Rapport Therapeutics Inc Stock

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 Bredt. 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 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 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 AMPA receptors are distributed widely in the central nervous system, TARP gamma-8 is selectively expressed in 4 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 3 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 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 mentioned, I'm at the University of New Mexico, and I've been -- I call myself a student, and 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 work for a number of pharmaceutical companies, advising on research design. And at some point, I was an industry scientist, 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. 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 and 20% are completed. In terms of the attempts, it's -- there is usually a family history, more common in females of young age when they're in a depressive polarity and frequently suffering from comorbidities, that's other conditions, other psychiatric conditions or substance use disorders. In terms of completed suicide, more common in males. Again, attempts are 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 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, 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 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 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 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 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 Diagnostic and Statistical Manual, now #5. And to diagnose 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. Those -- 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 conditions. 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 utero, trauma actually leads to -- also it's a factor that can lead to mania. Abuse, especially during 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, 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 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. Valproic 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 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. And then you have the typical antipsychotic agents, chlorpromazine that started in the 1950s and haloperidol actually effective, both available 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 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 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 alone 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, Mauricio, has given 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 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 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 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. And then I think, as Mauricio emphasized to you, 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 [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. And 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. 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 ward, the BMI of the patients who came in the ward 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 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 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. And that's what the kappa is. And what you see is that the agreement between 2 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-IV, the green bars are showing where both the rating systems agreed 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 rater, 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 to favor more specific diagnosis, enrich your trial with a sample that really has the disorder that you want to treat, right? That [is key]. 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 of onset, typical course of illness, family history and response to treatment.

These were other dimensions of illness that Kraepelin and Robins and Guze 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 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'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 YMRS 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 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. 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 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. 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 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. And then again, if somebody is 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 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/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 screen, 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 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'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 zero 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 Rapport 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 and 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, 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 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 and 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 next time you go first.

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 underutilize the long-acting, in this case intramuscular. 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 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? And as Gary mentioned, all treatments in similar drugs have been positive unless there is 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. 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. And 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. 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 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. And 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. 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 John 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 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 committee 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 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. 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, Abe 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 mania is about.

If I can add a point. This is a great example of the value of board -- of the monitoring board. Of course, it's unblinded. And 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. 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 patients will -- if the impulsivity arises, things can -- they can be -- something can be done about it.

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 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. And we also confirmed the diagnosis with measures such as the SCID-5-CT and using something, a scale that Dr. Sachs created called the Bipolarity 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 this time. 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 efforts 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, there are side effects, actually, and the reason why there is no adherence with most medications because of the side effects. So there's a big unmet need, better medications, better tolerated, so the patients can continue their medication.

And let me emphasize again the importance of the long lasting. The majority of patients with -- that are treated with mania initially, they improve, but later on, they'll stop the medication and -- because 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 patients' 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 AEs or neuropsych AEs 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 concerting -- 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. 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'll 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. 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 washed out of 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 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 a priori 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 do. 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.

It's an interesting question. Do we expect the same side effects in different conditions? And something that has been observed is that when patients have a certain condition and they take in 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. And as Gary mentioned, all of these patients at least had one previous episode. So they would tend to focus on symptoms that they've experienced before, like restlessness that is called like akathisia and so on. But the important thing of this design is it has a placebo control. So 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 and also in terms of the two -- symptoms that are side effects that appear in more than 2%. So those are going to be important findings. But I would pay attention to the medications that they've been on before, but it is an interesting question.

That's what's nice about a Phase II study. It's a learning kind of experience, yes.

Our next question comes from Jason Butler at Citizens.

Wondering if the two KOLs can maybe speak to the point of what is the historical -- historically, the predictive value of positive Phase II trials been in bipolar mania? And in other words, if this trial is positive, what would your confidence that, that would translate into a positive Phase III program? And 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 -- is improved with the long-acting injectable, both in terms of a likelihood of patient stays on therapy as well as how long they stay on therapy, with a long-acting injectable versus an oral daily?

Yes. So as mentioned, the fact that it improves mania does not necessarily mean that it's going to prevent mania. There's 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. So again, in most cases, if it works in the acute, it works on the maintenance. But there's another aspect is that the tolerability -- and so if you have full tolerability that you might not experience right away in the acute phase might be present in the maintenance space. 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. And there's another actually even better example, haloperidol, old drug in the -- developed in the 80s. In fact, it's one of the most widely used drug in this, in psych emergency. It has a good response, not great tolerability, but the problem is that it causes depression. So it's 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?

So I think you started, Jason, with what's the predictive value of a positive Phase II trial in acute mania. And 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.

Our next question comes from Kambiz Yazdi at BTIG.

Question for the company and then the question for Dr. Sachs and Dr. Tohen. For the company, the trial evaluates two titration schemes, a 2- and 4-day ramp for RAP-219. How should we think about the kinetics of effect there? And then for Dr. Sachs and Dr. Tohen, I guess, in your view, how do you view intertrial variability and comparability of YMRS. Are there any aspects of manic syndrome that it fails to capture?

Great. Jeff, do you want to take the first on the PK/RO perspective for the two dose titrations?

Yes. Thanks, Kambiz, for the questions. In terms of kinetics of effect, we -- based on the epilepsy animal model, we've pegged 50% or greater receptor occupancy as critical for efficacy. And that's been proven in our FOS study because we saw a terrific pharmacological effect, particularly with respect to decrease in long episodes after 1 or 2 doses of 0.75 milligrams, which is less than the 50% receptor occupancy. So 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 started at 0.25 milligrams for 1 day, then 0.5 milligrams for 1 day and then the target 0.75 milligrams for the remainder of the 3 weeks. And in the slower titration it's 0.25 milligrams for 2 days and 0.5 milligrams for 2 days and then 0.75 milligrams for the remainder of the 3 weeks. So the difference is really only 2 days. So in terms of onset of efficacy, and 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 2 days.

I would say that's not so important, at least for our primary endpoint in the study, though because that is at week 3. So we would not predict there would be any difference in outcomes at week 3 using those different titration schemes. Important to point out and 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. But at week 3, they will be pooled. And again, at week 3, we wouldn't expect there to be any difference clinically using either titration regimen. The receptor occupancy by 3 weeks is virtually the same independent of which titration the patient was on.

I think there was -- sorry, Tara, I think there was one question Kambiz had on the back end. And that was more on YMRS. Kambiz, maybe you could just repeat your question just so we have that clear for Dr. Tohen and Dr. Sachs.

Happy to, in your view, Dr. Sachs and Dr. Tohen, how do you view intertrial variability and comparability of YMRS. Are there aspects of the manic syndrome that it kind of systematically fails to capture?

Yes, I'll start with that first, because just last week in Philadelphia ISCTM, International Society for CNS Clinical Trial Methodology, had a session that was devoted to this question. And 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. But that said, there is concern that at the lower end of severity, it doesn't do a great job. But for acute mania, that's where it was strongest and again, that's the indication under study here.

So in terms of the various symptom domains, some of the items perform a lot better than others. So 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. And therefore, some of the items like that one will not be very informative. But overall, the domains on the YMRS performed quite well.

If I can add, yes, the YMRS is over half a century old, I think, 1970, it was published. And 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 are studying anxiety, you're using an anxiety disorder scale. What YMRS does not have is symptoms of depression. So in every single study from the ones that have 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 for that matter, the depression tools have been used. And as mentioned, the majority of cases have mixed symptoms actually in the 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.

And Tara, I believe we are at time. So I don't know if there's any other questions in the queue, we might be able to squeeze one more in, but...

Yes. We have one more from Myles Minter at William Blair.

Just a couple on mechanism as it relates to bipolar that I've been getting. One, I know that valproate, of course, is obviously used in mania considerably. That drug, I believe, is known to boost GABA levels and AMPA receptor inhibition, might do the opposite. So just the rationale behind RAP-219, and if there's any risk associated with the mechanism and showing efficacy. And 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, there's a 3-week study. You screen out depression patients here. So it's 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?

Yes. So maybe I'll have Jeff address the first question on the mechanism, and I'm sure Dr. Sachs and Dr. Tohen might have a perspective as well. I mean, what we know as I just tee up Jeff here is we know that the approved antiseizure 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. And then I think Dr. Tohen also pointed out, or it was Dr. Sachs or Dr. Tohen, I'm sorry, if -- I can't remember exactly which one, around kind of 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 kind of walk through maybe the mechanistic rationale, but on a higher order, how we think about the role of glutamate as well as the corticolimbic network.

Yes. 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, biological underpinnings of most psychiatric disorders is -- probably virtually all of them is not well known, and they're probably multifactorial. That's definitely the 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 that I believe are reasonably well understood and accepted.

And the first really starts with the understanding that bipolar mania specifically, is a disease or condition of excess glutamate activity. It may be also other things, but that's in part and parcel of the disease. And that's really where the biological rationale starts. So if it's related to glutamate transmission, glutamate mediates its effect to mostly the excitatory effects to the AMPA receptor and that's key here because TARP gamma-8 is, I think it was an amplifier of the AMPA or the glutamate-AMPA combination and RAP-219 inhibits that interaction. So we are targeting the right pathway.

And of course, the second really important piece here is are we targeting the right part of the brain. And the answer here, we can definitely say is, yes. It's been shown that the areas of the brain affected in mania, specifically bipolar mania are the mesial temporal lobes in the amygdala area and the frontal lobes. And in particular, there's a cortical network called the cortical -- there's a network called the corticolimbic network that seems to be particularly affected. And 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. So 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 the illness. It is very common for patients to go directly from a manic episode to a depressive phase. And so that kind of post mania depression is something the field has known about for a while. And again, as Mauricio told us, haloperidol produces more of that than would be expected otherwise, right? That's why we have a placebo comparison here.

It's possible, and 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'll be able to make a determination there.

I would just add is that's why we need to do studies. We have the basic science concepts that we are hoping are going to be accurate and that's what it indicates. But the studies need to be done and show empirically that we -- that our hypothesis was correct.

Another interesting point is also that not all antiseizure medications have been effective in mood disorders. In fact, most have not. It's been only a few and the interesting thing is that, again, the lamotrigine prevents depression, and that's basically it. While, on the other hand, valproate only improves mania. So it's -- again, the empirical studies are needed. And we hope that our basic science hypothesis are correct.

Let me add a coda to that point. It's important to understand that RAP-219 inhibits this pathway, but the inhibition is at maximum between 30% and 40%. So it's not turning the pathway off, this glutamate AMPA pathway. It's inhibiting a maximally 30% to 40% overall.

Tara, I think we probably have one -- 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. So do you consider anti-seizure medications as a distinct class of agents for treating acute mania? And given the MOA of RAP-219, do you consider this drug to be a part of that group? Or could we expect a meaningfully different profile?

Yes. 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. When you look at the distinct mechanism of RAP-219, the fact that, one, it is a novel MOA that would be introduced for this indication. And two, it's 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. And 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 impairments that we know traditional antiseizure 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.

Yes. I'll just say that I think terms like antiseizure, anticonvulsant, antidepressant. These are more marketing terms. And as Abe, I think, rightly emphasizes it's the mechanism of action. We're 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.

Yes. And 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 that we should also think about tolerability because the majority of -- when patients stop their medication, well, sometimes because they're having no symptoms. But many times, it has to do with side effects and side effects that many times, us, prescribers, providers think are minor a little bit of sedation, maybe side effects but for the side effects of sexual nature. For patients, these are very important. They cannot function if they're 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.

Good afternoon, everyone. Thank you so much for joining us. Really pleased to have with us the Rapport team. With me, I have Abe Ceesay, Chief Executive Officer; and Troy Ignelzi, Chief Financial Officer.

To start here, Abe, Rapport is about to initiate its first pivotal program following positive proof-of-concept data in focal onset epilepsy. In this context, can you lay out the company's key priorities and catalysts over the next 12 to 18 months?

Sure. So thank you, Salveen, for having us here today. So as a reminder, we released our Phase II data in September of '25, and it was phenomenal data. We are very encouraged by that data with RAP-219 in focal onset seizures. That data was really marked by what we saw was pretty much unprecedented results in terms of seizure reduction, roughly a 78% median reduction in seizure frequency. That data puts us in a great position where we're now actively enrolling our Phase III studies. So we're able to really accelerate the start of those studies.

In addition to that, we are currently wrapping up our Phase II study in bipolar mania also with RAP-219, and we have brought-in the guidance for the readout of that trial from the first half of '27 into the fourth quarter of this year. And then as we think about really furthering kind of the clinical utility of RAP-219, we're also moving forward into primary generalized tonic-clonic seizures, which is the next largest form of seizures next to focal onset seizures. That trial will start in the first -- in '27. And then we're also looking to expand the profile of RAP-219 with a long-acting injectable. We're currently in IND-enabling activities for that program and look to initiate that PK study in '27 as well.

With regard to the Phase III program epilepsy here in focal onset seizures, can you provide an update on the current status of site activation and patient screening for the program?

Yes. So we are currently activating sites as we speak. This is a large global trial that is across many continents. And the site is a rolling -- the study is a rolling site activation. So we'll be continuing to bring sites on-board over the coming months. We're also currently enrolling patients. So we feel really good about what we see thus far.

Now as I mentioned, these are large trials. They're global trials. And what we've seen in terms of other sponsors is that there's really two ends of the spectrum. One, in the Xenon program that took a long time to enroll, but ultimately, they did a great job with their program. And then we've seen some other sponsors that are on kind of the shorter end of the spectrum. As we've kind of laid-out our program in terms of overall enrollment, we think we can deliver data faster than Xenon. But quite frankly, we don't want to be on that short side because we think that really could impact trial quality.

One other thing maybe to add to that, we did sign a partnership with Tenacia. Tenacia is the [ main ] company that focuses specifically on CNS in China. They have rights to commercialization in China, but they'll also be part of our global Phase III patient accumulation. So we think that's going to help us as well with the overall recruitment time [Audio Gap] this trial executed efficiently, but with the quality that they referred to.

And what percentage of your overall trial size will come out of the China site?

Yes. We haven't guided to that. We think it's going to be kind of an appreciable percentage of overall patients, but we haven't guided to that. And quite frankly, we'll be really kind of monitoring trial quality across all of our sites. So that will be a key aspect of seeing what the overall total patient volume is coming from sites in China.

And that will be fine in terms of a regulatory pathway with...

Yes, we do. We think it's going to be fine. I think it's been somewhat overlooked or underappreciated that these focal onset seizure trials are global. You're going to far-reaching countries in Eastern Europe, as an example. So the FDA has been very open to making sure that they understand that these data are being accumulated across many countries, and we don't see any issues with one of those countries being China.

Given the Phase IIa data shared in September demonstrated about a 78% reduction in clinical seizures and a 24% seizure freedom rate. How do these metrics inform your confidence in the powering of the registrational Phase III trial?

Yes. I'll talk about it in two aspects exactly how you framed it. One is confidence and then talk a little bit about the power of a study because I think those are two interrelated, yet separate concepts.

In terms of confidence, it gave us a lot of confidence going into Phase III in two regards. First is if you just look at the base study, as you mentioned, we had a 78.7% reduction in clinical seizure frequency. But what was really important in our study is we also had an objective biomarker that really corroborates that [indiscernible]. So when we look at that data, coupled with a 24% seizure freedom rate, which is really one of the highest levels of seizure freedom that has been seen in recent trials and also is really not impacted by a placebo rate. That gave us a lot of confidence, again, corroborated by that objective biomarker that we could replicate and really see those types of results in Phase III. The second aspect that we were really bullish about is what we saw in our AAN release, which was the 8-week washout period that was part of our trial. So it was an 8-week treatment period and an 8-week washout period. And what we now understand about RAP-219 is it has a 22-day half-life. So in that washout period, although patients were off drug, there were still therapeutic concentrations of drug on board, and we saw that seizure reduction go from that roughly 80% range up to a 90% reduction in clinical seizure frequency.

And when you look at what a Phase III trial, the endpoints are at 12-weeks. So now we see even further deepening of a response. So we feel really confident going into Phase III.

Now that doesn't exactly translate into the powering of a study because when you think about powering of the study, you want to be conservative. So we have taken kind of that traditional powering of other programs into the study. But the other reason for that is when you think about an indication like focal onset seizures, there is a level of safety exposures that you need to accumulate. So by being a little bit more conservative on the powering, that ensures a higher probability of success, but it will also allow us to accumulate those safety exposures that are going to be required for registration.

One thing to add on the probability of success because there's been discussion about it recently. Over the last 50 years, 9 out of every 10 drugs that had good Phase II data, robust Phase II data also had robust Phase III data. So it's a very predictable therapeutic area to begin with, but adding the patients on, we think, even adds more credibility to the opportunity for Rapport.

What generally happens to the 1 out of 10 that doesn't make it -- that doesn't translate...

Yes. The ones that -- there's really been about 3. And those are -- it's pretty clear. One is when you look at their Phase II results, they have not been definitive in terms of a very clear efficacy signal. That has been really kind of the major outlier.

Got it. Given the Phase II study was conducted in a highly refractory population with an implanted RNS device, speak to your confidence or just your view on the ability of this data to translate to a broader FOS population in the Phase III?

Yes. So when you look at the demographics of the patients that were enrolled in our study, really the only difference is that they had this RNS device. When you look at their demographics outside of that, they look like a typical focal onset seizure patient. If anything, these patients were probably a little bit more refractory. In our study, 70% of patients were on 3 to 4 antiseizure medications, that is in addition to the device. So you can really think about them being on 4 to 5 treatments for their epilepsy. So we think it was a highly refractory patient population where we saw these very robust results. So we think that they will translate well, again, because we're seeing all of the seizure reduction that is corroborated by that biomarker.

The other question we get around this patient population is that this patient population in terms of where their foci was for their seizure onset zone was in the mesial temporal lobe that they had to have that confirmed and defined. But the reality is that's representative of the entire FOS patient population. The majority of patients have their foci in the mesial temporal lobe. If they don't, the majority of the seizures outside of that are starting in the neocortex. That's exactly where TARP-gamma-8, the target of RAP-219 is expressed. So we think that the representation in the broader FOS population will definitely be there.

And what additional insights do you expect to glean from the open-label extension data in the fourth quarter, particularly around durability and dose optimization?

Yes. So all patients that were in the 211 study, completers had the opportunity to roll-over into an open-label extension study. One of the important aspects here is to just think about the nature of this study. We were working on some long-term tox data to enable the open-label extension study. The importance of that is that patients weren't able to roll directly into the open-label extension study. So the first in the Phase II study, there was an 8-week treatment period, an 8-week washout period where they were washed-out of drug. And then they had a gap of time before they were able to roll into the open-label extension. So from an efficacy standpoint, they are re-baseline. We will be measuring efficacy but we won't be able to make the comparison back to the baseline data from the Phase II treatment period.

It just won't be -- you just can't really do that in a very clean way because of that gap in time. So we will measure efficacy, but primarily, we're looking at the study for safety reasons. And that's usually the most important aspect, especially in epilepsy to really understand kind of long-term safety exposure as you think about open-label extension. And we're actively enrolling that study. We're really encouraged with what we're seeing in terms of the available patients and those patients rolling into the open-label extension study. We'll release that data or the first cut of that data in the fourth quarter of this year. And we think in the range of kind of 3 to 6-months exposure is what we're going to be able to evaluate.

And given the open-label nature of the Phase IIa, talk to how you're managing for placebo response in the Phase III?

Yes. So one of the things in the Phase II study is that, yes, it was open label, but we think that this washout period from this study really helps clarify the -- any potential perceived placebo effect because remember, these patients were washed off drug. They had no idea what the half-life of the drug was. And if one were to believe in a placebo effect in this study, what you would see is a really rapid return to baseline in the patients in the Phase II study. We didn't see that. We didn't see that because there was still drug on board given the 22-day half-life.

And then when you really follow those patients for that second, 8-weeks, what you do see is this really nice PK to PD relationship. So as concentrations are starting to wear off, you are starting to see the return of both the electrographic biomarker and long episodes as well as clinical seizures. So we feel that -- confident in the results that we saw in Phase II. Now for Phase III, when you're really thinking about managing placebo, there are a couple of things that you want to do from a clinical trial conduct standpoint and a protocol standpoint. One is you really want to make sure that the patients you're enrolling really are focal onset patients and have a really well-defined baseline. So we are doing, we think, the right things there to ensure that we're capturing the right patients, adjudicating the right patients and the right patients are enrolling in the study.

And then the second aspect is really seizure capture throughout the study. And that really comes down to the e-diaries and really making sure that patients are trained really well on how to capture their seizures. And these are really the things that we believe were done by Xenon as well, and we also employ the work of the epilepsy study consortium to really help us along that path as well.

One other thing to point back to on the Phase II was the seizure freedom rate. That gives us a lot of confidence in the path forward too because regardless of placebo, you don't see that significant of a reduction in seizure freedom in -- even in the placebo arm ever. It's usually around 2%, and we were at 25%. We're at 20% at 12-weeks, and that was with 8-weeks on drug and 4-weeks without the drug being administered. So the seizure freedom rate is also a pretty directional piece of data.

You recently revised the estimated half-life of the drug from 14 days to 22 days. So in that context and the long-acting injectable, just touch on the clinical and strategic rationale for developing a long-acting injectable and what we should expect to learn from the human PK data next year?

So first is there's never been a long-acting injectable for epilepsy patients, and when we talk to the community, the feedback that we get from the community and the words that we hear are transformational for patients. Patients living with various forms of epilepsy, both for the patient, their caregivers as well as the clinician, one of the biggest concerns is about missing a dose because many antiseizure medications have very short half-lives. You miss a dose and you have the risk of a breakthrough seizure, which has high morbidity, but in some cases, actually mortality. So one of the reasons we're looking forward to this long-acting injectable and the primary reason is we think it could be transformational for patients.

Then when you look at the value side of the equation, we think that it could completely change the way that RAP-219 is looked at as an asset in the market. The first is to access a long-acting injectable, you first step through an oral therapy. So we think that, that will ultimately drive uptake of the oral formulation of RAP-219 in order for patients to be able to access that long-acting injectable formulation. The second piece is what it does for the terminal value of the asset. So what we see is the potential to extend the IP runway pretty significantly into the late 2040s with the first formulation, and any formulation we do beyond that would be additive. So when you think about a program that has a multibillion-dollar sales potential and you're able to extend that for potentially another decade in terms of IP runway, that really changes the terminal value of the program as well.

And how does it play out in a patient if the patient becomes refractory to the drug?

Yes. So that's the strategy when you look at an LAI formulation and how it's introduced. The first thing that the clinician would most likely do is start the patient on an oral formulation. So they would want that, a good probably month or so under their belt to ensure that the patient is getting -- driving efficacy from the therapy, but also able to tolerate it. So moving into an LAI, you would want to be confident that really all I'm switching is the formulation, and I've already confirmed that the patient is achieving efficacy and can tolerate the drug, and that's usually the way the LAIs are introduced. Not only are they introduced that way in clinical practice, but they're also often delayed in terms of their introduction to the market. So roughly anywhere from 2 to 4 years after the launch of the oral formulation is when you're going to see an LAI introduced to the market.

And can you speak to the regulatory strategy, both in the U.S. and globally?

Yes. So the first step for us from a [indiscernible] standpoint is really confirm PK, and that's the data that we'll have in '27. [indiscernible] information, we'll have some discussions with the FDA around how to move this program forward. So we don't have yet an understanding on do we just need to do a bridging type of study or would we need to do a full efficacy study with LAI. You've seen approaches across both paths, and we'll just have to have that dialogue with the FDA once we have some PK results.

Got it. We're going to see top line Phase II bipolar mania data in the fourth quarter. Just help us understand the bar for success here?

Yes. So there's reasons to believe in RAP-219 in bipolar. Inherently, it is a more challenging indication in terms of preclinical to clinical translation than epilepsy. But it's one based on a whole host of reasons thinking about the role of glutamate in bipolar, really the areas of the brain that one believes is really a culprit in terms of the excitability in bipolar mania and then analogs of other ASMs that have been shown to be effective in bipolar mania. When you look at results in bipolar mania trials and you look at both antipsychotics as well as antiseizure medications, what you see is a range of anywhere from a 4-point to a 6-point improvement in the YMRS on a placebo-adjusted basis. So we've powered the study to detect a 4-point change.

What's important here is when you look at the efficacy is to look at the totality of the profile in bipolar mania. The reality is even if you achieve, say, a 6-point placebo-adjusted difference in the YMRS, the primary endpoint, the reality of those therapies is that many of those therapies are not well tolerated. So you think about antipsychotics as an example, they're sedating, extrapyramidal symptoms, weight gain. What all that leads to is patients have a very low adherence. So we think we have the ability to not only deliver that efficacy, but also carry forward the tolerability profile that we saw in epilepsy, which is non-sedating, no impact on gait as well as no weight gain, which we -- and non-dopaminergic, which we think would be a highly differentiated profile.

How much risk do you think there is in terms of this indication playing out via the data?

Yes. As I said, it is a lower probability of success indication. And at the same time, we look at the value of the company right now, and we don't think that there's a lot of value built-in, in bipolar as well. So we see that it could be significant upside for the asset and for the company overall. The reality is if we saw a positive result in bipolar, we're talking about multibillion-dollar market opportunity, not only in epilepsy, but an additional multibillion-dollar opportunity in bipolar. But as I said, it's a lower probability of success indication just given the fact that there is not a lot of preclinical to clinical translation that exists in bipolar.

Great. And you also talked about your other programs here, maybe walk us through the strategy with the rest of the pipeline.

Sure. So we built this company to really be a fully integrated leading precision neuroscience company. And as part of the founding of the company was to really apply receptor-associated protein science across other ion channels and other areas where our discovery team really believed that by getting to either subunits or specific receptor-associated proteins, we ultimately can drive efficacy while dialing out tolerability.

So our first approach there beyond RAP-219 and targeting the AMPA receptor and TARP-gamma-8 being the receptor-associated protein was to look at nicotinic receptors and specifically look at a nicotinic receptor that has some history as well as a level of genetic as well as clinical validation for being a really interesting target for pain, and that is the alpha 6 receptor, nicotinic receptor. There was a historic program here, one that showed a lot of promise, but unfortunately, given the fact that it was a pan-nicotinic agonist really has some tolerability liabilities.

What we believe through receptor-associated protein science, we've been able to identify the subunit that is really driving analgesia, and that is our alpha-6 beta-4 program. That program is currently in IND-enabling activities, and based on that, we should be in the clinic next year.

We also have another nicotinic program, alpha-9 alpha-10 that is targeting vestibular disorders. And what I can say is we're actively working on several other programs that we continue to make some progress on. And as those programs progress, we think we're going to be in a great position to bring those into the clinic as well.

Troy, remind us of your current cash runway here and how you plan to prioritize capital allocation between the Phase III FOS trials and then the primary generalized tonic-clonic seizure study that's planned to start in the first half of next year?

Yes. We've got enough cash to get into the second half of 2029. And while we haven't given guidance externally on our time line for the FOS Phase III program, we think it's sufficient to get to the end of that trial. Also in that period, as you mentioned, we will start the PGTCS next year, but we'll have the Bipolar Mania trial that we'll read out, and we'll also have the long-acting injectable Phase I PK results that we think provide opportunities for catalysts for the company along the way.

And what is the read-through from FOS mechanistically to PGTCS?

Yes. So we think that the translation is high. One is the robust results that we saw in the FOS trial and the level of seizure reduction that we're able to see. The second is when you think about, again, the expression of TARP-gamma8, although primary generalized tonic-clonic seizures generalize in nature, i.e., the name, the origination point and the propagation point overlaps really nice with where TARP-gamma-8 is expressed. So we think that the anatomy is right, the target is right, and then there are models that are pretty informative of primary generalized tonic-clonic seizures, one of them being the PTZ model, which we saw really robust results with RAP-219 and other gamma-8 TARP compounds.

Great. Maybe a last question here, one on commercialization. So we've seen cases where we've had really good clinical data, but the market opportunity hasn't played-out commercially. I guess, help us understand what's played out with some of these companies, but how you ensure that you have this nice read-through here to your peak sales opportunity or your actual resulting peak sales?

I think there's a couple of things to think about here. First is to really ground on what the market is looking for, for a novel antiseizure medication. The first is a novel MOA. That's first and foremost. This is a treatment paradigm of polypharmacy. So when clinicians look to add on a new antiseizure medication into polypharmacy, they want a novel mechanism of action, one that can provide that additive efficacy. The second is they want a drug that is well tolerated and most importantly, a drug that is not going to exacerbate the most bothersome adverse events that are associated with the ASMs that they're on, primarily sedation as well as gait impairment. And then the last is a compound that can be broadly utilized. So one that doesn't have drug-drug interactions, has a pretty straightforward dosing and administration profile.

And why that's most important is because having that type of profile allows not only the epileptologist to be comfortable using it, but most importantly, the general neurologist. Without that profile [indiscernible] not get the patient exposures [indiscernible] that it's going to make you a multibillion-dollar asset. And that's where you look at a drug like Xcopri as an example, that had really strong efficacy results. But when you look at the rest of the profile, tolerability, dosing administration, what you see with Xcopri is it's really only being used by the epileptologist. It's still on track to be a $1 billion drug. But the challenge for that drug will always be if you don't have general neurologist utilization, your ability to get to multibillion-dollar utilization is just challenging.

We just completed a set of market research with over 100 epileptologist and neurologists. In that market research, we had our TPP, we have the Xenon TPP, and we were really encouraged with what we saw.

First, we saw that RAP-219, both in the context of currently available ASMs as well as novel ASMs was seen as a best-in-class profile. We saw broad utilization and a desire for broad utilization across general neurologists as well as epileptologist, and really interestingly, we saw a desire to use RAP-219 as early as first line. That's really unheard of for a novel agent in terms of epilepsy and antiseizure medications. Now we don't believe we're going to see first-line utilization because patients will step through generics, but seeing second-line utilization just completely change the trajectory of what we could see in overall utilization and top line sales.

Great. With that, thank you so much. Really appreciate the time today.

Thank you.

Thank you, Salveen. Appreciate it.

Great. Good morning, everybody. Happy to be here, moderating this panel with Abe Ceesay, CEO of Rapport Therapeutics. I'm sure most folks know Rapport well, a company focused on developing RAP-219 and epilepsy a number of other indications.

But maybe without doing too much background Abe, you could just sort of set the stage on where the company is at. And I think it would be good too, to set the stage on the 219 pivotal program in epilepsy and where things are going there. So I'll let you take it away. Thank you.

Sure. Thanks, Paul, and good morning, everyone. I appreciate the opportunity. So 2025 was truly a foundational and transformational year for us at Rapport. As Paul alluded to, we had our Phase II data readout for RAP-219, our lead program, which is a TARP gamma-8 AMPAR modulator program. We have -- we see as potentially best-in-class data in focal onset seizures, which put us in a position coming into 2026 to really move several things forward.

First and most importantly is our pivotal program. So we are going to be initiating two parallel Phase III studies starting in the second quarter of this year. We are able to expedite that time line. We had originally guided to the third quarter initiation. But given what we saw as a very efficient end of Phase II meeting with the FDA in December, it put us in a position to really accelerate those time lines and initiate those programs in the second quarter.

In addition to that, we're currently executing our Phase II study with RAP-219 and Bipolar mania. We expect data from that study in the first half of '27. We're currently really pleased with the enrollment of seeing in that study. And we think middle of this year, we'll be in a better place to really tighten those time lines in terms of overall guidance on when that data will come in.

In addition to that, we continue to progress our long-acting injectable program, which I'm sure we'll talk about, Paul, which we think will be transformational for this asset and also move forward some of our discovery programs, most notably our nicotinic program, our alpha 6 beta 4 program, which was a program that was really foundational to the founding of the company. We were just doing the necessary work through discovery, but we feel like we have a really interesting program in areas of both chronic pain as well as migraine.

Good stuff. Troy did ping me and say he's on here as well, but we can see them. Troy, are you doing I couldn't see you before, but it's good to see you, too. So thank you for joining. Really appreciate it.

I'm blending into the back.

It's all good, man. Yes. All right. Great. So I think from a time line's perspective, that's one question I get a lot, and I think people -- obviously, the Street, I think, appreciates that maybe the Xenon data recently was worth a wait and that, that was a really well-run study, but that study took a long time to conduct. I think when the Phase II read out, that might have been 5 years ago, right? So how do you guys think about executing a high-quality Phase III FOS program, but also trying to move quickly?

Yes. And I would like to congratulate the Xenon team on the data and also the execution of the study. I can remember when that study started. At that time, I was with Cerevel and we were also running a program in refractory focal onset seizures. And I can tell you, at the start of those studies, it was one of the hardest times to broaden these studies, these Phase III studies.

And I think that's an important point because it will reflect back on why we think we efficiently. So at the time of Xenon, as well as us at Cerevel with Darigabat running those studies, it was an extremely competitive time. You had [ core ] ramping up. You had several studies ramping up. And then you also have the COVID dynamic, as well as the Ukraine war dynamic that was really impacting the enrollment of these studies.

One shouldn't forget that many of these studies are global in nature. There's many Eastern European sites, and those sites were really disrupted by the Ukraine war. So when we think about our program with RAP-219, we do believe we're in a position to do it a bit more efficiently. And there's two ends of the pole here. There's the Xenon end of the pole in terms of timing. And then as you look at some other sponsors such as Praxis and Biohaven, there's another end of the pole, which they've guided to much more efficient time lines.

What we continue to say internally is we don't want to be on either end of that pole, quite frankly. We want to balance quality, which we think we could do, but also building efficiency. And we think there's a few things that we've done that will put us in really good shape to do that.

The first is just the overall excitement around our study in the market. The community is very excited about this study, the novel MOA and the opportunity for RAP-219. So we think that, that excitement with sites will drive pretty efficient enrollment. The second aspect is as you think about these studies, we have to think about what is the top of the funnel look like in your program. I think this often misunderstood as people think about these studies. If you have a study that has a competing MOA in -- as an example, if you look at Biohaven and Xenon, they're competing for the same patients, they can be in the same trial in two Kv7 agents.

If you have a redundant MOA with currently marketed drugs, that's going to limit your -- the top of the funnel in terms of what MOAs and what medications, background medications patients can be on. If you have drug-drug interactions, it causes you to have to limit the number of therapies that patients may be on or what types of therapies they're on. As you look at RAP-219, we feel like we're in an ideal position. The drug does not have drug-drug interactions. We don't have overlapping mechanisms of action, except for perampanel, but we know perampanel is not widely used. So we think the top of the funnel is going to be pretty wide open for us.

The last aspect is we've been very thoughtful about how to enroll these trials from a global perspective. A couple of weeks ago, we announced a strategic collaboration with a company in China by the name of Tenacia. We were really thoughtful about that collaboration. What that collaboration does for us is, one, it has a partner in Tenacia that has the global commercialization rights for RAP-219 in China. But in terms of our development plan, we are actually an integrated development.

So as they work towards the Chinese FDA, and we work through the Chinese NDA and we work through the U.S. NDA, our studies are one of the same. So we have now opened up China as a country for enrollment into these studies in addition to the historic countries that have been utilized to enroll these trials. So we think it puts us in the ideal position to enroll two studies, but also to enroll those de novo exposures that you ultimately need and sometimes is a long tent in the pole as you think about ICH guidance for this indication. So we're not going to guide on time lines, but suffice it to say, at this point, we want to get a little bit more experience under our belt. But suffice it to say, we believe we can enroll these programs more efficient than Xenon did.

Yes. Yes. Okay. Makes sense. So I think most folks listening in know the RNS study readout well, the data were amazing way above expectations. The one question I still just get is how generalizable are those data to a Phase III, both in terms of the lack of placebo arm and this specific population. I'm not going to drive Troy crazy by asking the hippocampus electrode question, which I think he's named the poll question now. But you get what I'm saying, right? Amazing data, but it's a specific type of study, and it's going to be a different population to some degree in Phase III. How different in your mind?

Yes. And it's an appropriate question in terms of the translation from Phase II to Phase III. The question we have to answer for ourselves too, as we think about the design of the Phase III program. So as you think about the design of our Phase III program, this is a very traditional study as you were to look at all of the contemporary studies that are either ongoing or have recently wrapped up in refractory focal onset seizures.

When we think about the Phase II study in those results, we're very confident in the translation from Phase II to Phase III for a few reasons. One is, although there is not a placebo arm in our Phase II study was an open-label study. Quite frankly, we did the study because of the high translation that exists with the objective biomarker and making sure that the objective biomarker correlated well with clinical seizure reduction.

So when we look at that data and we see how tight that correlation is between long episodes, which in our study were electrographic seizures, 92% of the long episodes were electrographic seizures, and how we tightly correlated that was with the reduction of clinical seizures, that gives us a real confidence that the response we're seeing in clinical seizures is truly drug effect versus placebo effect. The second aspect is when you look at the demographics of this patient population that was enrolled in our Phase II study, demographically, these patients are refractory focal onset seizure patients. If you were to look at these patients outside of the RNS device, you would look at their demographics and that you would believe that these patients have the demographic and the baseline characteristics of patients that are enrolled in contemporary studies

These patients were on three to four medications. In addition to the device. So you could recall four to five medications when you include the device, the patients were had 10 clinical seizures at baseline. So if anything, we believe this is a harder-to-treat patient in terms of like the refractive status. So our ability to show real robust results in Phase III, we think that there's an opportunity to do that.

The other aspect that we are really encouraged by is the fact that from Xenon's Phase II data, the Phase III data, which I think was a real question in the market and with investors is can you maintain efficacy Phase II to Phase III has now been seen with the Xenon study. And when we look at our data, we believe that our data, again, with that objective biomarker in Phase II, we really believe in the results we saw. So we believe there's an opportunity to again translate that into Phase III.

What we're really also encouraged by from our data is you cannot not look at our data and appreciate the seizure freedom rate of 24%, a very conservative measurement of seizure freedom truly day 1 to 56, week 1 through 8, where we saw a 24% seizure freedom rate. And as you know, Paul, seizure freedom historically is not impacted by placebo. We're talking about 1 to 2 points of placebo change with seizure freedom. So we look at all of these pieces of data and feel, again, that the data is highly objective and will be translatable to Phase III.

Yes. Yes. Okay. Makes sense. you want to switch gears and talk a little bit about safety. One, just like how much you've kind of accumulated the safety database now? And two, like should we be basing the safety comparison of looking at Fycompa and kind of working backwards towards the AEs we think you can mitigate and avoid? Or is that the wrong way to kind of try to do this analysis and from an investor perspective, sort of think about like safety potential on the upside, but safety risk on the other side?

Yes. So we have -- we're in the hundreds now in terms of exposures to RAP-219. In our Phase I program, our traditional SAD/MAD, we had 100 subjects exposed and then obviously, 30 additional when the Phase II, those are patients and then we've had several Phase I pharmacology studies that have been done as well just as we kind of think about overall development. So we're well into the hundreds.

I think we're very confident in what we know about the pharmacology of RAP-219, both in terms of what AEs are on target. How those AEs show up and ultimately, how they resolve. So what we know about RAP-219 is the half-life is really important in the overall PK profile. Based on everything we know, AEs with this mechanism are definitely Cmax-driven versus Tmax driven. We've really learned that in our Phase I experience. And what we saw in our Phase II study, as you recall, is we saw no severe AEs in the treatment period.

All AEs were mild to moderate. And what we also know about those AEs is the vast majority of AEs are showing up early in the treatment and resolving on their own through the course of treatment. And that's really consistent with our Phase I study. So as we think about expectations moving into a larger Phase III study, there's a couple of things that I think are important to the space, and then there may be some things that are more specific to RAP-219. The first is you're never going to have a drug in refractory focal onset seizure patients. And I think Paul, you can appreciate this, that it's not going to have AEs, both neurological AEs as well as psychiatric AEs.

These patients are on multiple therapies background medications, part of their comorbidities based on their epilepsy or neurological disorders, as well as psychiatric disorders. And what you see even in the placebo group of Phase III studies is you're seeing neurological AEs as well as psychiatric AEs manifest. That is understood. So what we believe in terms of this mechanism is the real benefit is we don't believe we're going to see high levels of sedation that when you ask a patient or a clinician is one of the most bothersome AEs associated with current antiseizure medications.

The second aspect is we believe we're going to see lower rates of gait impairment, ataxia gait impairment, again, based on the biology and mechanism. What we get questions on is the perampanel comparison and the perampanel comparison primarily on psychiatric AEs in terms of aggression and rage. And there's two ways to look at that as well. The first is have we seen those AEs in our experience, on treatment with RAP-219? We have not seen that. We have not observed that with RAP-219.

The second aspect is when you think about this class of drugs, antiseizure medications and if you were to talk to clinicians, the most prevalent drug or the most -- the highest prevalence of psychiatric AEs, rage, and aggression is not with perampanel. It's actually with Keppra. So this is seen with other mechanisms. Now we don't believe we're going to see it with our drug. We believe that our drug is definitely different than perampanel, but we're going to obviously continue to capture all of that AE data through our Phase IIIs. What we can say is this is not an AE of special interest in terms of our Phase III development nor was it pointed out are brought up by the FDA in our Phase II and the Phase II conversations.

Right. Okay. Makes sense. Anything else to add on FOS and epilepsy? Or should we maybe talk about bipolar a little bit?

The only thing that I will add is our progress of a long-acting injectable formulation. What we have heard from the community is that this would be transformational for patients. Through our market research, we've learned the same thing. And we believe, based on everything we know about other antiseizure medications and really the characteristics of those compounds is we will be the only antiseizure medication that will be able to develop a long-acting injectable formulation.

We've nominated the development candidate for that formulation. We're currently in IND-enabling studies, and we think we'll have our first human PK data in 2027. What we've also really appreciated is when you think about the commercial opportunity around LAI, and you heard [ Bazena ] and folks talk about this, which I completely agree with, is there's definitely room for premium pricing in this space. We think that there's additional room with the addition of a long-acting injectable. And what that all boils up to is durable revenue.

When we think about a long-acting injectible formulation rather than a opposition of matter IP going from 2036 with PTE going to 2041, with our long-acting injectable formulation, we see with the first iteration, formulation IP going to the late 2040s. So when you think about a multibillion-dollar opportunity, that translates into an extra decade of durable revenue.

Great. No, that makes sense, Abe. Since you brought up the point on the pricing side, Xenon said on their call, right, they sort of alluded to this idea that core may have been underpriced. Is that your view as well?

It is. I think there's a lot of room for pricing. What we know about this space is that these are -- this is a protected class considered essential medicine with payers. So are you going to have step edits through or prior authorizations through generics, you are, but your drug is going to be covered. So definitely, we agree that there's room for additional pricing, more pricing elasticity in this space than what -- where the current [ scope ] repricing is.

Yes. Yes. Makes sense. Okay. As it relates to bipolar, I know the fact that, one, your drug works in epilepsy already gives you some base probability. you have the animal model data, but we know animal models, they're good, but they're not recapitulating the actual disease of bipolar. Those are two good points. Any other points you could kind of point to on just why this mechanism should or shouldn't work? Like is there anything we can leverage from Fycompa data or other or specific drugs that are like better analogs to this kind of mechanism? Or yes, maybe I'll let you take that.

Yes. So we think about kind of three pieces here. One is the biology. Two is the region of the brain that we think is most affected in bipolar. And then the third is when you think about precedent antiseizure medications that have been effective for bipolar, both in terms of median and mood stabilization.

From a biology standpoint, when you look at the literature, what is very clear with bipolar mania is it seems to be a disease driven by excessive glutamate. And specific that excessive glutamate seems to be contained in the corticolimbic circuit. So what we know about RAP-219 is, one, we are having pretty significant impacts on overall glutamate transmission, and that is through obviously antagonizing the AMPA target.

The second is from a corticolimbic standpoint, that is where the target is most enriched to. So we think right biology, right location of the brain. The third piece that gives us, I think, a lot of -- gave us really ultimately the conviction that we need to take this drug into this trial is when you look at both valproic acid as well as the lamotrigine, yes, they have multimodal effects in terms of how those drugs are effective for antiseizure medications.

But when you look specifically at bipolar, one of the areas that they affect is glutamate transmission. So that's another area where we've seen two effective antiseizure medications that are having an effect on glutamate, and that was really the conviction, again, tied to the biology and the brain location that really makes us believe that we have a shot here in bipolar. We're really excited about what we're seeing in the enrollment.

Ultimately, this is 100% going to be empirically driven based on the data, as you said, while there's not an animal model that anyone can point to say this is the bipolar animal model. but we're really excited with what we're seeing in the enrollment of the study.

I know the study is still ongoing, but you probably have at least some window into safety at a high level. We talked about the Fycompa dynamic in levetiracetam with like psychiatric AEs. I think we also saw some data from Neurocrine, right, showing that AMPA PAM was mood positive, right, in a different population. But I guess for the 219 mechanism from a safety perspective, like what's your level of comfort that the profile here is going to hold up and not be like more problematic in a bipolar population that might have like different things going on?

Yes. We say this internally all of the time, and we understand why we get the questions around perampanel. I think it should give the investor community, some level of understanding of how bullish we are on the safety profile given the fact that we're taking this drug into acutely manic patients. So if you're going to see a level of aggression or psychiatric AEs, this would be the patient population that you might observe it in.

But we've, again, always been really confident in what we understand about the pharmacology as well as the safety profile. So we have a standard data set safety monitoring board through this study. We evaluate blinded AEs as any well-controlled study would. And again, we continue to not see any major issues at all in our bipolar -- current bipolar study.

Okay. We only have a minute left guys. Anything else you'd like to highlight? And Troy, maybe you can chime in too and just talk about your guys' runway and ability to fund all the work that you're planning here?

Yes. We ended the year with $490 million, which we've indicated provides us capital into the second half of 2029, which allows us to complete the Phase III program for focal onset seizures. It will also allow us to complete the Phase II in bipolar mania. It will get us to Phase I PK results in the long-acting injectable. And we didn't talk about it, but we also have a discovery program around the alpha-6 beta4 subunit that we can complete Phase I work, again, also in next year. So we're very well funded to get through those milestones and excited about what we've got going on right now.

Okay. Great. All right. Well, thank you, guys. Appreciate it.

Thanks, Paul. Really appreciate it.

Hi, everyone, and thank you for joining us at our 2025 Fifth Annual Novel Mechanisms in Neuropsychiatry & Epilepsy Summit. I'm Joe Thome, one of the senior biotech analysts here on the team at TD Cowen. And it's my pleasure to have with us today the team from Rapport Therapeutics. We have Abe Ceesay, the CEO; and we have Troy Ignelzi, CFO of the company. So thanks, guys, for taking the time.

Maybe just to kick things off, obviously, impressive Phase II data readout last week that investors were looking for. Maybe at a topline, can you just briefly summarize, I guess, first, how this trial was conducted? And if you want to try and touch on the novel trial design and then maybe hit the high points of the efficacy that you saw and then you can kind of drill down into the details.

Sure. Happy to, Joe, and I really appreciate the opportunity to be here today and continue to share the story of Rapport, but also share the story on our most recent data.

I think prior to getting into kind of the trial design, just a couple of comments. One, just taking a really big step back. I mean, we are extremely excited about this data, most importantly for patients. This is a very large market, 1.8 million patients in the U.S., defined by the fact that 40% or roughly 560,000 patients continue to be treatment resistant. So these are patients that have been through multiple antiseizure medications, and continue to have breakthrough seizures, although the fact that they're currently treated.

When we think about the emerging profile with RAP-219, we see it as a best-in-class profile, one that we believe starts to translate into a multibillion-dollar market opportunity. And that's really defined by a novel MOA with RAP-219; two, efficacy that we think is really best-in-class from what we've seen from our proof-of-concept study, a drug that's generally well tolerated and consistent with precision biology.

And then finally, a drug that has a dosing and administration profile, once daily dosing, low to no risk of drug-drug interactions, long half-life to protect against breakthrough seizures. That ultimately, what we have heard feedback from the community starts to translate to a drug that will not only be used by epileptologists, but more importantly by general neurologists and internists, which really changes the trajectory that we think about for this program commercially.

In terms of the trial design, as you mentioned, we had a pretty unique trial design and an innovative trial design, one that was highly informed by the KOL community and the epilepsy community at large. This trial enrolled drug-resistant or treatment-resistant focal epilepsy patients. So from a demographic standpoint, these patients look very similar to your traditional treatment resistant focal onset seizure patients.

The difference is that these patients had an implantable RNS device. This is a neurostimulation device. What the neurostimulation device allows for in clinical trials is the ability to leverage an electrographic biomarker. That through our work as well as work that's done in the community and has been published, really correlates well to the reduction of clinical seizures. And that threshold was roughly a 30% reduction in long episodes or electrographic seizures, can predict a greater or at least or greater of 50% reduction in clinical seizures.

So the study enrolled these patients, what we're able to see in this study is very robust results. We are able to see a meaningful and statistically significant reduction in the primary endpoint of long episodes or electrographic seizures. We are also able to see a statistically significant and robust reduction in clinical seizures. Roughly 78% median reduction and then a 24% seizure freedom rate. And as I mentioned, we really believe that this starts to emerge as a best-in-class profile for an antiseizure medication.

Perfect. And maybe can you talk a little bit about the next steps for moving into a Phase III? And maybe specifically, how -- you alluded to it a little bit in the opening remarks, but how translatable is the patient population that you enrolled in the Phase II to some of the more "traditional" Phase III focal onset seizure studies that we've seen?

Yes. Maybe I'll start with your second question first and then move into our next steps. Because I think, the second question informs kind of the next steps. So one of the questions we've quite frankly, had enrolling this study is to ensure that the demographics were translatable. So when we saw this patient population and ultimately, the results that we believe that it was going to be translatable into registrational studies that ultimately improve the probability of success in registrational studies. We think we've really confirmed that in this study.

So specifically, when you look at this patient population that we enrolled, one could almost see this patient as more refractory than the traditional patient that they enrolled in Phase III trials. On average, our patients in this study were on three anti -- background antiseizure medications. Actually, 70% of the patients were on three or four background antiseizure medications. 37% of patients were on Cenobamate. So these are patients that have really tried many antiseizure medications and we're on some of the most powerful currently marketed antiseizure medications.

In addition to that, they have the RNS device that historically is a treatment for these patients. In our study, it really wasn't a treatment given the fact that they could not change the settings of the device and really their baseline was what's consistent through not only the baseline period, but also through the treatment period.

So when you look at this patient population and then you look at the results that we've seen, we think that the data is highly translatable going into Phase III studies. And we also think that, that's really corroborated by the novelty of this design, given the fact that when you look at clinical seizure reductions in our study, unlike any study that has ever been done in proof-of-concept, you can corroborate all of your clinical seizure reduction with a highly objective really non-placebo affected electrographic biomarker.

And we saw that biomarker and clinical seizures move in the exact direction as we predicted, but also as the community has predicted in the publications. So we're really pleased with that. And as I said, we think it's highly translatable going into Phase III.

So for us, next steps, we want to have an end of Phase II meeting with the FDA, which we're on track to do that by the end of this year. And then we're looking to initiate our Phase III studies, which will be two parallel Phase III studies in the third quarter of '26.

We've been conservative in our trial initiation based on the fact that we really just want to make sure we get in front of the FDA and have the discussion, but what we can say is that there are no gating items at this point to get us into Phase III from a CMC and a drug product perspective, we're in a great shape. We've also completed what we believe is all the necessary items from a tox standpoint to really put us in a position for Phase III.

Perfect. And the one question that we did get going into the study, and it's a little bit -- maybe a little bit more specific to the long episode design, but is the positioning of the leads for patients. And in the study, you did have five patients with a lead outside of the mesial temporal lobe. I guess what do we know about those patients? Was there a seizure reduction similar to the broader population? And maybe how do those data give you confidence on sort of the overall expression of TARP-gamma-8 and the efficacy of RAP-219?

Yes. So our confidence in the expression of TARP-gamma-8 and the target of RAP-219 really starts with what we know about the target, and we confirm this in our human PET study. And what we know about this target is that, it's broadly expressed through the -- throughout the mesial temporal lobe as well as the neocortex. That's the exact areas of the brand that you want to be in for focal seizures, both from an origination perspective as well as a propagation perspective.

Really, there's no role for targeting areas outside of the neocortex, in the mesial temporal lobe, because quite frankly, focal seizures are originating or propagating in areas such as the brainstem or the cerebellum. And what that also allows for is, we believe, and we think we've confirmed this in our Phase I work as well as this study is that by not targeting those areas, we really see a differentiated tolerability profile as well.

So specifically in this study, patients had to have at least one lead in the mesial-temporal lobe. That is not by coincidence given the fact that the majority of focal seizures have a focus within the mesial temporal lobe. And then one lead could be either another lead in the mesial temporal lobe or outside of the mesial temporal lobe.

Specifically, in this patient -- in this study, we had five patients, as you mentioned, that had that second lead outside of the mesial temporal lobe and what we were really encouraged by, and again, it wasn't a surprise to us, because we believe in this target biology. But in all five of those patients, those patients were all clinical seizure responders. So it really gives us real great confidence that the target is where it needs to be for the broad patient population.

And as we think about kind of, for lack of a better term, all-comer study in Phase III that the drug is going to be very well positioned. And we're not really conceding any decrement in efficacy. Now you're going to have natural variability as you think about more sites and a larger patient population in Phase III. That's just the nature of clinical trials and variability, but we don't believe that there should be a significant decrement in terms of efficacy.

Perfect. And one of the differentiating factors for the design of 219 is obviously on the safety profile versus Fycompa. And so maybe we can dive in a little bit to the tolerability profile that you did see in the Phase II. I guess overall, maybe to put it into context, what would you have expected from these 30 patients if they were treated with Fycompa? And maybe what did you see that was potentially differentiated?

And just a reminder to investors, because we are getting some questions through the chat. Feel free to send us questions through the Wall Street Webcasting Chatbox or my e-mail.

Yes. So a couple of things here. One is, I think, to think about the drug-resistant focal onset seizure patient population overall. These patients are sick patients. They've been living with the disease for a significant amount of time, and they all have been through many antiseizure medications by the time they are enrolled in a trial. So there is a natural kind of background AE rate in this patient population.

When you think of nervous system disorders, psychiatric disorders, both as a function of their disease, but also as a function of their previous medications as well as our background medications, there is always kind of this background rate that exists in this patient population.

What we were really encouraged by as we think about our study and the results from our study is, again, remind you that these patients run an average of three medications. 70% were on three or four in addition to the device. And what we saw is a highly differentiated tolerability profile. And that was defined by not only the AEs we saw, but the rate of AEs we saw, the severity of AEs we observed, which none were greater than Grade 2. The majority of those were greater than Grade 1.

And then ultimately, what I think clinicians are most interested in is the discontinuation rate, both in terms of the rate as well as those AEs that are driving discontinuation. And what we saw was a 10% discontinuation rate, which is one of the lowest that has been seen in proof-of-concept studies or any studies in this patient population.

So specific to our mechanism, what we're looking for to really confirm the target biology first, is when you think about Fycompa being a pan-AMPAR antagonist, but this, I think, also applies to almost all other antiseizure medications when they're modulating receptors in areas like the cerebellum, in the brainstem, and some of the most burdensome AEs that patients have are really around sedation, somnolence as well as gait impairment, ataxia, or tremor. And we really just did not see the rates nearly close to what you would see with Fycompa or other antiseizure medications.

The other AE of interest that we often get questions about is the aggression or rage that is a associated with Fycompa. What we should say is, first of all, with Fycompa, that is at a very low rate. It's actually higher with levetiracetam, the most utilized antiseizure medication. But we did not see any aggression or a rage in this study. So we think the tolerability profile is very consistent with what we assume based on the target biology and also very consistent with what we saw in our preclinical models.

And on that point, just because this is something that investors are drilling down on. I mean, if you look back at the Fycompa studies, it does look like anxiety, anger and aggression are kind of documented as separate presentations of neuropsychiatric AEs. I guess what has your team and maybe the feedback from KOLs that you've spoken to, since the data, are they confident that the panic attack AEs and the anxiety AE, I think it was one of each in the study that those are differentiated from what you would have seen, I guess, with the Fycompa.

Yes, completely. These are distinct MedDRA terms, in distinct classification. So what I think is really important for everyone -- for people to understand is, to look again at kind of the baseline of these patients.

If you look at every trial that has been done in refractory focal onset seizure patients, there are psychiatric AEs, and there are nervous system disorder AEs. When you look at anxiety as an example, that is kind of a baseline condition or co-morbid condition that many of these patients live with as well as cognitive impairment or memory impairment.

So specifically, when you look at the AEs that we highlighted, and we did that to be highly transparent and objective, we had three discontinuations. One was worsening of memory based on a patient's baseline memory impairment. Second was worsening anxiety based on a patient's baseline anxiety. And then the third was a panic attack. All of these are distinct. They're not the same AE. And what's important also to understand it as well as the overall AEs, these three discontinuations were all Grade 2 or less.

So we're, again, really pleased with the tolerability profile. We think this is a tolerability profile that really meets the bar of being highly differentiated. And one that, again, most importantly, you want to compound that the general neurologist or an internist is comfortable using. And we think that this profile really meets that mark.

And maybe on that latter point, because I do think it's important because that has come up a lot with Xcopri, is that often the epileptologist that we talk to actually recommend that neurologists don't necessarily manage their patients with Xcopri. Because it is difficult. I guess how has your, I guess, peak sales opportunity or kind of overall commercial impact of 219 changed at all, pre-data and then kind of post the level of efficacy that you saw in the study? I guess has anything changed? Obviously, you blew away the bars on long episodes and clinical seizures that you're even hoping for a target product profile. So just kind of curious, a, has your internal opportunity changed? And second, I guess, how big is that jump from the general neurologist from just an epileptology audience?

Yes. It shifted significantly in our opinion. And it's not just our opinion. It's really an opinion that is based on feedback from the community as well as the market research that we have done. So you're right, when you look at multibillion-dollar brands in focal onset seizures, the real distinguishing factor is, will the drug be used and adopted by the neurologist as well as the internist and do you have a profile that supports that. And that's really the distinguishing point.

So when we -- what we believe was a given, and I think the kind of key census around peak sales prior to data was in the $1.5 billion range, which is a very successful product. But now I think everyone has shifted to this could be a much bigger drug, a levetiracetam type of drug in terms of utilization. And we should remind people that this is a multibillion-dollar market opportunity, 560,000 patients that are treatment-resistant as being the immediate TAM and then increasing from that as you think about moving up the treatment algorithm or moving into more secondary care such as -- not tertiary care, which would be the epileptologist, but secondary care that may be something like the general neurologist.

So, when we think about the profile, what really drives that is the robust efficacy that we've seen. The second is a novel mechanism of action. If you were to ask the community what do they want. They want a novel MOA. Their belief that another GABAergic drug, another sodium channel drug, another calcium channel agent on top of what they've already -- patients already failed in those existing mechanisms, the belief that they're going to get additional efficacy is somewhat limited.

And then, you want a drug that is well tolerated and then can be added to rational polypharmacy. And the key there is obviously, the tolerability profile, but also the drug-drug interactions.

And when you have a drug that has DDIs, the general neurologist is somewhat hesitant to use that drug, because it just becomes really challenging adjusting the dose of other background medications. So we think, again, this profile fits the middle of kind of a drug that would be widely adopted across the spectrum.

The last opportunity here that we're really excited about and this is on top of what we already believe is a multibillion-dollar opportunity, is the opportunity for a long-acting injectable. There's never been a long-acting injectable in epilepsy, and that is not based on the lack of need. That's based on the limitations of current antiseizure medications. So if you have a drug that is not that potent, which means more drug on board in terms of volume. Second, has drug-drug interactions. Third has a very complex titration schedule. It's just not amenable to a long-acting injectable.

RAP-219 is unique. It's a highly potent drug. So really low drug volumes, low or no risk of drug-drug interactions, the titration in terms of long-acting injectable, it really self-titrates just given the long half-life of the compound. We've done some feasibility work here. We think we're on a path to develop a long-acting injectable. And what we hear from the community is that would be transformational for patients.

You think about parents managing or taking care of an adolescent with focal onset seizures. It's a daily fear of these parents and patients that they miss a dose, breakthrough seizure. Not only is there morbidity associated with that, there's actually mortality associated with that. So we think a long-acting injectable would be transformational as to how these patients are managed and would just be additive to the overall market opportunity.

That's great. And I do want to touch a little bit on the pace of enrollment for epilepsy studies. This has obviously been a big focus for investors. For your Phase II is almost helpful that they had the RNS device, because they feel like you almost call them up and offer the trial to patients which made it a little -- maybe a little comparably easier to at least locate the patients. I guess what sort of best practices as the team focused on for the Phase III enrolling? Obviously, you want the right kind of patient, but also kind of delivering the results in a reasonable time frame. I guess how are you thinking about that? And what are you hearing from KOLs?

Yes. So quality of patients is paramount. You really want to make sure that you're enrolling the right patient primarily based on the baseline seizure frequency that patients have. So you're able to detect a clinically meaningful difference and think about that just from an effect size and statistical power assumptions. But taking a step back from this, and I can speak to this based on my previous experience at Cerevel, where we had a program in darigabat for focal onset seizures, there's a few really important aspects as you think about what drives enrollment or what limits enrollment in the recruitment of these studies.

The first is the competitive context. How many trials are ongoing at a given time to recruit these studies? And these are all global studies by nature. We believe we're going to be in a very good position, because a lot of those investigational programs will either be completed or at their tail ends as we think about enrolling our study.

The second is the profile of the drug. And I think this often goes overlooked. When you have a drug that has drug-drug interactions, when you have a drug that has a tolerability profile that may exacerbate the current background AEs that the patients have with their existing antiseizure medications, you really limit top of your funnel significantly.

So if you have to exclude a whole bunch of drugs based on a DDI profile. Patients aren't willing to come off of their background seizure medications. They just don't want to do that as well as they don't want to be more sedated or have greater impairment on motor function.

And then the last piece that is, I think, often overlooked as well is, how does the community really look at your drug? Are they aware of your drug? And we've been very thoughtful in the design of our proof-of-concept study in a manner which we believe the receptivity around our drug, the awareness around drug is really high, especially with these results, which we think will be a motivating factor for both clinicians, investigators as well as patients to enroll.

Ultimately, there's kind of wide error bars here. You have one program that's taken a really long time. You have a few other programs that are saying they're going to enroll in record time. I don't think we're going to be on either end of those error bars. We're going to be somewhere in the middle. And I think we'll have a little bit more specific guidance here in the beginning of the year after we get out of our end of Phase II meeting and once we finalize our protocols.

Perfect. And I want to dive into the translatability to some other indications, but maybe a way to get there is to bring Troy into the conversation a little bit, obviously, just completed the -- that how could you raise last week and kind of just curious where your current cash balance stands now? And when you think about catalysts for the company, kind of what are you funded through and kind of walk us through, I guess, what that recent raise got you in terms of runway?

Joe, so we ended Q2 with $260 million. We'll obviously update that number along with the net proceeds of the financing that we completed last week. But the whole objective was to ensure that we had enough cash to get to the end of 2021, basically. That allows under all conservative scenarios of starting the trials for focal onset in third quarter. And as Abe mentioned, even on the outlier timelines that we've seen on both ends of the spectrum to get through the focal onset pivotal programs. That was the primary objective.

It also allows us to advance the LAI, that Abe referenced, because we think that brings a lot to the opportunity, both from a loss of exclusivity, extension of the IP rights but also as you think about the market opportunity with both a small molecule and a long-acting injectable with the profile like RAP-219. It also will allow us obviously to get through bipolar mania trial and some discovery work. So we're very well funded now, as I said, into the second half of 2029.

Perfect. And maybe on some of those next indications, how much does the Phase II in epilepsy help derisk, I guess, bipolar and pain? What were you able to kind of learn from that study that you maybe didn't know 2 weeks ago for those indications? Or are you kind of viewing them as sort of discrete populations at this point?

They're definitely discrete populations. But I do think that we have raised internally our probability of success for other indications based on what we see -- what we've seen and observed with these results.

There are a couple of things on that. One is really confirming target engagement. I think what we know from our proof-of-concept study in epilepsy is that, we have a pharmacologically active dose clearly. But what's really important there, again, it's the benefit of the study that we did is that we're able to define that not only by clinical seizure reduction, but also by electrographic activity.

So as you think about bipolar as an example, really where does the biology take you and it takes you to excitability in four brain regions, specifically the amygdala and the hippocampus. We know based on the electrographic readings from our epilepsy study, we are having a robust and immediate effect on electrographic activity, an excitatory transmission in the brain.

So we think that, that puts us in a really good position as we think about bipolar and also ultimately getting there in a rapid fashion, which you need to do in bipolar mania studies.

And the second is the tolerability profile. When you look at the unmet needs in bipolar, you have drugs that are marginally effective, but the problem with these drugs, as you think about atypical antipsychotics or mood stabilizers such as lithium or the anticonvulsants that are lamotrigine, lamictal, and carbamazepine that are approved either as anti-mania agents or mood stabilization agents. These are drugs that have very poor tolerability profiles. And ultimately, patients come off of their meds and cycle back through a manic phase. So we think the tolerability profile here would be very supportive in this patient population.

Perfect. Awesome. With that, unfortunately, we are at time, but thank you both for a great discussion and best of luck on continued development.

Thanks, Joe.

Great. Thank you so much, Joe. I appreciate the time.

Thank you. Talk to you soon.

Bye-bye.