Supernus Pharmaceuticals, Inc. (SUPN) Earnings Call Transcript & Summary

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 going to be sharing with you about the future of Supernus. Now before I get started, I just want to 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 of slides on Qelbree at the beginning 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. And we will close the day with a general session, including the Q&A. So 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 are 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 2 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 2 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 to $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 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 a 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 830, which is a complex drug-device combination that we resubmitted very recently to 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 '06 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 that we develop 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 I 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 to our 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, mechanism of action to treat in these therapeutic areas. That pipeline, in addition to our execution on 4 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 would continue to have that. I guess we have shown the track record in the past several years and making 3 acquisitions, 2 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, 820, 817 and do what we always do very well, proven commercial expertise, launch the products, and build a multibillion-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 multibillion-dollar market value. So what is that capability that we're talking about today and that produced 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. And we have been screening hundreds of molecules that allowed us today to be able to talk about SPN-443 and 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 had, which is amazing capabilities in drug delivery. In pharmaceutics, PK, formulations, GMP manufacturing and so forth. So coupling the 2 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 day and 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 IIb 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. During 2025, and we will communicate these a little bit more specifically as time goes on. 817 Phase IIa 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 817. And then 817 also next year, we will initiate a Phase IIb study in epilepsy as well. 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 3 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 are very well differentiated versus marketed products as well as pipeline products, and then finally, continue to execute on the corporate development side to augment our growth through external growth opportunities. So with that, I will move forward and transfer it to Dr. Rubin to start the discussion on the pipeline.

Good morning, everybody. So 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 a moderate-to-high symptom level. And you can see in this data that there was a change at week 8 of minus 18, which was about a 50% change, a fairly significant impact on people who are 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 [ markedly ill ] 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 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 trial 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 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 want to 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 want to know is, can -- 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 because we know that viloxazine in 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 to 600 milligrams 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 our -- of Qelbree in adults with ADHD. And we're going to look at the change in the AISRS in adults with ADHD who have mood symptoms. But in addition to that, we are also going to look at depression symptoms with the MADRS, the PHQ. We're going to look at anxiety symptoms with Hamilton-A and the GAD-7, and we'll be looking at a variety of other assessments, including work in home functioning, executive functioning and sleep. Last week, we announced that we submitted 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. 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 will be -- is intended to treat depression. Now before I go on, I want to clarify some nomenclature. SPN-820 is what we will refer to as the product. SPN-820 is 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 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 and onset can take 6 to 8 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. And 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 1/3, 1/3, 1/3. Roughly, 1/3 do not respond to the first treatment, 1/3 do not respond to the second treatment and 1/3 do not respond to the third treatment. So let's talk about the diagnosis. Major depression disorder, or MDD, is classified by the DSM-5, the diagnostic statistical manual of the APA as having 5 or more symptoms in a 2-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 -- the 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 2 or more antidepressants or ADTs of adequate dose and duration of each of those treatments. But within the field, health care practitioners, and an evolving literature suggests that TRD may be considered as a failure of just 1 drug. And when you think about it, both clinicians and patients, they don't want to wait to go through 3 or 4 drugs to have treatment. They are at risk for suicide, impairment at home or at work, and they want something that's going to 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, noropinephrine, dopamine or a combination of some of those. The only exception to that is esketamine or Spravato, which works as an MDA 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. Those -- 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 MDA 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 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 synapsis 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 that -- with good response frequency, fast onset of effect on depression symptoms, 1 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 for -- 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 or 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 treatment 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 efforts 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 1950s, there was a large -- as a matter of fact, largest in the nation, TB sanatorium in Staten Island, it's called Seaview 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 who are sitting there in melancholy mood, dejected, uncommunicative, absolutely no interest in anything that could be known pleasurable. 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 a relatively short-lived because it was proven to cause liver problems. But it became parent compound to 2 different medications. One is called isoniazid. So iproniazid is the medicine I'm talking about. Isoniazid is still used in TB medicine. Isocarboxazid, it's 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 or effective antidepressant treatments. Theory suggested that patients who have depression have something abnormal in their monoamine transmission. And we have been stuck in that mode for a better part of 7 decades. I'm not going to diminish the benefits of monoamine modulating antidepressants. But I do want to balance it with limitations. And limitations that about 40%, which is significant number of patients, is about as much as one would hope to achieve remission. And if we look at functional remission, in addition to clinical remission, the number is lower. And 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, 4 steps. Step 4, 12% of the patients achieved remission, 12%. How many retained at 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 they're also GABA modulating medicine 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 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 microscopic level. There is a change in neural network connectivity that may underline symptoms of depression. And 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 with 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. So speaking about communication between brain networks, let me provide very simple outline of what these brand networks are all about. So salience network receives all the sensory information about changes in our external and internal environment. And in response to the 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 adapt or 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, 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 hot-wired 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, engaged default mode network and individual starts ruminating. It's nonproductive 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 and make these networks function in a 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 up activity, rumination. Salience network goes from focusing on exploration, reward signals, interest, ability to enjoy life to 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 vesicular glycoprotein. Its abbreviation is SV2A, which we can attach a radio label to, and we can actually look at synaptic density in the brains of individuals who have major depressive disorder. And here's what we are 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, or 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 over 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 820 and NV. And as you have heard, 820 will reflect more on clinical studies, NV will reflect more in 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 very clear idea of what it does. Number one, it is making the 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 or amino acids. It senses amino acids. Two, we need blueprint for bringing -- 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. And third, if you want to be manufacturing something, you need energy. And energy is ATP, adenosine triphosphate. That is what it senses. So it senses resources and if they are 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. So it is docked at lysosome at the breakdown plant, if you will, and informs ribosome, which is manufacturing plant. So 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 are 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 has dropped into a large beaker that is 2/3 filled with the 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 mobility 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 starved for 24 hours, they're receiving no food, and then they're given 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 at 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 2 options to drink, plain water or sucrose, sweet water. In usual situations, they will prefer sweetwater 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 suggests 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 the 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 the depressed mood in human beings. So what we are 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. Post-synaptic 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. You have seen in one of the imaging studies. So there are 3 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 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 seems these thin synaptic spines that have complement 1q attached to it, it's going to get gobbled up, that memory is gone. But if something that I'm seeing 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. And we do see that stubby -- again, these are formed memories, they're not going to change much. There is a lot more sustained thin spine and especially mushrooms spines. 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 are 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 2A receptors or it can be simulated 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 the 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 underway. And two, it will impact mTOR, which again is associated with proliferation of cells, but also increased synaptic density. And it would increased BDNF transmission, which is one of the main neurotrophic factors, which we have 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 or 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 -- or a kinase that is aside mTOR because mTOR is a kinase. So yes, it will impact mTOR, but not other kinase. Also metabolic enzymes, CYP, P450s 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. It's about 1/10 of what it is in plasma. So about 1/10 makes it into cerebrospinal fluid. Pretty rapid absorption, again, rounding it off. Peak in plasma is about an 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 study 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 CFS (sic) [ 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 be 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 800 to 1,600 milligrams 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 the 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 milligrams 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, 6 are going to be an active drug, 2 are going to be on placebo. The range of doses that was explored was 150 to 2,400 milligrams. 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 onetime dosing and that onetime dosing starts very low, around 150 milligrams. And you can have pretty high doses up to 2,400 milligrams. So you'll have 6 individuals receiving 150 and then the various other doses in the range altogether, 6 groups, 6 dosing strengths from 150 to 2,400 explored in 6 individuals each on NV and 2 on placebo. So that is one. It's onetime dosing. There is a different regimen. Different regimen is 2 doses that are 48 hours apart. And the third dosing regimen is they're receiving the NV daily, right? So 3 dosing regimen to determine PK, to determine biochemical markers, to determine electrophysiological changes into -- 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. HAM-D, Hamilton Depression Rating Scale is a very standard instrument in the field, measures a variety of different symptoms of depression. HAM-D6 is abbreviated version. So there's still depressed mood there. The second is working 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 bodily aches and pains. So these are some of the acute manifestations of major depressive disorder, and there 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 time frame is different and there's a lot of variability, small sample sizes. HAM-D6 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 in CGI, clinical global impression of severity, 7-point scale: 1, no symptoms whatsoever to minimal symptoms, 3 mild symptoms, 4 moderate symptoms, 5 markedly, 6 severe, 7 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 noticed that green and blue curves have a different starting point. And that is because these have been dosed daily for 7 days. So at that point, age 20 is at steady state. On the other hand, the red line is 2,400, this is one time. So we're looking at blood levels, and we're seeing that 800, 1,600 daily dosing up, seems like a good option. But I mentioned biochemical markers and something that would be appropriate to reflect the activity of mTOR Complex 1. 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 going to create some smoke. So you're going to create some oxidative damage or potential for, 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 mitochondrias so far. They are 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 800 and 1,600 milligrams of NV, indeed, there is appropriate increase in these biochemical markers of the activity. So 820 Phase IIb. Now these are large clinical trials. It is a multicenter, it will be flexible dose treatment, starts at 1,600 milligrams a day, maybe tapered to 800 milligrams. About 268 subjects might be enrolled, up to 50 sites, screening up to 6 weeks. It is, remember, adjunctive. So there will be another 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 820. So primary efficacy Montgomery-Asberg Depression Rating Scale, very standard. That's what FDA wants to see. Key secondary is this clinical global impression of severity. HAM-D6, you have heard about. Onset of effect, how soon will it separate from placebo. Response and remission, response, 50% reduction in the depressive symptomatology. Remission, MADRS score less than 10 or equal. Individual disability measured by Sheehan Disability Scale. Anxiety measured by GAD-7, general anxiety, a 7-item scale. And then rate of improvement is also important as well as safety signals. Where are we right now with this Phase IIb? 62 patients or subjects randomized. In-treatment, 6. 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, 3 days later after administration of a single 2,400 milligram dose every 3 days. That is the pulsatile dosing. Rapid onset will be evaluated with HAM-D6, which we have shown detects this rapid onset, and then we will evaluate the efficacy based on MADRS, Montgomery-Asberg Depression Rating Scale, a very standard scale. So in summary, what are some of the attributes of 820? 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 HAM-D6 was 0.6, which is a very robust effect. Rapid onset per dose sustained for 72 hours. Overall, it appears well tolerated, unlikely to be 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 IIb in 2025. And with that, I will thank you on your kind attention and conclude this talk. So thank you very much.

Yes. Thanks, Dr Maletic. Before we go to questions, we would like to play a brief video if we could queue that up. [Presentation]

Thank you. I'd like to open up to questions from the audience.

There'll be a microphone going around [Operator Instructions].

Okay. Stacy Ku from Cowen. Thanks so much for your insightful commentary. So first, Dr. Maletic, do you want to 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 1 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. And I have a follow-up.

Right. So that would be the hope, right? The hope would be not only that it is noticeable separation from placebo at week 1, but it actually may be noted earlier, that it may be noted at 24 hours, that maybe even noted at 4 hours. So a 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 have seen that it's sustained for 7 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 7 days or 10 days, how many times would we need to treat or retreat, what is the optimal interval of treatment of 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 a 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 an onset of activity at 1 week or less, you can be classified as a rapid-acting antidepressant. In the ongoing Phase IIb study, the first time that efficacy will be measured, the first visit will be at 1 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 measured, which hasn't yet started and will start soon, we will be looking at onset of effect on the first day. So we're going to see just how good this drug does and when it starts its action. The second study is supposed to start soon. The readout will be early next year. It's a small study, and it's a short study.

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 in balance 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.

Has the blind been broken? Do we...

No, no, no. We won't know until we lock the database -- well, we know the adverse event occurred. We don't know in what group.

Is it placebo or an 820.

Andrew Tsai, Jefferies. Thanks for hosting this. So maybe the first question asked another way. What is your expectation at week 5, drug versus placebo on the MADRS separation? Understanding this as our TRD indication, only 2 drugs technically approved, limited number of treatments. So what is a meaningful MADRS separation to you? And then secondly -- go ahead.

So -- I mean, within the field of depression, MDD in general, the SSRIs have an effect size of about 0.3 to 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. We -- this study is powered to detect at least that and hopefully more. So we saw effect on the HAM-D6 of 0.6 to 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 the 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'd 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 we'll at least hope to see something like that.

Makes sense. Maybe second question, 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.

Safer. Is it limiting the number of patients per site balancing enrollment per site, so forth, or educating patients. Talk about what you're doing, basically?

Yes. Thank you. I acknowledge your comment. This is a very challenging area. It 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 to 20 years. So we are taking a number of measures to mitigate. We'll never eliminate it. It's always going to 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, without any expectation. And then we'll see what the drug does.

Just wondering...

This is a U.S. study, one-to-one randomization. I don't see any other questions in the audience. Anything from the chat? Anyone? Yes.

Given the novelty of the mechanism and just how long it's going to take to recruit the study, is there a thought to taking an interim look or potentially even shrinking the Phase IIb to something like 150 patients to get a readout sooner?

Yes. I've contemplated that because 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 of 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 going to get into this, but SPN-821, is that also in development for depression, just help us understand, is it a different formulation? Any other details if you could...

Yes. 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 will be used.

Jack Padovano with Stifel. If you show consistency on some of the secondary measures in Phase II like the Hamilton Scale on the Phase I, could you still expect to move forward with Phase II? I know you mentioned that the MADRS wasn't reliable for the time frame 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 -- 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 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 going to be the MADRS. Anything online? Okay. We're going to go forward. Thank you, Dr. Maletic.

Thank you very much.

Okay. So now we're going to 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 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 and polypharmacy. If you think about the treatment journey. Providers start on a generic anti-seizure medication or ASM, and they'll take that medication, they'll titrate it. Over time, they'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. And then if that doesn't work, then they may go to neurostimulation or using a ketogenic diet. And 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 -- social relationships. The probability of achieving full seizure freedom is substantially reduced with each medication that you add. So 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 improved quality of life and improved 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. And 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. And 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. But both providers see the benefit of a drug that may be pro-cognitive and maybe 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 metabolizes 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 derived a broad and potent -- we have found a broad and potent antiseizure effect in various seizure and genetic models of epilepsy, and I'm going to show you one right here. So this is a screening program from the NIH. Looking at a broad variety of antiseizure medications, which are well known. And in this paradigm, you take an animal, and you administer a current, an electrical shock to induce the seizure. If the medication is protective, you're not going to see the seizure and you look at the ED50, the effective dose at which 50% of the time, the seizures are going to be eliminated. And you can provide -- what you see here are different amounts of current. The standard model is 32 milliamperes, which is in the middle column. And if you look, as 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 60x more potent than Keppra, and a lot more potent than the other drugs, which are standard antiseizure 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/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 both in the periphery and the brain. And because of this, in comparison to other drugs, the SPN-817, you need lower doses to get to the brain, the place where you want to have activity. And in comparison, if you look at another acetylcholinesterase inhibitor such as donepezil, it has similar activity to 817. But because it works on butyrylcholinesterase, you have to give very high doses to get to that similar activity, and they're going to be dose-limiting. You're going to have significant side effects and you're not going to be able to get it to the brain. So we have completed a Phase IIa study, 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. And 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 extension that was 6 months or more. In this study -- there were 3 subjects in this study, it 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 milligrams, twice a day. In looking at the 3 patients, looking at the 28-day seizure rate, which is the standard of which drugs are assessed for in terms of a primary efficacy measure. There was a 71% reduction for all 3 subjects obtained until month 14, a 90% reduction until month 40 and -- for 2 subjects. And a 98% reduction until month 51 for 1 subject. The graph that you see is a sample from 1 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. So we currently have an ongoing Phase IIa study. This is an open-label study, 8 sites, again, in Australia, and we intend to enroll about 35 subjects who have treatment-resistant seizures. The intended indication for this product, as I mentioned, is focal seizures in adults. This study has a similar design to the FIAS study that I mentioned earlier. There's going to be a screening period where we're going to look at seizure diary and make sure they have a certain amount of seizures before they come into the study, 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 milligrams twice a day and then get titrated up 0.25 or 0.5 milligram increments up to a maximum of 4 milligrams BID. The endpoints, it's an open-label study. So safety and tolerability is the primary endpoint. Secondary endpoints, the percent change from baseline in the seizure frequency. That's going to be the key efficacy endpoint, and we're also going to be looking at seizure symptoms, seizure severity, quality of life, disability. We're going to be looking at the PK profile of huperzine A, and we're going to be looking at some exploratory endpoints, including change in inflammatory biomarkers. There is evidence that suggest that huperzine can be anti-inflammatory. We're going to 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 on 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, 7 of the 35 and 10 enrolled subjects have completed titration. They finished titration at doses ranging from 1 to 4 milligrams twice a day. Safety is the primary endpoint here. And the most common adverse events were diarrhea, nausea, headache, insomnia and affect 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, 2 of them have gotten all the way to maintenance. We had almost a 64% reduction, which is clinically significant. And furthermore, 2 of the patients who made it through titration are completely seizure-free. Again, consistent with the study that I reported earlier of 1 subject out of the 3 who are seizure-free. There's 1 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 want to 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 IIb 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. This study is going to have a screening phase, again, where we'll count baseline seizures, titration period of 9 to 11 weeks, and then going to a maintenance phase, and then for those who qualify, going to an open-label study. It's going to be a randomized, double-blind, placebo-controlled study, will be -- the randomization will be 1:1:1:1. So there's going to be 4 arms: placebo, 2-milligram bid, 3-milligram bid and 4-milligram bid. And roughly 109 subjects per arm. We want to achieve 76 subjects per arm in the full analysis set, the completers. It's going to be a large study, up to 100 sites. It will be a global study. It will be in the U.S., will be in Europe and it will be in Australia and Asia. The primary endpoint will be a 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 Phase II study, we saw a mean reduction in 3 subjects of 70%. The subject -- the compound so far has been well tolerated in clinical trials. It has shown a broad and potent antiseizure 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. And as I mentioned, we'll be entering a Phase IIb study at the end of next year. So 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. First, how long -- maybe I might have missed this, but how long is the titration, up to 4 milligrams bid? What's the timing like? And then for the 2 patients that showed -- that finished their -- that entered maintenance, are they -- essentially, they all hit 4 milligrams bid. Is that correct? So 2 clarifying questions. And then could you clarify again that third point, you said 2 patients achieved seizure freedom during titration. These are the same patients? Or how should we think about that data?

Okay. So they're not the same patients. But getting back -- the ongoing Phase IIa study has an 8-week titration. For the Phase IIb study, we're going to go to a 9-week titration. We're going to make it a little bit longer. And forgive me, your second question?

Was on the 2 patients that we saw, the 63.5% mean reduction in seizures, those were all the patients that were kind of stable now on 4 milligrams bid. Is that the right way to think about it?

The dosing. One got to 4 milligrams bid. I don't remember off the top of my head, the second, but I can check on that. There was -- within the data reported of the 6 to 7, it ranged from 1 milligram bid to 4 milligrams bid. And even some -- 1 of the subjects who had seizure freedom was either at 1 or 1.25 milligram bid. So at a very low dose, had complete seizure freedom.