Welcome to the Rapport Therapeutics KOL call on bipolar mania and Rapport's RAP-219 clinical program. Following prepared remarks, we will take questions. Please limit yourselves to one question and one follow-up. During this call, management will make forward-looking statements, including related to its phase II trial of RAP-219 and bipolar mania, as well as the timing of data, the company's development plans, and the potential commercial opportunity for RAP-219. Actual results and timing of events could differ materially from those anticipated in such forward-looking statements as a result of risks and uncertainties caused by factors described in the company's securities filings. Rapport undertakes no duty or obligation to update any forward-looking statements. Rapport sponsors this presentation. Any opinions identified as those of the key opinion leaders reflect their independent clinical and scientific judgment and do not necessarily represent the views of their employer or affiliated institutions.
Information is current as of September 22nd, 2026. Do not record, reproduce, or distribute this presentation without prior written permission. I will now turn the call over to Abe Ceesay, Chief Executive Officer of Rapport Therapeutics. Please go ahead, Abe.
Good afternoon, everyone, and thanks for joining us today. My name is Abe Ceesay, Chief Executive Officer of Rapport Therapeutics. To help provide context for the bipolar mania phase II trial top-line data expected next month, we've invited two leading bipolar disorder experts, Dr. Mauricio Tohen and Dr. Gary Sachs, to share their perspectives. Dr. Tohen is University Distinguished Professor and Chairman of the Department of Psychiatry and Behavioral Science at the University of New Mexico Health Sciences Center. He trained in psychiatry at the University of Toronto and completed a psychopharmacology fellowship at McLean Hospital, Harvard Medical School, later earning a doctorate in epidemiology from Harvard and an MBA from Indiana University. He is currently President of the American Association of Chairs of Departments of Psychiatry.
Dr. Sachs is the Founding Director of the Bipolar Clinic and Research Program at Massachusetts General Hospital and an Associate Clinical Professor of Psychiatry at Harvard Medical School. He trained at the University of Pennsylvania and the University of Maryland School of Medicine, completing his residency at MGH and later led the NIMH's STEP-BD program, the largest treatment study ever conducted for bipolar disorder. He is also past president of the International Society for CNS Clinical Trial Methodology.
Thank you both for being here. I'll begin today with a brief overview. Dr. Tohen will then provide background on bipolar mania and the current treatment landscape, and Dr. Sachs will review the RAP-219 results. Following our prepared remarks, we'll open the call for questions, where we'll be joined by Rapport's Chief Medical Officer, Jeff Sevigny, and our Chief Financial Officer, Troy Ignelzi. Rapport's vision is to create the leading precision neuroscience company.
Our technology platform is based on receptor-associated proteins or RAPs, biology discovered by our Chief Scientific Officer, David Bredt. RAPs have distinct neuroanatomical and cell-type expression. Targeting receptors through their receptor-associated proteins provides a more precise way to modulate receptors that are otherwise broadly distributed throughout the brain, allowing us to potentially address long-standing challenges in neuroscience. RAP-219 is an investigational potential first-in-class TARP gamma-8 AMPA modulator. TARP gamma-8 is expressed in brain regions that are directly implicated in focal seizures and, we believe, bipolar mania. Last September, we announced positive phase II results with RAP-219 in patients with focal onset seizures. Treatment with RAP-219 resulted in a 71% reduction in long episodes, which is an objective biomarker of abnormal epileptiform activity, a 78% median reduction in clinical seizures, with 24% of patients achieving seizure freedom during the entire eight week treatment period and a generally well-tolerated profile.
The majority of those patients have enrolled in the open-label long-term safety trial. Our phase III FOS program is underway, with two global placebo-controlled trials currently recruiting patients. Additionally, we're evaluating RAP-219 in patients with primary generalized tonic-clonic seizures or PGTCs. We believe that RAP-219 could also be a transformational treatment for bipolar mania, the focus of today's call. We're also developing a long-acting injectable formulation. This would potentially be the first LAI approved in epilepsy and also an important option for the treatment of bipolar mania, if approved. RAP-219 was designed to inhibit AMPA receptors associated with TARP gamma-8, a transmembrane regulatory protein that amplifies the effects of glutamate on the receptor. The structure on the left shows the TARP gamma-8 AMPA receptor complex. Our drug binds at the interface between TARP gamma-8 and the AMPA receptor to inhibit its amplifying effects.
Whereas AMPA receptors are distributed widely in the central nervous system, TARP gamma-8 is selectively expressed in forebrain structures and largely absent from the hindbrain, as shown in these PET images. This gives RAP-219 the potential to act in the areas of the brain where it matters for treatment and avoid tolerability issues associated with broad AMPA receptor inhibition. The scientific rationale to test RAP-219 as a potential therapy for bipolar mania is based on three points. First, while the exact cause of bipolar mania is not yet fully elucidated, there is a growing body of evidence characterizing it as a condition of excess glutamate activity. As you know, glutamate is the brain's main excitatory neurotransmitter, and AMPA receptors mediate most of these excitatory transmissions. By inhibiting the TARP gamma-8 AMPA receptor complex, RAP-219 may inhibit an underlying mechanistic pathway of bipolar mania.
Second, the areas of the brain that appear to be hyperactive in bipolar mania are the mesial temporal and frontal lobes, and in particular, the corticolimbic network that connects them. This is relevant for RAP-219 because these are the regions where TARP gamma-8 is expressed. Lastly, three commonly used treatments for bipolar disorder, lithium, valproic acid, and lamotrigine, mediate their effects through multiple mechanisms, including modulating glutamate signaling or suppressing AMPA activity, which is the mechanism central to our hypothesis with RAP-219. If successful, bipolar mania represents a significant potential expansion opportunity for RAP-219. Approximately 8 million U.S. adults have bipolar disorder. Roughly 3.5 million are diagnosed, and half of these have bipolar mania. Current standard of care is limited by side effects of dopaminergic atypical antipsychotics and anti-seizure medications, including weight gain, metabolic changes, extrapyramidal symptoms, and sedation or somnolence, which drive low adherence.
We'll hear more on this from Dr. Tohen and Dr. Sachs. With that, I'll turn it over to Dr. Tohen. Dr. Tohen?
Great to be here. As [Abe] mentioned, I'm at the University of New Mexico, and I call myself a student. Always things to learn about bipolar disorder for all my career. Actually, my doctoral thesis was an outcome in bipolar disorder. I should mention that in terms of conflicts of interest, I've worked for a number of pharmaceutical companies advising on research design, and at some point I was an industry scientist. I worked at Eli Lilly and Company during a number of years. Let's talk now about bipolar disorder. First, let's talk about the epidemiology, and the epidemiology is what gives us the numbers. It's not that we have an epidemic. Sometimes we have what we think is epidemic, but it's because more cases are being identified. It affects approximately 1% of the population, regardless of gender, race, or socioeconomic status. It actually can be a lethal condition.
It is the most lethal of all psychiatric conditions, and that is by suicide. Up to a third, to 20% is completed. In terms of the attempts, there's usually a family history, more common in females of young age when they're in a depressive polarity and frequently suffering from comorbid, that's other conditions, other psychiatric conditions or substance use disorders. In terms of completed suicide, more common in males. Again, attempts more common in females, but completed suicides more common in males. I mentioned comorbidities. Having another condition is not the exception. The majority of individuals with bipolar disorder have another psychiatric condition, like anxiety disorder, substance use disorder. After a number of years, more than 60% of them suffer from substance use disorder, and medical conditions. As we will mention, bipolar disorder does not only affect the brain, it is systemic.
That's why there's more conditions with inflammation in patients with bipolar disorder. Diagnosis is challenging, because we don't have a valid biomarker. We cannot do a blood test and diagnose. For that matter, even doing a brain scan will not tell us that the patient suffers from bipolar disorder. It's really what we call observation. What are the symptoms that we observe or that the patient reports? In the clinical assessment, there's different phases. We have to identify mania, hypomania, which is less severe mania. I'll talk a little bit about it, the depressive phase, and then the combination of both. We can have patients who have both symptoms of mania and symptoms of depression at the same time. Something that is quite challenging in bipolar disorder is that there's disability. Actually, some individuals have no disability.
I am sure that among us there are some who suffer from bipolar disorder. In other words, high-functioning individuals. But in the majority of individuals, there is poor functioning and cognitive impairment. That is in the majority. The challenge is that sometimes the condition starts, and we don't diagnose it right away. It usually starts with depression or anxiety, and studies have shown that sometimes it takes up to 5- 10 years from the beginning of the first symptoms until the patient is appropriately diagnosed and therefore treated. Course of the illness. The condition of bipolar disorder, as we mentioned, it has many different phases. So there is fluctuations of mood, and then, as mentioned, there is impairment. So this graph illustrates bipolar disorder. So you can have what we call the prodrome, that is mild symptoms early on. This would be the first episode.
So we have mild symptoms early on, and then you can have episodes of hypomania, less severe mania, and you have episodes of mania and episodes of depression. Something that I don't think it's emphasized enough is that it's not that you have periods of wellness and then you have the episodes. In most cases, you have patients who have mild depressions or mild manias, and sometimes that does not lead to good functioning. So it's not only the episode of mania. Also, when you have hypomania, there's impairment, and as mentioned, you also have the mixed states where you can have both symptoms of mania and symptoms of depression. Unfortunately, the condition doesn't burn out. It unfortunately is with the individual until the end of life. So let's talk about the diagnosis. As mentioned, we have no biomarkers.
What we use is the Diagnostic and Statistical Manual, now number five. And to diagnose a mania, we have to have a number of symptoms. First is elevated mood, but actually in most cases it's irritable, and it is abnormal to the individual. And then there must be persistent increased activity or energy. This specific symptom, change in mood, lasts at least a week. And then, out of seven symptoms, there needs to be at least three of them. As you can see, it can be grandiosity, self-esteem, decreased need for sleep, talkative, racing thoughts, distractibility, increase in goal-directed activity. Then you have psychomotor agitation, and then another one is impulsive behavior, and that's what leads to self-harm, harm to others, sexual indiscretions, use of substances. Importantly, there has to be impairment.
In other words, someone who is functioning well, unless there's impairment in their functioning, that's when you have the diagnosis. When you have some of the symptoms, you can call it unspecified bipolar disorder, but it's not full bipolar disorder. And then it does not result from intoxication from substances. Some recreational substances, like the stimulants, actually produce symptoms that are similar to mania. Sometimes it's difficult to make the differential diagnosis. Is this intoxication from a substance or actually some medical conditions? And some medication actually can also mimic the symptoms of mania. There's some specifiers, more than four episodes. You can have, as mentioned, the mixed features. That is when you have features of both poles. A little bit about the pathophysiology. It is one of the most heritable psychiatric condition. It is a combination of the genetics and the environment.
And actually, in terms of the genes, some overlap with schizophrenia, not all. Key point is it's not only genes, it's also the environment. It can start in utero. Trauma actually is a factor that can lead to mania. Abuse, especially during childhood. So there are environmental factors that actually contribute to the condition. At the end, what we have is an imbalance in the neurotransmitter systems. In the past, what was emphasized was the serotonin, noradrenergic, dopamine, and acetylcholine, and also glutamatergic, and that has been found in a number of the mood stabilizers. There's a problem with the connectivity of the neurons and changes in the mitochondria. Key thing is that you actually see changes in the brain. So in a biopsy, you can identify changes.
However, as we've mentioned before, we're not yet at a stage that we can make the diagnosis through biomarkers or even necessarily postmortem. Key point that I've—bipolar disorder have a larger percent of conditions such as diabetes or hypertension than the general population. So that's what contributes to the medical comorbidities. Some of the treatments that we have available. First, we have what are called the mood stabilizers. The first one was lithium, mid-20th century, and then we have a number of the anticonvulsants. And what I have here is the effects in the different phases of bipolar disorder, the advantages and disadvantages. As you can see, there is no perfect treatment. Valproate, effective in mania, doesn't help with depression, not that effective in maintenance, and it's contraindicated in women of childbearing age. Lamotrigine, it's another anticonvulsant. The only thing that it does, it prevents depression.
It doesn't treat mania, it doesn't treat depression. Lithium, it is the oldest. It does treat some patients with mania and depression. Maintenance mostly prevents mania rather than depression. And the problem is that after 25, 30 years, there's long-term renal side effects. Carbamazepine and oxcarbazepine, other anticonvulsants, the only FDA approval that they have is with mania. Then you have the typical antipsychotic agents, chlorpromazine, that started in the 1950s, and haloperidol. Actually effective, but unavailable intramuscular and long-acting, but it has the risk of switching patients to mania. So definitely not an ideal treatment. It works in terms of treating symptoms of mania, but with the risk of switching into depression. Then we move into the atypical antipsychotics. You have a number of them. Out of close to a dozen atypical antipsychotics, only one has not proven to be effective in mania.
As you can see, there's effectiveness in mania, not always in depression. Maintenance, it varies, and all of them have disadvantages. Antidepressants don't work in bipolar depression and may also lead to a switch into mania. Then we have other treatments. The ECT, electroconvulsive treatment, and TMS, not FDA approved for mania or for bipolar depression. So there's a need for better treatments. What are the current unmet needs for the treatment of mania? We need more effective and better-tolerated treatments, and I'm focusing right now on mania. We need new mechanism of action. The atypicals all work in a similar way, same with the atypicals. When you see improvement, say, compared to placebo, you have 60%, 65% of patients with the medication, lower with placebo, but you never see above 60%- 75%. And also the improvement that you see with existing medications is limited.
We need medications with a faster onset of action. The medications that we have available work within days, not right away. We need more treatments for the prevention of both mania and depression, and we need a long-lasting option. In other words, a medication that, given in most cases by injection, that will keep the patient well for a month or more. This is a condition that doesn't go away, so a long-lasting option is definitely what is needed. The ones that we have available only prevent mania. Long term, at the end, what we need is treatments that are curative, not just that improve symptoms. We need, of course, personalized medicine like in other areas of medicine where you have the specific patient, and then you can determine what is the right treatment. Let me stop there, and I'll have our dear colleague, Dr. Sachs, go on.
Dr. Sachs.
Thanks, Mauricio. Pleasure to be with you all this morning. I want to go through and give you a little bit of a different perspective. I'm going to start with more of a clinical trialist perspective. I think Mauricio's given you a really good start on the epidemiology. What I'd like to do is just go through a little bit of the unmet need as well, the chance of success, some of the diagnostic challenges, and then talk a little bit about the outcome assessment, design issues, and what is a clinical meaningful difference to find in a trial like this. So that's the overall view. I need to give you my disclosures. The most significant here is that I have had some opportunity to have input into the design of the study as a consultant to Rapport. Good news.
We start with the fact that most acute mania trials actually have succeeded, and you can see the effect sizes vary. But the efficacy here, if you have an efficacious treatment, there's a very good chance that a well-designed trial will pick that up, and that's certainly the good news. But if you looked at the end of all the acute mania trials we just looked at, as well as the ones that have failed, average participant in those trials, at the end of three or four weeks, would still be eligible to enter the trial anew. So that gets us to the same listing of unmet needs, very similar to what you heard from Dr. Tohen. Fully resolving mania would be a wonderful outcome, right? Something that worked faster. Then I think, as Mauricio emphasized to you, less burden.
If you had a long-acting agent that was fault-tolerant, you missed a dose or two, and your symptoms didn't come back, that would be great. But there are a variety of other adverse effects that cause patients to go off their treatment, and if it was less burdensome, that wouldn't be such a big problem. The churn here through treatments, on and off treatment, is really a big problem for patients and their families, as well as for our national economy. How well do the drugs work? Here's a listing of the successful trials, and you see the placebo response, which is an issue in these trials, in the blue bars and the active treatment. You get an idea that first of all, the last one listed, olanzapine 1999, Dr. Tohen's trial, which had a huge treatment effect. Same for the risperidone.
You can see that atypical antipsychotics overall really look quite good. However, just to say that the listing of these trials out this way is not something that really can give you an opportunity to make a valid comparison of efficacy. I just point out a couple things about this slide. Here, we're looking at the number needed to treat in these acute mania trials. There's an interesting issue here. You look at the two aripiprazole studies, they came out pretty similar. The olanzapine study's pretty similar. But if you look, risperidone looks like it's one of the most potent treatments in this first blue bar, but when we go out here to the sixth bar, it's starting to look less effective. That's in part because of who was brought into these studies.
In the left-hand column, this is a study done in India, where the acuity of the patients who came into the ward, the BMI of the patients who came into the ward, actually can impact the effect size that you observe in these studies. So I just point that out as a way to say you can't necessarily say one treatment is better than the other on these, but you also see the variability that can come from the sample that is brought into a study, and that is going to turn out to be really important for most studies, including the RAP-219. We had the good news that studies in acute mania tend to work, but they don't all work. You see here an interesting issue that came up in the brexpiprazole acute mania trial. Here we see two trials with very similar findings.
You can see in the two left-hand pairs of bars that in both of those, placebo looks at least as good as brexpiprazole. In fact, in the U.S., it looks better than brexpiprazole. But that the drug-placebo difference was statistically significant in favor of the active in the studies done from the centers in Europe. That kind of regional effect makes you wonder, how can we make America safe for clinical trials? That is something that the study team at Rapport really did put a lot of thought into, and we're going to be talking a bit about how that works. But I also want to give you an idea of how impactful this can be and why.
A lot of times you go through the diagnostic criteria that Dr. Tohen listed, and you think that patient meets criteria for mania and automatically by the DSM, that means they meet criteria for bipolar disorder. But notice this DSM field trial that looked at the rate of agreement between two independent raters. That is what the kappa is. What you see is that the agreement between two independent raters are pretty modest. One of the best ways to not show an effect in any research study is to have patients in that study who do not have the disease that you are trying to treat. This really is a very big problem.
Again, we could talk about this in detail, but if you said about half the time people are going to agree about the diagnosis, you would probably want to restrict your study to those cases where both the independent raters actually thought the disease was present. That is one of the strategies that Rapport used here, and we will come back to that. This is data from a failed ziprasidone acute mania trial.
What you see here is in this case, we are back at DSM-IV. The green bars are showing where both the rating systems agreed with the diagnosis of acute mania, and those results favor ziprasidone. This is the low-dose arm of this trial. But notice that for those that were only eligible by the site-based rater, you have only a tiny effect or one that goes in the wrong direction. In the high-dose arm, it is even worse.
You have a small effect from the high diagnostic confidence subjects in the right direction, but it is really. So in planning any trial, you want to favor more specific diagnosis, enrich your trial with a sample that really has the disorder that you want to treat. That alone makes sense. I wish we could have a biomarker, but as Dr. Tohen told you, we do not have one. So in the absence of a biomarker, what can we do now? It turns out that we can use some of the epidemiological factors, things that we know are associated with the picture of the illness. DSM limits the diagnosis to criteria based on the index episode characteristics that Dr. Tohen listed out for you. But we also know that there is a characteristic age of onset, typical course of illness, family history, and response to treatment.
These were other dimensions of illness that Emil and Robins emphasized. What we did for STEP-BD is make a quantitative scale, this so-called Bipolarity Index, just to give you an idea of what it is. It produces a 0- 100 kind of score, with scores over 50 being very likely to be true bipolar illness, as opposed to somebody who might have had manic symptoms, perhaps for those other reasons Mauricio mentioned. Good news about the scale is that not only was it helpful in STEP-BD, but it has been validated in clinical samples in the U.S., Russia, and China. So good reason to think that it might be helpful here, and it is part of the design. You can see the overall picture of the design here. The way this study works, we have a screening period for the first week.
We are assessing the patients to make sure that they meet the entry criteria for diagnosis. They've had not just this one episode, but at least one prior episode. The key endpoints are the change in the Young Mania Rating Scale, from baseline to week three. There are other secondary endpoints that are similar based on the YMRS and the clinical global impression of bipolar disorder. Then we have, in addition to the placebo arm, two titration schedules for RAP-219. One that's a little bit faster, goes over two to four days, and the other is a four day titration. So that's the overall design. The key inclusion/exclusion criteria, these are critically important to the success of a trial. The key ones that I will point out to you, the YMRS total score requirement of 25.
That is consistent with a lesson learned in past studies, that patients with less severe symptoms don't have as good separation of drug from placebo. So that's typical. There's also particular item scores that are required. Again, prior studies have taught us, particularly for patients who have irritability, disruptive, aggressive behavior at screening and baseline, they are more likely to separate drug from placebo. I mentioned the bipolarity index score greater than 50, and then that this episode has been present for at least 12 weeks. We're also looking at patients who have more manic than depressive symptoms, so we cut off the Montgomery-Åsberg Depression Rating Scale score at 18. Patients have to be hospitalized for this, and that has been one of the real lessons. Those trials that have failed in the past, most of them have been outpatient mania trials. So, those are the inclusion criteria.
We exclude people with other conditions like schizophrenia, patients with rapid cycling who tend not to do as well with treatment. Current episode, if it resulted from another condition or another agent, obviously out. Then importantly, inability to report the symptoms reliably. I'm going to talk to you a little bit about this idea of the YMRS score. We have a computer interview, a rules-based AI, that can establish that score by administering and scoring an interview just like a site-based rater would do. Seven points, as you'll see, is a huge difference. It really means that the subject is not a reliable reporter. Then again, if somebody's acutely suicidal, they wouldn't be in the trial. Those are the basic inclusion/exclusion criteria, and there's a lot that has been done. I've mentioned some of the things to ensure data quality.
This idea of confirming the diagnosis with the bipolarity index, and making sure that there's at least one prior manic episode within the last five years. That is critical. We have that mania-predominant profile that I mentioned, so that people who have the mixed features where they may have a lot of depression, they're excluded. Every single patient, their eligibility is reviewed by the study team, and we're making sure that they meet all the inclusion/exclusion criteria, especially that diagnostic assessment as well as the symptom severity requirement, both for the YMRS total and the individual items that I mentioned. The symptom stability screening, we don't want to take in patients who may have a high score today, but their trend is getting better. So if they have a 20% or more improvement from screen to baseline, they're excluded.
And then, as I mentioned, we have this rules-based AI monitoring of the blinded data. That allows the study team to call out poor performing raters and poor performing sites. So those are things that give me a lot more confidence that whatever the result is of this study, it is not going to be that the study failed the drug. And those quality metrics are really important. As I mentioned before, you see on the right-hand side, this is the agreement between a site-based rater and that rules-based AI. And actually, the agreement between the computer and the site-based rater is actually quite good. You can see the average difference here is zero. And getting seven points more, that is meaningful.
It turns out that subjects who have more than seven points difference on either side of this curve are much more likely to do well with placebo than with active agents, and therefore, their exclusion absolutely helps the study. So I think I have given you an overview of the study design and some of the needs, as well as these quality points that Rapport has incorporated into the design. So I will stop here, and I think we are on to questions.
Great. Well, thank you so much to Dr. Tohen and Dr. Sachs. Before we open up to questions, I would just like to review some of our upcoming milestones. We have got several catalysts over the next year or so, and a balance sheet to fund them into the second half of 2029. We expect top-line data from the phase II bipolar mania trial next month, including efficacy and safety tolerability over the three week treatment period. We expect that this will add meaningful safety data that informs the RAP-219 program more broadly. By the end of the year, we expect to share initial data from our open label long-term safety trial in FOS. We expect to guide on completion timing of our ongoing phase III trials next year. This will allow us to have more recruitment data under our belt.
We also plan to initiate the PGTCs phase III trial in the first half of next year. Our LAI program is progressing well, and we expect the PK results in 2027. I want to leave you with three things before we open up to Q&A. First, by targeting TARP gamma-8 rather than the AMPA receptor broadly, RAP-219's precision profile was designed to enable differentiated tolerability. As in epilepsy, safety and tolerability concerns are a significant limitation, as Dr. Tohen and Dr. Sachs mentioned, in the current bipolar treatment landscape. Second, while bipolar lacks a highly translatable preclinical model, we believe that the biology and the anatomic rationale support pursuing this indication, and it could be a very meaningful treatment option for physicians and patients. Finally, a positive result opens a significant new market for RAP-219.
Bipolar mania is a large and underserved population with roughly 1.6 million bipolar patients in the U.S., where poor tolerability drives low adherence to the current standards of care. Underpinning all of this is our focal onset seizure program. We have a highly translatable phase II data set and a $2 billion-$2.5 billion market opportunity that roughly doubles with the addition of a long-acting injectable. With that, let's open the call for questions.
Great. Thank you, Abe. Yes, at this time, we'll be conducting a question and answer session with our speakers. To our analysts joining us live, just a friendly reminder that we kindly ask you to limit yourself to one question. Please hold for a brief moment. Our first question comes from Lydia Erdman at Goldman Sachs. Please go ahead, Lydia.
Hi, this is Lydia on for Salveen. Thank you so much for hosting this and to Dr. Sachs and Dr. Tohen for the time here. Maybe just one for the two KOLs on the clinical practice side. If you could just speak to your strategy for prescribing a drug in the acute versus the maintenance setting, and then what you would look for in the upcoming data to potentially support maintenance dosing, both on the efficacy and the safety tolerability side. Then maybe as a follow-up, just how a potential long-acting injectable formulation could impact that maintenance use. Thanks so much.
Great. Dr. Tohen and Dr. Sachs, I'll let you jump right in. Maybe both have perspectives on both questions.
So probably, Gary, we will both be answering similar questions. Why don't I start and then you next time you go first.
Sure. Absolutely.
Okay. No, that's a great question. Of course, what you want is the treatment that works in the acute phase
For also to work on the maintenance phase. The reason is very clear, because if you treat someone with mania and then you have to move to a different medication, of course, there's a step there that if you do it too fast, it can cause withdrawal. You always want the same medication to work. Although that's not always the case. In acute phase are larger than in maintenance. The point about a long-lasting is key. I must mention, we psychiatrists underutilize the long-acting, in this case, intramuscular. There's a little bit of a stigma, not necessarily from patients, but also from us prescribers, that we only always think about long-acting is for those patients with schizophrenia, who in general have a worse outcome, but not for bipolar. But actually, here at UNM, we have a first episode clinic, and we start talking about LAIs early on.
The key thing is, of course, that it is well-tolerated. So why a new drug? As Gary mentioned, all treatments in similar drugs have been positive unless there's a problem with the design, but we need new mechanism of action. If we were dealing with a drug that is the same mechanism of action, unless it's a poorly designed study, it's going to be positive. But as mentioned before, not all patients respond, and not all patients have full symptom remission that's in the acute phase or the maintenance. Gary, please.
Yeah. Lydia, I look at it as acute mania falls into two big baskets. There is what we might call the urgent care side of this. Mauricio told you that there's actually mortality associated with this. People are doing things that ruin their lives, their prospects for employment, et cetera. Those treatment decisions are driven by the clinician's judgment about what's going to work fast. It's an absolute emergency. That's probably fewer than 5% of the cases, though. The rest of the cases are treated in a style that we might call sequential care. What you're doing there is having the patient participate in a collaborative way and choose reasonable choices. Right now, when we present that menu to them, it's really not encouraging. Every one of these options that's approved has a black box warning.
Every one of them is associated with things like sedation and weight gain. A lot of them are only partially effective. So when we start talking about that sequential care phase, we'd like to be able to have patients participate in some of the decision-making. We'd like them to be able to make a choice of a drug that will be more completely effective. That's an important part of it. When we get out of that acute phase, we'd like the drug to have a burden of staying on it that is more desirable to the patient than coming off the drug and seeing if their symptoms come back. Again, that happens all too often. That's where a fault-tolerant treatment, like a long-acting injectable, could be really helpful, especially if it's paired with a desirable adverse effect profile.
Super helpful. Thank you.
Thanks for the question, Lydia. Our next question comes from John Cox at Jefferies. Please go ahead, John.
Hey, guys, this is John Cox on for Andrew Tsai. Thanks so much for taking our questions and really appreciate the great event and all the color. Obviously, FYCOMPA has a black box warning for hostility-related AEs and understanding the mechanistic differentiation between RAP-219 and FYCOMPA. What are you expecting RAP-219 to show on these sorts of special AEs, especially since this is going to be a bipolar mania population? To you, is a win on safety to show no imbalances on these types of AEs of aggression, hostility, and irritability, or should the street maybe be focused on no imbalance to placebo? Thanks.
Great, John. Thanks for the question. First thing is, I really want to make sure that we are accurate around the black box warning for FYCOMPA, and that is specific to homicidal ideation. When you think about our experience thus far with RAP-219, we have not observed that AE associated with treatment with RAP-219. Also, these are very different mechanisms. Although there is a commonality with AMPA, that's where it really ends, is the commonality across AMPA. But the binding site, the way that we are actually antagonizing the AMPA receptor, our 219 is antagonizing the AMPA receptor via TARP gamma-8, is a completely different mechanism. In terms of this bipolar study, a couple things about the ongoing study. First, there are no adverse events of special interest, so we did not go into this trial assessing any AEs of special interest.
That was both our perspective as well as the regulator's perspective. The second is there is an independent data safety monitoring committee that is looking at the data in an unblinded fashion. We at Rapport, and specifically not me or not Troy, but our clinical development organization is hearing those report outs in a blinded fashion. But the independent data safety monitoring committee is looking at that data in an unblinded fashion. As you may be aware, there's really three domains that you can hear from an independent safety monitoring committee. One is continue the study with no changes, two is to continue the study with changes, and three is to recommend to stop the study. All recommendations that we have received through this trial are to continue the study with no changes.
I think what's really important, and I think both Dr. Sachs and Dr. Tohen could elaborate on this, is that part of both aggression and some other dynamics of this patient population are actually the domains of the YMRS. These patients will come in with some of that symptomatology. The obvious direction here is the YMRS should improve on treatment, but it also improves on placebo, as Dr. Tohen and Dr. Sachs had mentioned. I think it's important to understand that that is an actual domain of the YMRS. Dr. Sachs and Dr. Tohen, please add in there.
Go ahead, Gary.
Yeah. The YMRS does have items that look at aggressive behavior, irritability, risk-taking, et cetera. All of those things that could show up as improvement with treatment or in the context of a safety issue, which is, I think Abe is saying so far we haven't seen that signal. We do have hope that there'll be therapeutic benefit for those specific symptoms because they're core to what mania is about.
If I can add a point. This is a great example of the value of a monitoring board. Of course, it's unblinded. As Abe mentioned, impulsivity is one of the symptoms of mania. For that matter, as mentioned, it is the condition with the highest degree of self-harm or harm to others. This is going to be key to have the data monitoring board, because there are going to be patients, those who receive placebo, one would expect, are going to be the ones where you see that. Hopefully, that's not going to be the case. The other key thing is that this is an inpatient study, so if the impulsivity arises, something can be done about it. Thank you for the question.
Thank you, guys, very much.
Thank you for the questions, John. Our next question comes from Joseph Thome at TD Cowen. Please go ahead.
Hi there. Good afternoon, and thank you for the presentations. Maybe for the KOLs, can you comment a little bit more on maybe what proportion of your patients are, I guess, quote-unquote, well-maintained on available options? Obviously, there is a high unmet need, but would that be 30%, 50%, 100% of patients looking for something else to manage their symptoms? Then maybe for the company, are you commenting at all on the baseline population that you enrolled? Are you confident that the population is severe enough based on baseline, just given what we heard in the presentation? Thank you.
Yes. So maybe we can address the latter first. We have not communicated on or disclosed the baseline population. But as Dr. Sachs mentioned, we have an ongoing assessment of trial quality. Maybe Jeff, our CMO, could just speak to that process and some, not detailed observations, but just the fact that we feel that trial quality is in the right place. Then we will hand it over to Dr. Tohen and Dr. Sachs on the unmet need question. Jeff?
Yeah. Thanks, Abe. Thanks, Joe, for the question. We are confident in the patient population. We are really taking every measure possible to ensure we have enrolled the right patients in this study. Dr. Sachs reviewed some of the measures that we have taken, but this includes using a YMRS score of 25 or greater. He explained the reasons for that. Typically, studies enroll a YMRS score of 20 or 21. We selected 25 or greater. One of the problems in recruiting for mania studies is that people may have mania for reasons that are not related to bipolar disorder. In our case, all the cases of every subject that was being reviewed for eligibility in the study was reviewed by us, the sponsor, and by our CRO with experts in bipolar mania disorder.
We also confirm the diagnosis with measures such as the SCID-5-CT and using a scale that Dr. Sachs created called the Bipolarity Index. So we feel really confident that we have enrolled the right population for this study. One other point, this is a U.S.-only study as well, so that should help with decreasing variability by using a single country.
Dr. Sachs did mention this, but we did implement a blinded analytics throughout the entire duration of the study. Data were reviewed in a blinded fashion to look for potential trends or unusual trends at a site level, at a patient level. When trends were identified, our CRO went back to the site to discuss the finding. There was no changes to the data, but what it ensured was that if the site felt like something was being done improperly in the future, that was corrected. So I think we have taken a conventional study design and we have gone out of our way and implemented every potential measure we think that we could use to ensure that we have run the best clinical experiment to test RAP-219.
Let me go first this time. We have the advantage that there has been a dozen studies in mania with other medications, so we have learned from that. Actually, Gary and I have been involved in many of those studies, actually going back to the past century. So we have seen the things that we should and should not do. So I think from the point of view of the design, with Gary leading the effort there, I think we are in terrific hands. Let me talk a little bit about the unmet need. So the treatments that we have available, they are really not great. They do not help everybody. They do not work fast enough. Then there is residual symptoms. In addition to that, there are side effects, actually, and the reason why there is non-adherence with most medications is because of the side effects.
There's a big unmet need, better medications, better tolerated, so the patient can continue the medication. Let me emphasize again the importance of the long-acting. The majority of patients that are treated with mania, initially, they improve, but later on, they'll stop the medication and because of it's inconvenient, what have you. Having in mind a long-acting, meaning maintenance treatment is key. This is going to be welcome for our patients, better treatments that are better tolerated. Gary.
Yeah, let me just address that question of how well satisfied the patient population is with the treatment. The Bridging study, which was a European study, looked at how long it took for patients to go from drug A to drug B, their second drug, and the average was half the patients were done with the drug in three months. That tells you that there's a terrific churn from one treatment to the other, and patients are not happy with the choices that they have. They will change treatments, sometimes multiple times in a year. The average patient is receiving three or more of the treatments. Sadly, with acute mania is still an antidepressant. All of which are very sad commentary on the options that are available, mainly because, as Mauricio said, the tolerability issues with the currently available treatments limits patient acceptance.
Very helpful. Thank you very much.
Thanks for the questions. Our next question comes from Paul Matteis at Stifel. Please go ahead, Paul.
Hey, thanks a lot for taking my questions. I appreciate it. One for the Rapport team and one for the specialists on the call. For the Rapport team, just as you think about your expectations for the safety of RAP-219, are you anticipating that the safety profile in bipolar should be similar to what we've seen in epilepsy? Asking with the context here that some ASMs, it looks like the rates of certain AEs or neuropsych AEs can be higher in, say, bipolar patients versus epilepsy patients. Then for the specialists on the call, just again, as I think about interpreting the safety data from the study, looking at other bipolar trials, there can be a pretty high rate of different background or CNS side effects even on placebo in these studies, things like agitation or anxiety.
So maybe from your perspective, how do you look at safety data for a new agent in a bipolar mania study? What is typical that's going to pop up in this population versus what would be something that is, I guess, maybe more disconcerting and would lead you concerned about a new drug?
Thanks, Paul. Maybe I'll start. I'll ask Jeff to provide additional comments, and then we'll hand it over to Dr. Tohen and Dr. Sachs. In terms of our expectation around the safety profile, it's really going to be empirically driven. We, as mentioned, go through a blinded data safety monitoring committee, and we have made no adjustments to the trial. I think going back to the earlier point, will the tolerability profile of the drug be different in bipolar mania versus focal onset seizures? I'm not sure that the tolerability profile will be different, but what we can say is that the patient population is very different.
Going back to the earlier comments that were made, and I think were also reinforced by Dr. Sachs and Dr. Tohen, some of these neuropsychiatric AEs, as an example, are part of the actual symptomatology of a bipolar mania patient. So, I think we'll be looking at that data, but also looking at the discrepancy between placebo and drug as it relates to some of those domains. So, my view here is it's going to be data-driven. And obviously, we're going to be seeing that data relatively soon. Jeff, I don't know if you have additional comments.
I will just add, I have no a priori expectations regarding adverse events in the bipolar mania study, except we will observe events that are related to bipolar mania symptoms themselves. I say that because it is an important potential differentiation from other clinical studies in that rescue benzodiazepines are typically used during the treatment period, in the inpatient treatment period. This is a common way to treat symptoms, because they have washed out in all their other background medications. In our clinical study, when a physician wanted to use a rescue benzodiazepine, they had to disclose an AE, and oftentimes that AE is going to be related to one of their bipolar symptoms. This is not a conventional practice among other clinical studies, but we implemented it in order to take into account and to have true account of why rescue benzos were used.
We will have a higher incidence across the study of bipolar-related symptoms. But I have no a priori expectations regarding any other types of adverse events with RAP-219.
Gary?
Yeah. I will add a couple little pieces. One is acute mania in that initial phase of treatment for a hospitalized patient. They are surprisingly tolerant of adverse effects. Right? Very different kind of thing than, let us say, a bipolar depression study or even a schizophrenia study. Patients with acute mania often tolerate higher doses of the drugs that are also approved for schizophrenia than schizophrenics do. So, that is an interesting thing. Remember, we have a design that has an arm that has a faster titration schedule. It will be interesting to see how the tolerability compares between those two arms, but I am going to bet that the rapid titration arm is no different than the slower arm. That would be my expectation. Then going forward, what you typically see is that whatever the adverse effects might be, remember, bipolar, a lifetime condition.
Patients become tolerant to some of the symptoms more than other. In sedation and weight gain, the possibility of staying on the drug becomes a lot higher, and that is something that over time, again, I expect to be a major advantage here.
It's an interesting question. Do we expect the same side effects in different conditions? Something that has been observed is that when patients have a certain condition and they've taken other medications, they focus on side effects that they experienced on the previous medication. Let's say in the case of patients with mania and the treatments that they've experienced before. As Gary mentioned, all of these patients have at least had one previous episode. They would tend to focus on symptoms that they've experienced before, like restlessness that is called akathisia and so on. The important thing of this design is it has a placebo control. The key thing is not the number of times that certain symptoms like nausea, sometimes it's more common with placebo, is that you can compare with placebo.
Also in terms of the two symptoms that are side effects that appear in more than 2%. Those are going to be important findings. I would pay attention to the medications that they've been before. It is an interesting question.
That's what's nice about a phase II study. It's a learning kind of experience. Yeah.
Great. Thank you. Tara, next question.
Yes. Thanks for the questions, Paul. Our next question comes from Jason Butler at Citizens. Please go ahead, Jason.
Hi. Thanks for taking the questions, and appreciate you hosting this. I am wondering if the two KOLs could maybe speak to the point of what is historically the predictive value of positive phase II trials been in bipolar mania. In other words, if this trial is positive, what would your confidence that would translate into a positive phase III program? Then just quickly, Dr. Tohen touched on this before, but could you maybe talk a little bit more about treatment persistence and how that has improved with a long-acting injectable both in terms of the likelihood a patient stays on therapy, as well as how long they stay on therapy with a long-acting injectable versus an oral daily? Thanks.
Yeah. As mentioned, the fact that it improves mania does not necessarily mean that it is going to prevent mania. There is actually an interesting case with one of the drugs that was mentioned, lamotrigine, which actually the opposite happened, that it did not improve the depressive phase. There were four negative trials. But then the maintenance trial was positive. Again, in most cases, if it works in the acute, it works on the maintenance. But there is another aspect, is that the tolerability. So if you have full tolerability that you might not experience right away in the acute phase might be present in the maintenance phase, so a trial might be negative. The same thing with the long-acting intramuscular. There is not a single one that prevents both phases. So the acute phase is likely to predict the maintenance, but not necessarily.
There is another actually even better example, haloperidol, old drug developed in the 1980s. In fact, it is one of the most widely used drug in psych emergency. It has a good response, not great tolerability, but the problem is that it causes depression. So it is actually, one has to use it very carefully. It treats the acute mania, but then it causes depression, so that it is contraindicated. So the studies need to be done. Gary?
Right. I think you started, Jason, with what's the predictive value of a positive phase II trial in acute mania. Overall it has been, I don't know if excellent is entirely fair because there are failed trials, but it's so much better than depression or even bipolar depression. Acute mania trials, when you have learned from phase II, for instance, the correct dose and titration schedule, those drugs do very well in phase III as a rule. Not always, but usually.
Great. Thanks for the questions, Jason. Our next question comes from Kambiz Yazdi at BTIG. Please go ahead.
Thank you for the great event. Question for the company and then question for Dr. Sachs and Dr. Tohen. For the company, the trial evaluates two titration schemes, a two and a four day ramp for RAP-219. How should we think about the kinetics of effect there? Then for Dr. Sachs and Dr. Tohen, I guess in your view, how do you view inter-trial variability and comparability of YMRS? Are there any aspects of manic syndrome that it fails to capture? Thank you.
Great. Jeff, do you want to take the first on the PK, RO perspective for the two dose titrations?
Yeah. Thanks, Kambiz, for the questions. In terms of kinetics of effect, based on the epilepsy animal model, we've critical for efficacy. That's been proven in our FOS study because we saw a terrific pharmacological effect, particularly with respect to decrease in long episodes after one or two doses of 0.75 mg, which is less than a 50% receptor occupancy. We know the drug is pharmacologically highly active at 50% and probably lower. In terms of the dose levels used in the bipolar mania study, we start at 0.25 mg for one day, then 0.5 mg for one day, and then the target 0.75 mg for the remainder of the three weeks. In the slower titration, it's 0.25 mg for two days and 0.5 mg for two days, and then 0.75 mg for the remainder of the three weeks. The difference is really only two days.
In terms of onset of efficacy, in an early onset, I would say it's likely to be no difference. If there is a difference, it's only going to be by a maximum of two days. I would say it's not so important, at least for our primary endpoint in the study, though, because that is at week three. We would not predict there would be any difference, in outcomes at week three using those different titration schemes. Important to point out, please keep in mind, we are pooling both groups for the final analysis. At some point, we may do exploratory analysis. This will not be top line for sure, but we could look at exploratory analysis looking at the two different titration schemes. At week three, they'll be pooled.
Again, at week three, we wouldn't expect there to be any difference clinically using either titration regimen. The receptor occupancy by three week is virtually the same, independent of which titration the patient was on.
Great. Thanks for the questions, Kambiz.
I think there was a Sorry, Tara. I think there was one question Kambiz had on the back end.
Okay.
That was more on the YMRS. Kambiz, maybe you could just repeat your question just so we have that clear for Dr. Tohen and Dr. Sachs.
Yeah. Happy to. In your view, Dr. Sachs and Dr. Tohen, how do you view inter-trial variability and comparability of YMRS? Are there aspects of the manic syndrome that it kind of systematically fails to capture? Thank you.
Yeah. I will start with that first because, just last week, in Philadelphia, International Society for CNS Clinical Trial Methodology had a session that was devoted to this question. Of the scales that we use, actually, satisfaction with the YMRS was rated considerably higher than most of the psychosis scales or depression scales that we use. That said, there is concern that at the lower end of severity, it does not do a great job. But for acute mania, that is where it was strongest, and again, that is the indication under study here. So in terms of the various symptom domains, some of the items perform a lot better than others.
For instance, the YMRS has an insight item, which basically, you have good enough insight, believe it or not, if you know you have mania and you think you need treatment, which of course, the consent form requires you to acknowledge. Therefore, some of the items like that one will not be very informative. But overall, the domains on the YMRS perform quite well.
If I can add, the YMRS is over half a century old. I think 1970 it was published. Every single study done for indication has used the YMRS, and as Gary mentioned, it is well accepted. It actually has a problem that we've addressed. In most conditions, like if you're studying anxiety, you use an anxiety disorder scale. What YMRS does not have is symptoms of depression. So in every single study, from the ones done for lithium and then valproate, the ones we did with olanzapine, there's always been a need to add a depression scale. So I would say that is a deficiency of the YMRS, and for that matter, the depression to have been used. As mentioned, the majority of cases have mixed symptoms.
Actually, in a study we did, if you look at just one symptom of the opposite pole, 88% had of the opposite pole. So that's why all studies with mania do not rely just on the YMRS. They need a depression scale as well. So it's not perfect.
Thank you so much.
Tara, I believe we are at time. I do not know if there is any other questions in the queue. We might be able to squeeze one more in.
Yes, we have one more from Myles Minter at William Blair.
Great.
Thanks for squeezing me in. Appreciate this. Just a couple on mechanism as it relates to bipolar that I have been getting. One, I know the valproic class is obviously used in mania considerably. That drug, I believe, is known to boost GABA levels, and an AMPA receptor inhibition might do the opposite. Just the rationale behind RAP-219 and if there is any risk associated with the mechanism in showing efficacy. Then kind of getting into this depression concept and the need to stay on therapy long term, is there any sort of risk that we overshoot glutamate signaling reductions here with RAP-219? Obviously, this is a three week study. You are screening out depression patients here. So it is probably not going to show up here, but just as we think about the longer-term commercial application of this, is that something to consider as well? Thanks very much.
Yeah. Maybe I will have Jeff address the first question on the mechanism, and I am sure Dr. Sachs and Dr. Tohen might have a perspective as well. What we know, as I just tee up Jeff here, is we know that the approved anti-seizure medications for bipolar disorder are clearly multimodal and multifactorial. I think our belief and our understanding is that there might be some commonality across them. Then I think Dr. Tohen also pointed out, or it was Dr. Sachs or Dr. Tohen, I am sorry if I cannot remember exactly which one, around the distinction between the drugs that are approved in the acute phase versus the drugs in terms of lamotrigine that is more of a maintenance medication. But Jeff, maybe you can just walk through maybe the mecha- as well as the corticolimbic network.
Yeah. Thanks, Myles, for the question. A great question, and it's great because it's a hard one to answer, actually. Psychiatry is a difficult indication. The biological underpinnings of most psychiatric disorders is, for probably virtually all of them, is not well known, and they're probably multifactorial. That's definitely true with bipolar mania. But we are still standing on firm ground here when we looked at whether we should pursue bipolar mania with RAP-219, because there are some things I believe are reasonably well understood and accepted. The first really starts with the understanding that bipolar mania specifically is a disease or a condition of excess glutamate activity. It may be also other things, but that's in part and parcel of the disease. That's really where the biological rationale starts.
If it's related to glutamate transmission, glutamate mediates its effect through mostly the excitatory effects through the AMPA receptor. That's key here because TARP gamma-8 is, I think it was an amplifier of the AMPA or the glutamate AMPA combination. RAP-219 inhibits that interaction. So we are targeting the right pathway. Of course, the second really important piece here is are we targeting the right part of the brain? The answer here we can definitively say is yes. It's been shown that the areas of the brain affected in mania, specifically bipolar mania, are the mesial temporal lobes and the amygdala area in the frontal lobes. In particular, there's a network called the corticolimbic network that seems to be particularly affected. That's precisely where TARP gamma-8 is expressed.
So we believe we're targeting the right pathway, and we know we're targeting that pathway in the right part of the brain. At least the target is there. That's really the strongest part of our rationale. The third piece of our rationale is looking at other treatments for bipolar disorder, and of course, there are three, of which lamotrigine, valproic acid, and lithium. All dirty drugs. They mediate their effects through multiple mechanisms. But one mechanism that is common is that they also inhibit, in some way, the glutamate system, which is central to our hypothesis. That's not the strongest rationale, but does lend support for why we went forward with this condition with RAP-219. So overall, all things considered, in a psychiatric indication with a new mechanism of action, I think that's as good as it's going to get for any type of new modality.
I'll also add, going back to some of the squiggles that Mauricio showed us for the course of illness. It is very common for patients to go directly from a manic episode to a depressive phase. That kind of post-mania depression is something the field's known about for a while. Again, as Mauricio told us, haloperidol produces more of that than would be expected otherwise. That's why we have a placebo comparison here. It's a very sophisticated question, Myles. It is possible that there'll be overshoot on a glutamatergic mechanism here. We're going to learn that when we see it. But I suspect that that will not be the case. We'll see how the data turns out. But that is one of the more common issues. Anybody making a transition from mania directly to depression may tend to blame the drug.
But since we have placebo in this study, we will be able to make a determination there.
I would just add, that is why we need to do studies. We have the basic science concepts that we are hoping are going to be accurate, and that is what it indicates. But the studies need to be done and show empirically that our hypothesis was correct. Another interesting point is also that not all anti-seizure medications have been effective in mood disorders. In fact, most have not. It has been only a few. The interesting thing is that, again, lamotrigine prevents depression, and that is basically it. Well, on the other hand, valproate only improves mania. So again, the empirical studies are needed, and we hope that our basic science hypothesis are correct. Good question.
If I may add a coda to that point. It is important to understand that RAP-219 inhibits this pathway, but the inhibition is at maximum between 30% and 40%. So it is not turning the pathway off, this glutamate AMPA pathway. It is inhibiting it maximally at 30%- 40% overall.
Thanks, everyone. Really appreciate it.
Great. Tara, I think we can squeeze one more in, and then we'll probably have to wrap up.
Yes. So this one came over the webcast from Imogen Mansfield at Cantor Fitzgerald. Do you consider anti-seizure medications as a distinct class of agents for treating acute mania? Given the MOA of RAP-219, do you consider this drug to be a part of that group, or could we expect a meaningful, fully different profile?
Yeah. I'll maybe provide a perspective on that, and then I'll ask Dr. Sachs and Dr. Tohen to provide their perspective as well. I think the commonality is the fact that there's an indication for treating seizures. That's where it kind of starts and ends. I think in our view, the fact that, one, it is a novel MOA that would be introduced for this indication, and two, its specificity, really targeting four brain structures, as we discussed in our prepared remarks and as Jeff has reinforced in some of his answers. I think this is going to be seen as a novel MOA for the potential treatment of bipolar disorder. I do not think it will be bucketed into it's another anti-seizure medication to treat this disorder.
I think that is one reinforced by the novel MOA, but it's also reinforced by, I think, an overall efficacy and tolerability profile that is very distinct. One that we hope is not causing sedation, not causing gait impairment, that we know traditional anti-seizure medications can affect. So I think our feeling here is, if efficacious and tolerable, that this would represent really a new modality for this patient population. I don't know, Dr. Sachs, Dr. Tohen, Jeff, open up for additional comments on that.
Yeah. I will just say that I think terms like anti-seizure, anticonvulsant, antidepressant, these are more marketing terms. As Abe, I think, rightly emphasizes, it is the mechanism of action. We are going to find out what the drug is good for. But the fact that it may have already been studied for a different therapeutic indication shouldn't limit our interest in that drug for another indication that mechanistically makes sense.
Yeah. As mentioned, not all anti-seizure drugs are effective. Another good example is gabapentin. I think in one of the trials, placebo did better. I think we should also think about tolerability, because when patients stop their medication, well, sometimes because they are having no symptoms. But many times, it has to do with side effects. Side effects that, many times, us prescribers, providers think are minor. A little bit of sedation, maybe side effects. But for the side effects that are of sexual nature. For patients, these are very important. They cannot function if they are mildly sedated or if they have other side effects that are actually not life-threatening. So tolerability is also a key thing, and it is a major reason why our patients stop their medications. Key point.
Great. Thank you all. So this concludes the Rapport Therapeutics KOL call on bipolar mania. Please note that in anticipation of Rapport's bipolar mania data next month, the company plans to enter a quiet period. Thank you again for joining, and have a good day. You may now disconnect.