Rapport Therapeutics, Inc. (RAPP) Earnings Call Transcript & Summary

Welcome to the Rapport Therapeutics KOL call on bipolar mania and Rapport's RAP-219 clinical program. [Operator Instructions] During this call, management will make forward-looking statements, including related to its Phase II trial of RAP-219 in 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 22, 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 Science 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 Medical School, 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 Phase II bipolar mania trial design and what to look for in the top line 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 Brett. RAPS have distinct neuroanatomical and cell type expression. Targeting receptors through the 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 indicated 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 8-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 ample receptors are distributed widely in the central nervous system, TARP gamma-8 is selectively expressed in four brain 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 amp 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 corticolimpic 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 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 to the effects by side effects of dopaminergic atypical antipsychotics and antiseizure 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. So as a mentioned, I'm at the university of New Mexico, and I've been -- I call myself, I stood and always thinks to learn about [indiscernible] 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 work for a number of pharmaceutical companies, advising and research design. And at some point, I was an industry scientists, I worked at Lilly during a number of years. So 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. So it affects approximately 1% of the population regardless of gender, race or socioeconomic status. The -- Dave, it actually can be a lethal condition. It is the most lethal of all psychiatric conditions, and that is by suicide, up to 1/3 to 1/2 of individuals with bipolar disorder attempt suicide on 20% is completed. In terms of the attempts, it's usually a family history, more common in females of young age when they're in a depressive [indiscernible] and frequently suffering from comorbid that's other conditions, other psychiatric conditions or substance use stores. 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 of bipolar disorder have another psychiatric conditions like anxiety disorder, substance use disorder. After a number of years, more than 60% of them suffer from substance users, so the -- and medical conditions, as we will mention bipolar disorder does not only affect the brain. It is systemic. That's why we -- 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. So 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, and I'll talk a little bit about it, the presser 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 our individuals, there is poor functioning and cognitive impairment. That is in the majority. Now 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 to 10 years from the beginning of the first symptoms until the patient is appropriately diagnosed and therefore, treated. Course of the illness. So 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 have, 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 of 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 appearance 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 mix states where you can have both symptoms of mania and symptoms of the pressure. 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 biomarker that we uses diagnostic and statistical manual now #5. And to diagnose mania, we have to have a number of symptoms versus 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. Those -- this specific symptom change in mood last 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, destructability, increase in goal-directed activity then you have psychomotor agitation. And then another one is a positive behavior, and that's what leads to self-harm, harm to others, sexual and discretions, use of substances. Importantly, there has to be impairment. In other words, someone who is functioning well unless there's impairment functioning, that's when you have the diagnosis. When you have some of the symptoms, you can call it unspecified by 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 mix features. That is when you have features of both poles. A little bit about the pathology. It is one of the most horrible 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 not -- it's not only genes, it's also the environment. It can start in utro, trauma actually leads to -- also it's a factor that can lead to mania. Abuse, especially there in childhood. So there are environmental factors that actually contribute to the condition. It's -- at the end, what we have is an imbalance in the neurotransmitter systems. In the past, it was mostly what was emphasized was serotonin, [indiscernible], dopamine and acetylcholine and also [indiscernible]. 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 post-order. Key point that I mentioned before is that there's a systemic neuroinflammation. Patients with 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. [indiscernible] 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, depression, maintenance mostly prevents mania rather than depression. And net 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. And then you have the typical antipsychotic agents chlorpromazine that started in the 1950s. And haloperidol actually effective, but an available intramuscular and long acting, but it has the risk of switching patients to to mania. So definitely not an ideal treatment. It works in terms of treating symptoms of mania, but with the reach 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. And 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 switch -- 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 need for better treatments. So 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 typicals or work in a similar way, same with atypicals. So when you see improvement, say, compared to placebo, you have like 60% -- 65% of patients with medication loan with placebo, but you never see above 60% to 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 at improve symptoms. And 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. So 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 is giving you a really good start on the epidemiology. But 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 the 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, we'll 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 other ones that have failed, they are all 3 to 4 weeks in duration, but the average participant in those trials at the end of 3 or 4 weeks would still be eligible to enter the trial new. 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. And then I think as it is less burden, if you had a long-acting agent, that was fault tolerant, you missed the dose or 2 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. And 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. So 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 accrete. 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. And you can see that [indiscernible] psychotics 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. And I'll just point out a couple of things about the slide. Here, we're looking at the number needed to treat in these acute mania trials. And there's an interesting issue here. You look at the two aripiprazole studies, they came out pretty similar. The olanzapine study is 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. And 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 award, the BMI of the patients who came in the word actually can impact the effect size that you observed in these studies. So I'd 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. And you see here an interesting issue that came up in the brexpiprazole acute mania trial. Here, we see two trials with very similar findings. And 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 the drug placebo difference was statistically significant in favor of the active in the studies done in Europe -- from the centers in Europe. So that kind of regional effect makes you wonder, how can we make America safe for clinical trials. And that is something that the study team at Rapport really did put a lot of thought into it, 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 unwind. A lot of times you go through the diagnostic criteria that Dr. Tohen listed, and you think that patient meet 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. And that's what the CAPA is. And what you see is that the agreement between two independent raters are pretty modest. And one of the best ways to not show an effect in any research study is to have patients in that study who don't have the disease that you're trying to treat. And 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 probably want to restrict your study to those cases where both the independent raters actually thought the disease was present. And that's one of the strategies that Rapport used here. We'll come back to that. This is data from a failed ziprasidone acute mania trial. And what you see here is, in this case, we're back at DSM-4, the green bars are showing where both the rating systems a breed with the diagnosis of acute mania and those results favor ziprasidone, and this is the low-dose arm of this trial, but noticed that for those that were only eligible by the site-based radar, you have only a tiny effect or one that goes in the wrong direction. And in the high dose arm, it's even worse, right? You have a small effect from the high diagnostic confidence subjects in the right direction, but it's really dragged down by those that have low diagnostic confidence. So in planning any trial, you want out to favor more specific diagnosis enrich your trial with a sample that really has the disorder that you want to treat, right? That [indiscernible]. I wish we could have a biomarker, but as Dr. Tohen told you, we don't have one. So in the absence of a biomarker, what can we do now. And 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's a characteristic age onset, typical course of illness, salon history in response to treatment. These were other dimensions of illness that [indiscernible] and [indiscernible] use emphasized. And 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 to 50 -- 0 to 100 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's been validated in samples in the U.S., 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 3. There are other secondary endpoints that are similar based on the MRS and the clinical global impression of bipolar disorder. And then we have -- in addition to the placebo arm, two titration schedules for RAP-219, one that's a little bit faster goes over 2 to 4 days and the other is a 4-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 [indiscernible] 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 to placebo. So that's typical. There's also particular item scores that are required. And 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 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-Asberg Depression Rating Scale score 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 help. And then importantly, inability to report the symptoms reliably. And 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's scored by administering and scoring an interview just like a site-based rater would do. 7 points, as you'll see, is a huge difference. It really means that the subject is not a liable reporter. And then again, if somebody is acutely so they wouldn't be in the trial. Those are the basic inclusion/exclusion criteria. And there's a lot that has been done. I 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 5 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 exclusive 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 [indiscernible] right? 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 for concordance. And ongoing monitoring of the blinded data that allows the study team to call out for 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's 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 0, and getting 7 points more, that is meaningful. It turns out that subjects who have more than 7 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've given you an overview of the study design and some of the needs as well as these quality points that report has incorporated into the design. So I will stop here, and I think we're on to questions.

Great. Well, thank you so much to Dr. Tohen and Dr. Sachs. Before we open up to questions, I'd just like to review some of our upcoming milestones. We've 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 3-week treatment period. We expect that this will add meaningful safety data that informs a 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, why 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 United States where poor tolerability drives low adherence to the current standards of care. And underpinning all of this is our focal onset seizure program. We have a highly translatable Phase II data set and a $2 billion to $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.

[Operator Instructions] So our first question comes from Lydia Erdman at Goldman Sachs.

This is Lydia on for Salveen. Maybe just one for the two KOLs kind of on the clinical practice side. If you could just speak to your strategy for prescribing a drug in the acute versus a 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. And maybe as a follow-up, just how a potential long-acting injectable formulation could impact that maintenance use.

Great. So Dr. Tohen and Dr. Sachs, I'll let you jump right in and maybe both have perspectives on both questions.

Probably, Gary will both be answering similar questions, why don't I start and then you takes from there.

Sure.

Okay. So no, no, that's a great question. And of course, what you want is the treatment that works in the acute phase for also to work on the maintenance phase. And 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. So you always want the same medication to work, although that's not always the case. In terms of the dose, it varies, but in general, doses in acute phase are larger than in maintenance. The point about a long lasting is key I must mention we psychiatrists underutilized the long-acting, in this case intramusclar. And there's a little bit of a stigma not necessarily from patients, but also from us prescribers that we always think about long-acting is for those patients with schizophrenia who, in general, have a worse outcome, but not for bipolar. But actually, we have here at [indiscernible], we have a first-episode clinic, and we start talking about LA ICE early on. The key thing is, of course, that it is well tolerated. So why a new drug? And as Gary mentioned, all treatments in similar drugs have been positive on this there's a problem with the design, but we need new mechanisms 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?

Yes. I look at it as acute many falls into two big baskets. There is what we might call the urgent care side of this. And Eric [indiscernible] you that there's actually mortality associated with this. People are doing things that ruling their lives, their are prospects for employment, et cetera. And 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. And what you're doing there is having the patient participate in a collaborative way and choose reasonable choices. And 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 and a lot of them are only partially affected. 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. And that's an important part of it. When we get out of that acute phase, we'd like the drug to have a 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. And again, that happens all too often. And 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.

Our next question comes from Jon Cox at Jefferies.

This is John Cox on for Andrew Tsai. So 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? And 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?

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. And 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 R-219 (sic) [ RAP-219 ] is antagonizing the AMPA receptor via TARP gamma-8 is a completely different mechanism. In terms of this bipolar study, a couple of 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. And then 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 community is looking at that data in an unblinded fashion. And as you may be aware, there's really kind of 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 3 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. So these patients will come in with some of that symptomatology. And 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, but I think it's important to understand that, that is an actual domain of the YMRS and Dr. Sachs and Dr. Tohen, please add in there.

Go ahead, Gary.

Yes. 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 is saying, so far, we haven't seen that signal. But we do have hope that there'll be a therapeutic benefit for those specific symptoms because they're core to what many is about.

If I can add a point. This is a great example of the value boarding monitoring board. Of course, it's unblinded. And as Eve mentioned, impulsivity is one of the symptoms of mania. For that matter, as mentioned, it is the condition with the high degree of self-harm are harm to others. So this is going to be key to have the data monitoring board because there are going to be patients that those who received placebo, one would expect are going to be the ones where you see that problem. So hopefully, that's not going to be the case. The other key thing is that this is an inpatient study. So that patient will -- if the impulsivity arises, things they can be something can be done about.

Our next question comes from Joseph Thome at TD Cowen.

Maybe for the KOLs, can you comment a little bit more on maybe what proportion of your patients are, I guess, "well maintained" on available options. Obviously, there's a high unmet need, but would that be 30%, 50%, 100% of patients looking for something else to manage their symptoms. And 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.

Yes. So maybe we can address the latter first, and we have not communicated on or disclosed the baseline population. But as Dr. Sachs mentioned, we have an ongoing assessment of the trial quality. And maybe Jeff, our CMO, could kind of just speak to that process and some not detailed observations, but just the fact that we are we feel that trial quality is in the right place and then we'll hand it over to Dr. Tohen and Dr. Sachs on the unmet need question. Jeff?

Yes. Thanks, Abe, and thanks, Joe, for the question. Yes, we are confident in the patient population. I mean, we're really taking every measure possible to ensure we've enrolled the right patients in this study. Dr. Sachs reviewed some of the measures that we've taken, but this includes using a YRMS score of 25 or greater. We explained the reasons for that. Typically, studies enrolled a YRMS score of 20 or 21, we selected 25 or greater. One of the problems in recruiting for mania studies is that people they had 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. And we also confirm the diagnosis with measures such as the SCID-5 CT and using something a scale that Dr. Sachs created called the Bipolar Index. So we feel really confident that we've 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 do -- we did implement 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. And when trends were identified, we went -- 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've gone really -- we've tried -- we've taken a conventional study design. We've gone out of our way and implemented every potential measure. We think that we could use to ensure that we've run the best clinical experiment to test RAP-219.

Let me go first system. Well, we have the advantage that there's been a dozen studies in mania with other medications. So we've learned from that. And actually, Gary and I have been involved in many of those studies actually going back to the past century. And so we've 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're in terrific hands. But let me talk a little bit about the unmet need. So the treatments that we have available, they're really not great. They don't help everybody. They don't work fast enough and then there's residual symptoms. In addition to that, the side effects, actually, and the reason why there is no adherence with most medications because of the side effects. So there's a big meat better medications better tolerated, so the patients who can continue the medication. And let me emphasize again the importance of the long lasting. The majority of patients with -- that are treated with many initially, they improve, but later on, they'll stop the medication and because of it's inconvenient, what have you. So having in mind a long-acting meaning maintenance treatment is key. So this is going to be welcome for a patient's better treatments that are better tolerated. Gary?

Yes. Let me just address that question of how well satisfied the patient population is with the treatment. The BRIDGE 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. So 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 3 or more of the treatments. And sadly, the most common treatment for a patient who's admitted 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.

Our next question comes from Paul Matteis at Stifel.

One for the Rapport team and one for the specialists on the call. So 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 or neurosis can be higher in say, bipolar patients versus epilepsy patients. And then for the specialist on the call, just again, as I think about interpreting the safety data from the study looking at other bipolar trials, there can be like a pretty high rate of different background or CNS side effects, even on placebo in these studies, like things like agitation or anxiety. So maybe from your perspective, like how do you look at safety data for a new agent in a bipolar mania study. What is kind of 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. So going back to the earlier comments that were made, and I think we're also reinforced by Dr. Sacs and Dr. Ton 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'll just add, I have no priority expectations regarding adverse events in the bipolar mania study, except we will observe events that are related to bipolar media symptoms themselves. And I say that because it's 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've washed out in all their other background medications. In our clinical study, when a physician wanted to use a rescue benzodiazepine had to disclose an AE. And oftentimes, that AE is going to be related to 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. So we will have a higher incidence across the study of bipolar-related symptoms, but I have no our prior expectations regarding any other types of adverse events with RAP-219.

Gary. Yes, I'll add a couple of little pieces. One is acute mania in that initial phase of treatment for hospitalized patients. They are surprisingly tolerant of adverse effects, right, very different kind of thing than, let's 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 deal. So that's an interesting thing. And 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'm going to bet that the rapid titration arm is no different than the slower arm. That would be my expectation. And then going forward, what you typically see is that whatever the adverse effects might be, remember, bipolar lifetime condition patients become tolerant to some of the symptoms more than others. And as long as we're not seeing impacts on cognition, sedation and weight gain, the possibility of staying on the drug becomes a lot higher. And that's something that, over time, again, I expect to be a major advantage here.