Okay, good morning, and thank you so much for joining us today. We're very excited about the R&D Day and what we're gonna be sharing with you about the future of Supernus. Now, before I get started, I just wanna remind everyone that we will be making forward-looking statements throughout the day, so please check our SEC filings for all the risk factors associated with our business. As far as our agenda today, I'll be making very brief introductions and going through a brief corporate overview, and then we'll get into the details behind some of the key product candidates that we have in our pipeline. We will have a couple slides on Qelbree at the beginning, as in the R&D setting, and then we'll get into 820, SPN-820 for depression. We'll have a small Q&A session behind 820. We'll get into the details behind SPN-817. We'll also have a Q&A session after that, and then we will share with you some early data we have on SPN-443 for ADHD and SPN-446 for narcolepsy. We will close the day with a general session, including the Q&A. Today with me is Dr. Jonathan Rubin, who is Senior VP of R&D and Chief Medical Officer, Bryan Roecklein, Senior VP of Corporate Development; Tim Dec, our Senior VP and Chief Financial Officer. We're also very fortunate today to have with us Dr. Maletic from the University of South Carolina. Thank you for being with us. He's a clinical professor of neuropsychiatry and behavioral science. Also with us is Tom Hughes, who is the CEO of Navitor Pharmaceuticals, who's our partner in the development of SPN-820. So I thought I'll start the day by sharing this slide with you. Basically, to make two key points here, to give you a snapshot of how we were able to build the company over time, but more importantly, how we're managing the transition that we are going through today behind Trokendi XR. So if you look at 2013, way back when we first launched our first two products, Trokendi XR, Oxtellar XR, leading all the way to 2022, that's basically delivering a compounded annual growth rate of about 56% over the years. In addition to that, as you look at 2023, and this is the last guidance we talked about in August of this year, the $580 million-$620 million. If you put that in perspective, losing Trokendi XR, the exclusivity, which peaked at $320 million, and being able, in 2023, to deliver those levels of revenues, is fairly remarkable. The team put really extremely well-designed plans in the earlier lead years leading to the transition and executed extremely well through corporate development, of course, the growth of Qelbree and GOCOVRI, and allowing us to maintain very healthy and solid revenue numbers despite the fact we lost exclusivity on Trokendi XR and losing significant revenues behind that brand. Also, behind that commercial success is also an exciting pipeline, which is the future of Supernus, and that's why we're all here today. So if you look at this pipeline, one very important observation, all these molecules are new chemical entities, some of which are also first-in-class mechanisms of action to treat multiple therapeutic areas in CNS. With the exception of SPN-830, which is a complex drug device combination that we resubmitted very recently, the NDA, and hope to launch in 2024. So how did we get to this point in building this pipeline, which is very different than the pipeline we built back in 2005 and 2006 when we started Supernus, which really shows you the evolution of the company, and that Supernus today is a very different Supernus than the Supernus started way back. Well, that really goes back all the way to the product development strategy, R&D strategy, that we had in place. We wanted to start first with known drugs, which is the bottom left corner, modify these products with new drug delivery, reformulation technologies, that we have a very strong expertise in, to deliver unique differentiation. And then as time goes on, as we get bigger, we have the resources, we can take on more risk, higher development costs, and also wait longer for a product to be developed to get to the market. We could also migrate on this risk ladder from an R&D perspective towards new chemical entities and products that are first in class, and that's exactly what we have done. So if you look at, as time went on and you overlay our portfolio, and here I just put some examples, this is not the whole portfolio that we have. You'll see how we started with Oxtellar XR, Trokendi XR, as known drugs, reformulated products, moving up from a strategic perspective toward products that have higher market value. Yes, higher risk, but also building towards a bigger market value and towards our vision as a company. As we will share with you today, you will see that 820 and 817 are actually first-in-class molecules, mechanisms of action to treat in these therapeutic areas. That pipeline, in addition to our execution on four key strategic imperatives, is going to allow us to achieve our vision of being a leading CNS pharmaceutical company with a multibillion-dollar market value. These key strategic imperatives start with corporate development. We have an intensive effort in corporate development. We will continue to have that. I guess we have shown the track record in the past several years in making three acquisitions, two different corporate development agreements with partners to augment our pipeline, our commercial portfolio, and allowing us to continue to deliver solid cash flows. We will continue to do that in CNS as well, in other areas potentially could be adjacent to CNS or other verticals that could make a lot of sense for us and could allow us to run the business in an efficient way. In addition to that, continue to capitalize on our R&D capability, which I will explain in a minute, what is that capability, what does it consist of? And then, of course, complete the development of SPN-830, SPN-820, SPN-817, and do what we always do very well, proven commercial expertise, launch the products, and build a multi-billion-dollar CNS franchise. By executing on these strategic imperatives, we have no doubt in our mind we will get to becoming a leading CNS company and a multi-billion dollar market value. So what is that capability that we're talking about today and that produce the pipeline, which we will be discussing for the rest of the day? On the left side, you're looking at the discovery platform, which we haven't really talked about in length in a public forum. This is a discovery capability that we have built over the years behind the scenes, basically focusing on new chemical entities. We have been screening hundreds of molecules that allowed us today to be able to talk about SPN-443 and SPN-446, and talk to you about the use of these products, the differentiated profile of these products versus the market and the pipeline products that are out there. On the right side, clearly, those are capabilities that we always have, which is amazing capabilities in drug delivery, in pharmaceutics, PK formulations, GMP manufacturing, and so forth. So coupling the two together is what have been allowing us to really put a very strong pipeline together and will give us the confidence that we will be able to execute on that pipeline and get these products eventually to the marketplace. So looking at the near term, what kind of milestones we will be talking about, and as we get into the details, you will see these programs. We will be talking in more specifics about timing. But in general, SPN-830, as I mentioned, the resubmission, which everybody knows about now, we just announced it recently. Potential launch next year. Then you look at SPN-820, where we have the phase II-B clinical study that is ongoing right now. That will go through 2025. And just to note, these bars don't necessarily mean we're getting data at the end of 2025, but during 2025, and we will communicate these a little bit more specifically as time goes on. SPN-817, phase II-A data. We are very excited that today we will be sharing with you some interim data from the open label study that is going on with SPN-817. And then SPN-817 also next year, we will initiate a phase II-B study in epilepsy as well. SPN-443, which is the new molecule for ADHD, we did a lot of work in the previous years, especially this year on the preclinical side, and we're very excited that we will be filing the IND in 2024. So we have a lot of near-term milestones that we will talk about for the rest of the day in more details. Very briefly, we are very well positioned for continued growth with three key areas. First, the existing portfolio that we have today with Qelbree and GOCOVRI, that will continue to grow and continue to give us the cash flow that we need to be able to invest in the pipeline that we will be talking about today. A very innovative R&D portfolio that we will get into more details, as I mentioned earlier, first-in-class molecules. We will share with you the mechanisms of actions, the details behind these molecules, and why we believe they're not only first-in-class, but also they're very well differentiated versus marketed products as well as pipeline products. Then finally, continue to execute on the corporate development side to augment our growth through external growth opportunities. With that, I will move forward and transfer it to Dr. Rubin to start the discussion on the pipeline. Thank you. Good morning, everybody. First, I'd like to give you an update on some Qelbree studies. About a month ago, we announced the results of a study that showed co-administration of Qelbree with a stimulant provides incremental efficacy above and beyond that of a stimulant. This was a phase IV open label, flexible dose study in children and adolescents with ADHD. The primary objective of this study was safety, and the secondary objective was looking at efficacy outcomes, notably the ADHD-RS-5, a traditional way of assessing ADHD symptoms, as well as the CGI severity, looking at functional improvement. The baseline ADHD symptom rating was 37.2, which is moderate to high symptom low. You can see in this data that there was a change at week eight of -18, which was about a 50% change, a fairly significant impact on people who were already being treated with stimulants, either amphetamine or methylphenidate. In addition, there was functional change. If you look at the CGI severity score, people came in at a rating of 4.4, which is moderate to marked level of symptoms at baseline. And after treatment, that was moved by 1.4, which is getting into the mild to moderate range. A big jump for, again, for people who were coming in being treated with stimulants. Now, the primary objective was safety, and the adverse events you can see were fairly consistent with what we saw in monotherapy trials, and the discontinuation rate under 4% was fairly low. So this offers some evidence to clinicians, many of whom are using Qelbree in combination with a stimulant. This gives them some data and some confidence about this treatment paradigm. So we are about to launch a study looking at the efficacy of Qelbree in adults with ADHD who have mood symptoms, either depression symptoms or anxiety symptoms. Now, in our phase III registration studies of an ADHD, we looked at a group of subjects who had ADHD with no comorbidity. They did not have anxiety, they did not have depression. We excluded them. This was intentional. We wanna have a good look at the effect on ADHD and not have the confound of comorbidities during our phase III program. However, in the real world, there's only a small percentage of subjects who have ADHD without comorbidity, and what clinicians really wanna know is, will this work if someone has ADHD plus a comorbidity? So, and I mean, the impact of this, there are 60% of adults with ADHD who have depression, and almost 60% of adults with ADHD who have anxiety. So this is quite common, and we have reason to believe that this could work 'cause we know that viloxazine in an immediate-release preparation was approved for the treatment of depression in Europe. So we will be starting this quarter, a phase IV, open-label, decentralized clinical trial. The decentralized study enables us to reach a broad range of people. They can complete rating scales and do interviews in the comfort of their home. The study will have a treatment period of 14 weeks. We'll use Qelbree 200-600 mg a day. We intend to enroll 750 subjects, which is quite a large study, and hope to get 500 completers from that study. The primary efficacy analysis will be a change in the AISRS. This is the same ADHD rating scale that we used in our adult ADHD 306 study, which was the basis for approval of Qelbree in adults with ADHD. And we're gonna look at the change in the AISRS in adults with ADHD who have mood symptoms. But in addition to that, we are also gonna look at depression symptoms with the MADRS, the PHQ. We're gonna look at anxiety symptoms with the Hamilton A and the GAD-7, and we'll be looking at a variety of other assessments, including work and home functioning, executive functioning, and sleep. Last week, we announced that we submitted the filing, as Jack noted, of SPN-830, the infusion device. This is SPN-830 is a subcutaneous infusion of apomorphine, and our intent is to get an approval for the continuous treatment of motor fluctuations, also known as OFF episodes, in Parkinson's disease, in people who are not adequately controlled with oral levodopa and one or more adjunctive Parkinson's disease medications. If approved, this gives Parkinson's disease patients an option of a continuous daily infusion above and beyond what they might get from as-needed injections. This could be a change in the paradigm of Parkinson's disease treatment, so it could be an intermediate option from oral treatments in between oral treatments and advanced invasive surgical treatments. And this could be a nice intermediate place that gives both patients and clinicians a new option. This, the NDA was resubmitted, as I said, a week ago, and the submission is in response to FDA's complete response letter, which we received about a year ago. So now I'd like to switch gears and talk about a new product, SPN-820. This is a first-in-class product that has a unique intracellular mechanism that it will be, is intended to treat depression. Now, before I go on, I wanna clarify some nomenclature. SPN-820 is what we will refer to as the product. SPN-820 is you... What you will hear for the product that was used in humans. We will also refer to NV-5138. This is the active product ingredient. We'll talk about NV-5138 when we talk about mechanism and when we talk about a substance that was given to animals in the animal experiments. So you'll hear both terms, but it's referring to a similar thing. Before we get to SPN-820, I want to talk a little bit about the depression market. It's a huge therapeutic area, 195 million prescriptions. About 8% of adults have had at least one episode of major depression, and the COVID pandemic triggered a huge increase in mental health problems, including a 25% increase in depression. Roughly 1/3 of adults will have depression, slightly more in women than males, but it-- there's a lot of depression out there, unfortunately. The current treatment paradigm involves using generic SSRIs or SNRIs. Significant issues with these medications, they're slow in onset, can take six-eight weeks to work, if they work, they don't always work, and they can have significant side effects, including sexual side effects and GI side effects that may cause patients to discontinue or switch to another medication. A lot of patients within this class do not respond to treatment. If you look at the results of the seminal STAR*D study, roughly, you can think about this as a third, a third, a third. Roughly, a third do not respond to the first treatment, a third do not respond to the second treatment, and a third do not respond to the third treatment. So let's talk about the diagnosis. Major depressive disorder, or MDD, is classified by the DSM-5, the Diagnostic Statistical Manual of the APA, as having five or more symptoms in a two-week period, at least one of which has to be a depressed mood or loss of interest or pleasure, also known as anhedonia. Treatment-resistant depression are t he definition, there's some debate in the field. So if you look at FDA's guidance, they define treatment resistant depression, or TRD, as a failure of two or more antidepressants, or ADTs, of adequate dose and duration of each of those treatments. But within the field, healthcare practitioners and an evolving literature suggest that TRD may be considered as a failure of just one drug. And when you think about it, both clinicians and patients, they don't want to wait to go through three or four drugs to have treatment. They are at risk for suicide, impairment at home or at work, and they want something that's gonna work fairly quickly. So hence the debate about how you define TRD. But regardless of how you define it, we do know that the managed care environment is going to ask that patients and providers step through generic SSRIs and SNRIs. And so, in practicality, it may not make a difference. So let's take a look at the drugs that are being used to treat depression, and there really hasn't been a lot of innovation over the last several decades. If you look at this list, practically every drug on this list is working either through serotonin, norepinephrine, dopamine, or a combination of some of those. The only exception to that is esketamine or Spravato, which works as an NMDA antagonist. I'll talk about more about that in a moment. So if you look at the future of the treatment category for depression, drugs that provide faster relief, greater tolerability, and improvement of neuroplasticity, this is an emerging term. You'll be hearing more about that. A drug that provides that now or in the future could provide long-term benefit. The current leading brand, Trintellix, differentiates based on efficacy, pointing to effects on the DSST, Digit Symbol Substitution Test, and lower sexual dysfunction side effects. But newer products, such as Spravato and Auvelity, are differentiating by faster onset. But Spravato has onset within the first day, but it has restricted use related to the NMDA antagonism, including a REMS and a risk of abuse liability. Auvelity has separation from placebo within a week. So, going back to the current treatment paradigm of the monoamines, serotonin, norepinephrine, and dopamine modulators, the field is moving towards molecules that will impact neuroplasticity. We have development of the psychedelics, which is a really interesting and challenging field, and we'll see how that plays out. But there could be significant adverse events, including dissociation, and when you administer psycho... When you administer psychedelics, they have to be administered in the office in conjunction with psychotherapy, which some people may or may not want to do. But looking towards the future, be it psychedelics or other drugs, remodeling of the brain, of the synapses, could produce long-lasting benefits. So we're getting away from the monoamine model and looking more towards a synaptic plasticity model and field. This could be a large field, possibly $5 billion plus. So in thinking about what an ideal product could look like, a high effect size on depression symptoms with good response frequency, fast onset of effect on depression symptoms, one week or less, no cognitive impairment, and possibly even cognitive improvement, no impact on sexual dysfunction, and a positive impact on neuroplasticity, low to no dissociative side effects, and at-home use as opposed to needing to go to the office to administer psychotherapy or getting esketamine during an office visit. So now it's my pleasure to introduce Dr. Vladimir Maletic. Thank you very much, Dr. Rubin. Indeed, we will provide a very brief overview of relevant neurobiology of major depressive disorder, and we'll also talk about what be it NV-5138 or SPN-820 can bring that is novel, that is different. So speaking about the evolution of treatment of depression, we see that ECT was one of the first focused treatments of major depressive disorder. It emerged in the late 1920s, although frankly, attempts to use electricity to treat psychiatric illness started in 16th century. Ben Franklin was involved with some of the experiments. In late 1700s, there was documented effort to treat and improve psychiatric disorders via electricity. So it's a very old idea. There were chemical compounds used to induce seizures, which were believed to be effective even before ECT was approved as a valid treatment modality. I will not go any further into that discussion, but suffice it to say, first, true new antidepressants were developed by accident within miles of where we sit now. So in the 1950s, there was a large, as a matter of fact, largest in the nation, TB sanatorium in Staten Island. It's called TB Hospital, and they were using a new treatment for TB. This medication was called iproniazid. It's a hospital that has large windows overlooking the ocean. Patients were sitting there in melancholy mood, dejected, uncommunicative, absolutely no interest in anything that would be neuropleasurable. They received this new TB medicine. They started joking, they started singing. There were some reports of dancing in the hallways. A dramatic change. What in the world happened? This TB medicine was relatively short-lived because it was proven to cause liver problems. But it became parent compound to two different medications. One is called Isoniazid, so Iproniazid is the medicine I'm talking about. Isoniazid is still used TB medicine. Isocarboxazid, its close relative, was the first monoamine oxidase inhibiting agent, the first antidepressant. Tricyclics followed, also completely accidentally noted. Medicines that were being initially developed for treatment of motion sickness, were found to, by accident, have antidepressant effects. What do they have in common? They boost serotonin, norepinephrine, and dopamine. If medicines that boost monoamines are effective antidepressant treatments, theory suggested that patients who have depression have something abnormal in their monoamine transmission. We have been stuck in that mode for a better part of seven decades. I'm not going to diminish the benefits of monoamine modulating antidepressants, but I do want to balance it with limitations. Limitations that about 40%, which is significant, number of patients, is about as much as one would hope to achieve remission. If we look at functional remission, in addition to clinical remission, the number is lower. Then if we look at remission that is sustained over time, the number is yet lower. You've heard from Dr. Rubin about STAR*D. Going through different treatment modalities, four steps. Step four, 12% of the patients achieved remission. 12%. How many retained that remission after 12 months? About 3.5%. So the more we cycle to antidepressant treatments, the less hope there is for our patients, number one, that they will achieve remission status, and number two, even if they do, that they'll be able to sustain it over 12 months. So what it suggests to us is we need something new. I think that with monoamines, we've pretty much exhausted our options, and we do see a need for something new and different. You have heard that there are glutamate modulating medicines, not mentioned, but there are also GABA modulating medicines that are approved, too, for treatment of major depressive episode, but very specific scenario with postpartum onset. And of course, there are so-called neuromodulatory treatments. ECT is a neuromodulatory treatment. Transcranial magnetic stimulation is a neuromodulatory treatment. Not mentioned here, vagal nerve stimulation is actually approved for treatment-resistant depression, and there's a lot of effort to update it to where it would now have proven efficacy, not only for treatment-resistant depression, but also for treatment-resistant bipolar depression. So there is a lot of going on. People are trying the different things. There are several compounds in development, not only psychedelic type, but also glutamate platform. So, what about neurobiology of major depressive disorder? Is something that has become relevant to us. Well, we're finding out that, in a very macroscopic level, there is a change in neural network connectivity that may underlie symptoms of depression. And you, you have heard a lot of qualifiers in this sentence for a very simple reason. Major depressive disorder is one of the most neurobiologically diverse conditions. So we are not to assume that we should be speaking about MDD in singular. As a matter of fact, assume the opposite. Correctly, we should be talking about major depressive disorders because they do not have common underlying neurobiology. More recent theories, along with monoamines, are entertaining the option of GABA and glutamate relationship being disturbed, changes in neuroplasticity. How do we know about this? From postmortem studies. So BDNF, Brain-Derived Neurotrophic Factor, VEGF, Vascular Endothelial Growth Factor, and glial-derived neurotrophic factor, GDNF, have been found in postmortem studies to be altered in patients who have major depressive disorder. Where? In anterior cingulate and hippocampus. We have also seen that these can be altered based on the peripheral blood samples. So there are changes in neuroplasticity, along with GABA glutamate transmission, which are now being looked into. Speaking about communication between brain networks, let me provide very simple outline of what these brain networks are all about. Salience network receives all the sensory information about changes in our external and internal environment. In response to these sensory changes, it generates an emotion, which is a warning sign to let us know that some form of adaptation is necessary. It's not activated easily. Right now, your bodies are in touch with the back of the chair. That is not something that will trigger an adaptive response. But on the other hand, if you were to notice smoke billowing from the back of the room, that would warrant adaptive change, and therefore, salience network is going to signal to central executive network. Main component of central executive network, the dorsolateral prefrontal cortex, posterior parietal cortices, not that much important. What do they do? They will immediately reallocate your attention. You'll stop paying attention to what I'm speaking about. You will focus on seeing where the exit signs are. Where is the fire? How do I get out of here? You will start planning. You will start storing relative information into the working memory. Central executive network. And another one, the name is default mode network. The name suggests function. It is involved in self-reflection, it is involved in reminiscing, it is involved in processing social information. So when we are off task, what—that is when default mode network is engaged. Communication between these networks is aberrant in major depressive disorder, and there are specific patterns. So in general, central executive network has diminished activity. Salience network, which again generates emotions, becomes hotwired with default mode network. How does this work? Think about negative emotions: anxiety, depressed mood, irritability, feeling dejected. Those negative emotions, instead of engaging central executive network and problem-solving, engage default mode network, and individual starts ruminating. It's non-productive elaboration of sad, disturbing events that have taken place in our past. So rumination is facing backward, worry is facing forward. This is what is happening in individuals who have major depressive disorder, right? So we need to realign, realign and make these networks function in more adaptive way. So what went wrong? This is just a summary of how aberrant network connectivity may translate into some symptoms of depression. So central executive network, diminished function, cognitive problems, very common in major depressive disorder. Default mode network, upped activity, rumination. Salience network goes from focusing on exploration, reward signals, interest, ability to enjoy life, to priorities and prioritizing now negative emotions, response to threat, danger, being anxious, being irritable, being sad. Well, up to recently, we could speculate, but we had no direct way of looking at key interface between these networks, and key interface has to do with synaptic connections. Now, there is synaptic vesicle glycoprotein. Its abbreviation is SV2A, which we can attach a radiolabel to, and we can actually look at synaptic density in the brains of individuals who have major depressive disorder. And here's what we're finding out. If they have mild symptoms of depression, there does not appear to be anything grossly abnormal about their synaptic connectivity. But if they have more severe form of depression, we see disruption, reduction in synaptic density. And where does that occur? It occurs in the hubs of these functional networks that I just described for you. So dorsolateral prefrontal cortex, hub of central executive network. Anterior cingulate is kind of the crossroads between salience network and default mode network. As you can see, severely depressed people diminish synaptic density, and hippocampus is a component of default mode network, actually, underpinning some of the self-reflection and reminiscing of the past events. So it is in these key brain areas, hubs of these major functional networks, that we have diminished synaptic connectivity. So the question is: Is there something that we can do about it? So now we'll speak about SPN-820 and NV-5138, and as you have heard, SPN-820 will reflect more on clinical studies, NV-5138 will reflect more on preclinical studies. So before I go into that, a very brief intro into what is mTOR and mTOR complex 1, mTORC1. So mTOR is a moderator, a regulatory molecule, that has been conserved throughout evolution. Amoebas have it, flatworms have it, dinosaurs had it, human beings have it, and in some ways, it is existential crossroads. And here is what I mean. What are some of the inputs into mTOR? This will give you a clear, clear idea of what it does. Number one, it is making a decision: Do we build things, or do we break down things? So if we're going to build peptides, we need raw material. Raw materials are amino acids. It senses amino acids. Two, we need blueprint for building new peptides. Blueprint will be provided by RNA and DNA. In order to build RNA and DNA, you need nucleotides. It senses the presence of nucleotides. Most of these nucleotides, about 60%, are going to go to ribosomal RNA, which essentially instructs building of new proteins. Third, if you want to be manufacturing something, you need energy, and energy is ATP, Adenosine Triphosphate. That is what it senses. It senses resources, and if they're present, the outcome will be engagement of ribosome, which is the central manufacturing. On the other hand, if there is absence of resources, you don't want to starve the cell, and that is when lysosome becomes activated and starts breaking down things. Actually, its location and function reflect what I've just described to you. It is docked at lysosome, at the breakdown plant, if you will, and informs ribosome, which is manufacturing plant. So it, those are the dualities that are tied down. Now, I mentioned amino acids. There are some amino acids that matter even more. Leucine is one of them. Why? Because it is essential. In other words, our body cannot create it. It has to come from outside. So leucine is one of the regulators of activation of mTOR. Have we brought in enough external resources? Now, what is interesting is, NV is a leucine-like molecule, but is it going to be built into proteins? Well, in that case, it would provide limited support to our mission. And what we're seeing is, look at yellow, that is leucine. NV is the analog, that's the blue bar, and if you look at all other bodily areas, they seem to be similar, but that is not the case in the brain. NV maintains its high concentration. Leucine concentration is much lower, hypothetically, because it's being built into proteins. So this suggests to us that one of the regulators of mTOR is preserved in the brain, and that's what we want because we want it to regulate mTOR function. So if we start screening molecules, especially for treatment of depression and anxiety, we go through certain standard tests. Forced Swim Test. A rodent is dropped into a large beaker that is 2/3 filled with water. Rodent starts paddling. After a while, I'm tired, there's no way of getting out of this beaker, stops paddling. Stopwatch clicks. You measure the period of immobility. This is not the same as depression in human beings, but shortening the immobility time is strongly correlated with antidepressant effect. Novelty-suppressed feeding test, what is that all about? Rodents don't like being out in the open, especially if out in the open is very well lit. So these animals, I hate to say it, are kind of stars. For 22, for, 24 hours, they're receiving no food, and then they're giving this option. Right in the middle of this open space is a juicy burger. It's not really a burger, but it's tasty food. Your option is, since you're hungry, you're going to overcome your anxiety and come in and eat, or you're going to be remaining in the safe place, deliberating what is the risk that I'm willing to take? A risk of continuing to stay hungry versus overcoming my anxiety and going out in this central open, area that is well lit. Novelty, female urine sniffing test is, part of reward-seeking behavior, as is sucrose preference test. Animal have two options to drink plain water or sucrose, sweet water. In usual situations, they will prefer sweet water to regular water. If they are stressed out, their hedonic tone, pursuit of pleasure, will diminish, and that ratio is going to change. And then human threat test suggest to us that primates have a lot of common sense. And when human, when primates notice a human intruder, it paralyzes them. They freeze. So an anxiolytic effect would be detected on human intruder test. So let us see how this medicine performs in some of these very simple tests. First, we need to explain what CUS is. It's chronic unpredictable stress. These poor rodents are put through motions, so you know that they're nocturnal. You're messing with their sleep cycle. You're turning on the lights and turning them off in random intervals throughout the day. You're messing with their feeding schedule. You're messing with their surface. They're in cage, and all of a sudden, you tilt the cage and make it where they're sliding all over the place. You keep on doing it. You're going to induce a behavioral change that, in some ways, can be assumed to have shared neurophysiology with depressed mood in human beings. So what we're seeing is when it comes to sucrose preference, if the animal is not stressed out, there's no difference between vehicle and NV. But if you stress this animal out, all of a sudden, you will see the advantage of NV in that they will still be preferring sucrose more. So it will contribute to restoring their hedonic tone. And then we see novelty-suppressed feeding, this hesitation. Do I stay hungry and safe, or do I approach food in the middle of the open field? Less hesitation if the animal is stressed out and then treated with NV. So now let us look at plasticity, because we were talking about reduced synaptic density underlying some of the depressive symptoms. Can NV do something about it? Well, what we see is that if we stress the animal out, GluR1, which is a component of an AMPA receptor, it's one of the fast ionotropic glutamate receptors, it is reduced. Activation of AMPA translates into activation of neuroplasticity. If we use NV, we will see that AMPA will be restored. Postsynaptic density peptide 95, again, suggests alteration in synaptic structure, and what we're seeing with stress, it is reduced. If we add NV to stressed out animals, it brings it back to the baseline. So there is a potential, based on these indicators, that it may normalize synaptic function in stressed out animals. So now let us look at what happens with dendritic spines. There is ample evidence, both in stressed out animals, so various chronic stress issues, and frankly, in human beings, that synaptic density is reduced. We have seen one of the imaging studies. So there are three types of synaptic spines. These stubby synaptic spines are stable, and they are supposed to be consequences of learning and acquired memory. Then we have these thin synaptic spines. They are being formed during our conversation right now. So a lot of this information is being very temporarily stored, and then we have these mushroom synaptic spines, which are supposed to be enduring. Why am I saying is being temporarily stored? Because you cannot keep on acquiring and storing new information in your memory. Your brain would become overwhelmed and would not function properly. So some of these synaptic spines are going to be eliminated tonight when you sleep. When it comes to these, these thin spines, they will actually be labeled. So microglia and astroglia have way of labeling these spines. They will either attach fractalkine or they will attach C1q. Now, this is not a pleasant thought, but while you're sleeping tonight, microglia will be crawling around in your brain, and if it sees these thin synaptic spines that have complement one q attached to it, it's gonna get gobbled up. That memory is gone. But if something that I'm saying this morning is emotionally important to you, or if it's being elaborated, that spine is preserved and turns into the mushroom. So what we're seeing here is this kind of selection of synaptic spines can actually be influenced by NV. We do see that stubby. Again, these are foreign memories, they're not gonna change much. There is a lot more sustained thin spine and especially mushroom spine. Why is this mushroom spine so important to us? Because these will contain more glutamate receptors, and if there's increased glutamatergic signaling, this is an electrochemical event. You should see more electrical activity. Is there more electrical activity? Well, let us stimulate these glutamate neurons in the presence of control versus NV and see what happens with electrical activity. So how do we stimulate them? Glutamate neuron can be stimulated by serotonin, predominantly serotonin 2 A receptors, or it can be stimulated by orexin. So these will be our inputs. The output will be the change in excitatory potential currents. So we're seeing change in electrical current, and if indeed animal is treated with a vehicle, with control, you will see no change in electrical currents, meaning glutamate transmission will not have a functional translation. But if you treat animals with NV, you will see change in electric activity, suggesting that there is change in glutamate transmission that is also linked with electrochemical events. So first in class, why is it different? This would be, if approved, the first intracellular antidepressant. Nothing like it so far. It does not work through surface receptors, and that may translate into different adverse reaction profile. This remains to be seen. Preliminary evidence so far is positive. Rapid effect within hours. Sustained, so far, the evidence is for 72 hours. More studies are on the way. And two, it will impact mTOR, which again is associated with proliferation of cells, but also increased synaptic density. And it would increase BDNF transmission, which is one of the main neurotrophic factors, which we've seen is negatively impacted in major depressive disorder. So this medicine is a good candidate because it has high brain exposure, and it has rapid but transient mTOR activation. So again, this is one of the key regulators, so you do not want to overstep your boundaries. It's a little bit like Goldilocks theory. Neither too little or too much is good. We need to be in that middle band. So now let us look at some of the pharmacology. Again, rapidly taken up in the brain, has no plasma protein binding. That is important because you can have potential for interaction for either with other highly plasma-bound compounds. There are no active metabolites. Majority of NV-820 is secreted through urine, and it has no significant binding or modulation of any particular receptor type. And I do want to point out here, other kinases aside mTOR, because mTOR is a kinase. So yes, it will impact mTOR, but not other kinase. Also, metabolic enzymes, CYP 450s, will not be influenced by this medicine. So it is a novel mechanism. Based on what we know so far, it's unlikely to be abusable. Unlike leucine, it's not incorporated into proteins. It is available in the brain, and it seems that its antidepressant is mTOR dependent... Now, what does mTOR stand for? Mammalian Target of Rapamycin. Rapamycin is a type of antibiotic which would paralyze mTOR, and if indeed you use rapamycin, it will abolish antidepressant effect of NV-820. So indeed, it does support this hypothesis. Let's look at the phase I studies, and before that, we'll go very briefly into the pharmacokinetics. So plasma half-life, about 11 hours. I'm rounding off these numbers. Cerebrospinal fluid half-life, about 12 hours. Exposure in CSF, this is not an unusual ratio, is about 1/10 of what it is in plasma. So about 1/10 makes it into cerebrospinal fluid. Pretty rapid absorption, I'm again rounding it off. Peak in plasma is about 1 hour later. Peak in cerebrospinal fluid is about 4 hours later, and if it is combined with food, although it will not change the area under a curve remarkably, it will push down the peak to about 2.5 hours later. So these are phase I studies. Now, what are phase I studies all about? Majority of these studies, unless I point out differently, there is one that's a proof of concept studies, are done in healthy volunteers. So we know what the input in. Input is going to be NV. What are we interested in finding out in terms of output? We want to find out what the plasma concentrations and CSF concentration is We want to find out if there are side effects, and we want to find out if there are functional consequences, and for that purpose, we have various markers, be it biochemical markers, be it electrophysiological markers. So brain exposure, we have seen, is pretty rapid, and based on the studies that have been done so far, it seems that doses of 8-1600 mg a day should be within the efficacy band. It is consistent with what we have seen in the animal studies, and then we see in human beings, indeed, as part of the outcome, electrophysiological measures, electroencephalogram, EEG, will reflect changes in various bands. These will be theta, gamma, and delta bands will be altered, supposedly associated with increase in alertness and cognitive functioning. So this is the proof of concept study. Part A is essentially healthy subjects, and it has the same goals that I've just outlined. Part B is the proof of concept study, and this is in treatment-resistant patients. It will be 2,400 mg of SPN-820 versus placebo. Randomization is about equal, 16 to 15. When it comes to healthy subjects, one usually does not waste a whole lot of energy on placebo in healthy studies, so the ratio is about 2/3 of subjects will be randomized to active ingredient, about 1/3 to placebo. So it will be in each cohort, six are going to be on active drug, two are going to be on placebo. The range of doses that was explored was 150-2,400 mg. So how were the studies conducted? The idea was to try different regimens, and before I get to this proof of concept study. So you could have one-time dosing, and that one-time dosing starts very low, around 150 mg, and you can have pretty high doses, up to 2400 mg. So you'll have six individuals receiving 150, and then the various other doses in the range, altogether six groups, six dosing strengths from 150 to 2400, explored in six individuals, each on NV and two on placebo. So that is one. It's one-time dosing. There is a different regimen. Different regimen is two doses that are 48 hours apart, and the third dosing regimen is they're receiving the NV daily. Right? So three dosing regimen to determine PK, to determine biochemical markers, to determine electrophysiological changes, and to determine if there are safety signals. So here we're now looking at proof of concept. This is the study that was done in treatment-resistant patients. There are several clinical measures that are utilized. HAMD, Hamilton Depression Rating Scale, is a very standard instrument in the field, measures a variety of different symptoms of depression. HAMD-6 is abbreviated version, so there's still depressed mood there. The second is work and activities, reflecting potentially energy levels. Third will have to do with psychomotor retardation. There will be one that will deal with psychic anxiety. There will be one that will deal with somatic symptoms, and that will be change of sleep, appetite, and, body aches and pain. So these are some of the acute manifestations of major depressive disorder, and it is a quick and dirty way of looking. Are these depressive symptoms, acutely changing? And what we're seeing is with MADRS. Now, I want to point out, we're looking at the effect sizes, and with MADRS, you may say: "Well, it doesn't look very impressive." Two things, it's a very small cohort of patients, that is number one. Number two, MADRS is not really suited to measure hour-to-hour changes, right? So the time frame is different, and there's a lot of variability, small sample sizes. HAMD-6 does show significant effect, so this is relatively robust. This is a strong effect. IDS-SR 30, so this is Inventory of Depressive Symptoms, SR, self-rated 30, is showing very mild effect. And then CGI, Clinical Global Impression of Severity, seven-point scale. One, no symptoms whatsoever. Two, minimal symptoms. Three, mild symptoms. Four, moderate symptoms. Five, marked. Six, severe. Seven, very severe. Again, to provide that kind of global change within a matter of hours, it's really not the best-suited instrument. Now, here we go about how do we decide about dosing regimens. So you notice that green and blue curves have a different starting point, and that is because these have been dosed daily for seven days. So, at that point, 800 is at steady state. On the other hand, red line is 2,400. This is one time. So we're looking at blood levels, and we're seeing that 800 and 1600 daily dosing seems like a good option. But I mentioned biochemical markers and something that would be appropriate to reflect the activity of mTOR complex one. So orotate, what is all that about? It is a byproduct of activation of mTOR. It is down the line, and it is in this synthetic sequence that leads to nucleotides, which means by activating mTOR, we're essentially on the right path to synthesize more nucleotides. N-acetylmethionine is a precursor to methionine, which is a precursor to glutathione. Now, if you're going to go full bore into the production, you're gonna create some smoke. So you're going to create some oxidative damage or potential for it. Glutathione is going to limit oxidative damage. And then we have N-formylmethionine. N-formylmethionine is upstream from peptides that are in mitochondria. So I've not mentioned mitochondria so far. They're the power plants of the cell. They're the ones that produce ATP, Adenosine Triphosphate. That is how our body stores energy. When ATP is degraded down to ADP, one phosphorus bond is broken, energy is released. So it ensures that energy supply for the synthetic process is going to be there. And we see at relevant doses of 8 and 1600 mg of NV, indeed, there is appropriate increase in these, biochemical markers of the activity. So, eight, twenty, phase II-B. Now, these are large clinical trials. It is a multicenter, it will be flexible-dose treatment, starts at 1600 mg a day, may be tapered to 800 mg. About 268 subjects might be enrolled, up to 50 sites. Screening up to six weeks. It is remember, adjunctive, so they will be on other antidepressants. They need to be on a stable dose of certain antidepressants and show that they're not having greater than 50% reduction in their symptoms, and then they will receive H 20. So primary efficacy, Montgomery-Åsberg Depression Rating Scale, very standard. That's what FDA wants to see. Key secondary is this Clinical Global Impression of Severity. HAMD-6, you have heard about. Onset of effect, how soon will it separate from placebo? Response and remission. Response, 50% reduction in depressive symptomatology. Remission, MADRS score, less than 10 or equal. Individual disability measured by Sheehan Disability Scale. Anxiety measured by GAD-7, General Anxiety 7-item scale. And then rate of improvement is also important, as well as safety signals. Where are we right now with this phase II, II-B? 62 patients or subjects randomized. In treatment, six. Completed treatment, 44. Discontinued due to adverse reactions, 3%. So indeed, very favorable safety signal. So looking at the new phase study, it will be pulsatile dosing, so it will be a few days apart. Efficacy in major depressive disorder will indeed demonstrate rapid onset of action. It's open label, 40 subjects. Sustained efficacy starting from 2, 4, 8, and then 72 hours, three days later, after administration of a single 2400 mg dose every three days. That is the pulsatile dosing. Rapid onset will be evaluated with HAMD-6, which we have shown detects this rapid onset, and then we will evaluate the efficacy based on MADRS, Montgomery-Åsberg Depression Rating Scale, very standard scale. So this. In summary, what are some of the attributes of 8 20? So it does increase mTOR complex 1 signaling, which is upstream from increasing synaptic skeletal protein synthesis. It does have unique intracellular mechanism. It is being explored for these patients who have treatment-resistant depression. Effect size on HAMD-6 was 0.6, which is very robust effect. Drop rapid onset per dose sustained for 72 hours. Overall, it appears well-tolerated, unlikely to be a controlled substance because there are no these reward signals in terms of increased activity in ventral striatum. This is always a warning sign. This is not a place where this medicine appears to be very active. And then do expect some top-line results for 2B in 2025. And with that, I will thank you for your kind attention and conclude this talk. Thank you very much. Yeah. Thanks, Dr. Maletic. Before we go to questions, we would like to play a brief video. If we could cue that up. NV-5138, a promising antidepressant with a novel mechanism of action. Major depressive disorder is a leading cause of disability with many symptoms. First-line treatments for depression, including monoamine reuptake inhibitors, can take weeks to have effects, don't work for everyone, and don't resolve all symptoms. Although monoamine imbalances have historically been the focus of depression etiology and treatment, recent data shows that depression may result from a loss of excitatory synaptic connections in some brain regions, including the prefrontal cortex. This is reflected as a loss of dendritic spines, the site of synaptic connections, resulting in an inability of neurons to undergo changes in strength in response to inputs, termed synaptic plasticity. Central to these changes are reduced capacity for the brain to produce proteins that regulate synaptic plasticity and health. The mechanistic target of rapamycin complex 1, or mTORC1, is a master regulator of protein synthesis inside cells, and in neurons, is critical for maintaining plasticity-related proteins, including glutamate receptors and PSD-95. mTORC1 activation is associated with synaptic health, and its activity is regulated by glutamate and Brain-Derived Neurotrophic Factor or BDNF signaling. Research shows that loss of synaptic proteins and plasticity in depression may be due to reduced mTORC1 and BDNF signaling. Thus, pharmacologically targeting mTORC1 to restore synaptic proteins and health is a promising treatment for depression. Some newer antidepressants work more rapidly than traditional ones. Most of these rapid-acting antidepressants increase mTORC1 and BDNF signaling in the prefrontal cortex, providing sustained benefits by increasing synaptic proteins and plasticity. However, these rapid-acting antidepressants target different cell surface receptors to activate mTORC1. This can contribute to unwanted side effects. There is an unmet need for treatments that increase mTORC1 activity in the prefrontal cortex through an intracellular mechanism with the potential for rapid action and fewer side effects. So how might this work? mTORC1 senses both amino acids and BDNF signaling to increase synaptic proteins. Subcellular localization of mTORC1 is important for its activation. The lysosome is where amino acids are sensed. Therefore, recruiting mTORC1 to the lysosome allows its activation by BDNF signaling. This mechanism is regulated by additional protein complexes, like the sestrins, that keep mTORC1 activation in check. Sestrins are increased during amino acid deprivation and prevent mTORC1 activation through interactions with the multi-protein GATOR complexes. The amino acid leucine is known to bind to sestrin, facilitating mTORC1 activation. NV-5138 is a leucine analog that has similar but also different effects within the cell. Like leucine, NV-5138 binds sestrin to activate mTORC1 signaling. However, in the brain, leucine is rapidly diverted to be used in other processes, such as neurotransmitter and protein synthesis. NV-5138 is not used for these purposes, and thus is more available than leucine to bind sestrin in the brain. NV-5138 rapidly and transiently activates mTORC1 in brain regions implicated in depression, including the prefrontal cortex. In doing so, NV-5138 increases the number of functional synapses, reverses synaptic protein loss, and provides antidepressant effects within 24 hours of oral administration in preclinical models of depression. Overall, NV-5138 is the first sestrin selective leucine analog that restores synaptic proteins by transiently activating mTORC1 signaling in the brain through an intracellular mechanism. Its novel mechanism of action that efficiently engages mTORC1 activation may bring hope to many individuals suffering from depression. Thank you. I'd like to open up to questions from the audience. There'll be a microphone going around, and for those of you who are listening online, there'll be the opportunity to submit questions via the chat. Okay. Stacy Ku from TD Cowen. Thanks so much for your insightful commentary. So first, Dr. Maletic, do you wanna talk about the potential pathway forward for the studies for SPN-820? What do you want to see? Do you want to see onset of efficacy within one week? Is that important for the studies to move forward, just given the patient population? And I guess you guys had talked about very briefly the second study. Do you believe you can capture potential initial onset of efficacy with the first study, or do we have to wait for the second study? That's our first question. I'd like to follow up. Right. So that would be the hope, right? The hope would be not only that it is a noticeable separation from placebo at week 1, but it actually may be noted earlier, that it may be noted at 24 hours, that may be even noted at 4 hours. So rapid onset is something that is really important. The second aspect that would be important is sustained. We've seen that it's sustained for 72 hours. We've seen that it's sustained for seven days. Now we need to see, is it going to last for months? And we need to see what will be eventually what will be the frequency of administration, if it is daily for seven days or 10 days, how many times would we need to treat or retreat? What is the optimal interval of treatment in depression that will work for majority of the patients? Lastly, we need to see, will it be effective for numerous symptoms of depression? So obviously, it does need to address depressed mood. Will it be able to restore energy? Will it be able to restore hedonic function? Based on animal models, there's a lot of hope. Based on animal models of chronic uncontrollable stress, there is suggestion it may help with anxiety symptoms as part of depression. But again, all including cognition, alertness, based on electrophysiological studies, all of these need to be translated clinically. We need to see improvement in all those domains because that will ultimately lead to what matters the most to our patients, and that is not improvement on scales, but improvement in quality of life and functioning. So I'd like to add to that. The FDA's guidance on major depression suggests that if you have onset of activity at one week or less, you can be classified as a rapid-acting antidepressant. In the ongoing phase II-B study, the first time that efficacy will be measured, the first visit will be at one week, and so if we hit that, that would be suggestive that we have rapid onset. But in addition to that, in the second study that Dr. Maletic mentioned, which hasn't yet started and will start soon, we will be looking at onset of effect on the first day. So we're gonna see just how good this drug does and when it starts its action. The second study is supposed to start soon. Perhaps for the other year. Oh, the readout will be early next year. It's a small study, and it's a short study. And then our second question is on the situation of those 13 patients. Looks like it's not related to tolerability, but can you just comment, a little bit more? Is it related to efficacy? Is it an imbalance between placebo groups and the treatment arm? Any other details would be appreciated. Most of it was administrative, people who just didn't want to be in the study, who withdrew consent, so not a lot of issues related to tolerability or efficacy, yeah. Has the blind been broken? Do we know? No, no, no. So we won't- We won't know until we lock the database. Well, well, we know the adverse event occurred. We don't know in what group it occurred. Is it placebo- Yeah ... or in 820. Okay, wonderful. Thank you. Andrew Tsai, Jefferies. Thanks for hosting this. So maybe the first question asked another way, what is your expectation at week five, drug versus placebo on the MADRS separation? Understanding this is our TRD indication, only two drugs technically approved, limited number of treatments. So what is a meaningful MADRS separation to you? And then secondly, Oh, go ahead. So, I mean, within the field of depression, MDD in general, the SSRIs have an effect size about 0.3-0.4, which is actually pretty small. And I mean, if you're treating a patient, you don't have a lot of confidence, and that's why you get these treatment switches. This study is powered to detect at least that and hopefully more. So we saw effect on the HAMD-6 of 0.6-0.8, and if we can see that, then we feel like this provides meaningful clinical differentiation. In terms of what we're seeing in clinical studies, right? The cutoff point is MADRS change more than 2 points separating from placebo. If you power up this study, you can sometimes even get a statistical separation with 2 points, but that does not, it's not likely to translate into noticeable clinical effect. So we like to see more than 2 points. In terms of some of the products that are on the market, there are products on the market as adjunctive treatment in MDD that have 3-point separation. So you, you'll at least hope to see something like that. Makes sense. Maybe second question. You know, depression studies are very challenging due to a high placebo risk. So what measures have you taken to control for a placebo effect? Are you using- We just spoke about that s afer and, you know, limiting the number of patients per site, balancing enrollment per site, so forth, or, you know, educating patients and, you know, talk about what you're doing basically. Yes, thank you. I acknowledge your comment. This is a very challenging area and has been for some time, and if you look at CNS in general and depression specifically, placebo effect has risen substantially over the past 10-20 years. So we are taking a number of measures to mitigate. We'll never eliminate it. It's always gonna be there. It's just a question of how much there is. So careful site selection. We're speaking with some of our vendors in terms of who have knowledge of these sites. We're doing rater training. We are surveying, in a blinded fashion, the ratings to see if there's anything that sticks out, whereby a rater may need additional training. We do placebo training to both raters and to subjects during the study to make sure that or to try to help them to rate accurately what they see, you know, without any expectation. And then we'll see what the drug does. Is one-on-one, and then is it a global study or...? This is a U.S. study. One-on-one? One-to-one randomization. I don't see any other questions in the audience. Anything from the chat? Anyone? Yes. Oh. Hi. Given the novelty of the mechanism and just how long it's gonna take to accrue the study, is there a thought to taking an interim look or potentially even shrinking the phase II-B to something like 150 patients to get a readout sooner? Yeah, I've contemplated that 'cause I really would like to see the results, but you take a statistical penalty when you do an interim readout. I'd rather not do that. I'd rather power the study to the full amount, to roughly 268 enrolled, about 200 completers, and there's a few reasons to do that. One, more likely to see an effect. Two, we'll be doing a variety of subgroup analyses, and in order to have a sufficient number in the subgroups, you really need to take it out all the way. Stacy Ku from TD Cowen. Again, just a quick question, maybe you're gonna get into this, but SPN-821, is that also in development for depression? Just help us understand, is it different formulation? Any other details that you- Yeah, thank you. SPN-820 is technically API in a capsule. That's what's being used for the current phase II study and the planned phase II study. In the future, for our pivotal phase III, we'll be using SPN-821. Same drug substance, but this will be a tablet formulation that'll be used. So would SPN-820, SPN-821 be for the same project? Thank you. Hi, Jack Padovano with Stifel. If you show consistency on some of the secondary measures in the phase II, like the Hamilton Scale on the phase I, could you still expect to move forward with the phase II? I know you mentioned that the MADRS wasn't reliable for the timeframe of the phase I. How reliable would that be for the phase II? We'll have to see what the data shows. And so the MADRS is a well-accepted measure that FDA seems to prefer over... If you look at phase III pivotal studies over the last several years, they've... And so for that reason, we're going with the path of least resistance with the FDA, and we'll see what that data shows. Now, if for some reason the MADRS doesn't work, but we see something, a good signal, we'd have to have discussions with the FDA, but for right now, it's gonna be the MADRS. Anything online? Okay, we're gonna go forward. Okay. Thank you, Dr. Maletic. Thank you very much. Okay, so, now we're gonna switch gears to a new product, SPN-817. This product, the active ingredient is Huperzine A. This product is a novel, first-in-class, highly selective acetylcholinesterase inhibitor, which is intended to for the treatment of focal epilepsy or focal seizures. So in thinking about the field as a whole, refractory epilepsy results in a lot of switching in polypharmacy. If you think about the treatment journey, providers start on a generic anti-seizure medication, or ASM, and they'll take that medication, will titrate it over time, we'll see if it works. If it doesn't work, they may switch to another treatment, they may add a treatment on top of that, and then go through various combination of drugs. Then if that doesn't work, then they may go to neurostimulation or using a ketogenic diet. In general, it's not working. We see about a little over 1% in the U.S. have epilepsy, and focal seizures affect about 61% of people who have epilepsy, but 40% of those will be drug resistant. There are about 29 million prescriptions in the marketplace, and it can be a lifelong chronic disease that can have significant impact on quality of life, on driving, on working, on relations, on social relationships. The probability of achieving full seizure freedom is substantially reduced with each medication that you add. After the second medication, about 12% will achieve seizure freedom, and then it goes lower down to the fourth medication, about 1%. So, unfortunately, a lot of these patients never achieve full seizure freedom. In addition to that, in addition to having ongoing seizures, they can have adverse events from their medications, from the combinations of the medications, which can have drug-drug interactions. And this can cause issues related to employment, related to issues with, their quality of life. So, both, here it says patients, but I would add clinicians, are looking for treatments that have better seizure control and improve quality of life and improve tolerability. So if you look at the overall market, for seizures, almost 29 million people, 29 million, excuse me, prescriptions for epilepsy and seizure disorders, of which focal seizures accounts for 17 million prescription, and refractory focal seizures accounts for about 7 million prescriptions. The epilepsy market, in general, is almost a $3 billion market. Now, our internal market research shows that there's a need for effective pharmacologic treatments for epilepsy. It's clear that providers are looking for drugs that reduce seizure frequency and achieve seizure freedom, and they also are looking for reducing the severity of seizures. They're not happy with the current treatment paradigm. Efficacy is most important to them. In thinking about the pediatric treaters versus the adult treaters, the adult treaters are more aggressive, and the pediatric treaters are more cautious and slower to adopt. By the way, I'm a pediatrician, and so I understand that perspective. Both providers see the benefit of a drug that may be procognitive and may be neuroprotective. So if you look at the overall pipeline for focal seizures, SPN-817, which is an acetylcholinesterase inhibitor, it's the only acetylcholinesterase inhibitor in development, and there are a variety of other drugs using other mechanisms in other phases, in various phases of development. This is a new class of therapy. So when you think about a seizure, a seizure is sustained hyperexcitability of the neuron. If it's throughout the brain, it's a generalized seizure. If it's a specific portion of the brain, it's a focal seizure. And so a drug, what you're trying to do is reduce that hyperexcitability, and you can do that either by decreasing the excitation or increasing inhibition. If you decrease excitation, there are sodium channel blockers, and there are drugs that inhibit glutamate, which is excitatory. On the inhibitory end, you have drugs that work on GABA, an inhibitory neuron, and now we have a new MOA, which is SPN-817 or Huperzine, which is increasing acetylcholine in the prefrontal cortex, as well as the hippocampus. So I'd like to talk about some of the pharmacology of SPN-817. As I said, this is a novel mechanism for the treatment of focal seizures. Huperzine A, it's a potent, selective, and reversible acetylcholinesterase inhibitor. Acetylcholinesterase is an enzyme that metabolize acetylcholine after synaptic release. If you inhibit the enzyme, then there's more acetylcholine that's available in the synaptic cleft, and then that can have activity downstream to potentially reduce seizures. We have found a broad and potent anti-seizure effect in various seizure and genetic models of epilepsy, and I'm gonna show you one right here. So this is a screening program from the NIH, looking at a broad variety of anti-seizure medications, which are well known. In this paradigm, you take an animal, and you administer a current, an electrical shock, to induce a seizure. If the medication is protective, you're not gonna see the seizure, and you look at the ED50, the effective dose at which 50% of the time the seizures are gonna be eliminated. You can provide what you see here are different amounts of current. The standard model is 32 milliamperes, which is in the middle column. If you look, SPN-817 is very high potency, very low dose achieved for the ED50, and in comparison to Keppra, 19.4, we see that SPN-817 is almost 60 times more potent than Keppra. And a lot more potent than the other drugs, which are standard anti-seizure drugs. If you go over to the right, to the 44 milliampere column, SPN-817 was the only drug that really had potency at that level of electrical stimulation. So our current hypothesis for seizure control, you have acetylcholinesterase inhibition that leads to elevated acetylcholine. And there are acetylcholine receptors, there's a variety of receptors that are located on inhibitory neurons, excitatory neurons, and glial cells. Dr. Maletic talked about that. These are support cells. And in doing this, you can reduce excitation, you can increase inhibition, and you can restore this excitatory inhibitory or E to I balance that will thereby reduce seizures. So there are other acetylcholinesterase inhibitors. This compound, SPN-817, is more selective than other acetylcholinesterase inhibitors. It's more selective against acetylcholinesterase in comparison to butyrylcholinesterase, which is a cholinesterase that is found in the periphery. Acetylcholinesterase is found in both in the periphery and the brain, and because of this, in comparison to other drugs, it, the SPN-817, you need lower doses to get to the brain, the place where you wanna have activity. In comparison, if you look at another acetylcholinesterase inhibitor, such as donepezil, it has similar activity to SPN-817, but because it works on butyrylcholinesterase, you have to give very high doses to get to that similar activity, and they're gonna be dose limiting. You're gonna have significant side effects, and you're not gonna be able to get it to the brain. So we've completed a phase II- A study, a focal onset impaired awareness seizure. We call this the FIAS study. In this study, we looked at patients with focal seizures, and they had to have a certain number of seizures to enroll. They had to have a certain number of seizures that were counted during a baseline diary that was obtained over a month. Then they went into a baseline state where video EEG was obtained, titrated over 4 weeks, had another video EEG, and then had a maintenance and an extension that was 6 months or more. In this study, there were 3 subjects in this study. This was done in Australia. It showed significant seizure reduction, and all the patients had the focal seizures. They were treated up to a maximum dose of 4 mg twice a day. In looking at the three patients, looking at the 28-day seizure rate, which is the standard at which drugs are assessed for in terms of a primary efficacy measure, there was a 71% reduction for all three subjects obtained until month 14, a 90% reduction until month 40, and a for two subjects, and a 98% reduction until month 51 for one subject. The graph that you see is a sample from one subject. That subject was at about 160 seizures per month at baseline, and then by month 24, was completely seizure-free. This subject was able to obtain their driver's license, which is difficult to do for someone who has a known seizure disorder. It shows good seizure control, and the subject has been on the drug for over 3.5 years and is also now working. There were treatment-emergent adverse events. They were mild to moderate in intensity. They included insomnia and nausea, and a few other side effects as well. We currently have an ongoing phase II-A study. This is an open label study, eight sites, again in Australia, and we intend to enroll about 35 subjects who have treatment-resistant seizures. The intended indication for this product, but, as I mentioned, is focal seizures in adults. This study has a similar design to the FIAS study that I mentioned earlier. There's gonna be a screening period, where we're gonna look at seizure diary, make sure they have a certain amount of seizures before they come into the study. There will be an 8-week dose titration and optimization period, a maintenance phase of 12 weeks, and then, if they want to, they can enroll in an open label study. All patients start at 0.25 mg twice a day, and they get titrated up, 0.25 or 0.5 mg increments, up to a maximum of 4 mg BID. BID. The endpoints is an open-label study, so safety and tolerability is the primary endpoint. Secondary endpoints, the% change from baseline in the seizure frequency, that's gonna be the key efficacy endpoint, and we're also gonna be looking at seizure symptoms, seizure severity, quality of life, disability. We're gonna be looking at the PK profile of Huperzine A, and we're gonna be looking at some exploratory endpoints, including change in inflammatory biomarkers. There's evidence to suggest that Huperzine can be anti-inflammatory. We're gonna be looking at cognitive assessments. So there's evidence to suggest that Huperzine could be a pro-cognitive compound. This is in contrast to other seizure medications that can cause cognitive impairment. And we'll also be looking at the EEG data in the study. So because this is an open-label study, we can do an interim data cut to kind of see where we are. This data cut was obtained about a week ago. So this is fresh off the press. The study is still ongoing, and this is preliminary results. We'll see, we'll report later when the study completes. So far, seven of the 35 intended enrolled subjects have completed titration. They finished titration at doses ranging from 1-4 mg twice a day. Safety is the primary endpoint here, and the most common adverse events were diarrhea, nausea, headaches, insomnia, and affective lability. Diarrhea and nausea, by the way, are cholinergic side effects, which are to be expected with a drug that elevates acetylcholine. All of these were mild to moderate in severity. But I'm excited to report some interesting data. So of the 6 patients who completed the titration that had available seizure diary data, two of them have gotten all the way to maintenance. We had almost a 64% reduction, which is clinically significant. And furthermore, two of the patients who made it through titration are completely seizure-free. Again, consistent with the study that I reported earlier of one subject out of the three who was seizure-free. There's one subject who's made it all the way through the study, and that subject had a 68% reduction in seizures. Again, a clinically meaningful difference. So now I wanna switch gears again to another to a planned study. So this study is going to start towards the end of next year. This is a planned phase II-B study for treatment-resistant focal seizures. We're going to use data from the ongoing study that I just talked about is helping to inform the design of this study. The study is going to have a screening phase, again, where we'll count baseline seizures, titration period of 9-11 weeks, and then going to a maintenance phase, and then for those who qualify, going to an open-label study. It's gonna be a randomized, double-blind, placebo-controlled study. The randomization will be 1:1 to 1: 1. So there's gonna be four arms: placebo, 2 mg BID, 3 mg BID, and 4 mg BID. And roughly 109 subjects per arm. We want to achieve 76 subjects per arm in the full analysis set, the completers. It's gonna be a large study, up to 100 sites. It will be a global study. It'll be in the U.S., it'll be in Europe, and it'll be in Australia and Asia. The primary endpoint will be change from baseline in the focal seizure frequency over a 28-day period. We'll be looking at safety and tolerability. We'll be looking at pharmacokinetics, and again, we'll be looking at some exploratory markers, inflammation, cognition, and EEG. So to sum it up, this compound, it's a novel, first-in-class, selective acetylcholinesterase inhibitor intended for the treatment of focal seizures. In the phase II study, we saw a mean reduction in three subjects of 70%. The compound so far has been well tolerated in clinical trials. It has shown a broad and potent anti-seizure effect in various seizure models and genetic models of epilepsy. This is a unique acetylcholinesterase inhibitor. It has high selectivity and low activity on butyrylcholinesterase. It has the potential, which we need to see in our data, for pro-cognitive, neuroprotective, and anti-inflammatory effects. As I mentioned, we'll be entering a phase II-A study at the end of next year. Now I will open it up for questions. Stacy Ku from TD Cowen. So first, a few follow-up questions on the data that you just presented. Mm-hmm. First, how long is the titration up to 4 mg BID? What's the timing like? And then for the two patients that entered maintenance, are they essentially, they all hit 4 mg BID, is that correct? So two clarifying questions. And then could you clarify again that third point, you said two patients achieved seizure freedom during titration. Are these the same patients, or how should we think about that data? So the- Thank you. Okay, so they're not the same patients. But getting back, one on the ongoing phase II-A study has an eight-week titration. For the phase II-B study, we're gonna go to a 9-week titration. We're gonna make it a little bit longer. And, forgive me, your second question? Was on the two patients, that we saw the 63.5% mean reduction- Mm-hmm. -seizures. Those were all the patients that were kind of stable now on 4 mg BID. Is that the right? Oh, oh, the dosing. 1-4 mg BID. I don't remember off the top of my head the second, but I can check on that. Okay. Within the data reported, of the 6-7, it ranged from 1 mg BID to 4 mg BID, and even so, one of the subjects who had seizure freedom was either at 1 or 1.25 mg BID, so at a very low dose, had complete seizure freedom. Okay, understood. Thank you. Andrew Tsai at Jefferies. Thanks, again. So maybe one, taking one step back, bigger picture question in epilepsy is: How are you guys... What is your philosophy on balancing efficacy with safety and ease of use attributes? And, you know, how would you compare this compound on the safety and ease of the use attributes to what's available today? Well, this gets back to the market research data that I showed. I mean, the first thing, physicians, they prescribe a medication 'cause it works, okay? And we have to balance both the safety and efficacy, the risk-benefit profile. So it's gotta work, it's gotta show reduction in seizures, and the safety profile has to be acceptable to allow that. Now, if someone's seizures are really bad, maybe you would have a different risk tolerance. But this is something we're gonna have to collect the data and show it to FDA, analyze it internally, and have clinicians view the data as well. Makes sense. And when can we get another glimpse of your interim data cut to? And at what point will you feel compelled to move to the phase B portion? How many patients worth of data from the phase II-A? Well, we're already committed to going to the phase II-B, and that's gonna start towards the end of next year. Okay. Whether or not we do an interim data cut, I haven't decided yet. We could. I mean, we can look at this every day if we wanted to. So, we may... And, I mean, possibly, we may report out, like in a poster format or setting. But, this study, it's fortunately, it's recruiting very well, and so, we hope to have top-line data next year. Thanks. Thanks. I had a few follow-ups. Stacy Ku from TD Cowen. So, one last follow-up on the study. Did you comment on the number of anti-seizure medications that these patients were already on? Since we're looking at a refractory population. I can't specifically state for each patient, but they have to come in anywhere from 1 to 4 seizure medications that they could take concomitantly. So this is an adjunctive trial. Whatever they're coming in on is being continued- Okay. in the study. So, a lot of these patients have really intractable seizures, and the fact that we're getting seizure freedom in someone who's on multiple medications with intractable seizures is quite promising. Okay. And then we think about kind of future, potential for this product. What clinical profile are you looking for as we think about other agents in development and focal onset seizures, as we consider maybe Kv7, agonists? What are the different features that you're looking for? Well, so in terms of differentiation, so as I mentioned, we have a novel mechanism action, and one key feature, again, is gonna be, does this work on seizures? And to what extent, does it cause seizure freedom? Does it... What's the magnitude of seizure reduction? And then that will show how we compare to both drugs that are approved and drugs in development. But as I mentioned, this drug, we're gonna explore other aspects of where this drug could go that could provide differentiation. So this drug could be pro-cognitive. So there have been studies of Huperzine A in Alzheimer's disease, which suggests to us, and I mean, if you think about, cholinergic stimulation could be pro-cognitive, it makes sense. So we will have to generate data to show that. This drug could be anti-inflammatory. There's some suggestive evidence that that could have a beneficial effect, that could have, across a variety of conditions, be it seizure or even beyond seizures. There are also some preliminary evidence about potentially a cardioprotective effect. We'll be looking at cardiac enzymes, and seeing if this is somewhat supportive of a cardioprotective effect. We are also looking, could this be neuroprotective? When we do these studies, as is traditional, you look at changes in seizures, but we are exploring the concept of could this prevent seizures from occurring, in an animal model of animals that are likely to have seizures? All those things could be compelling differentiation. From an efficacy perspective, we've been in this space for a long time, in epilepsy, obviously with Oxtellar XR, Trokendi XR, and so forth. I mean, we've seen so many agents being developed, and at the end of the day, you're looking at 50% reduction or maybe 60% reduction. Mm-hmm. So if this holds as we move forward, and we're hitting in the 68%-70% reduction, that's huge for these patients. As Jonathan mentioned, I mean, we're getting these levels even on top of three or four other anticonvulsants that they're already on, and we're bringing that incremental benefit on top of that. And that's what we've seen so far with this molecule, that strong potency, efficacy that it brings to the table. And then if you add to it procognition, anti-inflammatory effect, or whatever else we might be able, obviously, we've got to do a lot of work to get there. We're not saying it's a slam dunk. Clearly, we'll bring this to the top from a differentiation, not just among molecules that are already on the market, but also molecules that are being developed in the pipeline. It's a tough disease. We've seen it. There's so many agents out there, you really need to differentiate pretty well, and that's what so far the profile looks like at this point. And I would add, to state the obvious, seizure-free in three subjects, that's 100%. It is only three subjects, but- Right. That's quite remarkable. Yes? Really interesting data that you have for 817. Could you just remind me, I think in the literature for donepezil, which is another acetylcholinesterase inhibitor, there have been some mixed reports about lowering seizures, but also increasing seizures as well. So, can you just remind of the differences between Huperzine A and donepezil, whether chemically or anything that you can think about? I can't speak to the molecular structure. I haven't heard of that with Huperzine A, as far as it being pro-seizure. And we really haven't seen much of that in our data so far. We'll have to see in a larger group. So we have this 35 subject, and then we'll have, like, roughly 400 subjects. So we'll see in a larger sample size. I did mention there's a difference in the selectivity, and so donepezil. There may be issues related to its selectivity, related to its pharmacology, and that's as much as I can comment on. Thank you. Anything else? Any online? No. Okay. I think, are we at a break? Yeah, we'll take a break. How long are we gonna take the break? 10 minutes, John. Okay. So for those on the line, we're gonna take about a 10-minute break. Thank you. How you doing? I'm good. What do you think? I'm good. Yeah. You did well. Thank you. No, I do. Okay, welcome back, everybody. We're gonna get started again. For those of you online, we're gonna get started now. So I'm excited to talk to you about two products that Supernus has developed organically. So I'm very proud of the fact that the team has discovered these molecules, and I'll tell you a little bit about each of them. And Jack, at the outset, talked about the transformation of Supernus from a company that started out as a formulation company, but really now is a lot more than that. The first compound I'm gonna talk to you about is called SPN-443. This compound, again, has a novel mechanism of action, and it has potential... the potential for stimulant-like efficacy, and the potential for reduced abuse liability. So looking at the ADHD market, Supernus is quite familiar with this market. Most of it, almost 90% of the treatment of ADHD is stimulants. The market is rewarding medications such as stimulants, which have a fast onset of effect, a high effect size, a predictable response. This is a significant advantage for stimulants. The rapid onset, an effect size in neighborhood of 1.0, allows for as-needed dosing with some patients. Now, this is both a good and a bad thing. Patients like it, although this is not the treatment paradigm that clinicians should be advocating, but it's out there in the market. People want something, they wanna take, college students wanna take it before they take a test, or someone wants to take it before they do a presentation at work. This is a highly genericized market. Stimulants have been around for decades. But there are significant drawbacks to stimulants. They're classified by the DEA as a C-II drug. Healthcare providers need to do a prescription every 30 days. They cannot call in a prescription. They have to input the prescription online. There's a lot of controls around the use of C-II drugs. Also, these drugs have a risk, not only for abuse liability but also for misuse and diversion, particularly on college campuses and in the young adult population. They are widely used in a manner that they were not intended for. And stimulants don't always work. They can have side effects, insomnia, weight loss, changes in mood, blunting of affect. There can be issues where stimulants can cause or exacerbate anxiety. And also, you may have read in the news, there's a significant issue with shortage of stimulants. So we are planning on taking SPN-443 into the ADHD space, and this can leverage Supernus' investment with Qelbree and knowledge of the space. We currently have a sales force of 245 representatives that are calling on ADHD providers. And by taking SPN-443, we can capitalize on this sales force, utilize their knowledge of the market, their relationships with professionals. But even beyond that, beyond the sales force, our commercial team has knowledge of the ADHD space. And our medical affairs and clinical development team have extensive knowledge of the ADHD space, and we have well-established relationships with key opinion leaders in the space. We also have a leadership position among ADHD societies, such as APSARD. We have a significant knowledge of, of this market. Of the market, the medication, how to conduct the studies, and for the sales and commercial team, how to sell it. We can utilize all of these various aspects to provide efficiencies for a faster commercial ramp. SPN-443 is a new chemical entity. It's an NCE. It has triple reuptake activity, and we believe that it has a low risk of drug-drug interaction, DDI, and a low risk for abuse. The active parent, 443, and the major metabolites from 443, in preclinical models, show that this is. They inhibit reuptake of dopamine, norepinephrine, and serotonin. There's high blood-brain barrier penetration, which you wanna see in a drug that should have CNS activity and low risk for drug-drug interaction or DDI. So as I mentioned, this is a triple reuptake inhibitor, both for the parent and the active metabolites. So here I'm gonna present some binding data. It was done in animals. So if we look at SPN-443, the parent, it has nanomolar potency at the NET. This is just binding, and the metabolite one has even stronger potency at the NET. There's the parent has potency at the DAT, the dopamine transporter, and even stronger potency for the metabolites. And there's not much of serotonin binding, the binding of the serotonin transporter for the parent, but there is binding for the serotonin transporter for the two metabolites. MOP is mu-opioid receptor. There's not much binding there. If we switch over from binding to functional activity, in IC50, an inhibitory concentration, you see roughly a similar story as what we saw in the binding. So SPN-443 has some activity at the NET, norepinephrine transporter, some activity at the dopamine transporter, not a lot at the serotonin transporter. Both metabolite one is highly potent to inhibit the NET and highly potent for the DAT. Again, these are nanomolar concentrations, very tiny concentration. Not just a little tiny bit at serotonin transporter, and a little, metabolite two is a little less potent. Metabolite two, we're in the process of characterizing it, but it may have a slightly longer half-life that could provide longer duration of effect. So, further looking at the various neurotransmitters, we did a microdialysis study in rodent. We administered SPN-443, 0.3 mg per kg intraperitoneal, and in the prefrontal cortex, in comparison from baseline to after the drug was administered, we saw a significant elevation of dopamine, 300%; a significant elevation of norepinephrine, 391%; and a slight elevation of serotonin, 141%. Now, we saw this elevation of the monoamines in the prefrontal cortex. We did not see it in the nucleus accumbens, and that is very important because in the nucleus accumbens is the site in the brain related to motivation and reward. And when you have elevation of dopamine in the nucleus accumbens, that's where you get into problems with abuse liability. That suggests to us that this compound has a reduced risk of abuse liability. It doesn't prove it, but it's highly suggestive, and we will have to do more preclinical studies, as well as human abuse liability studies, to actually establish whether or not there's abuse potential. So our toxicology or non-clinical safety studies support advancing this molecule into the clinic. No genotoxicity, safety pharmacology studies in cardiovascular and CNS give us large safety margins. No hERG signal. We have a safety margin of almost 40 times the human equivalent dose in 14-day studies. And we will be starting a clinical trial early next year, of a PK study. And here's the study. This is a first-in-human study that will be a phase I study. Single dose, we'll be looking at PK of 443 and its metabolites in healthy adults. Approximately 24 to be enrolled, and we'll be looking at two different formulations, single dose, and then observe for seven days, and then crossover, single dose of the other formulation, and then observe for seven days. So in summary of the potential attributes, based on the triple reuptake activity, we believe that this could provide an effect size of the order of 1.0, within the range of leading stimulants. We have to prove that out in doing the clinical trials. Because of the lack of activity on dopamine in the microdialysis study, in the nucleus accumbens, we believe that we may be able to get DEA scheduling of four or even better than that. But again, we're gonna have to do the preclinical studies as well as the human abuse liability clinical studies to demonstrate that and have discussions with DEA and FDA. So we believe that this compound could be well tolerated. We will examine it in clinical trials, and we believe it could have a long duration of activity. So now I'm gonna switch to SPN-446 for narcolepsy. So again, as I mentioned earlier, this compound was discovered and developed by Supernus, by our team. So just a preliminary about sleep. So when all of us sleep, we have cycling through various phases of sleep. There's non-REM sleep, stage one to three, light to deep sleep, and then REM sleep. REM is rapid eye movement. And you can think of the REM phase as vivid dreaming, an active brain with an inactive body, and it's important to think about it that way. It's an inactive body, except for the eye movements. The eye movements are very active, but the rest of the body, there's not much tone, there's not much activity going on at all. That has consequences for narcolepsy, which we'll talk about momentarily. As all of us sleep, we're going through these different phases, and actually, many of us wake during the sleep phase as well. We may or may not be aware that we wake up, but there's cycling throughout the night continuously, and then there's also a sleep cycle, and then during the day, we have a wake cycle. If you have problems with neurochemistry or neurocircuitry within the brain, the sleep cycle and also the wake cycle can be altered, and that can cause a variety of sleep disorders, which are also called parasomnias. So narcolepsy Type 1 is characterized by excessive daytime sleepiness, falling asleep without warning at a time when you don't want to be falling asleep. It's also associated with excessive REM induction, and associated with that is what's called daytime cataplexy, where there's sudden loss of muscle tone. So when I'm standing up here, I have... well, I may be standing still, my muscles have enough tone to keep me upright. If all of a sudden I lose muscle tone, I'm gonna drop, I'm gonna fall, and that's what happens in people who have cataplexy, and it's highly impairing. So narcolepsy Type 1 represents 60% of the narcolepsy population. It's an orphan indication. About 165,000 people have narcolepsy Type 1 in the U.S., and it's typically associated with a loss of orexin signaling, and that has a bearing in terms of the animal models that we use. If you look at the market for narcolepsy Type 1, this is the branded market. There's a lot of generics that have been used with varying degrees of success. But you see here that XYWAV and XYREM, two oxybate products, are the majority of the market. There's a significant need for new treatments for narcolepsy Type 1. About three-quarters of the population still have issues with daily activity, 84% have issues with work or school performance, and 70% report having excessive daytime sleepiness every day. It's really impairing. Almost a third of patients have continued to have cataplexy despite being on treatment, one or more treatments. Sodium oxybate, as I mentioned before, has some issues related to black box warning, and risk of abuse liability, and it's under a REMS program, which is cumbersome to healthcare providers. So let's take a little look at the neurocircuitry of narcolepsy Type 1, and with specific focus on the role of norepinephrine. So orexin is a neurotransmitter that is involved in maintaining wakefulness. It's keeping us, hopefully keeping this whole group awake right now. And if you have loss of orexin, which happens in narcolepsy Type 1, there are a number of downstream neurotransmitters that it modulates, that can, you can have inconsistent levels of those. So acetylcholine, histamine, norepinephrine, serotonin, and dopamine are all, there's modulation of all of those. If you have inconsistent release or decreased orexin, what happens during the daytime, where you should be alert and vigilant, you become excessively sleepy, which is a problem. In addition to that, orexin modulates norepinephrine, and norepinephrine is involved with shutting down REM sleep, as well as maintaining tone. If you have loss of orexin or reduced orexin, you can all of a sudden, particularly with an emotional signal, get induction of REM sleep while you're awake, and you can go into this active brain and inactive body mode, causing loss of muscle tone, and you get someone during the day who's standing, and then all of a sudden they'll drop to the ground. A compound that will modulate norepinephrine can potentially help with the symptoms of sleepiness and help with cataplexy. So SPN-446 is a norepinephrine transporter inhibitor, and it has activity on several serotonin receptors. So if we take a look at this, the second column shows binding data, and the third and fourth column show functional data. So this compound is a norepinephrine transporter inhibitor. It binds at nanomolar potency, and it's also binding to various serotonin subtype receptors. Binds to serotonin 2C, and it does this as a partial agonist. You see the Emax 56%-74%, a full agonist would be 100%. A serotonin 2B antagonist and a serotonin 7 antagonist. And helping to facilitate norepinephrine activity, so elevating norepinephrine, could potentially reduce the induction of REM sleep during the day, reduce the cataplexy activity. And this has been studied in animal models. Other norepinephrine transporter inhibitors have been studied, and in a moment I'm gonna show you our preliminary data. Again, we did a microdialysis experiment in rodents, and we saw a dose-dependent increase, dopamine, norepinephrine, and serotonin in the prefrontal cortex. We also did a novel object recognition test, which showed improved episodic memory, and this potentially could be differentiating. We looked at an orexin neuron ablation animal model. This is a mouse model of narcolepsy Type 1. Recall that narcolepsy Type 1 is a deficiency of orexin. So here we have an animal model that will replicate the human phenotype. And in this model, and I'm gonna show you data in a moment, we saw a decrease in Cataplexy, a decrease in REM sleep when you didn't want to have it, and that was sustained for up to 12 hours after dosing. So we see dose-dependent decreases in REM sleep and cataplexy. The data I'm showing you here is on cataplexy, but we saw something similar for REM sleep. The animals were dosed at the beginning of their active time, which is denoted ZT12 at baseline. And these are mice, and their active time, they're nocturnal, their active time is at night. And we see the y-axis is cumulative time in cataplexy, so the larger the number, the worse you are. So the animal, they're supposed to be active, they get cataplexic, and then they drop. They don't move, when typically they would be moving. The vehicle is dark, and you see the vehicle over time in this animal model, which should have cataplexy. You see the phenotype. There's a lot of cataplexy attacks over time, over the course of 12 hours. You see, for all three doses, from 30 mg per kg to 120 mg per kg, for the first 6 hours, there are zero cataplexy effects. Now, that starts to wear off for the low dose at about 6 hours, where you start to see cataplexy attacks... but you see sustained effects at the medium dose and the high dose. There's reduction of cataplexy attacks. And that wraps it up. I invite now for full Q&A, invite Jack to join me. Thank you. Stacy Ku from TD Cowen. So I wanted to ask one quick question on the narcolepsy program. How do you think about other candidates that are in development? There's a lot of interest in orexin agonism in narcolepsy. So that's the first question, lots of competitive landscape. And then the second is, as you target norepinephrine, are you trying to find a balance between helping narcolepsy treatment symptoms, but then also working on hypervigilance? Help us understand what you're looking for in terms of dosing and kind of the profile of the asset. And then a second question, I know this is not the point of today's presentation, but Jack, just given the importance of Qelbree, are you willing to comment on what you're seeing, just back to school, progress, any progress? Any comments would be appreciated there. Thank you. Well, let me take the first question, which is the easy one. Unfortunately, I can't comment on Qelbree today from a commercial perspective or, you know, back to school, because we, we are, for the obvious reason, we're in a closed period at this point. But many of you do see the prescriptions. You know, we had a good back-to-school season, and I'll just leave it that way, on the Qelbree. For the other questions, Jonathan. Sure. So, as I mentioned, orexin is thought to be the basis for the pathophysiology. Orexin loss is the basis for pathophysiology of this disorder, so an orexin agonist could potentially be effective. So you have to take a look at the data, and so I can't comment any further than that. As far as the norepinephrine, the main intention here is for the norepinephrine to reduce cataplexy events, and that's one of the main elements that FDA requires to show efficacy to get an indication, the other being daytime sleepiness. And norepinephrine could reduce daytime sleepiness as well. So it's actually serving two functions. And we'll have to see if this bears out if we get to clinical trials and what the clinical trials look like. Hi, Andrew Tsai, Jefferies. Just a bigger picture question for you guys is, you know, you've shown a great amount of data today, across multiple pipeline assets. So let's just say one to two years down the road, how would you want investors to perceive Supernus? Is it, you know, with the existing product launches, BD or pipeline? How do you balance all of this, or do you want to do it all? Yeah, I mean, our strategy for many years has been a balanced strategy, meaning we value equally, you know, the internal development, the R&D capability that we've had for so many years, our heritage, clearly, in developing internally our own products. I've shared with you today the strategy that evolved over time, you know, starting with known molecules and so forth, differentiating them through drug delivery technologies, and then over time, migrating towards new chemical entities and higher market value potential type of projects. Today, when we looked at the pipeline, as I mentioned earlier, interestingly, you look at it, it's all new chemical entities, with the exception, of course, of SPN-830, which is a very complex product. It's a molecule plus a device combination. That's really what we've been working on historically, so hard to get to this point, and I think we are at a very interesting crossroads right now, where the profile of the company has changed dramatically. We are still in the universe on a lot of people's minds as a specialty pharma or a reformulation drug delivery, but we've moved away from that long time ago, and, and hopefully today is a clear demonstration of what we've been working on. We balance that, to your question, with clearly growing external growth opportunities. And as I mentioned earlier, we are very active in the corporate development side, looking for opportunities. We did three acquisitions, one in 2018, one in 2020, another one in 2021, and we did couple of strong collaborations. 820 is one of them with Navitor Pharmaceuticals. So clearly, we're very active in the BDs, and we will continue to do that. And many of you know us pretty well also. We try to be selective. We try to be, you know, reasonable in how we do these kind of transactions. One thing I missed to mention earlier when I showed you that growth chart, the revenue chart. If you really think about it, since 2013, May 2013, when we did the last convertible deal, we haven't issued one share of Supernus to fund any of that growth. And that tells you how careful we are in being a good host of capital without using dilutive capital. We try very hard, and the strength of the operation, generating all this cash that gave us that significant growth that you saw, 56% CAGR over the last 10 years, without even issuing one share of Supernus. That's what we do. We run our operation very efficiently. We value cash flow, but also we value, you know, high science, and hopefully today we shared a significant amount of data behind our programs to show you that Supernus is a very different company today than it used to be. We will continue to work in parallel on both ends, because I do realize people are going to say, "Well, Jack, you're going to make me wait for all these data points. What do I do in the meantime?" Well, in the meantime, Qelbree is going to continue to grow. GOCOVRI is going to continue to grow, and we will deliver, and that's what we've done historically, and we will do it again and again, and again. We have the infusion pump, which we believe is a significant opportunity, and we're completing a quantitative study as we speak, and we'll share with you what those results could show as far as the potential of that product. That could be a very meaningful opportunity that, you know, at this point, rightfully so, a lot of people have taken the back seat and say, "Let's see if it even gets approved." We take the same attitude. We need to get it approved first, of course, and then launch it hopefully next year. So that could be a very strong intermediate opportunity that will bridge us to some of the exciting programs that we talked about today, in addition to the corporate development, as what else could we do in between to bring, you know, these opportunities? And I know I'm getting into my closing remarks, but since you opened the door for me, I might as well keep going. If you really think about some of these programs we just shared with you today, and if these programs were to be in a biotech company on its own, that doesn't have an LOE of Trokendi XR or an LOE of Oxtellar XR, I bet you if I do a survey in this room or the folks who are attending virtually, that probably will be a biotech company with a billion-dollar or more, way more than that, just on the promise of an 820 and the very strong preclinical data that we've shown you on 820, the mechanism of action and how selective and first in class that mechanism is. But just because it's embedded in a company like Supernus that has an LOE, short-term LOE issue, which also we've shown that we've actually managed extremely well, we're sitting with no value, of course, for that pipeline. So I can bet you that we do get a positive phase II-B data on that molecule. We're off to the races, and this is a very different company. So I will just leave you with that thought. And the same thing with 817. If 817 continues with a profile like the one we just saw today as an emerging profile, we have to generate a lot of data. Absolutely, we're not there yet. But all the early signals and initial data points we're seeing with a 60%-70% seizure reduction, potential, and I emphasize potential, of course, procognitive and other issues that could, could really differentiate this molecule in a market that for decades, unfortunately, has been a tough market for patients. There hasn't been anything really meaningfully that moved the needle for a lot of these patients. Why do we still have 34% of patients are refractory in epilepsy after decades and decades, and decades of all these molecules coming and going in the marketplace? Because nothing really has moved the needle in a meaningful way. And we sure hope that SPN-817, with everything that we've shown so far, early data, very small studies, an N of one or two, or three, or five patients, of course. But I would rather see it this way than see something else. And everything we know about the mechanism of action and how potent this drug is, and how selective it is versus all the other molecules out there, we have a strong confidence and conviction that we actually have something really, really remarkable on our hands with SPN-817 in epilepsy. So now you have two first-in-class molecules across two therapeutic areas in CNS, in addition to the other stuff we're working on, whether it's 443, 446. Yes, these are very early, and we have other molecules actually in the pipeline that we are doing right now, characterizing, screening, preparing preclinical work to even get them nominated as clinical candidates as well. So that's in a nutshell, you know, pretty much I went through my closing remarks. We are truly building a very strong foundation here for future growth, and we are a company that historically delivered and will continue to deliver. Nothing in drug development is a straight line, so we, we'll all be fooling ourselves if we think there will be no hiccups on the way. That's how this business is. We are in it for the long term, and we certainly are building for the future. Hopefully today, we really showed you that we have incredible assets that will give us that future growth if they work, of course, scientifically, and if we continue to execute the way we've been executing over the years. Makes sense. Thank you. Thank you. Hi, I'm David Amsellem from Piper Sandler. Could you comment on the IP for these NCE opportunities, particularly 817, their composition IP year, and how should we think about the broader IP estate? And then the same question for 443 and 446. Yeah, for as far as IP is concerned, for 817, obviously, Huperzine A, there is no IP on, on the drug itself. But this is a molecule that has never been studied in the U.S. as a drug, so by definition, it's a new chemical entity to start with. From a regulatory perspective, you'll get the five-year exclusivity, depending on where we end up on the indication. At one point, we were also considering orphan subtypes of epilepsy, but focal seizure is not orphan, clearly. We also, and will have IP from a formulation perspective, which is a huge area in this, specifically in this molecule. As you may have heard or remembered Jonathan, when he went through the program, if you take Huperzine A up to 4 mg BID with these supplements that exist on the marketplace, you pretty much spend the whole day in the restroom. Because it is a really nasty molecule to even get to the point, never mind being able to even take as many tablets or capsules, because they are available in 0.2 mg. So if you want to go up to 4 mg BID, you can imagine the amount of drug you have to take during that day of these supplements to even get the therapeutic level. So clearly, that's where the challenges are. When I use the word challenges in R&D, I always tell my scientists that's a great thing, because that means it's IP protection, if we can actually tackle these challenges and solve these challenges with patents, and that's what we're doing. So from a timing point of view, we're probably looking in the mid-30s or above, as, you know, 2035 and beyond that, or longer than that for SPN-817, SPN-820. For SPN-443 and SPN-446 will be even longer because we're just starting with these molecules, and they are much newer projects. Thank you. Hi, Jack Padovano with Stifel. Will there be any need to partner any of these programs out as far as clinical development is concerned? And what might R&D expense look like going forward? I mean, clearly, through all the session, you heard R&D, R&D investments, and we're very serious about that, as I mentioned earlier, and therefore, I don't think people should expect our R&D spending to go down over, you know, moving forward. As these molecules move into phase II-B, with 817 and then 820, God willing, we move into phase III and so forth. Clearly, the R&D is gonna go up, it's not gonna go down because of the extent of these, you know, studies and the number of studies you might have to do and so forth. Would partnering be a way for us, you know, to work with somebody else in this space and maybe, you know, give rights somewhere else or whatever? I mean, all this is open. You know, we would consider anything creative to keep this molecule moving clearly, or we'll do it ourselves regardless. So we will weigh all our options at that time. Let me put it this way, that will be a very, very, very high-quality problem to look at, and I would be very happy to be looking at that situation if I have, you know, strong phase II-B data on SPN-820. Hi, hi, Jack. It's Zuyogo from Mutual of America. I just wanted to quickly get your perspective on what the addressable market for you. W hat kind of TAM would this all this would create if you were to look at it, even on a conservative basis? The way you talk about ADHD, for example, if Qelbree is only relegated to what the non-stimulants have been in the past, even so, it's a, it's a meaningful product for you. If you were to think of these in the pipeline in a similar way, what could that mean for Supernus down the road? Thank you. I mean, individually, for example, Qelbree, and we've talked about that, although it is a non-stimulant, it's so differentiating on its own. And actually, some of the data we shared with you today, co-administration of Qelbree on top of a stimulant seems to give a very much, very strong incremental efficacy on top of the stimulant. So Qelbree is starting to prove, now three years on the marketplace, it's not the old non-stimulant that people have been used to, you know, with Strattera and Intuniv and so forth. It's clearly a product that is delivering and delivering good efficacy. And that's why we're also studying it in addition to that, as we mentioned today, with ADHD, with comorbidities, like depression, anxiety and so forth. The other thing is, we've talked about many times, is the source of the patients who are coming into the Qelbree franchise. About 71% of these patients are switchers, meaning they are being switched or they are add-ons from other therapies. They are not just from non-stimulants. 65% of these switchers are from stimulants. So we are actually looking at an environment, a clinical setting here, where physicians are looking at Qelbree potentially replacing a stimulant, because 65% of the switchers are coming from stimulants, and the majority like a product like Vyvanse and so forth. So that tells you something about how clinicians are looking at Qelbree, with them trying Qelbree even to replace a stimulant. Clearly, that shows some confidence that Qelbree is efficacious and should be efficacious for people if they use the right dose and get to the right dose, whether it's pediatric or adults. So Qelbree, in general, is not just a non-stimulant that's gonna compete in that 10%, you know, segment of the market. Now, SPN-443, obviously, as time goes on, as we develop it, and hopefully, you know, will take less time than longer time, you know, to get it to the marketplace. Clearly, that will go after the stimulant market and hopefully with the differentiation that we've seen so far, very early data, clearly, but it will be complementary potentially to Qelbree. It doesn't have to be. So it's a huge market, ADHD, you know, 92 million-plus prescriptions a year, so that's a very, very significant market from a potential perspective. The depression market, I think the number is 195, if I remember from the slides, 195 million prescriptions. So clearly, depending on where we end up with the product, is it for TRD only, or is it TRD and MDD? And we're studying it in both, because we're gonna be starting hopefully the study soon in the MDD setting. So that could open up the whole market, not just TRD. TRD, give or take, is 1/3 of the 195 million, or 1/3 of the market, so to speak, you know, just give and take. So it could be one-third of the depression if we are only limited to TRD, but it could be the whole market if we are able to show efficacy in both MDD and TRD. Then the epilepsy market, it's also, you know, a significant market, especially if we continue to see the profile that I mentioned and we talked about, you know, the high efficacy and so forth. I mean, that, that's, that's a multi-billion-dollar opportunity as well. Jack, historically, the company's focused on very large volume opportunities or getting, you know, small market shares of very significant prescription volume markets. But then you purchase GOCOVRI, you have the infusion pump. You mentioned a drug for narcolepsy today. These are more specialty-type markets. Do you feel like the company is equipped to handle those types of markets, vis-à-vis what the commercial organization has done historically? And as you think about the very long term, is that an area you'd like to build up more vis-à-vis business development? Yeah, sure. A good question. If you look at us today, we're actually active in both spaces, meaning the mass retail type of markets, big markets. I mean, ADHD is considered one of the bigger... Migraine, we used to be in that market as well, right? 200+ sales force type of, you know, sizing that you would need to really address the market of these products. Similarly, we are also in the rare orphan-type specialty products as well with our Parkinson's portfolio. So we actually have the capability for both type of products with our current infrastructure. So when we launch the pump, hopefully, if approved, you know, next year, it will actually benefit from the infrastructure we already have from a specialty perspective with the Parkinson's sales force, the nurse network that we have that supports our products, the hub services and patient services that already are in place to support patients. Reimbursement, all that is already in place. So we are equipped to handle both type of situations. Now, if an antidepressant, which could be way beyond an ADHD from a footprint point of view, you know, as time goes on, we can always evaluate partnerships and so forth, if we need to, to, you know, maximize the potential of that product. Stacy Ku from TD Cowen. Just one more question on Qelbree in the adult population. Sounds like you're running another study. So could you talk about maybe the reason to pursue that? And then what do you think broader about the opportunity there? Clearly, you've been in the market for now over a year, so what are, what are your major learnings, and where do you think it could grow to? Yeah, I mean, the adult market is about 67% of the ADHD market, and that's a huge opportunity for us to expand in the adult segment. The uses of ADHD medications in pediatric versus adult, there is a very, y ou know, there is variances in between. You know, physicians are treating sometimes slightly different things, you know, between a pediatric patient and adult patient, in general. Qelbree works as well in either, obviously, as the data has shown, you know, in pediatric and in adult. The adult setting, there is a lot of immediate release, as Jonathan mentioned earlier, a type of amphetamine stimulant type of use. It's not necessarily for ADHD. Sometimes it's for other reasons, that, you know, we have mentioned some of those. That kind of use, Qelbree is not gonna be appropriate for that type of use in adults. So clearly, that's a segment of that adult market that we may not be able to play. But if that IR or immediate release is being used as a supplement to supplement the extended-release amphetamines or methylphenidate are not giving you the duration that you need for that adult during the day, Qelbree could be a potential substitute because Qelbree is a long-acting 24-hour product. So that then will replace not just the IR, but it'll also replace the IR and the ER that is being used earlier in the day. So, so there are different pockets within the adult segment, where Qelbree can be a very, very useful medication, you know, to be used. In certain areas, stimulants, as we mentioned, also are very much associated with irritability. You know, you know, people tell you it changes the behavior of that person. You know, it changes their character, how they behave. So a lot of times, physicians wanna cut back on that irritability that is caused by amphetamines, methylphenidates, and so forth, and they supplement with, you know, a non-stimulant. And actually, we're seeing about 20% of the usage of Qelbree is with stimulants, and a lot of it could be because of that. You know, they wanna reduce a little bit the stimulant dose, so they don't bump against the irritability, the mood swings, and all these other issues, and they supplement it with Qelbree. So they're using the product, the point I'm trying to make, is for different purposes, whether it's adult or pediatric, but in general, Qelbree is being used across board. It's not being pigeonholed as just a non-stimulant, and that's it, or it's just another second line after Strattera. I think we've proven that. Even the study that Dr. Price, you know, published that study showing that Qelbree is way beyond atomoxetine. Forget atomoxetine for four weeks, doesn't do anything, basically. But then if you use and switch these patients to Qelbree, we show statistically significant impact by Qelbree, even those have tried already atomoxetine. So clearly, Qelbree is a very different drug. We just need the time to continue to educate, you know, clinicians out there about the profile of the drug, the usage of the drug. We need to help them continue to titrate to the right doses, because that's where the efficacy is. So I- Yeah. If I can add something, because I'm both academician and a clinician, so I actually treat ADHD quite a bit. The study that was mentioned, addressing comorbidities with anxiety and depression, has, in my mind, a very significant potential. Now, again, I'm also a consultant with Supernus, so take what I'm saying with a big grain of salt. But if indeed there is evidence supporting improvement in comorbidities, comorbidities in ADHD market are about 70% of ADHD patients. It may, there are a lot of conditional statements here, shift when Qelbree would be used. So, if in these individuals who do have comorbidities, Qelbree, based on evidence and based on medical education that will follow that evidence, becomes a first-rank agent for ADHD, again, in these patients, that completely changes the story. You are now there with Qelbree. If by some chance you do not have adequate control of conventional, narrowly defined ADHD symptoms, you can now always add stimulant, but you're shifting the paradigm. You're not going with stimulant and then potentially adding Qelbree. You're going with Qelbree and potentially adding stimulant. Again, all that hinges on these studies being positive and that evidence getting out in public domain via CME and disease state education. If that happens, it is no longer just a non-stimulant. It is a very different proposition. I would add to that. When you think about the treatment of ADHD plus a comorbid disorder, so ADHD plus depression, ADHD plus anxiety, the current treatment paradigm would be to use two medications, one for the ADHD and one for the comorbidity, and if we could treat with one medication, that's beneficial for clinicians and for patients. The other thing I would add, we haven't done any head-to-head studies against Atomoxetine, but what we do know is that Atomoxetine failed in studies of depression. And if we show that Qelbree reduces depression in people who have ADHD plus depression, and we believe that based on the European data that I cited, that that will work, this is another point of differentiation. This is a big if, but if 443 was commercialized today, would you be able to kind of meet the market with production in ways that Adderall and others are, are having issues right now? Do you, do you have sort of the capabilities to kind of do that? Yeah, I mean, especially if it is not scheduled as some of the... as the amphetamines. I mean, C-II scheduling is, you know, not a great place to be in. It really creates a lot of procedural, logistical issues for manufacturers, distribution and so forth, with the quotas and DEA and so forth. And I think, you know, part of the issue with the shortages is you have that, I don't want to say explosion in demand. But you have that significant increase in demand on these products during COVID, post-COVID, and so forth, and a lot of these manufacturers weren't ready, you know, to increase production, get increased quotas from the DEA, and be able to meet a nd some of it also is supply chain issues and so forth. Everybody blames everybody, but basically, you know. So if our profile stays like we think, meaning reduced abuse liability and potentially Schedule IV, that will eliminate and make it a much easier process, you know, to be able to produce the product and so forth. So that shouldn't be an issue at that time. Yeah. It also potentially, you know, if we get a Schedule IV or better, then also you could sample potentially the product, you know, versus a C-II, which you cannot sample as well. Yeah. So a question came online. Many children with epilepsy also have ADHD with focus. I assume that means trouble with focusing or maybe focal seizures. Has or will Qelbree be studied with anti-seizure medications? So, we haven't specifically studied that, nor do we plan to, but in our clinical trials, there was no evidence of any drug-drug interaction with seizure medications that we would anticipate. So that people could take an anti-seizure medication plus Qelbree, and there shouldn't be any concern about the drug on either side of the equation. Anything else online? Okay, well, I'll just close with my closing remarks. I'll repeat them since I mentioned most of them today. Hopefully, you know, after today and hopefully, it's been a very helpful session for you, couple hours here and giving you a different perspective who Supernus is. We are very excited about what the future holds for us. Not just the future, even in the near term, we have significant milestones and catalysts that we have talked about throughout the session. You know, with SPN-830, the approval, potential approval, launch next year, I mean, that is a big event for us, clearly will give us another leg for growth within our portfolio. And then clearly, the readouts behind SPN-820. I mean, 2024 is almost tomorrow. I mean, we're almost at the end of 2023, so 2024 and 2025 are not really that far off, and we will continue in parallel to execute hopefully on the corporate development side and bring other assets. So that makes a lot more commercial late-stage assets that could complement, you know, our pipeline and bring more momentum and energy behind the portfolio. So thank you so much for really being here today and attending our session. We really appreciate it very much, and enjoy the rest of the day. Thank you.