Definium Therapeutics, Inc. (DFTX) Earnings Call Transcript & Summary

Good morning, and welcome to MindMed's Investor Day. I'd like to thank you for joining us. I'm Max Jacobs, VP of Investor Relations and Corporate Communications for MindMed. I'm joined by members of the management team and team's 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 #2 of the presentation. And now I'd like to introduce Rob Barrow, CEO of MindMed for opening remarks.

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 that are 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, where we're going as an organization. All right. So the agenda for today. I'll give some brief opening remarks, and then 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 D-tartrate program for generalizing 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 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 think -- 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 have ever studied and we're exploring other innovative ways of using the molecule and using its pharmacology in a variety of indications. So what gets us so excited about the opportunity here as a drug developer, particularly as the 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 high-end 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 3 critical things. One is that there's a rapid reduction in clinical response. So 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 in acute pharmacological effects of LSD that are quite perceptible to the individual who's been administered the drug. But 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. And while there is a shorter window of sort of on-drug perceptional effects, the window for clinical benefit is much shorter as well. And so 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. And then importantly, in the drug class -- of the entire drug class, LSD is the most storied the most studied molecule out there. So 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. But 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. And ultimately, it was, I think, amazingly born out of Sandoz and research outside of psychiatry entirely. So it takes us to where we are today in the backdrop, and certainly, I won't steal Dr. Oquendo's thunder here, but the landscape in which we are developing our program, developing MM-120 is unfortunately very dire for patients. We have seen no real innovation in anxiety disorders in decades now. We've seen now a growth in both the expenses but also growth in the diagnosis and really, over the course of the 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. But today, CNS sales are on the rise. It's one of the highest growing therapeutic areas. And we also see as the drug classes 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. Now 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. And 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's talk about how payers think about bringing innovative treatments forward that could have that kind of dynamic. But also the thing that's really important 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 in 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 in neurotic illness. And the diagnostic drift to depression really left anxiety by the wayside. We've all seen the commercials in the '90s and 2000s of you have a chemical imbalance in your brain, and that's why you have depression and take Zoloft it will cure. And 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. And one of the core features one of the core characteristics of psychiatric disorders that is less well treated by the antidepressants is anxiety. And so 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 massive flood of individuals reporting increased anxiety levels, certainly increased levels of depression. But as we went through a global pandemic, the sort of underlying core feature of anxiety came to the front of many people's minds. And in the last year, we've seen now the USPSTF recommend anxiety screening for all adults and for adolescents and children, 8 and above. So now we're entering into a world where the epidemiological data tells us that diagnoses are growing. This is a growing problem. 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 for successful in our development program, will one day be available to these patients and help what we think as sort of trajectory authoring perhaps for these patients. Obviously, in psychiatry, we don't so much talk about disease modifying as you would in other therapeutic areas. But given the durability for many patients, we think it's a really unique opportunity that we wouldn't just be sort of masking symptoms chronically, but we'd rather offer sort of transformative treatment option that could take patients both acutely and long term into better outcomes. All of these dynamics are also a function of -- also play out in the reality that the GAD pipeline is less crowded than the MDD pipeline. And obviously, there's a significant overlap in terms of depression and anxiety diagnosis. When we look at the diagnostic criteria for anxiety depression, we internally look at it as something like an 80% overlap in symptomatology. And 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. And given the relative lack of certainly new treatments with the relative lack of treatments in general that are approved for finalizing anxiety disorder again, we think our opportunity within 20 really represents a sea-change that will be shepherding in over the next several years. And as I mentioned before, LSD, I think it gets lost, I think, on the reality of what the incredible opportunity we have in front of us. So 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. And LSD is one of the -- again, the most storied in some ways, the more stigmatize 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 have 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 psilocybin with less well known and there's an easier opportunity to bring it forward. But 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 the group in Switzerland that has been using LSD regularly. It's also have been using psilocybin and in many instances, we hear from these providers that they prefer LSD that in some cases, patients benefit -- in their opinion, benefit better from a longer treatment session. It gives a greater window of opportunity to have these sort of transformative insights and outcomes in their patients. And when we work 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. So where we are today? We announced about a month ago that we had exceeded 50% enrollment in our Phase IIb 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 2 important data readouts later this year, our Phase IIb study in generalized anxiety disorder. And our Phase II proof-of-concept study of low-repeated administration in ADHD, which is ongoing as well. So coming up on a critical period for us. And when we look at that long history of LSDs using, and I think it's an incredible opportunity and we're 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. And lastly, certainly, not least, is our intellectual property strategy and perspective -- and apologies for the technical issue on the image here. But 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. But what we have done or make important improvements at every step of the process, we believe. We've been -- made improvements in terms of synthetic pathways, in terms of stability of the drug, in terms of differentiated drug products that we ultimately would seek to take forward into 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. And Chad Shear later in the day, we'll talk much more extensively about IP strategy and considerations. But 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. And 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 is also the Psychiatrist in Chief at the hospital, the University of Pennsylvania, past President of the APA, and I could go on, but she has an incredibly impressive background, and we're very honored to have Dr. Oquendo here today. Thank you.

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 -- right. sharing some information with you and happy to chat later or take some questions. So 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 a constellation of symptoms was known as anxiety neurosis. And in the '80s, in fact, when it first arrived on the scene, many clinicians consider 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. So the clinicians were observing the co-occurrence of these 2 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 1-year period. And that translates into but it says 7.5 million but really, it's about 11 million people since we have 360 million people in the country, more or less. And 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 3 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. And importantly, individuals are oftentimes quite impaired in terms of work and estimates suggest that between 4 or 5 days per month of work are missed by individuals who have generalized anxiety disorder. So 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. And 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 we'll prescribe all sorts of SSRIs and 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. And 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. So of course, as the illness is more severe, the impairment from the illness is more pronounced. And 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 presentism right, when people show up at work but really are performing suboptimally. And it also worsens a multitude of physical conditions such as cardiovascular conditions, gastrointestinal conditions, migraine and many other conditions. So it has an impact also on the physical health of the individual. So 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. So it's not a one-size-fits-all. That also means that there are different approaches to treatment that may be considered. So for example, I also mentioned already that it's comorbid with depression very often. It's also comorbid with posttraumatic stress disorder very often and with substance use disorders, especially alcohol and benzodiazepine use disorder. So one of the things that clinicians think about when they're selecting a treatment is what are the other co-morbid considerations. So 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 pharmacologic intervention will fail this pharmacologic intervention and 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. So 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 -- serotonin and norepinephrine reuptake inhibitors. And again, it makes sense to choose these types of drugs because they're also very effective for major depression. And 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 2. Pregabalin is another option marketed as Lyrica and 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. And most individual clinicians will not prescribe benzodiazepine as a standing medication because of the propensity for addiction and individuals with anxiety. Antipsychotic medications have been used and perhaps the most commonly used 1 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 that's not unlikely uncommon for individuals to gain between 20 and 40 pounds on these medications, also increase cholesterol and increased waste girth. So very difficult. And although the bullet says that the patients would be considered treatment resistant after 4 failures, I would say that most clinicians consider 2 failures, an indication that this is a treatment-resistant individual. So this is just a bit of a summary. I already mentioned that these -- the SSRIs and SNRIs are the most commonly used. And they're -- the approvals for generalized anxiety disorders include paroxetine and escitalopram as well as duloxetine and venlafaxine. Benzodiazepines, only a few of them are approved, alprazolam and one other. But again, as I mentioned, very commonly issued by clinicians because of the risk of addiction. Buspirone is approved for treatment, and it does take quite a while to take effect as do antidepressants, the SSRIs and the SNRIs and tends not to be a go-to drug for this condition. Most individual clinicians will not select tricyclic antidepressant. They also have very significant side effects, including cardiac arrhythmias. And importantly, if taken an overdose are can be lethal. I would say that it would be exceedingly rare for a clinician to use a monoamine oxidase inhibitors for this condition, also very dangerous in overdose, lots of interactions with other drugs and with food, which can be fatal. And I mentioned already the GABAergic drugs such as pregabalin, which is a calcium channel blocker in has downstream effects on both GABA and glutamate. And again, the antipsychotics are kind of a last resort because of their significant side effects. And I didn't mention tardive dyskinesia and other movement disorders that can occur with their long-term use. So we definitely have some opportunities in this space in terms of finding other medications that can be useful. And some of the early data suggests that there can be rapid and pretty durable effects of psychedelics. They're -- because they don't have to be taken on an ongoing basis, necessarily be concern for safety issues is diminished by that. And also one of the most difficult things about treating any condition if you if you're a clinician, you know is getting the patient to take the medication. And so the fact that these are often taken not frequently and also under supervision increases the likelihood of compliance. And 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. And just let everyone know after the next speaker, we will have a Q&A session for you to be able to get in some questions. So next speaker is going to be Dr. David Feifel from the Kadima Neuropsychiatry Institute, and he will talk about some of the practical aspects of monitoring therapies. And 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, but 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 typical psychiatrists. A little bit about me. Rob wanted me to share a little bit about my journey. So I started my career as an academic psychiatrist at the University of California, San Diego. And my biggest focus really was trying to develop innovative treatments. I joined -- I decided to become a psychiatrist because I really felt that during my career...

While Dr. Feifel is getting set up here and I'll sit down as soon as he's...

Hello, you guys hear me?

There we are.

Can everyone hear me? I'm not sure because I had started and Rob sounded like maybe I wasn't coming through. Lisa, if you can let me know if I'm coming through now. Okay. Great. All right. Well, I'm just going to start all over. So hello, everybody. I'm Dr. David Feifel. Sorry, I couldn't be there in person with you. I'm over on the West Coast here in San Diego, California. And I wanted to talk to you today about some of the practical aspects of incorporating an innovative treatment like, I guess, my video is an -- let me see -- so you cannot start your video because the host has stopped it. I don't know 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 and into the sort of armamentarium of the typical psychiatrist. Rob wanted me to share some of my -- it says please open your camera. Well, I'm trying to, by the way, Lisa, I'm getting a little chat says you cannot start you did it because the host has stopped it. So that's on you guys. So I'll keep going until I get a little message that I've been enabled to start my video. But in any case, Rob wanted me to share a little bit about my journey. And 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 that neuroscience advances were accelerating in such an amazing way we were developing ways to image the brain non-invasively. And just really, it heralded -- was very auspicious for new treatments. And I thought this is going to be -- psychiatry is going to have a golden era much like some of the other fields like thoracic and cardiovascular surgery in the '60s and the heart transplants. I just wanted to be part of that, and I was really interested in research and also in clinical work. And 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 do research in humans to develop novel treatments. And 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 treatment, some of which the previous speaker had mentioned, same treatments that were developed in the 1960s in the original antidepressants and anti-anxiety medications and it was very disheartening because while they do help some people, they really fall short for very many people. And as everyone I'm sure knows, mental illness is just an incredible -- incredible scourge in society. And the prevalence is doing nothing but growing. And certainly, recently COVID instance, definitely sort of add gasoline to that fire. So there I was mid-career thinking, well, I might have missed the boat on this because really nothing is coming down the road. And in fact, and I just want to tell you that about almost a decade ago in 2013, There was a very well-known -- at least well known in our field -- in the New York Times by a prominent psychiatrist by the name of Richard Friedman. In August 19, 2013, he rolled out [indiscernible] that is called dry pipeline for psychiatric drugs. And he starts off by saying fully 1 in 5 Americans take at least 1 psychiatric medication when it comes to mental health, we are facing a crisis in drug innovation. And 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 decades ago at the beginning of the psychopharmacological revolution. And I remember that out and the gloominess of that era very well. I remember sort of the alarms kind of talk at conferences because actually pharmaceutical companies -- here I am -- pharmaceutical companies, actually, we're pulling out of CNS R&D because they just could not developing anything innovative. And it felt like we were on a ship in the middle of the Atlantic and no tailwind at all. We were just stuck. And it's interesting how things have changed. I'm going to talk a little bit about that. But anyway, 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 is developed in the late '60s and early '70s as an anesthetic being repurposed for depression and the results were just amazing. Infusions of ketamine were rapid and robust improvements in major depression. And since then, it's been extended to other things like anxiety and so forth. And there was also an approval of a very innovative treatment called transcranial magnetic stimulation, which really a lot of people didn't think was going to not be much, but I thought that this could really be revolutionary since it's a noninvasive way of stimulating the brain and treating things like major depression. Next slide, please. So in any case, I left UCSD around 6 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 trying to be nimble and highly innovative which might come as a surprise to some people. But I was -- I founded the very first ketamine infusion program in the real world, taking those -- the research that had been done in a few centers. And we're seeing remarkable results, and then I was one of the first in the country to start providing TMS therapy. But I felt that kind of 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 starting to be sort of rejuvenated or resurrected from their sort of the relegation to kind of schedule on taboo. And I felt that this was really going to be the tsunami that finding is going to push psychiatry over-the-top into sort of this modern era where we had really effective treatment. So in 2017, I left and I started private institute called Kadima Neuropsychiatry, where we provide ketamine treatments. We do transcranial magnetic stimulation, and 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. So I wanted to tell you a little bit about sort of how we run our ketamine program? Because I think the last -- been 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 have -- 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. So insurance companies tend not to want to pay for things that don't have the imprimatur of the FDA. But after a consultation, if patient is appropriate for ketamine, we started them off with a series of 6 treatments over 3 weeks, and then adjust the dose to 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 its durability, the fact that 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. So if they want to continue their benefit, they need to come in again and again. And because again, it's not covered by insurers. 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 per day. I wanted to show you this picture, it is sort of our setup. It's a little bit dated or the [ core ] is better now. But this is basically the setup. We have a 5 treatment room sort of in a semi-circle, patients are monitored through CCTV, and we have wireless blood pressure devices that give us -- allow us to monitor the patients vitals without intruding on them because they really don't like to be disturbed. They're experiencing this psychedelic-like experience. Ketamine, although you might add -- not have heard of it as a psychedelic or if you've heard of it, you've heard it as a as an anesthetic at the sub-anesthetic doses, it does produce a ketamine -- does produce a psychedelic experience. These patients are having psychedelic experiences often referred to associative experience because ketamine tends to kind of dissociate people's thoughts from the feeling of being in a body. But nevertheless, we have 5 simultaneous treatments going on with nurses and a doctor ready and available to intervene. And doing it this way, we're able to feed about 70 to 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 1.5 hours. Next slide, please. Now I wanted to give you a couple of examples of innovative treatments over the last few years that have been widely adopted in psychiatry because I know a lot of you are probably thinking psychedelics are such a different type of treatment than traditional treatments in medicine and psychiatry specifically, how is this going to be applied in the real world. Well, 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 esketamine, it's the enantiomer of -- one of the enantiomer of -- one of the components of ketamine but administered in a nasal spray. The 2 features, the esketamine versus ketamine and the nasal spray versus IV infusion or intramuscular injection, which is the typical ketamine that is delivered, allowed, I think, some innovation that allowed us the approval of a patent for Spravato. And because of that, Janssen thought that they could -- from a business point of view, go ahead and develop this drug that it approved in 2019. And initially, it fell flat because there really wasn't the appropriate codes for building this nasal spray that patients actually self-administer. I mean they don't get -- they don't actually get to be in possession of the spring. They need to come into our clinic but where they are given the spray, they're monitored as they administer it nasally. They take -- they put it in their nose and take puffs. And then they're required to be monitored for 2 hours according to the FDA regulations before being discharged and they can't drive. Initially, this was a very kind of unprecedented a nasal spray that needed to be done in the presence of a monitored environment and then watching the patient for 2 hours. It was very unusual. But within a short time, because there was such a need for treatments like this, especially something that was covered by insurance, ketamine within a short period of time, codes were developed and insurance companies put out rates for these codes. And today, there's a very robust business of Spravato, I would say, probably accounts for close to 1/3 of all of our -- all of those treatments that I mentioned that we administer in a week. So 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 psychedelic. I should also mention that the -- in order to administer Spravato, sites have to be certified and trained by the -- by Janssen. And so I think this is probably going to be the model for psychedelics at least initially because they require a distinct and somewhat specialized skill sets and trained personnel. But whereas when I started doing Spravato of maybe 1 or 2 providers 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 knowledge about this ketamine like treatment that's covered by insurance has grown. So 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. So 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 approved in 2008. And it's a very -- it's obviously a medical device. You can see a picture of our TMS device here. You see 3 helmets there. The middle helmet was approved initially by the FDA for treating depression. It is sort of a second-generation TMS device that was actually approved in 2013. It's called Deep TMS. It goes a little bit deeper than the original version of TMS but you can see now that there are 2 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 has been FDA approved for OCD. And when 1 on the left, targets to get 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 talk therapies or the medications or even the ketamines and Spravato because these still are medications. And this is a noninvasive device that stimulates parts of the brain. And then slowly over time, we'll strengthen those areas. The practical logistics of TMS are very unique because patients come in every single day, at least Monday to Friday for 6 weeks, and then there's a less frequent period of tapering down over 3 weeks. And so they actually come into the office. It doesn't actually require a physician to be present during the treatment just available. So that was kind of unique for those of us in the field allowing us to do treatments and actually be able to build for treatments while not necessarily being physically face-to-face with the patient. And 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 coming into the office every day, and it was only out of pocket. But it didn't take long until insurance companies started to write policies for that. And today, TMS is widely extensively covered by both public and commercial insurance policies. In fact, insurance has made it easier and easier over the years to get this approved, I think, because they see that it's something that can help patients who failed to benefit from medications. So it was hard to imagine when this device was first approved. In fact, when I went to my Chairman at UCSD, really pushing hard that we should get one of these new devices in 2008 that has just been approved. He scoffed at me, "You thought how can -- how can this device that emits sort of magnets to help anybody." And it was just kind of -- it was hard to envision that this could be an important new treatment. But I can say today that TMS is part of the conscience of every psychiatrist whether they actually do it themselves or just refer patients to psychiatrists like me who provide it. And it's an interesting model of something that sort of came out of the left field was totally not in line with the way we had been doing treatments up to that point. But in not too much time is widely accepted in the field in all the guidelines as even a potential first-line treatment and has wide insurance coverage and is actually very profitable, at least from the provider point of view. So I think that the important message here is that while psychedelics may seem like they are very different than additional medication treatments because of 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 present to be physically in a safe environment that's monitored for many, many hours. It seems like it's really doesn't -- it's a square peg in a round hole. I can tell you that there are precedents in our field for very, very different treatments integrating very well. And I think the important thing is that there is such a strong unmet need even with ketamine and TMS because there are limitations or something that can really, 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. And by all accounts, psychedelics are going to going to be the leader in terms of treatments that really, really make an impact on patients. And 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 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 a game changer for the field that it would otherwise probably be. So with that, I will end my presentation, and I think there might be a Q&A period opening up next. Thank you, everybody.

Thank you, Dr. Feifel. So some will now begin a Q&A session. Please wait for a microphone for asking your question. Brian?

Thanks for the great presentation. Brian Abrams 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 maybe 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 -- with the centers geared up for treatment of multiple -- 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 one of the -- I mean a lot of the patients that we see weekly with ketamine, for example, are patients that are coming in for maintenance. So at any given day, we have a mix of patients that are still in their initial phase, ramping up to get that optimal effect and then also patients that have already had the effect established coming in for their boosters. Now we anticipate that psychedelics require a lot less frequent boosters. So 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 meeting that. And I don't know if that sort of addressing the question you were asking. But I think that's going to be -- so I think it's going to be very, very applicable a setup like this. And you might be thinking, well, you're talking about now 8- to 12-hour sessions versus a 1-hour session, how is that going to be accommodated? But again, I think the big difference is that because patients aren't going to be needing that repeated dosing, certainly not as frequently as right now with ketamine that I think it's going to be a relatively easy adjustment.

Okay. Got it. No, that's really helpful. And then maybe just one quick follow-up. Can you give us a sense of scale? Like 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?

Well, it's remarkable how many ketamine clinics, and you're probably aware of this, have sprung up. And I think that a large proportion of them have capability, if not of doing simultaneous certainly more than 1 patient at a time. I think that probably the biggest lack in terms of adopting psychedelics would be staff trained to monitor. It's going to -- it's really going to -- we need to see exactly what the FDA REMS are going to be because I think there's already a push towards minimizing that monitoring. We've seen some initial Phase II studies going from 2 people in the room to 1 person in a room. We've seen a sort of a downgrade from 2 fully licensed therapists to 1 licensed therapists and 1 assistant who has a bachelor's degree with some experience in the mental health setting as is the case with MindMed's GAD study. And the FDA is agreeable to this. It seems to me as we -- as the safety is demonstrated at each phase to kind of lowering it. I think there's going to be a -- you asked about speed. So I think initially, this is going to be a bit of adjustment for a lot of the clinics getting people that especially the licensed clinicians who will have to go through the training associated to get them kind of higher than or get them affiliated with their sites. So that might affect the initial ability of some of these sites to kind of adapt this treatment and treatments like it. But I think over time, more and more of those sites will establish that staffing ability and also the requirements will continue to come down. So we find that like that margin where this is adequate to keep people safe, but isn't sort of excessive.

Great. Johnson Aschoff?

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 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 -- it's an interesting question. Right now for ketamine -- there's sort of the [ drug ] 6 to 8 treatments over 2 to 3 weeks at almost all the sites as an induction phase. So we -- unless patients are having just a horrible sort of reaction to it and just don't want to continue we at least we'll finish the 6 treatments before passing judgment because there is evidence that with ketamine that there's cumulative efficacy that multiple treatment stack over a short period of time will convert more and more patients from nonresponders to responders. So I would say that everyone does 6 treatments and at that point, if they don't have much efficacy, 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. And again, it becomes -- cost usually kind of plays a factor there. I think I think with these medications like the psychedelic, it's a little bit harder to know because they probably -- there's individual variability and depending on how the initial approval is, it's going to be one administration, are there going to be options for doing a second administration at a higher dose? Because also what we do is a just dose as during those 6 treatments of patients aren't showing evidence of the benefit and they're tolerating it well. So I think there will be -- the median time probably will be lower because we expect, I think, a robust efficacy from these treatments. But it's hard to know because we won't have the same flexibility like we do with off-label ketamine right now to just bring them back very quickly, adjust the dose. So that's a hard one for me to answer so I don't know the limitations, I'm going to 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 twice a week for 4 weeks. And after that, it drops down to once a week or less. So at the end of those 4 weeks, if patients haven't really had a good response they're probably not going to want to continue. But we do go for those 8 treatments because we do know that a lot of times, it takes those 8 treatments and sometimes longer, but it takes those treatments to -- for a lot of people to kind of experience the benefits or the benefits to emerge. So that's the protocol we can't deviate from that. That's part of the label. So I don't know what kind of label we're going to get, but we expect to see greater rates of efficacy and also we'll probably see less people dropping out because of just untenable short duration, which we see with ketamine. It has get great effects, but it's [indiscernible]. It's only lasting me 5 days, and I can't come in every 5 days. Even if I could afford it, we can't really do this every 5 days. So I'm sorry, that's a little trickier for me to predict.

Great. Thanks. Frank?

Frank Brisebois with Oppenheimer. So I was just wondering, we talked about first line, second line, third line, fourth line therapy and then treatment resistant. It seems like physicians kind of agree might be after 2 lines. I'm just wondering in the grand scheme of things, you're seeing developments with ketamine if LSD and psychedelics come to market, where would you kind of see it? Is it dependent on the patient? And then any thoughts on the duration of treatment relationship to durability of effect?

Well, I think that the label is going to dictate where these psychedelics start. Like for example, with TMS they have to fill -- by the FDA label, actually, they only have to fail 1 antidepressant, insurance companies initially put the bar at 4 because they were -- they were hesitant to be paying for this expensive multi-week treatment for all those patients. So they put the bar at 4, interestingly enough, they've lowered it, most of them to 2 now. But -- and ketamine, of course, was limited to patients who had failed multiple medications, mostly because of its controversial nature, and we felt that to justify providing this drug that a lot of people were worried about would cause addiction. And so forth, we had to be able to justify very few options being open to the patient. But I can tell you that because these drugs are usually in medicine if you're going to a more powerful treatment, there's a commensurate increase in the side effects and safety issues. But I think with psychedelics, as with the case with TMS and ketamine, we see less side effects even though we're getting higher efficacy. And so what I'm seeing over time is that more and more patients coming in with fewer failed trials and even no failed trials. With TMS, it's a little harder because patients want insurance coverage, insurance won't approve that. But with ketamine, I'm seeing patients coming in and 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 I don't think they are great treatments. And because there's no insurance barrier in the way their patients know they're paying on a pocket, they can make that decision. I tell a lot of patients, "Look, 5 years ago, I probably wouldn't have done this because it was still so controversial, but now as it's been more accepted and we see it safe. As long as you know that the guidelines in the field would still be sort of that you should try 1, 2, 3 antidepressants before doing ketamine, as long as you understand that there are other options to try which you knowingly want to forgo that. I'm okay with that. I might -- I probably would do the same thing if I were in your shoes." So I think initially, they're going to come out as a not first line. But from a clinical point of view, here's my prediction. I have a talk that I gave and the title to talk is Adios Prozac, psychedelics are revolutionizing the treatment of mental illness. I really believe that it won't be long before the conventional medication, the SSRIs and SNRIs that we've been using for 50 years are just no longer utilized. They're just I think it will be kind of a silly way to try patients on these medications when you've got these treatments that one session could potentially vaporize these -- these symptoms and are durable. So 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. We have time for 1 more question. Sorry, 2 more questions.

Sumant Kulkarni from Canaccord Genuity. And thanks to the company for hosting this event. So 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 initiatives to develop novel non-psychedelic drugs. I think that I'm not impressed that they're going to make a large impact. We've -- in our sight, 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 had a novel treatment for PTSD but just some data from other studies came back and they were disappointing and recruitment was kind of poor and they were difficult -- they were difficult to recruit and administer. So 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. But these -- I think this is sort of a 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 with Zuranolone. I think it's an interesting and it is a novel mechanism. I just don't think it's going to be revolutionary and take a real chunk out of the treatment-resistant patient population that we really, really need. So as far as I can see, really, there's nothing that comes close on the landscape in the pipeline to the psychedelic drugs and the treatment approach involved with those.

Great. And just one more question.

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? And then 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?

Well, I can address the second question first, and then I'm going to 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, very specialized psychotherapy. We talked about something called a psychedelic consistent psychotherapy, in ketamine, we call it ketamine-assisted therapies, but it's the same kind of concept. And there really isn't even an established standard of what approach should be used. There's family systems and other kinds of approaches that are being applied to this. And there really is almost no data that supports that adding very, very deliberate, highly skilled psychotherapy adds to just sort of support and setting considerations. And in fact, in the Phase II -- large Phase II COMPASS trial with psilocybin. We presented secondary analysis that showed that sort of the report or the therapeutic alliance between the patient and the therapist really had no impact on the outcome. And that was very disturbing for a lot of, I think, of people who really want therapy, want us to be a drug that facilitates therapy rather than the other way around. But I definitely see this as the other way around. And I do think the adjunctive therapeutic aspect is going to shrink over time to something much more kind of minimalistic because studies are going to show that the -- it isn't really the therapy that occurs afterwards the integration the specific nature of it that is really making the difference here. Not to say that that's not going to be important, but I think it's going to be much less -- there's going to be much less emphasis on the training and the scale of that. There are companies that sprung up certifying a therapist or psychedelics. And they have like 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. And this study, this Phase II MindMed's study is, I think, very interesting because the support isn't distinct therapy. It is mostly support -- and I think this is going to demonstrate that the need for that specialized super, super specific kind of training is not going to be required. In terms of your first question, if you could repeat it?

Yes. 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 evaluation of safety or other variables?

Well, I think because this is -- I think it's there's some probably going to be political pressure on the FDA. These are drugs that are associated with bad things. There's been schedule one. So the FDA is going to be super cautious at first. It's remarkable in my mind, I'm still -- I still find it hard to believe that drugs like LSD and MDMA are fast tracked and accepted by the FDA in terms of these registered studies, and they're actually facilitating that they want to. I think it speaks to the incredible need -- the unmet need that's pushing the FDA to say, look, we cannot stand in the way of potential game changers. So I'm always surprised to hear from our colleagues on the on the industry side, when we're talking about how the FDA is actually being very, very user-friendly with these medications. Now there are obviously going to be restrictions because they don't want anything bad to happen and they're going to start off with very specific REMS and requirements. And I also think the companies themselves are going to really be very, very vigilant and be selective initially and who gets to do these treatments and who they certify because they want to be done right at the beginning because that's when something untoward could really have a bad impact on the whole field. But 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. So specifically to answer your question, I think the approval is essentially the same but I think what the FDA is requiring for this. In other words, they approve -- they're going to approve what the studies have -- the way the studies have done it. That's the way they're going to improve it. They're still going to require 2 placebo-controlled Phase III studies. All the same requirements are going to be there. but I think that they're requiring more from studies in terms of built-in safety like the monitoring and so forth. And there's probably going to be a period of post-marketing very, very close vigilance were 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 our patients are able to be discharged typically at the 2-hour mark? Or do they have to be retained longer? Have there been any kind of untoward effects from the treatment? I think there's a little bit more -- a little bit more concern, so it will 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 these questions. So next, we have Dr. Michael Kobernick. He is a Senior Medical Director at Blue Cross Blue Shield, and he will discuss the payer landscape.

Well, I think we're pretty clear on the unmet need. And just to give you a little bit about my background. On a personal note, highlight from the payer perspective, what we're thinking about -- pretty much have heard at all. I have a couple of comments that relate to the questions that you had. I've been -- I spent the first 30 years of my career as an emergency physician and so all of these patients in the emergency department suffering from general -- generalized anxiety disorder, depression, PTSD. And I saw it in a lot of my colleagues, and I wouldn't underestimate these conditions in high-stress professions. I expect you see it in some of your colleagues. And so 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 and Michigan, and my primary role there is advising employers on strategies to manage health care benefits, which I've been doing in the last 5 years. I focus on both outcome and cost as a basic economic principle and was very active in Ascension health system that had many administrative positions there. So 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 on 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 5 years ago, when we looked at when we broke out the claims on musculoskeletal, 90% of the surgeries, joints and hips were done inpatient. And so today's question was, can we scale the treatment centers that was so elegantly described. And so 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. So 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. 5 years ago, when I was talking to employers, and we're like, yes, we're going to move all your knee replacements to the outpatient setting, they were like we're kidding. And results are better. Outcomes are better and fewer infections, people are back to work sooner. Employers are concerned about -- we heard nicely 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 going to save anything but they think people are going to do a better job. And they have a philosophy they're going to give benefits to people or share the cost of benefits with people, and they want to 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 cost and outcomes -- costs are higher, outcomes are worse. And so this slide gives you some sense of where this fits in the total -- the total scheme of cost. But 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, how 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. So 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. And as we've heard today, and I can't add anything to on the interest in ketamine and psychedelics. So 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 our specialty guidelines and subject matter expert opinion. So 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 their objective and 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 were doing -- when we developed it, very conservative approach. We were part of the group that we're saying, "Really? Magnetics?" And we had a whole committee of physicians and -- 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 includes Spravato. Sleep study is another good example. Sleep studies have -- are another good example of continuous observation that have coverage criteria. So really then a couple more comments. There is an unmet need. It's going to get covered. If it once it's FDA approved, I think that the sites of care will -- I think that the model that we saw will be a predominant model for this. A couple of other points I wanted to make. We wouldn't have expected that audios Prozac caught my attention. We wouldn't have expected to be saying goodbye to metformin in diabetes. And 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. And we're going to see that move forward in addiction. So 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. And so I think that you'll see the PA that will be based on the studies, probably failure of an SSRI and -- but 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.

Questions? Good. Yes.

Sumant from Canaccord Genuity. So 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 an FDA approval in a coverage determination. The only place that might come up is in a reauthorization. And so that will set how long it's approved for and if there's a reauthorization. Sometimes you'll see a 6-month reauthorization or after a durable time where the documentation required is evidence of improvement. So I think if they have improvement and then after 3 months, it needs a retreatment, we may or may not prior authorize it. But if we do it, it will just be to attest to evidence of improvement.

So do you see the prior auth as the key impediment to someone being able to use this product or use a product like this as psychedelics?

I don't see it really as an impediment. It's a validation. And what you heard was about TMS. What you heard from him is the established lines of treatment approval, same thing with Spravato, established lines of treatment approval. It really isn't -- it really isn't an impediment. Some people see -- clinicians because it's a paper process or an electronic process see as an impediment. But from a health plan perspective, we just see it as validating that the care is necessary in the right setting by the right individuals. And we see that -- and the PBMs will tell you the same thing. We see that as our responsibility to the employer and the member.

Frank with Oppenheimer. So just a quick question. So what do you think the biggest obstacle for this class will be on the payer coverage? And then could reimbursement happen quicker now that we've learned from TMS and we've learned from Spravato?

Yes. I think the once -- the biggest impediment is FDA approval. And I think that there's always a lag time between approval, release and policy, but there'll be -- 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. And most health plans that I'm associated with or have been associated with pride ourselves on having policy ready at release.

Can you give us any framework for what sort of -- Brian Abrams, RBC Capital Markets. Any framework for what sort of price would be supportable in terms of the cost of both a drug like this and the administration around it? Any framework based on precedent?

Yes. So I think that without -- I couldn't give you any numbers specifically I'm sure you guys have actuaries and teams of finance people. I would say the same price it applies to Spravato and other observation services will be appropriate for the treatment I don't have any concerns about that. And the price of the drug will really be left to what the manufacturer brings out.

And 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 in a typical plan level for this to become broadly available? And how long does it typically take?

Typically, we try to work to have these available at the time of release. Typically, during that 6-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. So there's a very robust payer access team and approach that every manufacturer has and they're aggressively marketing the plans. And so I would expect that to occur here, probably starting in some priority fashion with your biggest PBMs and health plans.

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 a 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...

So tiering -- so your tiering question has to -- really is about where will it fit in the form -- where in our what co-pay will be attached to it, what out-of-pocket expense. So the oral agents usually come in, employers have in commercial mostly 3- to 5-tier plans. So a 3-tier plan, as you know, generic preferred brand, nonpreferred brand, specialty and preferred and nonpreferred. The -- I would say this would be a preferred specialty preferred brand, nonspecialty. And that's where I think it would land because we don't want to disadvantage the member and employers are not going to want a disadvantage of the member with an overly high out-of-pocket expense. You got to 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 2 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 nonclinical negotiating teams that manage this and for good reason. And so -- that's how I see the landscape playing out preferred brand. And I don't think you'll have a lot of excess limitations. I don't even think your PA will say administered by a psychiatrist because nobody else is going to administer it anyway.

I'm just wondering what -- 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 when I said that things start out narrow and evolve, that will evolve that way. And there will be patients who have generalized anxiety disorder. PTSD is probably the place you're going to see at the moment. Most often, People aren't getting to the psychiatrist without seeing a primary care physician who might start an SSRI anyway. But I think as there are certain case parameters, and we heard from 2 experts today. And they really know -- will know the patients that will benefit from first-line therapy of these medications. Since it's going to be in a controlled setting, I honestly don't think that will 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? As maybe they were 2, 3, 4 indications, does that then help get the drug more into that frontline site?

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. So it gives you a little more information. You spend less time worrying about safety, more time worrying about the evidence of the indication. And of course, the indications are the key. And again, everything when you're looking at this, it's really what is the evidence say. That's what we see.

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, but they put me on a clock, so I won't be up here too long. My name is Chad Shear. For the last, I don't know, 20, 25 years, I have been helping innovative drug companies maintain or rather analyze their market position, their exclusivity position and then ultimately try the cases and try to maintain that position. The focus of really what I'm going to 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. So 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. So a 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 2 different sources of exclusivity. There's patent exclusivities, there's regulatory exclusivities and they both interrelate. So patents good for 20 years. There are 3 ways that it got extended. Two of them are unique to drugs. The one that's not unique to drugs is what we call PTA patent term adjustment is basically when the patent office isn't super diligent and how quickly they move things through the office, you can actually get some of that time back, 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 going to 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. So the PTE, it can be a max of 5 years. So there's -- it's I'm going to 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 time frame. And that can be anywhere from a couple of years up to 5 is the max. Now you'll see on this slide, it says 14 years from approval. So if by happenstance, just the way things work out, you're allowed to get patent term extension on 1 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 patent issue -- when your drug is approved, you don't get PTE. So that's the sort of the 14-year caveat. You can add up to 5 years, but they're not going to let you have more than 14 years of sort of your drug being on the market. That's the -- that's sort of the patent side of the exclusivity -- there's -- 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. So you can literally just look at the grid and sort of map out the time frame 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. So if the FDA invites you to do studies for pediatric indication, whether that's successful or not, it's not always successful. But because the FDA has asked you to spend those additional resources on that study, you get 6 more months. It's 6 more months of patent effect, but not patent life. Let me explain what that means because it sounds really stupid. Your patent actually isn't enforced for 6 more months. Your patent expires when it expires. But the FDA will give you a 6-month period of an additional regulatory exclusivity that gets added on to the end of your patent life. So most people just sort of confusingly think my patent is going to be around for 6 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. So there are 2 main kinds of exclusivities that you get from FDA. There's what we call NCE exclusivity, new chemical entities. So if it's the first time that a drug has ever been approved you get 5 years of NCE data exclusivity. That means no one is allowed to rely on your data for 5 years. Generics can actually rely on it a year earlier and file, but nobody actually gets approval in those 5 years. Now that's important because new chemical entity means never approved before. It doesn't mean that the chemical entity itself has never existed. So like in the context of LSD. LSD has been around a long time, but it's never been approved by FDA. So 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 3-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, 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 3 years of your formulation, but you don't get the NCE exclusivity because diclofenac has been around forever. And then the pediatric exclusivity, we sort of -- we talked a little bit about here. So 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 and NCE exclusivity, you get 5 years. Now there is a bonus if you have a patent. So if you have an NCE exclusivity that's 5 years and you have a patent you end up with a period of time of 30 months being added to the end of your 5-year exclusivity. So if a generic just to sort of break this out a little bit. You have a 5-year NCE exclusivity, a generic drug company files an application. They want to launch a generic version or product. They can do that a year before your 5-year exclusivity expires but the FDA will be statutorily prohibited from granting them final approval until 30 months after your 5-year window ends are 7.5 years. So that NCE exclusivity, if you have 1 patent in the Orange Book that NCE exclusivity turns into 7.5 years. So -- 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 you some examples in a second, so you can sort of figure out how some of this works and how it actually has a financial impact. But 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. And I'm going to give you some specific examples of that in a minute. But it ends up being, from a financial point of view, a big deal. So you can patent the new compound. As soon as you discover the molecule, forever ago, the chemist figured 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 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. And so everything else that you see that follows really tracks those innovative steps, whether that's drug formulation. So 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 track can be absorbed by the body. The way you make it, obviously, is a big -- is a big deal. Also, it's 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. And then finally, sort of the risk factors, the REMS, you can actually patent those processes as well. So 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 has expired, the compound was "old" and so 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 -- sorry, generic drug companies 2010, the company maintained the market until 2019, all because of some formulation patents. So the formulation patents in that context gave the company 8 additional years of exclusivity on the market. Another example did a case in the mental health space, where compound pat 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. I thought the market was going to completely. The drug 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 2 years. So these other patents, separate apart from the NCE patents can be incredibly, incredibly valuable. And 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. And I could sit here for the next 45 minutes -- this is why they put me on a clock. I could sit for the next 45 minutes to just tell stories about the number of times where we've seen products -- products protected by these patents that we call secondary, tertiary patents that the market has not priced into the value and then you see the jump when the dates come out. So 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 3 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 nonobvious. So from a scientist perspective, and this is the key, it's a scientist that's looking at this, it's not thankfully me. It has to be not obvious. It can't have been obvious to a person of skill just sort of looking at it. In Europe, they call it an 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. And then finally, it has to be useful. Sort of a basic idea, right, if the government is going to give you a monopoly on something, you actually have to be contributing something useful to the space. And then finally, this all plays out in the context of the Hatch-Waxman Act. So there are incredible resources available to you for free to help you figure all the 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, used to actually be a book that was published they haven't been published in a decade, I think. But it's an online database. Type in the drug's name and instantly, it will come up. It will give you everything you need to know about the drug, and there will be a little button on the bottom that you tap that says patents and exclusivity. It will take you to a new page that lists all of the patents, list when they expire. For some of them, it will even give you a use code as to what it is that the drug is related -- that the patent is related to. And then on the bottom, it will give you all of the exclusivities. There's other kinds of exclusivities that I didn't talk about today, but it will give you all of them across the bottom. So when you're trying to analyze any drug, it's an incredibly valuable tool. The last piece, and then I can -- 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. So regardless of what kind of exclusivity that you have, whether it's an NCE exclusivity that goes for 5 years or the commercial exclusivity that goes for 3. 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. So 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. So I can't think of another drug class that has so much anecdotal evidence of potential efficacy as the psychedelic. So how do you think that is going to impact the landscape for patentability from a method of use perspective? Or are we going to see inter parties 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, you 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. But that's never just -- so you say efficacy, right? It's never just about one thing. So I'm just going to give you an example. The case that I mentioned were 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. So 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 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. And oftentimes, anecdotal evidence, if it's -- a lot of it is not even admissible in court basically, how is it -- how you're going to get into evidence. So in the end of the day, I wouldn't put a lot of stock in anecdotal evidence and instead track what's been written in journals, what's been presented in conferences. Those are the things that really from an efficacy perspective, really matter.

And 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?

So carve-outs is a really sort of complicated topic. Just for the group. There's a portion of the Hatch-Waxman 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 anti-depressive. Later, it got an indication for PTSD and the patents on PTSD went way longer than the patent on depression. And so 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 anti-depressive because those patents had expired. So 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? So 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 1, 2, 3 -- if you have multiple indications sort of more than 1, 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. And 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 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. So you talked about the nonobvious bar. And that does that nonobvious bar move a lot depending on the country that you're in? And just anecdotally, have you seen experiences where as much as you would think something is not obvious, some scientists, I think it's extremely obvious, so 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. So the answer to your question is sort of at a high level, yes. So in the U.S., in Europe, Canada, Australia, in those markets, obviousness has really looked at the same way. I will -- just give you just -- the rest of the world, it just depends. So just to give you anecdotally some color, I have a case, I had a case, it's over now involving a patent on what many in this room would probably consider 1 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. So 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. But for the most part, the major markets, the major places where you're going to generate revenue, apply the same standard are close enough that you wouldn't really be able to tell the difference. Great. Thank you all very much. I appreciate it.

Okay. Great. So now just our concluding speaker, Rob Barrow, CEO of MindMed.

All right. 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. 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 into the organization. And then we look at what's ahead coming up from 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 coming up in a critical time with very important data that really takes us back. And for the first time, it was modern high-quality evidence, we hope will generate 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 psychedelic are unique phenomenologically, while there's 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 a number of other treatment centers, both academic and commercial or private treatment centers and 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. But over the past couple of years, again, I want to highlight, we've been incredibly fortunate to build out an extraordinary team. We have, from day 1, taking a very rigorous approach bringing in experts who have gotten CNS drugs approved in the past who know the landscape who have worked and many -- intersect with some of the cases that Chad was mentioning before, and have the experience to leverage market exclusivity. And ultimately, as we saw it out, and as I said before, IP is at the core of everything we do. And 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 affects the ability for providers to ultimately to rollout 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 [indiscernible] 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 of the serotonin 2A receptor. One of the most studied destroyed targets in all psychiatry, but one with LSD with MM-120, the most potent agonist that we have seen to date on serotonin 2A, but it also doesn't stop there. Again, we think of multiple modalities how we can use these drugs, a session-based delivery setting like in GAD, but also either sub-hallucinogenic dosing or innovative dosing paradigms and dosage forms that could be leveraged in the future and other creative ways of treating -- 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 Substance Act really coming into force, we held 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 and other anxiety disorders, such as our colleagues from University Hospital Basel last year reported out results where 2 treatment sessions of 200 micrograms of LSD resulted in rapid and 6 to 12 months durable effects. We've heard from Dr. Feifel and we heard from Dr. Kobernick, the importance of showing that durability. But 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. So I know in talking to Dr. Feifel about some of the patients, he see. He has patients that drive over half an hour to get to the treatment site for a 5-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 3-month durable effect as we'll ultimately be able to report from our Phase IIb 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 were able to get patients in, treat them and show that durable responses, what really sets this drug class and sets our asset apart. And then more recently, as we heard as well, results in other diagnoses, such as depression, open up new markets, open up new revenue sources, sources of profitability. But we also think of this as 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. And 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 2 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 [ labeling ] and also the 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 IIb study. We really believe that there is much more that could be brought into the pipeline in the future. So talking about our ongoing study. It's a Phase IIb study, many of you are familiar with 200 patients across 5 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. We know that there's a degree of correlation between the magnitude of the perceptual effects and the ultimate clinical response. But that correlation is not necessarily positive and we've also seen more recent research suggesting that the duration of a perceptual effect opens up things like social learning windows that could be correlated. So 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 differentiated treatment profile when you look at some of the other drugs in this class as well. But the other thing that's really important, and we talk about 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 1 that we feel very convicted about that we do not -- from day 1 when we designed our Phase II study, we went in with this concept in mind that we need to make sure that we are 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 in that things like generalizing anxiety disorder, depression and use disorders are not isolated to high-population metropolitan areas with good academic centers. Our view from again, from day 1 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 going to 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 of being Vivitrol, where in development, there's a very confined, very contained delivery modality and delivery paradigm that FDA mandates and 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, but we are ultimately getting to a label in a REMS if one is ultimately used for these drugs that we have to be thinking about all of the patients who can access these, all of the geographies where those patients live. And that's been our intent from day 1 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 III study. So when we've seen the field really move in the direction of walking back the psychotherapeutic intervention. From day 1, we've been talking about noninterventional psychosocial support. And our view is that our Phase II results will then be much more translatable in terms of predicting the effect size we can ultimately expect in Phase III 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 in our next earnings call, which will be in August and are very excited as we come up to the end of the year. I think we can't lose sight of the fact that while a lot of this research has been ongoing for several years, other programs that have been a similar size have taken years to complete studies. Our program, we dosed our first patient in August of 2022, and we really had all of our sites fully activated and rolling only at the beginning of this year. So 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 and as we think about the kind of treatment effect size as we've seen in historical literature, if we're ultimately able to replicate those, which, of course, we are optimistic about going into our data readout. We're [ not talking about ] studies of 5,000 patients either. I think it's really important to note that the study size that we are already executing 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. And so it gives us a really unique insight in terms of how we can be most effective in executing pivotal studies, how it can be really efficient and progressing from the end of a Phase II program, getting into Phase III as quickly as possible and then running those studies as quickly as possible because we have such a degree of optimism in our clinical program and our development strategy. We want to make sure we are pushing the envelope. It's also in some ways a benefit to be where we are in the position in the industry, coming out to an important readout this year where we have, obviously, peer companies, competitors who are embarking on Phase III programs who are, in many ways, going to be supporting and laying some of that infrastructure and help -- we hope, minimize the time line to maximize the efficiency for getting things like policy in place and getting reimbursement and laying that infrastructure out there when we get our drugs to market, they will ultimately be able to be rolled out and uptake 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. And it's not because I think it's always important for us to preface that is we believe that the psychotherapy has a place. We also believe that many of the patients that are going to be coming into these studies that ultimately will be treated, likely are already receiving some form of psychotherapy. And here in this country, that tends not to be from psychiatrists, it tends to be from lower degreed individuals. Our view from day 1 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 -- we put in the hands of clinicians and physicians. But ultimately, the observation and the oversight of delivery of these therapies could be done by other individuals who aren't necessarily MDs and don't have necessarily the doctor 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. And that ultimately, there's a kind of collaborative care model that can be rolled out where patients can be seen, be prescribed therapy and also ultimately being delivered that therapy by someone else. And then 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 come see me at some point in the future. So 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. And so we are developing tools and ways of monitoring patients and trying to ensure that patients who ultimately do see some benefit, but sometime in the future return to have relapse of their symptoms are able to come back in, be tracked and be helped again. That's also where our digital programs commence. Our 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. They use technology in their clinic to deliver multiple -- over 70 deliveries of ketamine and Spravato per week. And that's a fairly impressive throughput. And we think of the administrative overhead for doing that versus delivering perhaps 1 treatment session per room per day. We want to make sure that all the clinics that could ultimately be delivering these have those tools available. And so our digital medicine programs are very much aligned with facilitating adoption of these drug therapies that we're developing, particularly our recession-based delivery of MM-120. And 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. So when we think about pretreatment, we still anticipate that as with Spravato, there's going to be some prior to treatment education. 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 before going into a treatment session. During the 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 2 hours for Spravato is somewhat limiting because some of those patients may not need to be in the patient -- in the clinic for a full 2 hours. So 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. And so if we can do that, 1 patient may be held for a shorter period of time based on when they would ultimately be able to leave safely and return back to their home or back with oversight and release from the clinical setting. And 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 systems that they can be intervened with and brought back into a clinical setting for perhaps a retreatment. And 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. And at the end of the day, our path to commercial success. And I hope you leave here today understanding that providers, as all the providers that we speak to who are engaged and knowledgeable about the developments in our area and our program with MM-120, we see this consistent pool of 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 that 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. And then getting through payers and having these negotiations, but I think we're already seeing in psychiatry. There's been so little meaningful innovation every year as we're already seeing the kind of innovation where -- or excuse me, 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. And then 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 and core to our mission from day 1 and something that we feel very optimistic about the ability to get these drugs to patients that need them at scale. And finally, I see lunch is coming in for all of those of us who are here in person. I'll pause there, and 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 is on track. What are some of the learnings and the takeaways that you have, I guess, as both the good and the bad that you found that you can apply to your Phase III study and then ultimately to your commercial strategy? And then 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 be relatively similar to what you've already been -- what you're already doing with the Phase II?

Yes, absolutely. Dan, if you want to come up, we can certainly tag team Q&A. But I'll start by some of the learnings -- why don't we sit down or -- 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...

Yes, absolutely. One of our clinical sites, the Cleveland Clinic 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. But they didn't know that one of the study participants really commented on how much they appreciated not having 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 1 said, 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 some of the other approaches in the field, we think will be much easier to adopt. But the fact that, that's actually -- not only is that facilitating easier administration, but we're actually hearing that there's an appreciation by providers and by study participants that they're effectively left the loan to do their own work. We hear this with Spravato, hear this with ketamine as well as we hear from Dr. Feifel earlier. It's 1 of those funny oddities where in our drug class and with the psychedelic, there's this legacy of how things have been done. And 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 on, this is how they should be done in the absence of evidence that it really is hard to justify for us. So I think we've seen a really regulatory embrace, a practical embrace of the way we've been approaching this, which we are -- obviously, when you go into these things, you have a conviction about something that somewhat of an uncertainty because you don't know if the world is going to come back your way or stay the way it is. But I think we feel really justified in our approach and now the evidence is more and more supporting that. In terms of the time line to getting into pivotal studies and the gates there, yes, 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 as we think of our Phase II design, when we designed the study, gosh, almost a little over 2 years ago now. When we first set out on this approach, it started with thinking about the ultimate label and commercialization in our Phase IIb study, while it's 5 arms, and we don't expect to be doing 5 arms in Phase II almost everything else about the study design was set up to be like a Phase III study, where I don't think we anticipate any sort of massive changes in terms of our delivery protocols in terms of how we how we assess clinical outcome measures, primary endpoint, things such as this. And so certainly, there will be some differences as you go into a Phase III in terms of the number of sites perhaps or subjects and it's going to 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 is almost -- we would have copy pasted it 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.

Jonathan Aschoff with 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? Anything about that?

In terms of -- outside of the clinical setting and anecdotally?

[indiscernible] these are patients, they have the disease so it is clinical setting. But I guess what comes to mind is like [ cortico ], something that might embrace Western medicine but also have dropped these boundaries that we still have here?

Yes. I think -- and Dan, feel free to comment, of course. But where we often look to is Switzerland, and we have strong ties in Switzerland. But there's also -- this doesn't get talked about all that much, but there are dozens of psychiatrists in Switzerland who have a license, the right to use psychedelics in a compassionate use setting. And 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. So we've had a lot of learnings having those discussions and reaching out to those networks. And has informed -- our development approach has informed how we think about delivery models but 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. And over and over go, 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 it is shorter is better. And that's not something we've seen supported in data. It's also not something that we've heard from practitioners. I said when we have these discussions and interviews with the Swiss psychiatrists. In many cases, we choose LSD because either because of the duration or the reliability of getting to some sort of desired acute effect that they believe is translates into the meaningful clinical benefit. So 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.

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 psilocybin, will you be looking at redosing? And I have a quick follow-up.

Yes. So the exact design is something I think will 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. But our expectation is that we intentionally embarked on a Phase IIb study that is the most extensive exploration of dose response in a clinical setting ever conducted to our knowledge and 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. So 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 1 or most 2 doses depending on what we learn from the Phase IIb 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, there's interesting interplay. We've heard FDA now on multiple occasions, very publicly at conferences talking about the considerations that we feel need to be thinking about and generating evidence around so things like durability of response. There's many ways to tackle this, right? So 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 and that would be anesthetics. If you took an anesthetic got surgery the first time, and it worked great but the second time you came in, you didn't get any anesthetic effect, that would be a big problem. And we want to be thinking about that and characterize either such a long durability that we reasonably believe that on average, patients could have many, many, 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 the subsequent treatments would be additive not blunted. So that when we talk to the Swiss psychiatrists who use these drugs, they were continually kind of represent that 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. And so we see enormous excitement around the ability to retreat patients both because we'll generate the evidence for approval, but also because it could generate even more meaningful long-term kind of clinical response that would be important for the patients, an important for the value proposition of these drugs as well.

That's really helpful. And a quick follow-up. So 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 the 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?

Yes. 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, we have a multitude of scenarios in mind for what we will do in XYZ scenario. But 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'll 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. And so really, 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, 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 a 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 the interplay for which patient populations we should be targeting with which doses. And so we're not going to be constraining our thinking quite yet. We're just going to be waiting for the data and also make some decisions based on the safety and efficacy response we see in the Phase II study.

Patrick Trucchio with H.C. Wainwright. Just a few follow-up questions. First one is just you showed the slide on the digital strategy. Just curious how will your digital strategy potentially expand access to MM-120. And 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. So I'm wondering how does your -- well, your target product profile, will this enable you to kind of slide in with that Spravato infrastructure? What would that look like? And then just finally, earlier you mentioned approximately 76% of GAD is moderate to severe. What proportion of that group is going to be or could be appropriate for MM-120?

I can speak to digital. And 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 into appropriate patients. So we can provide towels to help ensure that that's the case. We'll see more prescription. And then a lot of this will be at the point of delivery. And this relates to your second question, which is who's actually going to be sitting with people while they're having the drug experience. And 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. And so 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 views. And it expands to your second point, the environments in which the drug can be administered. So there's the -- so ketamine like infrastructure where you think of a specialist clinic that does session-based therapies. But we think we can drive uptake in more routines like a therapeutic environment. So the kind of places where psychotherapy is delivered today by the folks who are doing the psychotherapy today.

I'll just make one other comment on digital, which is that 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 these procedural barriers that were put in place, really, were a challenge for adoption. And in some instances, there's certainly a negotiation that happens with FDA in latent development. But we have a number of learnings from the Spravato case, but also things like 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. And so where this intersection is in terms of where the drug can be used, how we can get your documentation and how we can develop, so 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. And so 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.

So to address your question, Patrick, about the percentage of patients that will [ reachable ] for 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, and the sizing of this market, the different segments there. But when you do primary market research and you ask the provider or 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 certainly are not going to be initial candidate for MM-120 until we have more information about the safety of the drug because those patients are actually excluded from the Phase IIb. But 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 launch eligible for MM-120.

And just from a psychiatric perspective, there's no reason that any patient with moderate to severe anxiety would be ineligible. So it's really who we can reach in the market, not so much appropriate as for treatment.

Sumant Kulkarni from Canaccord Genuity. So most of us seem to know, and Dr. Oquendo also mentioned this, that GAD is a very diverse disorder. So other than 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? And do you have any prespecified 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, people with psychotic disorder [ loading or family loading ] in that angle, PTSD, which is often comorbid, we've excluded for now. Comorbid MDD, we have not excluded. And we are, in fact, looking at measures of depression alongside measures of anxiety. So in general, I would say this is pretty close to an all comers with primary GAD.

So absolutely, we'll be exploring, I think, at this point. In terms of top line data, in particular, we're looking at the broad population. But there's going to be a number of subgroups that we're going to be assessing, certainly. Some of them will be prespecified. Some of this post-hoc analysis of what we'll conduct. With the size of the study across the 4 -- excuse me, 5 different treatment arms, 4 active drug, 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 -- and come away with some spurious conclusions, but there are certainly subgroups when we think about prior treatment history and 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 it is particularly meaningful in terms of the economic value proposition. And psychiatry is not something to talk about all that often. You don't think of limiting to moderate to severe anxiety like you do in other therapeutic areas. That's much more common. But it does have a meaningful differential effect in terms of health care utilization and the cost of the health care system. So 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 will also speak to the value that we could offer to that high-cost patient segment.

We got some questions from Elemer Piros at EF Hutton. So what would you consider to be a win in terms of efficacy when compared to the standard of care for the Phase IIb?

Yes. One of the things, I think it's often -- we talked about the SSRIs being fairly well tolerated, but in many cases, they are not. In many cases, and almost the majority of cases, patients are nonresponsive to SSRIs. And so 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, 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. Again, we think of Spravato as now getting a lot of uptake and the infrastructure being developed and now it has seen significant growth over the last quarters, over the last year and a significant revenue and profit source. Even if we were to show 1 month of durability, we have a better administration profile compared to Spravato. And so anything beyond that is only upside. Now we certainly -- historical evidence would suggest that that's a real possibility, that we have more than a month of durability of effect. But 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 -- fair minimum expectations would be we'd certainly want to meet the magnitude of response and have a better durability than, say, Spravato.

And just a comment on tolerability, which is that people will stay on a drug when there aren't other options even if it has difficult and, in many cases, upsetting side effects so that we can only consider tolerability, meaning going on drug, 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.