probably 20%, 30% of patients in certain way are not going to be initial candidates for MM-120, until we have more information about the safety of the drug, because those patients are actually excluded from the phase II-B. We are already conducting research, more extensive research, using U.S. claims and epidemiology to actually fully understand what is the size of the segment that will be at large eligible for MM-120. Just from a psychiatric perspective, there's no reason that any patient with moderate to severe anxiety would be ineligible. You know, it's really who we can reach in the market, not so much appropriateness for treatment. Sumant Kulkarni from Canaccord Genuity. Most of us seem to know, and Dr. Oquendo also mentioned this, that GAD is a very diverse disorder. Other than a HAM-A cutoff of 20, is there any kind of special characteristic or trait that a GAD patient might have that might make them more amenable to treatment with MM-120? Do you have any pre-specified subgroups that you're planning to analyze? To the first question, really, it's all comers with GAD. We want GAD to be the primary diagnosis. We have some exclusion criteria around other diagnoses that we might consider to bear some risk. You know, people with psychotic disorder loading or family loading in that, in that angle. PTSD, which is often comorbid, we've excluded for now. Comorbid MDD, we have not excluded, and we are in fact, you know, looking at measures of depression alongside measures of anxiety. In general, I would say this is pretty close to an all comers with primary GAD. Can you please specify, sir? Absolutely, we'll be exploring I think at this point, you know, as in terms of top-line data in particular, and we're looking at the broad population. There's going to be a number of subgroups that we're going to be assessing, certainly. You know, some of them will be pre-specified, some of them will be some post-hoc analysis we'll conduct. With the size of this study across the four, excuse me, five different treatment arms, four active drug. You know, there again, there's going to be a lot of learnings, and we want to make sure that we don't slice the data and torture it too hard to try to, you know, and then come away with some spurious conclusions. There are certainly subgroups when we think about prior treatment history, that we'll be looking at very closely to understand whether prior failure of standard of care would be predictive of better or worse response, severity. Some of this is particularly meaningful in terms of the economic value proposition. In psychiatry, it's not something that we talk about all that often. It's, you know, you don't think of limiting to moderate, severe anxiety like you do in other therapeutic areas that it is much more common. It does have a meaningful differential effect in terms of healthcare utilization and the cost of the healthcare system. If we can see, for instance, in higher-severity patients as good or even a better response, that would be hugely important, to understand, because it would also speak to the value that we could offer to that high-cost patient segment. Comorbidities would be also very important for payers because of the drug cost. We got some questions from Elemer Piros at EF Hutton. What would you consider to be a win in terms of efficacy when compared to the standard of care for the phase II-B? Well, one of the things I think it's often, you know, we talk about the SSRIs being fairly well tolerated, but in many cases, they are not. In many cases, you know, in almost the majority of cases, patients are non-responsive to SSRIs. A first and foremost, a positive, statistically significant result is, of course, for a phase II study, what is critically important and would support progression into reasonably sized pivotal studies. Beyond that, you know, a treatment modality that is administered and has a durable many week or even month effect, would be so different than the treatment options that are available today. That would be extraordinarily promising. We think of SPRAVATO as now getting a lot of uptake and the infrastructure being developed, and now it has a seen significant growth over the last quarters, over the last year, and a significant revenue and profit source. Even if we were to show one month of durability, we'd have a better kind of administration profile compared to SPRAVATO. Anything beyond that is only upside. Historical evidence would suggest that that's a real possibility, that we'd have more than a month of durability of effect. In terms of the magnitude of response and in terms of the durability of response, if we're even able to marginally exceed the standard of care, but show a single administration has a multi-week or multi-month effect, that would be a huge positive. Again, there's, I think, a lot more upside beyond that, but in thinking of sort of what bare minimum expectations would be, we would certainly want to meet the magnitude of response and have a better durability than, say, SPRAVATO. Just a comment on tolerability, which is that, you know, people will stay on a drug when there aren't other options, even if it has difficult, you know, and in many cases, upsetting side effects. We can only consider tolerability, meaning going on drug, staying, you know, staying on drug, going off drug, when there are meaningful alternative treatments. Great. any additional questions? Okay, great. Well, thanks, everyone, for attending, the MindMed Investor Day. Thanks, everyone.