Well, good afternoon, and welcome to the very first LB Pharma R&D Day. I am Heather Turner, CEO, and I am delighted that you all were able to navigate through the restaurant, through the TV set and to ultimately find your way to this hidden room here in New York. So thank you so much for being with us here today. Throughout this presentation, of course, we will be making forward-looking statements. Before we move into the agenda, I wanted to take a moment and reflect on the mission of LB Pharma. It is the North Star that guides us in the work that we do today.
I have had the privilege of leading this company for almost exactly two years to this day, and I have really developed a deep appreciation for the devastating impact that these brain disorders like schizophrenia, bipolar disorder, major depressive disorder, can have, not just on the patients who are suffering, but also their families, their care partners, and frankly, society. These are prevalent diseases. 3 million people in the United States suffer from schizophrenia, 7 million suffer from bipolar disorder, and 20 million suffer from major depressive disorder. I am sure that people in this room have friends or family members who have been and experienced the dimming of their lives that these types of disorders can accomplish. I am also certain that many of us know people who have been suffering from these disorders and can see firsthand the impact that they have on people's lives.
Our mission, as it is noted here, is to boldly advance high-impact therapies that will help people with brain disorders to live their life more fully, more brightly. Our aim is to alleviate the burden that many of these individuals feel, that their families feel, that their care partners feel. We have an amazing team. You will get to meet many of them throughout the day today, and you will see that this is a group that is passionate, they are experienced, and they are convicted in the pursuit that we have towards our mission. They are also fun to be around, quite honestly. Speaking today is our new CMO, Dr. Susan Kozauer, and our Chief Commercial Officer, Kaya Pai Panandiker. Gad Soffer and Joe Miller will also be available later today to answer questions.
You will also hear from our esteemed guest, Dr. Roger McIntyre, who is a Professor of Psychiatry and a Professor of Pharmacology and Toxicology at the University of Toronto. Let us turn to the agenda. I will be kicking off the day with a discussion around LB Pharma, as well as the LB-102 opportunity. Dr. Susan Kozauer will join and talk about the LB-102 clinical data, as well as some of the observations that we saw in our phase II NOVA-1 trial, and some of the additional research that we are going to be continuing to do. Dr. McIntyre is going to come up and present for the first time preclinical data supporting the potential differentiation of LB-102, and in particular, the observations that we observed in our phase II NOVA-1 trial.
He will also talk about the reasons to believe for that low rate of EPS, as well as the LB-102 mechanism. Ms. Kaya Pai Panandiker is going to come up and she'll talk about our approach to commercialization in schizophrenia. Then I'll come back and talk about what to expect with the NOVA-2 data readout. This is a snapshot of LB Pharma today. We have three important readouts over the next three years. We have our phase III NOVA-2 schizophrenia data reading out in 2027. We have our phase II bipolar depression data reading out in 2028, and we have the adjunctive MDD data reading out in 2029. All of these clinical trials are fully funded, and we have cash that takes us beyond the second quarter of 2029. What is LB-102? LB-102 is a structural modification of amisulpride.
Amisulpride is a generic antipsychotic that is available around the world, but was never approved as an antipsychotic in the United States It's a selective inhibitor of D2, D3, and 5-HT7, and it has very few other off-target effects. It's considered one of the most efficacious antipsychotics with one of the highest effect sizes, and it's also considered one of the more safe and tolerable antipsychotics with one of the lowest discontinuation rates. It does have limitations. It is actually very poor at permeating the blood-brain barrier. As a result, it requires high doses. For schizophrenia, it's dosed between 400 and 800 mg a day, and it also requires twice-daily dosing. It is a very widely prescribed antipsychotic. It was first approved in the late 1980s and continues to be used.
In 2023, you can see here on the left that almost 2 million prescriptions were written for amisulpride for a wide variety of indications, as noted in the pie chart. It has approvals in schizophrenia, negative symptoms of schizophrenia, as well as dysthymia, which is a persistent form of depression. The founders of LB Pharma set out to build and create a molecule that could address amisulpride's limitations, and they did this through methylating amisulpride. The resultant molecule is LB-102, and it's a molecule that has improved potency. What we determined was that 50 mg of LB-102 is about the same as 400 mg of amisulpride, and this is based on the human dopamine receptor occupancy data. Both of these doses have about 70% dopamine receptor occupancy. We also enabled once-daily dosing, and this is because there is a longer residence time in the CNS for LB-102.
We retained the binding profile of amisulpride, and this is important. LB-102, like amisulpride, is a selective inhibitor of D2, D3, and 5-HT7. This is important because it supports clinical development in a wide range of indications. D2 is, of course, important for treating psychosis and mania. D3 and 5-HT7 both are pathways that are related to depression, cognition, as well as anhedonia. LB-102 also has a unique mechanism that it shares with amisulpride, and that is it preferentially engages with the presynaptic autoreceptors that are implicated in mood, anhedonia, and cognition at lower doses. This is actually a part of the preclinical data that Dr. McIntyre will be presenting later. This is important because what it enables is a treatment of a wide variety of symptoms through dose.
What you see with amisulpride is that at its highest doses, which are reflected here in the red, it is used to treat psychosis, schizophrenia, psychotic related disorders. At its lowest doses, which are noted here in the yellow, it is used to treat depression. So at the high doses, amisulpride is used at 400- 800 mg a day. For depression, amisulpride is used between 50 and 100 mg a day. Emerging from the NOVA-1 clinical trial, we believe is a profile for LB-102 that supports an opportunity for it to be the branded antipsychotic of choice. We noted and we observed a compelling efficacy profile, one that was reflected by a clinically meaningful reduction in the PANSS total score, as well as a very strong, robust treatment effect. In addition, we saw an effect as early as week one, which we know is an attractive aspect for prescribers.
We also believe we have the potential for a class-leading safety profile. This is based on the low rate of EPS that we observed, the minimal QT prolongation, and the negligible sedation. We also had very few GI side effects. In addition, there are opportunities to potentially demonstrate a benefit in two significant areas of unmet need. The first is cognition and the second is negative symptoms. With respect to negative symptoms in the NOVA-1 trial, we observed a statistically significant effect on the PANSS negative symptom subscale at the 50-mg dose. This is consistent with that mechanism that we just talked about. With respect to cognition, we utilized CogState to assess a battery of tests, and we found a robust dose-dependent treatment effect on cognition. A benefit in either one of these areas of unmet need will be very attractive to prescribers.
In addition to all of that, we have a very simple-to-use profile. This is once-daily dosing. We are not expecting a food effect, no challenging drug-drug interactions, and all patients start at a therapeutic dose. There is no titration. Our goal in all of this is to really transform what is possible for people with schizophrenia. Too few people achieve long-lasting relief. 73% of patients do not experience a long-lasting quality of life. To us, this is unacceptable, and we are focused on changing that. I will now bring up Dr. Kozauer to talk through the clinical profile of LB-102, as well as why we believe we have an opportunity for meaningful differentiation. Great. Whoops.
Okay. Excuse me.
That was graceful.
Thank you, Heather, very much. I will be running through the development program with you at this point. First, I want to just take a minute to tell you just a little bit about myself. I am the newbie here. I have been CMO here, at LB for 44 days. What I will tell you about that, however, is that with every day, I am just increasingly excited about the potential of LB-102 and what it can bring to our patients. I started my career a few decades ago as an inpatient psychiatrist, treating the most severely mentally ill population. Quite honestly, I wish I had a drug that had the qualities of LB-102 in my toolbox back then. As we go through this presentation, I think you'll understand why. We're right in the middle of a development program in a range of neuropsychiatric disorders.
The left side of the slide here shows our completed clinical trials. We've got a phase I single ascending and multiple ascending dose study in healthy volunteers, a phase I-B PET receptor occupancy trial, and a phase II trial, NOVA-1, in patients experiencing an acute exacerbation of schizophrenia, all complete. On the right side of the slide, we have our ongoing and planned clinical trials. We've got NOVA-2, our phase III trial in schizophrenia. Those patients, as well as some de novo patients, can roll into NOVA-3, our open label 52-week safety and tolerability study. In addition to that, moving away from schizophrenia, we also have our phase II study, ILLUMINATE-1, in bipolar depression. Finally, we have a phase II trial in adjunctive MDD, which is slated to start early next year.
Let's step back and talk about the basics of antipsychotics, which essentially is typical D2 receptor occupancy. It has long been understood that antipsychotic efficacy has a relationship to D2 receptor occupancy, and that 60%-80% D2 receptor occupancy is ideal. What we see here in these PET study results on the screen show the receptor occupancy of LB-102 in our 1B study. If you look on the left side, this is our single-dose occupancy. We have 100 mg, 75 mg, and 50 mg from top to bottom. What you'll see is that the 100 and 50-mg doses were followed all the way out to 24 hours, and the 75-mg dose was followed out to two days, essentially. Receptor occupancy for that 75-mg dose was about 40%, nearly two days after that single dose at time zero.
The mean plasma concentration at that time period of two days was less than 10 ng per mil. In contrast, to give you a sense of scale, we expect Cmax, or our peak plasma concentration for that 75-mg dose to be actually 20 times higher than that. As Heather Turner was discussing, the increased residency in the brain is exemplified here. On the right side, we have our dopamine receptor occupancy of LB-102 at steady state. In this case, that means after four doses. What you can see here is that the orange line is a 50-mg dose, demonstrated a similar level of receptor occupancy to amisulpride at 300- 400 mg a day, around 70%, really right where we are targeting. The 100-mg dose, as you can see, actually hit over 80% receptor occupancy. I will talk about that in just one minute.
There was very little variability over the course of 24 hours in this steady state study, and what this tells us is that, again, yes, this supports steady state dosing. Once daily dosing at steady state here. The 100-mg dose did have greater than 80% receptor occupancy. Of course, as I stated before, what we know about that is that increased receptor occupancy does increase the risk of EPS, or extrapyramidal symptoms. What we did see, however, in our NOVA-1 trial, was a very low rate of EPS. How do we explain this? This is why we brought Dr. McIntyre with us, and later on in this presentation, you will see some very interesting preclinical data, which we hope really helps explain this low level of EPS. Let me step back and talk about the symptom domains of schizophrenia.
It is a complex brain disorder, and we can break it down into three symptom domains: positive symptoms, negative symptoms, and cognitive symptoms. In the world of positive and negative, we are not talking about good or bad, as that may connote. Positive symptoms are really symptoms that add to a patient's experience. How they experience the world. This includes hallucinations, so hearing things, seeing things, feeling things that are not there. Delusions, fixed false beliefs, as well as disorganized behavior and disorganized speech. Negative symptoms can take away, or we consider that they take away or subtract from a patient's usual functional abilities. I like to think of negative symptoms with the three A's: alogia, avolition, anhedonia. Alogia, a paucity of speech, not being able to communicate with more than one or two words, and an inability to really complete thoughts. Avolition.
Reduced will, a reduced desire and motivation to do things, as well as anhedonia, a decrease or absence of pleasure in activities that usually brought one pleasure. What does this result in? It results in decreased emotional expression, it results in decreased social engagement. Cognitive symptoms. We understand that cognitive symptoms are really endemic in schizophrenia. What is very interesting is that cognitive symptoms often start even before a diagnosis of schizophrenia. They start in that prodromal phase and can include difficulties with memory, attention, executive function, or processing information. This body of symptoms, when does it start? It hits the patient population in their adolescent, late adolescent, early adulthood phase. You can understand that a symptom cluster like this can be very profound for a patient.
These are patients at a time in their lives when they're just starting college, when they're getting their first job, when they're trying out their independence for the first time as young adults. This is why we want to find additional treatments for patients so that we can help them from the very beginning. Now let's go back to the clinical trial of NOVA-1. This study that was successful has the potential to be one of two pivotal trials that support FDA approval. The trial design, 359 patients at 25 sites in the U.S. were randomized in a four-week inpatient treatment period to 50 mg, 75 mg, 100 mg, as well as placebo. Our primary endpoint used the PANSS, the Positive and Negative Symptom Scale. It's a well-accepted efficacy scale that helps characterize the severity of illness.
We looked at the change from baseline to day 28, essentially throughout our entire treatment period. Our secondary endpoint, CGI-S, PANSS positive and negative subscales, as well as Marder factor, and finally, an exploratory endpoint of cognition. This trial was designed to be potentially pivotal, with a large sample size, robust statistical analyses, and a conservative imputation of missing data. Let me explain for a second. What does a conservative imputation of missing data actually mean? An imputation in lay terms, sorry for any statisticians here, an imputation is really filling in the missing blanks, filling in missing data using your imputation, using your analyses. To do this conservatively means that you do not give any advantage to LB-102. Essentially, you're not imputing data that would be in favor of LB-102.
The benefit of this is that if your study and your drug survives this analysis, you can be very confident that your results are real. The FDA noted, in fact, in writing, that our NOVA-1 trial appeared to have the characteristics of an adequate and well-controlled trial. This gives us the opportunity to seek approval with one additional successful registrational trial. So what did we see in NOVA-1? Well, we saw success. Statistically superior clinical activity to placebo at all three doses. If you look at this chart here, the downward slope really shows us the improvement in placebo as well as all three doses. Your gray line on top is going to be placebo, and then the three colored lines are going to be our 50 mg, 75 mg, and 100 mg doses. All had clinically significant separation.
What is very important to note here, as the effect was observed as early as one week and had sustained benefit. I think this one-week time point is very important. Quite honestly, we didn't check for an effect earlier than one week, but the one-week time point is very important because it shows to us that we have a quickly acting medication. These patients are sick. In this particular study, these patients were seriously ill. They had a baseline PANSS of 94. That indicates that this is a population that's severely ill and requires and will benefit from inpatient hospitalization. These patients don't have time to wait. They don't have time to titrate their medications upward. They don't have time to fast or not fast while they're taking their medications. Quite honestly, they don't have time to sit in the hospital waiting for their medications to work.
This one-week time point is really quite impactful for us. Now, let's look at this data with a different analysis. Effect size. What is effect size? Effect size essentially gives a number to the actual benefit that a drug has over placebo, the actual benefit that the drug is giving these patients. Why do we use effect size? We use it because it is, in some sense, a standardized way to compare antipsychotics to each other in absence of a head-to-head trial. What we see here is that the effect size for completers, all the patients who made it all the way through to the end of study, was 0.61 and 0.83 for our 50 and 100 mg dose. Using an MMRM analysis, which is a more conservative analysis, our effect size was 0.5 and 0.64 for those 50 and 100 mg doses.
These results here of LB-102 are near the top of the effect size reported for approved first-line antipsychotics. In addition, the effect size for the 100 mg dose are actually in range of those previously reported for amisulpride. This data, very compelling, and gave us the confidence to move these doses, 50 and 100 mg, into NOVA-2, our phase III study. Here's another way to look at the data. These tables look at the improvement in positive symptoms on the left side, negative symptoms on the right side. The cheat sheet here is that the longer the bar, the greater the improvement that you have. As we might expect in positive symptoms or PANSS positive symptoms, we have statistically significant improvement at all dose levels.
What is worthy of evaluation here is that despite the fact that this study was enriched for positive symptoms and not enriched for negative symptoms, we still showed improvement in the negative symptom domain. Statistically significant improvement at the 50 mg dose, numeric improvement at both 75 and 100 mg. This improvement in negative symptoms is in line with the bimodal mechanism of action that Heather has described. In addition to our improvements in the total PANSS score, positive symptoms, negative symptoms, we also saw improvement in cognition. Clearly, an unmet need in schizophrenia. We used a global composite effect. It's a group of assessments that look at psychomotor function, attention, memory, working memory, and executive function. What we saw here was an effect size that increased with dose here.
As you can see, clinically significant values of 0.26, 0.41, 0.66 for our 50 mg, 75 mg, and 100 mg dose. The magnitude of this observed effect is really considered clinically meaningful. A high rate of satisfactory completion of tests, essentially making sure that patients who took these evaluations were able to successfully complete them. What I really want to highlight here is that this evaluation looked at all comers who successfully completed this test battery. Meaning that we did not enrich for particularly severely cognitively impaired patients. We took all patients in an unenriched population of our acute schizophrenia patients. The cognitive deficits, they're highly prevalent. It is an unmet need spanning schizophrenia, but actually, in addition to that, also bipolar depression as well as MDD. The question that many people ask is that could this improvement in cognition essentially be pseudospecific?
Are these patients having improved cognition essentially because their acute schizophrenia episode is now subsiding, it is improving? To understand that question, which is very valid, we did a bivariate analysis. That is going to be your graph on the left side. What a bivariate analysis does is it looks at the change in two different values and compares them together to understand if there is actually a relationship or a correlation between the two. On the Y-axis, we have got the change from baseline in the PANSS score, an improvement generally, and on the X-axis, we have a change from baseline in that global cognition composite score that I showed you from the slide before. We did a Pearson's r analysis, and what we can see is that it is quite close to zero. It is a 0.05.
That is an absolute value, and the line that we can draw through that is nearly straight, essentially saying that there is not a significant correlation between change in PANSS score, or in this case, improvement in PANSS score, and improvement in cognition. We went a step further, just to really underscore the importance of this data, and we did a mediation analysis on the effect of LB-102 on the global cognition composite score. What we found here is that the direct effect, that is going to be your middle rectangle there, which is the effect that LB-102 specifically has on that cognition score, was 92.4%. The indirect effect, or the effect that we would generally attribute to another variable, and in this case, improvement in PANSS, was actually only 7.6%. This is a clinically meaningful change driven by LB-102.
Now, if we move on to safety aspects of LB-102, a very favorable adverse event profile in our NOVA-1 study. Most AEs were mild or moderate in severity and very similar to placebo. You can see that insomnia is on top. What you can also see is that the insomnia rate relative to placebo is actually very similar. What is interesting in this study is that 74% of patients actually had insomnia as a medical history. This helps define the kind of population that we have. Our AEs leading to discontinuation were very low, and our discontinuation rate overall was very low as well at 18%. EPS. Let us take a step back a little bit and talk about what EPS is. Extrapyramidal symptoms or extrapyramidal syndrome, I think it can be used interchangeably here. What is the pyramidal tract? What is pyramidal?
The pyramidal tract is actually the connection between our motor cortex down through our brain stem and our spinal cord. This tract, these fibers, actually go through the medullary pyramids, which is actually why it is called pyramidal. But this tract is the main tract that controls voluntary movement. So we call that the pyramidal tract. That leaves everything else, which is the extrapyramidal tract. And the extrapyramidal tract are actually all of the other tracts or all of the other systems that work to modulate voluntary movement. So modulation of voluntary movement could be, for example, tone, posture, smoothness of movement, automaticity of movement. These two systems, even though we would like to separate them, are actually very intimately intertwined. It is not a one-way street. This works both ways, and it is very complex.
What we do know, however, is that when we interfere with that extrapyramidal system, and in this case doing so by increasing dopamine occupancy in the relevant tracts, we risk disruption of the system, which results in extrapyramidal symptoms such as dystonia, akathisia, Parkinsonian-like symptoms, et cetera. What we see here is extremely low EPS, despite the fact that our receptor occupancy was within that 60%-80% range and perhaps even higher than that in our 100 mg dose. Now, EPS rates, including akathisia, observed in general with D2 antagonists and partial agonists, can reach up to 30%. So this is a really significant finding on our part, especially with the fact that our receptor occupancy rates really would lend itself to additional EPS.
Again, I am just foreshadowing what Dr. McIntyre will talk about with respect to regional selectivity and why this might actually be the case. Now, other adverse events in general were also very low. Our prolactin-related AEs, 1%-5.6%. AEs were mild to moderate, and none of them actually resulted in discontinuation from treatment. Sedation, a single case of sedation among 251 patients exposed to LB-102 in the NOVA-1 trial. I think it's safe to say that sedation is not going to be part of our side effect profile here. And finally, QTc prolongation. Generally, a minimal QTc prolongation in NOVA-1, 4.3-5.4 milliseconds, and in addition to that, no patients, zero patients, met our pre-specified stopping criteria. So in summary, LB-102 has the potential to be the branded antipsychotic of choice in schizophrenia.
I've shown you some compelling evidence of our clinical activity in NOVA-1, our potentially class-leading safety profile, and also information that really differentiates LB-102 with respect to negative and cognitive symptoms. Simple once-daily dosing. I can't highlight this enough how important this is as someone who spent years as a clinician for patients with schizophrenia, how simple daily dosing, easy to use, starting therapeutic dose, no titration, how important that really is for the patient population. And what does this mean for patients? Why are we doing this? This matters, because 80% of patients relapse within five years, and the consequences can be serious. I don't need to read all of these here for you, but I'll remind you that these are patients that the start of schizophrenia or their first episode is generally when they're moving out of adolescence and into adulthood.
So that profound impact on these patients in terms of their productivity, their functioning, their quality of life, can start very early, and we want treatments like potentially LB-102. We want treatments that can help maintain these patients over the long term, and what that means is a medication that's efficacious, that's tolerable, that's easy to take, and that a patient can stay with for the long term. Now, all of this very interesting clinical data for us has really led us, quite honestly, back to the laboratory. Meaning that we want to understand the mechanistic underpinnings of what we've observed with LB-102's clinical profile. This lower EPS potential, despite our 70%-80% receptor occupancy, why is our EPS rate so low? This is, again, what Dr. McIntyre will walk us through with the mechanistic hypothesis of regional selectivity.
In addition to that, our effect on negative symptoms, especially significant at that 50 mg dose. Again, Dr. McIntyre will talk us through the mechanistic hypothesis of this regarding the presynaptic autoreceptor antagonism. I think we've got a very interesting talk ahead, and I will not keep you one more minute away from Dr. McIntyre.
Thank you.
Thank you.
Thank you, Susan. Thanks, Heather, for your presentations. Good afternoon, everybody. What I thought I'd do is just maybe quickly just step away from the embroidery of my bona fides and just describe to you what I actually do. That's often an eye-opening experience. For me, going back over 30 years ago, I originated at the University of Toronto, a depression and bipolar clinical research center, and that center was dedicated to providing the highest quality of care to people who have lived experience. Little did I know at the time that depression and bipolar disorder were so difficult to treat. At that time, idealistic, recently graduated, I thought all the assets we had were sufficient, and my life would just simply be an enjoyable visual of patients often getting better. Little did I know that's not how it worked.
And clear and unmet need is a phrase we have. It is a phrase we are all familiar with. I can tell you we have clear and unmet needs in psychiatry, where most people with depression, bipolar, and schizophrenia are not being adequately improved with the available therapeutics. I expanded the program then to include all comers, which is including people with schizophrenia because they also suffer from presentations like depression. In addition to my clinical endeavors, which go way back, I am an academic, and I started at the University of Toronto working two different faculties in psychiatry and pharmacology. I also am a Professor of Psychiatry at two schools in the United States and three schools in Asia. Some people wonder, does this guy have academic promiscuity? Not really. I actually have a lot of interests, and my clinical research interests are global.
For this period of time, that is contemporaneous with my clinical endeavors, I have been involved in over 500 different programs in drug discovery and development. I am especially interested in a, frankly, a strategic imperative for the field, and that is to identify better therapeutics. We need better therapeutics, and better can be operationalized in many ways. You are hearing today about what could be a very better therapeutic for people with lived experience. I come at this, I use a lot of metaphors. I feel as though I am a football player. I spent 20, 30 years playing football. I did 20 years being a coach. Now I am in the broadcast booth, so I am coming at this from different perspectives, and I am looking at this and trying to share these thoughts and interpretation with you from each of those perspectives I enumerated.
We are going to talk about mechanistic research. I like to keep things succinct and organized around a theme. I think the theme here is differentiation. That is how I see the theme. The theme of differentiation is going to be supported by this mechanistic data, which I think is translationally very, very, very interesting. I frankly just saw this data recently in the last month or two or so, and my immediate reaction was, wow, this is something we have not seen before, and this is something very, very opportunistic for the patients who are suffering from these conditions. I have a financial relationship with LB Pharma, and I am here on behalf of LB Pharma. My style of presenting is I do not usually read the slides. I find it boring to read the slides. So I am going to tell you a little story.
We are going to actually quickly get into the datasets, and I want to share with you the methodology briefly. I also want to, in fact, share with you how I translate that and how this, I think, could be meaningful and how it really accords with what we see clinically. Again, the theme is differentiation. Towards this aspect of differentiation, you are going to hear me talk about regional selectivity in the brain, and you are going to hear me talk about this bimodal activity, which is very, very interesting. We have, in fact, seen many examples in medicine where differential activity at receptors result in profound differences in efficacy, tolerability, or safety. Before some of you, in fact, have a panic attack looking at that slide, let me just, in fact, maybe just walk us through this. This is obviously a visual of the human brain.
It's called a sagittal slice of the brain. What you can see that's been blown up for us is this area called the striatum. We like ROI. We like regions of interest. This is the region of interest for today's conversation. In other words, the striatum is a part of the brain that we depend on for many human functions. The striatum actually has been disaggregated into different territories or regions, and this disaggregation into different territories and regions has been done because it's been determined they actually have very different functional outputs. Let's walk through it. You can see the limbic part of the brain. That is the limbic striatum, the associative striatum, and the sensorimotor striatum. That's what we can just now shift our view to the left. Susan talked about positive symptoms and described it so eloquently.
The positive symptoms, the delusions, the hallucinations, the additional human phenomenon, are a phenomenon that are subserved by a disturbance in the associative striatum. There's dopaminergic overactivity in the associative striatum. The negative symptoms that you talked about. The negative symptoms, you see them, in fact, some of the structures here with very long multi-syllable names, but you see that those structures, which are structures captured in the striatal area, are related to the negative symptoms. Then below that, you see the cognition symptoms, and the cognition symptoms map onto the cortex of the human brain. Let's see if we can do a nice big leapfrog over to the other side here, hyperdopaminergia. The prevailing view, going back now almost seven decades, has been that the psychotic features, the positive symptoms, are a consequence of an increase in dopamine signaling.
Over the last couple of decades, we've refined our knowledge, and that hyperdopaminergia specifically is in the associative striatum. At the same time, we have hypodopaminergia, low dopamine signaling. That's occurring in other regions of the brain. Where? In regions that are relevant to aspects of cognitive function, like the cortex, the prefrontal cortex, but also in aspects of the striatum, which we lean on for aspects of motivation and interest, and is known to be the region of the brain relevant to negative symptoms and mood symptoms. Let's start off with the title of the slide. Many therapeutics that address positive symptoms also impact dopamine signaling in parts of the brain that can cause side effects. That is the message. Let's go through this carefully. In the top left-hand corner here, we see positive symptoms. Remember, positive symptoms arise from hyperdopaminergia in the associative striatum.
That is where most traditional antipsychotics work. In addition, most traditional antipsychotics are indiscriminate. Not only do they have activity in that region, but they also have activity in other regions, including the sensorimotor striatum. The sensorimotor striatum, as Susan eloquently described, are responsible for modulating much of our motor activity and is the area of the brain responsible for EPS. So EPS, including akathisia, dystonia, drug-induced Parkinsonism, and tardive dyskinesia. Tardive dyskinesia is a warning in all of the package inserts for all the commercially available antipsychotics. We actually have on-target, but we have off-target activity. Keep going. This study was designed, it was executed, it was completed to look at this question around selectivity and regional selectivity.
The question I wondered when I first saw the data was why is it that this medicine, LB-102, at 60%-80% D2 receptor occupancy, why does it not have akathisia at rates that we are used to, 30%, 40%, 50%, 60%? In fact, we had akathisia in the range of 1%-6%, much lower than we were used to. I agree with Susan as well. It would be nice to have treatments like this available clinically. This question was looked at in a very elegant study, and this was done in mice. Some might say, "Well, are mice the same as humans?" I think we are going to agree they are not. But it turns out that this part of the brain that we are looking at, that we are going to be showing you shortly, is remarkably conserved across species.
There is some degree of what we call pathologic validity to this. It is not identical, but there is some transferability because of the pathologic validity of the conservation of the area of the brain. Now, we are also looking at the activity of the neurons. There are different ways you can look at the activity of neurons. Just about a month ago, only the third psychiatrist won the Nobel Prize in Physiology or Medicine for work with optogenetics. You can light up a certain neuron by zooming a light onto it. You can chemically activate it. There are different ways that we can activate neurons. There are also different ways that we can measure the activation of that neuron. And there is, in fact, this protein called c-Fos. c-Fos just tells you the light has been turned on. It means that neuron has been activated.
We use it as a proxy of the neuron being activated, and that is the marker that has been evaluated herein. We are looking at LB-102. We are going to look at it in the mouse brain. And our question is: Is it regionally selective? And we are going to approach this with our prior knowledge, that being that the striatum has different regions with very different functional implications. If you were a developer and someone said, "I have got 40 acres of land for you," you probably would bring out one of your friends and say, "Let us map out all the lots and start selling lots." Well, that looks like a bunch of lots to me, all carved out into this space. What that is an atlas, and those lots represent different fields of the striatum.
And what you see in the dark blue is the motor striatum, and it is made easy because the letter M is next to those numbers. And what you see in the light blue is the associative striatum, and they have the letter A next to them. So there is a proximity, but there is not clear distinction in the boundaries here of these lots. So you have the motor striatum in the dark blue, the associative striatum in the light blue. Now, when we look at haloperidol, just a reminder, haloperidol is an antipsychotic discovered way back in the 1960s. It is a highly potent antipsychotic, also an antipsychotic known to have a very high rate of EPS. Which you can see here, looking at this map, you can see activation. This represents c-Fos activation across both the associative striatum and you see the motor striatum.
This is indiscriminate in the areas that it is activating. If you take the activity in the associative striatum and you quantify it, and you juxtapose that to the activity in the associative striatum, so you have, sorry, the associative striatum and the motor striatum, and you look at the activity in those two areas, you can do a quantitative and do a metric. The ratio of activity in the associative striatum to the motor striatum is about 0.5. That is telling me there is actually relatively more activity in the motor striatum, where I do not want activity, leading to EPS, than there is in the associative striatum, where I do want activity. I want on-target in the associative. What is really interesting, it is tempting to connect these dots, but we connect these dots through the lens of interpretive caution.
It is certainly very interesting that EPS rates of haloperidol approach about 50%, and it is quite interesting that this maps on so beautifully to this ratio. Watch this. This is really interesting. This is now looking at haloperidol on the far left. In the middle is amisulpride, and we have LB-102 in the far right. Again, we are looking at these maps. We are looking at activity as indexed by c-Fos expression.
We are looking at activity in the associative striatum, where the action is, that is where we want to be, and the motor striatum. I think just a quick visual would say there is haloperidol, indiscriminate in its activation. I want to differentiate haloperidol to amisulpride. Amisulpride, which you can see just simply by colors, is you can see that there is a lot more c-Fos expression in the associative striatum than there is in the motor striatum.
That is worth noting. In fact, that translates into a ratio. The ratio is three. In other words, there is a differential activity where it should be in the associative striatum, subserving psychosis, relative to the motor striatum, subserving the side effect. Further differentiation. Differentiation between amisulpride and LB-102, and LB-102 from haloperidol, you can see, in fact, there is greater selectivity with respect to c-Fos activation in the associative striatum versus the motor striatum. In fact, the ratio is just over eight. So we have, through this mechanistic model, differentiation of amisulpride from haloperidol, differentiation of LB-102 from amisulpride and haloperidol, and in keeping with the conceptual framework, we have, in fact, greater selectivity as indexed by c-Fos for the associative striatum, which subserve psychosis, less activity in the motor striatum. I like ratios myself.
I like histograms juxtaposed together, easier to digest, easier to put this as a heuristic in my mind. Cariprazine is an antipsychotic approved in the United States with multiple indications, known to have a rate of EPS relatively higher than many other of the second-generation antipsychotics, and its selectivity ratio, associative to motor striatum, comes in at 37. There is haloperidol at 45. I will keep going. Risperidone, olanzapine. There is amisulpride at three, and there is LB-102 at 8.37. So greater selectivity for the associative versus the motor striatum. This is, in fact, a summary of the rates of, expressed in ranges, of EPS across traditional antipsychotics. Haloperidol, about 50%, risperidone, olanzapine, cariprazine, about 30%, amisulpride, about 20%-25%, and there is LB-102 at 1%-6%. What I am saying is that this model provides some degree of potential explanation for what we are seeing clinically.
When I first saw this not too long ago, what I was reacting to was the alignment. Again, doing this as long as I've been doing this, you're often trying to. You got paradigm strain. You're trying to fit data into certain kind of frameworks that don't quite fit, but I was quite taken how this was really quite aligned. Now, with respect to the next steps, you can see here listed here that we have, in fact, a good reason to believe that despite the fact that LB-102 has 60%-80% D2 receptor occupancy, the EPS rates are quite low, which deserves explanation, and this explanation certainly is compelling. It obviously will need to be replicated and so on and so forth, but certainly was very compelling. When I was chatting with LB Pharma, I introduced this idea of zip codes. I guess it resonated.
I use a lot of metaphors, and for me, as I think about discovery and development, it's important to have the zip code just right. Zip code does matter, and with respect to brain regions relevant to psychosis, negative symptoms, mood symptoms, but also cognitive symptoms, we also need to keep in mind off-target. I don't want to be in the zip code that's off target, and LB-102 is staying away from the zip code it should be staying away from. Let's go back to our little figure here. We have negative symptoms. Remember I said that negative symptoms map onto regions of the brain, including the limbic striatum, which is listed here. The prevailing view in psychiatry has been these negative symptoms, which by the way, the FDA has never approved a treatment for negative symptoms.
The field has identified negative symptoms as the most debilitating aspect of schizophrenia, along with cognitive symptoms. So this is not just a dimension of psychopathology and schizophrenia, this is a major contributor to the human capital loss of this illness. We know that there's a decrease in dopamine functioning playing a role in the presentation of negative symptoms, but also in cognitive symptoms. Now, separately, we know that D3 specifically, but the D2, D3 receptors, play a role in cognition and negative symptoms. Just a reminder for those who are familiar with this, and perhaps a little refresher for those who have maybe forgotten it, the D2, D3 receptors represent two types of dopamine receptors. There's five in total. These receptors are located presynaptically and postsynaptically. Location matters, because they are receptors that when they are located presynaptically have a very different function than postsynaptically.
Presynaptically, they are inhibiting the release of dopamine. Postsynaptically, they're inhibiting the effect of dopamine on neurotransmission. But the key part I want to focus on is presynaptic. We have reasons to believe that LB-102 is preferentially binding to presynaptic D2, D3 receptors at the doses that you've been hearing about, the so-called bimodal effect, at the lower doses. Now, amisulpride, just so everyone's on the same page here, has been in psychiatry for quite some time in ex-U.S. markets. I work very globally. This is a drug I've used for decades. I know it well. I was just in Germany just about a few weeks back at the European Congress and meeting with European colleagues and international colleagues elsewhere as well.
This is a drug that is often talked about because in Europe, as Heather mentioned, there are indications for negative symptoms with this particular treatment, and also to treat depression in some markets of Europe. At the lower doses, it has been studied as part of randomized, double-blind, placebo-controlled studies, six weeks in duration, 12 weeks in duration, six months. So we've got different intervals of observation. We have replication. We have replication that across these three studies, amisulpride at relatively lower doses is reducing the severity of negative symptoms relative to placebo. I say relatively lower doses because the doses that are often prescribed to treat psychosis with this drug is in the range of around 400- 500, sometimes 600- 800 mg. So north of 300- 400 mg a day. So that's relatively low.
Moreover, in the treatment of depression, the doses are also around 50- 100 mg. In short, the doses that clinicians use to treat negative symptoms and mood symptoms is around 50- 100 mg approximately. And to treat psychosis, the doses are considerably higher, 400 mg, 500 mg, 600 mg, sometimes even higher. So that caught our attention. And the theory here is that you have the presynaptic neuron, the postsynaptic neuron, and in a low-dose situation, it is believed now that amisulpride has a preferential affinity for that presynaptic D2, D3 receptor. Remember, those D2, D3 receptors, when they are activated, they are inhibiting dopamine release. So if you bind to them and block the brake, you disinhibit the brake, which is what is releasing dopamine and treating the mood symptoms, the cognitive symptoms, the negative symptoms.
At higher doses, we have affinity for the postsynaptic D2, D3 receptor, which would be desired insofar as we believe that hyperdopaminergia treats psychosis. And this is a very, very elegant model that we've had now for a little while. This study was recently shown in Europe at the ECNP Congress, and this study tested the concept, this concept that LB-102 is differentially acting at presynaptic D2, D3 receptors, increasing dopamine release, dopamine efflux, thought to play a role in mitigating negative symptoms, mood symptoms, and cognitive symptoms. So bear with me on this. There's a bit of methodology. We take some mice. You put a little probe into the brain, a microdialysis probe, and you can stereotactically guide this right into the region of interest, that being the nucleus accumbens, the animals then receiving LB-102. What are we looking at here in the figure?
Well, along the X-axis is time. The Y-axis is dopamine release. Sorry for all these drugs. What the heck is quinpirole? Well, quinpirole is a dopamine agonist that binds to D2, D3 receptors. So if D2, D3 autoreceptors inhibit dopamine release, you want to start off to make sure your paradigm is behaving. So when you give quinpirole to the rodent and you check the synaptic dopamine availability in the nucleus accumbens, it is reduced. That tells us that quinpirole is binding to the presynaptic D2, D3 receptor and inhibiting dopamine release. Then when you give LB-102 at relatively low doses, you see a reversal. You see, in fact, an increase in dopamine release. So this provides indirect evidence that we have, in fact, presynaptic D2, D3 activity of LB-102 increasing dopamine efflux, which is thought to be critical in alleviating the mood symptoms, negative symptoms, and the cognitive symptoms.
So here we have two separate, but related, but separate mechanistic studies, regional selectivity, providing for us a framework for understanding why this highly effective antipsychotic at doses that are achieving D2 receptor occupancy at 60%-80% has such a low level of EPS. We think the zip code matters. We also have mechanistic data here looking at this question about presynaptic D2, D3 activity. What is the translation of that? This pharmacology and this mechanistic data gives us a framework for not only understanding why this drug's behaving as an antipsychotic, but why it's also treating negative symptoms and cognitive symptoms and gives, I guess, aspiration for thinking about its application in bipolar depression in major depressive disorder.
A reflection before I come off the stage and pass it over to Kaya, what I might say is, I started off by telling you what I've been doing throughout my career, and I can tell you that whenever I hear about new agents, I'm always thinking about the clinical ecosystem. And one of the advantages of seeing patients is that is a truth, and the rubber hits the road when you're seeing patients. And there's no question we have clear and unmet needs, and there's no question that there are differences across treatments with respect to efficacy and tolerability. What we have seen here is we have seen what seems to be even greater efficacy than amisulpride. I think it was mentioned earlier that there has been systematic studies looking at effect sizes of antipsychotics, and amisulpride has consistently been one of the most efficacious antipsychotics in psychiatry.
It's also been consistently one of the better acceptable treatments in psychiatry. LB-102 has been engineered, the structural modification Heather spoke to, and you're hearing about even greater efficacy with a lower risk for tolerability concerns and a kinetic that's going to make it much, much easier to prescribe in patients. So we need better treatments, and better treatments for me means not just reducing the overall psychopathology severity, but targeting key unmet needs like negative symptoms, like cognitive symptoms, like mood symptoms, at the same time reducing the burden of unacceptable side effects. So it's been very exciting and very hopeful. We hope it continues. I'm going to pass the floor over to Kaya. Thank you, everybody.
Thanks. Thank you. Well, good afternoon, everyone. It's a pleasure to be here today to talk about LB-102 and the potential opportunity ahead. We've heard about the clinical data. We've also heard about the science, and now what I'd like to do is shift our attention to early commercial planning, and more specifically, some of the learnings that we're finding as we look to better understand both what prescribers and patients face when they're making a treatment change, and how LB-102 could potentially fit within that paradigm. Now, when we take a look at the schizophrenia market overall, it's a large market. It's rife with patient heterogeneity, and despite the plethora of generic options that exist today, there still remains a trade-off that prescribers and patients are faced with by way of efficacy and tolerability. And we see that in the statistics.
Three out of four patients discontinue their medication within 18 months due to a number of issues, two of which include lack of efficacy and tolerability. We also see the heterogeneity that exists within this landscape. Six out of 10 patients are switching their oral antipsychotic because of insufficient clinical response. We know that the first reason a clinician reaches for an antipsychotic is to control positive symptoms. Yet, two key domains, as we have heard from multiple speakers today, remain unresolved, and that is negative symptoms and cognitive impairment. Both of these, if inadequately treated, and the current options today do not adequately treat them, can lead to significant functional burden and disable that patient from getting back to their everyday activities. So when we look at this market, large, highly heterogeneous, yes, treatment options exist, but trade-offs still remain.
We see that when we look at the classes and the evolution of treatment for schizophrenia overall, starting first with the D2 antagonists, which have helped to establish efficacy and the gold standard of efficacy within this class, followed by the partial agonists, and more recently, the muscarinics. Each of these classes offer a way for a patient to establish efficacy. However, we see trade-offs, and those trade-offs come by way of tolerability, whether that be EPS or sedation, GI side effects, or akathisia and activation. These side effects can have a significant impact to a patient's willingness and ability to sustain treatment. We also see this very interesting tension that exists within clinical practice, whereby a clinician starts a patient on a medication and they have to manage that tolerability profile while still getting someone to an efficacious dose.
Oftentimes what ends up happening is patients stay suboptimally treated because they are trying to manage this tolerability profile, which can lead to instability and ultimately to relapse. So finding this balance of medication is incredibly important for long-term outcomes. While we know efficacy is the entry ticket within schizophrenia, tolerability and simplicity of use are most certainly what is going to sustain treatment. You see that below from a quote here from one of our market research studies where one of our KOLs noted that, yes, historically the most efficacious agents have also had the highest side effect profiles. We have done a bunch of research over the past year or so with clinicians, with patients, and with payers to better understand what is this consideration set that they are faced with when making a treatment change. It really comes down to three key dimensions.
The first is clinical response. Does the product control positive symptoms? The second is tolerability. Looking at the totality of the adverse event profile, can a patient sustain treatment over the long run? The third is simplicity of use. Is it easy to get onto? Do you get an efficacious profile right away? Do you have to take it multiple times a day? Are there food restrictions? Will it cause friction in the day-to-day treatment for a chronic therapy? We also tested LB-102's target product profile in a blinded fashion to see how it resonated against these three dimensions. Across the board, based on the phase II data, we see very strong resonation of LB-102 against these dimensions. You see that in the quotes below from this research study, with one KOL noting LB-102 was a gentle giant.
Another talking about the totality of the tolerability profile and saying these are all really important attributes in order for a patient to sustain therapy. And a third talking about simplicity of use. Does the dosing and the tolerability profile enable a patient to get to that optimal dose? And can they retain and sustain stability? We also talked to payers, and what we heard overall is these three dimensions definitely impact two key drivers of cost within schizophrenia, relapse as well as emergency use care. So we know that these particular dimensions are incredibly important based on our research in terms of driving that treatment change. So when we think about LB-102 and the emerging profile, we see this opportunity for LB-102 to provide this balance of efficacy, tolerability, and simplicity of use.
As we think forward in terms of commercialization, we're really looking at this from a stage-gated, milestone-driven approach. And today where we are is really building the strategic foundation. We're thinking about better understanding the market. What is the lived experience of patients and care partners? How are prescribers resonating with our target product profile? What is the early positioning of this drug within the construct of the competitive landscape that exists today? We're talking to U.S. payers to understand what does the market look like today, but also what will it look like by the time that we launch, and what kind of evidence and access planning do we need to do to give patients the best shot of getting LB-102? We're also building relationships with clinicians and patient advocacy groups.
We just recently launched a small MSL team to conduct some scientific exchange, and we're thinking forward, above and beyond schizophrenia mood disorders, about what additional indications could lend utility to broader patient populations across neuropsychiatric disorders. Next, as we move to top-line data, we'll refine and then scale based on what we see and start to think forward to a potential launch. So today is very much about building that strategic foundation, so when data emerges, we can hit the ground running and scale appropriately. And with that, I'd like to reintroduce our fearless leader, Heather.
I'm obviously the only one that prefers not to stand on a stage, which we'll have to psychoanalyze that at a later point in time. Well, thank you all for the presentations to date. There's a very important step to getting to that point of commercial launch that Kaya was just talking about, and that is, of course, a successful completion of the phase III trial. Going the wrong way. So the phase III trial that is underway is one in which we really strived to try to fix something that wasn't broken. We think that the phase II NOVA-1 trial is a highly robust statistical trial that we think really demonstrated the potential for LB-102. So in designing the NOVA-2 trial, we really tried to not deviate too much from that trial. This is intending to enroll about 460 patients at 25 sites in the U.S.
We're evaluating two doses, 50 and 100 mg. This is one less arm than that which was evaluated in the NOVA-1 trial, which we do think should help with that placebo rate. Primary endpoint for this trial will be the change from baseline at day 42. This is a six-week inpatient trial. Secondary endpoints are the same as the phase II. We have included cognition here as a secondary endpoint. The data from this trial, as we've already mentioned about 1,000 times, is expected to read out in the first half of 2027. I mentioned that we tried to not fix something that wasn't broken. A lot of the same scales. We're utilizing the same CRO. There's a lot of the same team members. There's quite a bit of overlap between the sites from the phase II to the phase III.
We think that we've helped to mitigate some of that execution risk. In addition to this phase III trial, we're also conducting an open-label safety trial. As Susan mentioned, patients from NOVA-2 can roll into this open-label safety trial, and de novo patients are also going to come in. Goal here is to accrue the safety population that we need to have at the point at which we're ready to submit that NDA. When we're ready to announce this data, again, first half 2027, we will do a robust data announcement. The plan here is to disclose, of course, the primary endpoints for both doses, a full safety profile, all the treatment emergent adverse effects, as well as those of interest, similar to what we've done in the past, EPS, prolactin, sedation, et cetera.
We'll also disclose the secondary endpoints, CGI, PANSS positive and negative subscales, as well as cognition and PSP, which is the function scale. Looking ahead, we have three incredible opportunities for value creation. We've got this data coming from the NOVA-2 trial in the first half of 2027. We've got the bipolar depression data coming in 2028. And we have the adjunctive MDD data coming in 2029. All of this is fully funded with cash that takes us beyond the second quarter of 2029. Going back to the mission. The mission is to really strive boldly to advance medicines to help these patients with significant unmet need. And to do that, we're intent on building a fully integrated company, one that's ready, willing, able, and prepared to commercially launch these therapeutics, as Kaya already discussed. The top-line data will come next year.
We have an opportunity to provide what we believe to be a meaningful profile and one that's differentiated in the realm of schizophrenia. We have opportunities beyond schizophrenia into other psychosis indications, as well as the mood disorders and a long-acting injectable formulation, all of which we're pursuing at this point. And hopefully, as you've seen today, we have a highly seasoned team of people working here at LB Pharma. These people are convicted. Convicted is probably not the best word. They have conviction, and they are really dedicated to bringing forward what we believe to be a really meaningful asset to patients. And with that, we thank you for coming, and we're going to sit up here and take your questions. This is the first time all of us will be up here. It's kind of fun.
Yeah. Pleasure.
Thank you.
Can you hear me?
Yeah.
Great. Paul Matteis from Stifel. I will ask a couple and then pass it around. Thanks for the presentation. I wanted to ask one question around long-term safety and one question around the dose selection stuff. I thought the commentary around EPS and the mechanistic rationale there was very interesting. I was curious, when you look at other antipsychotic drugs, how predictive is four-week EPS data of how the profile actually shakes out over the long term, especially on things like tardive dyskinesia that could be a byproduct of cumulative exposure? On the dose selection side, super interesting to look at dopamine receptor occupancy. How well do you understand 5-HT7 at different doses? How core to the MDD or BPD hypothesis is hitting 5-HT7 hard at those lower doses? Thank you.
I will take the first question, and then I am going to hand it off to Susan to answer your second question regarding EPS. With respect to 5-HT7, we do not have as much information around specifics on that with respect to dose. What we do know is that it does target the pathways that are associated with depression and cognition. I think it is one of other mechanisms that are at play here. Hard to say which mechanism is driving the observations more than the other. Unfortunately, there really is not a ligand available with respect to 5-HT7 to really understand the receptor occupancy there. I think what we would say is that it is a part of the story. Hard to exactly predict how much of the story is it. Susan can jump in more on the EPS.
Yes, definitely talking about EPS. With respect to EPS, I am going to talk first about all antipsychotics. With all antipsychotics, we expect the majority of EPS symptoms, the akathisia, dystonia, drug-induced Parkinsonism, et cetera, to show up within the first few weeks of treatment. It is essentially an early onset adverse reaction that we would be seeing. Four weeks definitely is long enough for LB-102 to be able to evaluate the onset of EPS with respect to that. I imagine that you are also concerned about tardive dyskinesia. Tardive dyskinesia is a longer effect that takes months, sometimes years, to show up, if it shows up at all. Our long-term data, our one-year treatment period certainly could be helpful, but quite honestly, I do not expect to see a lot.
When we look at amisulpride and we look at the rates of tardive dyskinesia, they are very low, meaning that there is actually not a lot of literature about it because they are very low. This to us is comforting. It certainly helps us understand what our expectations are for the long-term safety, which is really basically what we have seen in our acute studies.
Great job team on your first R&D Day. I am looking forward to many more. A great one that you put together. Maybe questions that we have been getting quite a bit, and I am sure it comes up, and I want to pose it to you here at the R&D Day, is this disappointment among analysts and the branded products have never lived to its peak potential. Kaya, you did a nice job presenting the market research, what is holding it back. If you could just talk about, you talked about simplicity and clean safety. It seems like it is still not resonating, right? It is almost too simple of an answer to say it is the product profile that has led to that. I would love to think about what can you unlock in your commercial preparation and the product profile to really drive multi-blockbuster hit with this.
I have one initial follow-up. Maybe I will pause here.
Yeah, one point to make before Kaya jumps in. I would say that I do not think, or at least our perspective is that what has so far been observed with the most recent schizophrenia launch is not an indictment on the space.
I actually think that there is more at play there than just the market size. I think the market size is probably as expected. I think unfortunately there was a lot of expectation around that launch, and maybe that expectation was a little more robust than it should have been. But I do not think it is an indictment on the launch. You can get into the specifics.
Yeah, I think there has been, with some of the more recent launches, some challenges from a clinical profile standpoint, namely difficulty potentially with switching. Also some of the tolerability events that may prohibit someone getting to the optimal dose. Side effects like GI side effects can be pretty significant in terms of a patient's willingness to stay on medication. More than once a day dose can also create a lot of friction to long-term use. So there is something to be said to this point around the clinical profile itself as being really required to provide some level of balance for these patients. Additionally, I would say that schizophrenia is always the entry point for us with an additional expansion inflection to mood disorders over the life of the product as well.
This profile that we see as a potential advantage within schizophrenia should play very nicely also in a mood disorder population as well.
One of the things that actually Kaya and I have actually spent quite a bit of time talking about is just how important it is to really help prescribers understand how and when to use a therapeutic. That is something that we are already starting to talk about. That is something that we are already starting to really think through. How exactly do we want to present this so that physicians have a good understanding of when and how to use it within the treatment paradigm?
Yeah.
This is something you have been saying over and over again.
I will add in neuropsychiatry, having a very clear patient type from the get-go, to Heather's point, where specifically you are asking a clinician to use the product will be incredibly important. Because otherwise, we leave it up to them with all the treatments that they have in their armamentarium to figure that out. That will be a very strong focus for LB-102 as well.
And then maybe the second question, thank you for all the mechanistic data supporting negative symptoms. So in NOVA- 2, even though you're going to do a separate negative symptom study, let's say you show a trend. Is there a significant awareness among the U.S. physicians around amisulpride's effect on negative symptoms? Until you get the label to show negative symptoms, would there be a perception created of LB-102 with improvement on negative symptoms with just the NOVA- 2 data set?
I'm going to actually ask Roger to take this in a moment, but it's surprising how many physicians in the United States are aware of amisulpride. In the early market research that we did, that was a surprising fact for us, and a lot of these are community physicians. But I'd be curious, Roger, what you think on whether or not there'll be a halo for LB-102.
Yeah, I do. I think it's a fair characterization that there is, in fact, to some degree, I'm surprised by it, but to some degree, I'm not surprised that there is a fair bit of recognition amongst U.S. prescribers of amisulpride. I suspect what plays a part in that is that over the last certainly 10, 20 years, but certainly the last 10 years, there's been a tremendous emphasis with new entries into the area on negative symptoms, and the field has accepted that negative symptoms and cognitive symptoms disproportionately account for the loss of human function and disability in schizophrenia. So the topic of negative symptoms has received a lot of attention. And often at state level, regional level, national level meetings, data is presented for amisulpride. Of course, the clinician says, "What is this drug?
I don't have it." But amisulpride is presented often at meetings as an example, a hopeful example, that opportunities do exist for therapeutics in negative symptoms. So I suspect that's one aspect wherein they have exposure to this particular drug. So I agree with that entirely.
Hi. This is Kaveri Pohlman from Clear Street. Thanks for taking my question and thanks for hosting this insightful event today. Just on the negative symptoms, again, from the phase III trial. I know it's a secondary endpoint, but would you based on the mechanism and how you expect the bipolar and MDD programs to be, would you expect an inverse correlation between the negative symptoms benefit you see and the drug dose having higher with 50 mg versus 100 mg?
I just want to understand, I know 5-HT7 is not specifically clear, but how much contribution? Is that more like a cognitive impact only versus do you expect it to contribute towards negative symptoms as well? Just want to understand that. With the different scenarios, whether you see those negative symptoms benefit and cognitive benefits with the phase III study or you don't see it, is that going to impact your strategy for bipolar and MDD going forward in terms of dosing or anything else in the trial design?
Let's see. There were a number of questions there, so we'll start with the first one.
With respect to the dose, as we observed in the NOVA-1 trial, it wasn't surprising that the dose that did have the greatest impact on negative symptoms was the lower dose. So we would expect that to be the case. When you look at amisulpride and how it's used, it tends to be used, in the slide that Roger presented, it tends to be used between 100 and 300 mg for negative symptoms. The most predominantly used dose is 100 mg. It is definitely lower than that which is used for the schizophrenia dose. So I do think we would expect to see something similar to that. With respect to, I think I'll go to the third question because I may have forgotten your second one.
But with respect to the third question, it is very clear when you are looking at these two unmet needs of both cognition and negative symptoms, there is a concern for pseudospecificity, right? The fact that you might be treating the positive symptoms may inadvertently or indirectly have a benefit in both cognition and negative symptoms. So you really do need to ultimately study both of those in a patient population that has been stabilized. In the negative symptoms trial that we would conduct, we would be looking at both negative symptoms and cognition, since that would be a stabilized patient population. So if in the NOVA-2 trial, we do not see any sort of an effect on, say, negative symptoms, I do not think that would alter our plans with respect to pursuing a negative symptoms trial. And I think cognitive impairment-associated schizophrenia is a very difficult indication.
I think it is one where we have seen numerous failures, and I am sure you can attest to how difficult it is.
Yep.
So I do not know that that would ultimately change a plan to pursue CIAS as an indication. We would continue to study cognition, and we are studying cognition in all of our upcoming clinical trials. I think we would just continue to accrue the information. I do not remember your second question.
I think those were my questions.
Okay, great.
But just a quick one on prolactin-related AEs. I know there were low rates, but over long term, do you expect that to kind of become a barrier for compliance for LB-102?
We have a couple of perspectives to share on this. Susan can kind of jump in and just talk about what we saw with the prolactin, and maybe Kaya, you could jump in and talk a little bit about how physicians respond to it.
Yeah. So what I'd like to say first is in our NOVA-1 study, what we did see with prolactin elevation, which we know this is what happens with a D2 antagonist, that prolactin does increase, is that we saw a prolactin elevation early, within our first time point. What that really says to us is that the early elevation is something that we can see rather quickly, and we can respond to. What is also very interesting is over the course of that four-week treatment period, we did not see additional elevation in prolactin levels. So essentially, honestly, what you see is what you get.
Which is very valuable information, so that we believe that prolactin does not continue to increase over time. Physicians, prescribers, et cetera, as they are evaluating their patients, can see the tolerability of LB-102 with respect to, of course, other AEs, but specifically with respect to prolactin, right? If prolactin is elevated minimally, moderately, but not resulting in clinical adverse events, then there is no actual action to take. Understanding that it's likely not to increase over time, I think, brings prescribers as well as patients comfort.
Yeah. I would echo, we've seen that very consistently in our research. Clinicians expect that prolactin levels will increase because it's a D2 class effect. But as long as it doesn't precipitate into clinically relevant AEs that would prompt discontinuation, there hasn't been a significant concern with respect to that for LB-102.
That's true in the market research we did in schizophrenia, but it's also true in the market research we've conducted in the mood disorders as well.
Hello? Can you hear me? Yeah. Okay. Delma Caiati from Guggenheim. Thank you for taking my question and for organizing the event. I have a question for Dr. McIntyre on the dose selection. You have shown the rationale behind that, the PET occupancy. But when we look at the equivalency of dosing between amisulpride and LB-102 in MDD, and in particular in dysthymia, the 50 mg- 100 mg is above what is used for dysthymia. If you look at the 8:1 ratio. Can you help me to understand where did you anchor the dose selection specifically? Have you used in particular the animal's data as an anchor for the dopamine increase or the level, the PET study itself support a prevalent binding at the presynaptic site?
I think I'll rescue you from this one, Dr. McIntyre. He actually wasn't involved in the dose selection process for these trials. Gad, why don't you take that one?
Yeah, sure. The way we thought about dose selection was to take the successful clinical and real-world experience of amisulpride and the doses that were used in all those indications, map them to their dopamine receptor occupancy.
Then use what we know about LB-102 from its human dopamine receptor occupancy studies from our PK data to scale our LB-102 doses to fall within those ranges. At 50- 100 mg of LB-102, you're at 70%-80% receptor occupancy where you fall for the way amisulpride is used in schizophrenia, 400- 800 mg. Receptor occupancy doesn't scale linearly. It sort of rises steeply as you increase in dose, and then the curve sort of flattens from there. It was really that modeling exercise and wanting to map LB-102 doses onto the successful empirical experience with amisulpride.
Got it. Would you expect the protection from switching to mania in bipolar by being above the 50 mg?
Yeah. That's a really excellent point. I think if you remember the slide that Heather showed where you see, at high doses, you're suppressing dopamine signaling, where it's used for schizophrenia and at very low doses where it's used for depression. There's a reason that you see doses for negative symptoms and bipolar falling within the mid-range. That's for precisely the reason you said. That when you're in those diseases, whether it's bipolar or depression, you have risk of a manic event. If you're in negative symptoms, of course, this is a schizophrenia patient, so there is risk of relapse. So you do need to have dopamine receptor occupancy that's a little bit higher to provide that coverage.
You'll see that in the doses selected for the mood disorder trials, right? So for the adjunctive MDD trial, we're evaluating 15 and 25, and for the bipolar depression trial, we're evaluating 25 and 50.
We have time for two more questions.
Sumant Kulkarni from Canaccord Genuity. Thanks for taking our questions and for organizing this event. A couple for Dr. McIntyre, and then based off of what Dr. McIntyre says, a question for you, Kaya. So for Dr. McIntyre on your like to bringing you psychopharmacology perspective to the fore here-
Yeah.
If three patients present to you, one with schizophrenia, one with bipolar, one depression, and another with major depressive disorder, which one would you select as the first one to prescribe LB-102 for? Second, from your global perspective, is there anything you would like to say would be a nitpick on amisulpride's, I guess, profile?
Yeah. So with respect to the pharmacology and taking pharmacology and taking early evidence and then sort of thinking out loud what, in fact, would be my priority target, would it be bipolar mania, bipolar depression, major depressive disorder as adjunct, or schizophrenia? My answer is yes. In other words, all three. Over the last 30 years, that's what I do. I started off my discovery and development career in major depression and bipolar disorder. Just a bit of a historical background to this, that historically, these areas were very much siloed. In the 1990s, with the development of olanzapine and risperidone as mood stabilizers in bipolar disorder, what the additional indications did was they took away the silos.
It really is a contemporaneous approach, and I work in many different areas in early discovery and development, and it's always the case that when we have a new asset, we actually look at its role in depression, bipolar, and schizophrenia simultaneously. Some might say, "Well, that seems to be apples and oranges." But actually, it's not apples and oranges because underneath the neurobiological systems that are known to be relevant to depression, known to be relevant to psychosis, known to be relevant to cognition, and negative symptoms are not identical, but they're considerably overlapping. It's a contemporaneous consideration, quite frankly. On the second part, I didn't hear, because I'm hearing the pots and pans back here. I didn't hear the second part.
Yeah. The second part was on amisulpride's product profile in its global use. If you had to nitpick on anything, what would it be?
The nitpick, and full disclosure, I have used amisulpride a lot over the years. We have it at Special Access in Canada. It is approved in ex-U.S. markets, as you probably know, in over 40, 50 markets. So it is a very, very common drug, and I work in other parts of the world, in Asia, for example, where it is a very popular drug. I would say that for me at least, the issue has been the BID dosing has certainly been a problem. For no other reason than if given the opportunity to take something once a day versus twice a day, what would you prefer? Human nature gets in the way. Second is that there is no question that, and related to the fact we did not say a whole lot about this, amisulpride is a drug that does not readily cross the blood-brain barrier.
As a consequence, you have to use a considerably higher dose, hence more of an exposure. That has been a very difficult thread for people to stitch in the sense of getting the dosing right, because the dose exposure had to be so high in other parts of the world. So I think, in fact, the clarion call has been loud and clear, which is, you have heard here today, is a way to simplify the dosing into once a day dose. We have heard about how that has been enabled. We have also, in fact, heard that this has been structurally modified to create better blood-brain barrier penetrability, which allows for this lower dosing.
So in short, the Achilles' heel has been this issue related to the BID dosing, the total daily exposure, which then becomes in a conversation about the world everyday use of the medication and knowing what is the right dose across depression, bipolar, schizophrenia, where it is used quite a bit.
Yeah. I think you made my question for Kaya , so close.
Last question.
Thank you. Malcolm Hoffman here from BMO Capital Markets. It was noted on one of the slides that relapse related inpatient and emergency care is one of the primary drivers of consideration from a payer perspective. Thinking about the long-term extension study, how important is that study in developing an understanding for payers what that relapse rate would look like in a longer-term setting?
Before Kaya answered that question, one thing I will note, one of the things that we will be required to do post-approval is a relapse prevention study. So that will be a required trial that we need to conduct, which will obviously be the real metric on what that data looks like. But go ahead.
Certainly, the open label data will be useful, as well as the acute program that we have underway right now for payer negotiations. I would say, the relapse prevention data will be core to setting up that argument for contract negotiations.
Okay.
Oh, great. I just got the sign. Well, thank you all for coming. We really appreciate it, and we really appreciate your support. We look forward to the months ahead and the coming year and all of the hopeful potential for LB-102 playing out. Thank you, all.