Rapport Therapeutics Inc Stock

Good morning, and welcome to the Rapport Therapeutics Bipolar Program Update Call. [Operator Instructions] As a reminder, this webcast is being recorded today, October 20, 2026.

I will now turn the call over to Julie DiCarlo, Head of Communications and Investor Relations at Rapport. Please go ahead.

Thank you, operator, and good morning, everyone. Thank you for joining us today. Earlier this morning, Rapport issued a press release reporting top-line results from the Phase II trial evaluating RAP-219 in bipolar mania. The release is available on the company's website and through our SEC filings.

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, our ongoing planned and future clinical trials, the company's development plans, and the potential commercial opportunity for RAP-219. These statements are subject to risks and uncertainties described in our filings with the Securities and Exchange Commission. Actual results may differ materially from those expressed or implied. Please refer to our SEC filings for a discussion of those risks. The company undertakes no obligation to update these statements, except as required by law.

With me on today's call from Rapport are Abe Ceesay, Chief Executive Officer; Dr. Jeff Sevigny, Rapport's Chief Medical Officer; and Troy Ignelzi, Chief Financial Officer. We'll provide an overview of RAP-219 and the need and opportunity in bipolar mania. We'll then share top-line results of our Phase II trial in bipolar mania and walk through our near-term catalysts and provide a financial overview.

We are joined by Dr. Gary Sachs, Founding Director of the Bipolar Clinic and Research Program at Mass General Hospital and Associate Clinical Professor of Psychiatry at Harvard Medical School, who will share his perspective on the clinical trial results. At the end of the prepared remarks, we'll open the call up for questions.

With that, I'll now turn the call over to Abe.

Thank you, Julie, and good morning to everyone, and thank you for joining us today on the call. This is a very exciting day for patients and for Rapport. We're pleased to share results from our Phase II proof-of-concept trial of RAP-219 in bipolar mania. On our path to building the leading precision neuroscience company, our vision was always to establish a pipeline-in-a-product with RAP-219. We took our first step towards that vision last year when we established proof-of-concept in focal onset seizures with our robust Phase II data. Today, we take the next step, achieving proof-of-concept in bipolar mania.

On an individual basis, focal onset seizures and bipolar mania each represent multibillion-dollar market opportunities. Our Phase II trial achieved statistically significant results on both the primary and secondary endpoints, and the product candidate was well tolerated. In neuropsych trials, it's important to see a consistent pattern of benefit across measures. Importantly, the clinical benefit was seen consistently across measures. A key way to evaluate and understand efficacy data in clinical trials with this patient population is to look at the single items that make up the YMRS. As Jeff will share shortly, RAP-219 improved more than placebo on every YMRS single-item score, achieving nominal significance on several key scores.

From a tolerability standpoint, the drug was well tolerated. All TEAEs were mild to moderate, and the incidence was similar to placebo. There was a low discontinuation rate due to adverse events, and we continue to see a favorable tolerability profile. Like in FOS, in bipolar mania, a differentiated tolerability profile achieved by its novel mechanism positions RAP-219 to be potentially transformational for this patient population. The data clearly support us advancing to Phase III, and the team is preparing for that as we speak.

After walking through the data in more detail, Jeff will talk about our next steps for the program and some enhancements that we think we can bring to the Phase III program to potentially build further on these results. I'd like to briefly review the scientific rationale for advancing RAP-219 into bipolar mania. Unlike our work in focal onset seizures, this program did not have the same degree of direct preclinical translation. Instead, our decision to study RAP-219 in bipolar mania was grounded in the scientific literature and our understanding of the mechanism.

That rationale rests on 2 key themes. First, the growing body of literature identifies excess glutamate as a key driver of bipolar mania. Second, this excess glutamate is highly expressed in the corticolimbic network, which directly overlaps with the expression of TARP gamma-8-containing AMPA receptors, the target of RAP-219. Fundamentally, we believe that if we achieved proof-of-concept, RAP-219 could represent a novel precision-based approach to treating bipolar mania, one to drive clinical activity while potentially mitigating the burdensome adverse events associated with current therapies.

In terms of the market opportunity, bipolar mania could significantly expand the potential of RAP-219. About 8 million U.S. adults have bipolar disorder. Of those, roughly 3.6 million are diagnosed, and an estimated 1.6 million experience bipolar mania. We believe the immediate TAM is the more than 1 million adults receiving second-line or third-line treatment where combination therapy and switching is common.

To help frame these data, it's useful to understand the current treatment landscape for patients living with bipolar mania and where RAP-219 could potentially fit in. This is a population with substantial unmet need. Patients present in both inpatient and outpatient settings and are treated acutely primarily with atypical antipsychotics, antiseizure medications approved for this condition, and lithium. These broadly acting agents are associated with well-known burdensome adverse events, including sedation, akathisia, extrapyramidal symptoms, weight gain and metabolic changes. These tolerability challenges are unacceptable for patients and carry a significant burden, often driving them to stop taking their medication. Discontinuation and non-adherence rates are high, with roughly 40% of patients discontinuing treatment. And as a result, many patients relapse and continue to cycle through their illness.

Before I turn it over to Jeff, I'd like to put the patients who entered this trial into context. Bipolar mania is a complex condition. At the top of this slide are the DSM-5 criteria that define a manic episode, 7 core symptoms, of which 3 or more characterize an episode. At the bottom are the symptoms these patients actually present with. At baseline, they are agitated and often display disruptive and aggressive behavior, psychotic features, anxiety, substance abuse, suicidal ideation, and impaired insight.

As you review the data that Jeff will share, I'd encourage you to keep 2 considerations in mind. First, where is the drug having an impact from an efficacy standpoint? Second, how does it perform on tolerability? Behavioral adverse events such as aggression have been a consideration for this mechanism. And on our data, we did not observe those adverse events with RAP-219 to date. In fact, we saw improvements in the behavioral domains of the YMRS. We believe these data support our path forward in bipolar mania and also inform the broader development of RAP-219, including in epilepsy.

With that, I'll turn it over to Jeff.

Okay. Great. Thank you, Abe. Good morning, and thank you for joining us this morning. I'm Jeff Sevigny, Chief Medical Officer of Rapport Therapeutics.

The Phase II proof-of-concept trial in bipolar mania met both the primary and the secondary endpoints and was well tolerated. The placebo-adjusted change from baseline on the YMRS at week 3, that was the primary endpoint, was 3.1 points and statistically significant. The effect was driven by an absolute reduction of 15.4 points in the RAP-219 treatment arm. The secondary endpoint was the placebo-adjusted CGI Bipolar Severity of Mania score, which demonstrated a statistically significant improvement of 0.4 points at week 3.

In a prespecified exploratory analysis, all 11 items on the YMRS numerically favored the RAP-219 treatment arm with 4 items, including irritability and aggressive behavior, achieving nominal significance. In terms of safety, RAP-219 was well tolerated, and there were no severe or serious AEs during the treatment period. Discontinuations due to AEs were below 5%. The incidence of TEAEs and of psychiatric TEAEs were balanced between the 2 groups. Lastly, adverse events commonly reported with atypical antipsychotics such as somnolence, dizziness, akathisia, and other extrapyramidal symptoms were not reported or occurred at a very low rate in the study.

The design of the study was a conventional one. It enrolled patients with acute bipolar mania in accordance with DSM-5 criteria and having a YMRS score of 25 or greater. Eligible patients were randomized to RAP-219 using a 2- or 4-day titration to 0.75 milligrams or to placebo and then followed in an inpatient setting for a 3-week treatment period. After completing a 3-week treatment period, patients entered an 8-week safety follow-up period. I would point out that this was a monotherapy study, so patients were required to wash out of any treatment used for bipolar disorder and any anxiolytics or hypnotics prior to enrollment, and a protocol-defined rescue lorazepam was permitted during the screening and treatment period.

The primary endpoint was placebo-adjusted change from baseline on the YMRS scale, and the secondary endpoint was placebo-adjusted change from baseline on the CGI Bipolar Mania Severity scale, both at week 3. Today, we are presenting the results from the 3-week treatment period. Regarding patient disposition of the 253 patients randomized, 127 received placebo and 126 received RAP-219, of which 112 and 95, respectively, completed the 3-week treatment period. The main reason for early discontinuation in both groups was withdrawal of consent. The reasons are listed on the right. And as you'll notice, the most common reasons were for personal or for family reasons.

Early discontinuation due to adverse events was low, 0.8% in placebo and 3.2% in RAP-219. The most adverse events were agitation, 1 patient in each arm. And in the RAP-219 arm, there was a case of shingles, ankle sprain and suicidal ideation. I would add that there was also a case of suicidal ideation in the placebo arm. And in both cases, it was considered unrelated to study treatment by the investigator.

The 2 treatment groups were well balanced for demographic and baseline characteristics. The baseline YMRS and CGI Bipolar Mania Severity scores are at the bottom of the table and were consistent with the population of moderate to severe bipolar mania. The primary endpoint was met with a statistically significant 3.1 placebo-adjusted change from baseline on the YMRS at week 3. As shown in the figure, the placebo-adjusted effect continued to grow over the 3-week dosing period with lines never touching, never crossing. The absolute treatment effect of the YMRS at week 3 was minus 15.4 points, an effect that is consistent with those reported in more recently conducted studies in bipolar mania. The placebo response, however, was at the upper end of the recently reported ranges.

We completed a prespecified single-item score analysis of the YMRS, and all scores numerically improved and favored RAP-219 over placebo at week 3. The 4 items showing the greatest improvement were irritability, thought content, disruptive and aggressive behavior, and sexual interest, and these were nominally significant at week 3. The improvements in the irritability and disruptive aggressive behavior items were also nominally significant at week 2. I would emphasize that these results suggest that RAP-219 is treating the core and the most disabling features of bipolar mania, particularly irritability and aggressive behavior, which are the issues that often lead to hospitalization.

The secondary endpoint was also met with a statistically significant 0.4 placebo-adjusted change from baseline on the CGI Bipolar Severity Mania scale at week 3. Mirroring the effect I described with the YMRS, the placebo-adjusted effect of the CGI continued to grow over the 3-week dosing period with the lines never touching and never crossing. As a reminder, the CGI Bipolar Mania Severity scale is a clinician-rated 7-point scale of how ill a patient is with mania with scores reflecting the severity of mania from normal to very severely ill. It captures the clinician's overall judgment of the patient's clinical status. And therefore, these results provide an important complementary evidence of clinical activity and add clinical context to the improvement observed on the YMRS.

RAP-219 was well tolerated. The overall incidence of TEAEs and of psychiatric TEAEs was similar between the 2 groups, and all TEAEs were mild or moderate. TEAEs that occurred in 5% or greater of patients were agitation, insomnia, restlessness, anxiety, headache and nausea. Of these, nausea was the only TEAE that was reported at least 2x more in the patients on RAP-219 than placebo. The most common TEAE on RAP-219 was agitation. It usually occurred during the first week of treatment. It lasted a median of 2 days and was considered unrelated by the investigator in greater than 80% of patients who reported it.

Regarding the incidence rates of psychiatric TEAEs, they are likely inflated in both the placebo and the RAP-219 arms because the protocol required investigators to report a TEAE whenever rescue lorazepam was used, whether the reason was true were due to an event associated with the underlying disease, in this case, symptoms of bipolar mania. Therefore, a potentially more informative way to appreciate the tolerability of RAP-219 without this confounder is to consider TEAEs that are considered related by the investigator. And when doing so, the incidence of all of these TEAEs is less than 5%.

This brings us back to the top-line summary. The study achieved what it was designed to do, that is demonstrate proof-of-concept of RAP-219 in bipolar mania patients at a dose of 0.75 milligrams. Both the primary and secondary endpoints were met with statistical significance, and RAP-219 demonstrated a well-tolerated and, I believe, a potentially differentiated tolerability profile compared to current treatments.

Given these positive results, we're excited to move the program to Phase III in bipolar mania. We anticipate an end-of-Phase II meeting with the FDA in 1Q 2027 with the initiation of the Phase III study anticipated in the second half of 2027. We've learned a lot from the Phase II study and believe there are ways to enhance the design of the Phase III study, including testing a higher dose of 1.25 milligrams.

As a reminder, 1.25 milligrams was tested in our Phase II study of focal onset seizures in which it was well tolerated and is one of the dose levels now being tested in the Phase III program in FOS. The figure on the right compares the exposures and the associated receptor occupancies of 0.75 milligram dose used in the Phase II study. This is the orange line with what 1.25 milligrams would achieve, this is the green line.

As you can see, a higher exposure and receptor occupancy is achieved with 1.25 milligrams at week 3, and we believe this higher exposure making for a greater clinical efficacy. Moreover, 1.25 milligrams achieves receptor occupancy more quickly than the 0.75 milligrams. For example, the receptor occupancy of 1.25 milligrams at day 7 is approximately equivalent to the receptor occupancy achieved with 0.75 milligrams at day 17. Secondly, we are also considering expanding the Phase III study footprint to include certain ex U.S. regions that have historically shown stronger signals than U.S. studies in bipolar mania. Finally, there will be other learnings from the Phase II study that will help optimize the Phase III study design and conduct.

I'm now pleased to turn the call over to a leading bipolar disorder expert, Dr. Gary Sachs, to share his perspective. Dr. Sachs is the Founding Director of the Bipolar Clinic and Research Program at Massachusetts General Hospital and is 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 Mass General Hospital, and later led the NIMH STEP-Bipolar Disorder program, the largest treatment ever conducted for bipolar disorder. He is also past President of the International Society for CNS Clinical Trial Methodology.

Great. Let me offer a clinical and a research perspective on these results. First, I think it's important to keep in mind, bipolar disorder is a serious lifelong condition in which people experience often disabling abnormal mood states such as mania and periods of full or partial recovery. When we look at the results for RAP-219, we have to say this is a great day for patients with bipolar disorder. RAP-219 is a mechanistically informed therapeutic aimed at a novel target. We have not had a novel antimanic mechanism for more than 50 years. So this is a really important finding from that perspective.

The results are especially encouraging because they not only come from a study done exclusively in the U.S., a region known to have lots of research sites that have high placebo response rates, but also because the data suggests that the observed benefits were not carried by functional unblinding or nonspecific sedative effects. So those advantages that you heard for RAP-219 over placebo in key items on the YMRS like irritability and disruptive aggressive behavior. These are not only present, but they're widening over time. And they are the main reason that acutely manic patients get hospitalized. That encourages the possibility that this drug will have widespread use in not only the acute treatment in the hospital, but maybe even earlier and offer -- you saw the completion rates for RAP-219, which are extremely high compared to the other acute mania trials that we've seen.

So this may offer a user-friendly option for long-term treatment. Or said another way, all approved treatments for acute mania demonstrate efficacy in clinical trials. But the currently available treatments lack real-world effectiveness because patients frequently stop them. The adverse effects are too much for them, and they go on and they suffer recurrent episodes. So RAP-219 has real promise to lessen that efficacy effectiveness gap that is so problematic for patients and their families.

Thank you for the insightful comments, Gary. Before handing it back to Abe for closing remarks, I'd like to give some perspective on our upcoming milestones following these data, focusing on those now through 2027.

In the fourth quarter of this year, we expect to report initial additional long-term safety data for RAP-219 in focal onset seizures. These initial data come from the Phase II participants who had the opportunity to enroll in the open-label extension study. Moving into 2027, we expect to hold our end-of-Phase II meeting with the FDA for the bipolar mania program in the first quarter.

In the first half of next year, we anticipate the initiation of our trial in primary generalized tonic-clonic seizures. In the third quarter of next year, we expect to report initial Phase I PK data for our long-acting injectable formulation. In the second half of 2027, we anticipate initiation of our Phase III program in bipolar mania and also expect to report Phase I results from our pipeline program, RAP-641.

By the end of 2027, we expect to have 5 Phase III trials underway, 2 in focal onset seizures, 2 in bipolar mania, and 1 in primary generalized tonic-clonic seizures. This will be an exceptionally busy and exciting period for the company as we advance RAP-219 across multiple indications.

Thank you, and back to Abe.

Thank you, Troy, and also thank you to Dr. Sachs for your comments as well. Given the data presented today, we believe the Phase II results clearly support advancing RAP-219 in bipolar mania. Together with the positive Phase II data in focal epilepsy, they position RAP-219 to potentially become a pivotal stage pipeline-in-a-product across neurology and psychiatry. These data also add to the RAP-219 profile across all indications given the exposures in this trial and its tolerability profile. Long-term focal onset seizure safety data this year is anticipated to further build on that.

This novel mechanism has the potential to be transformational. What will drive utilization is whether patients can remain on treatment, and that is what drives physician preference. With today's results, we're positioned to pursue 2 multibillion-dollar market opportunities with RAP-219 across neurology and psychiatry with one molecule. We're advancing in focal onset seizures, primary generalized tonic-clonic seizures, and bipolar mania. Importantly, we're also advancing a long-acting injectable formulation that would extend the RAP-219 program life cycle across all indications.

Across focal onset seizures and primary generalized tonic-clonic seizures, the opportunity spans approximately 2.6 million patients. Many patients still need treatment options that are effective and well tolerated. Bipolar mania represents another significant opportunity with approximately 1.6 million patients in the U.S. alone. Poor tolerability with current treatments can contribute to low adherence, underscoring the need for new options. Few programs have the opportunity to address this breadth of unmet need, and we believe RAP-219 is uniquely positioned for this.

These programs reflect our strategy to build a precision neuroscience company focused on receptor-associated proteins or RAPs, which may enable more selective modulation of broadly distributed receptors. Behind this, we continue to advance an exciting early-stage pipeline.

To close, these results mark an important step for RAP-219 and for the patients we hope to serve. We have a clear set of near-term milestones, a team focused on execution, and a growing body of data that supports continued development in both epilepsy and bipolar mania. We appreciate your time and your interest in Rapport.

We will now open the call for questions. The operator will provide instructions. Operator?

[Operator Instructions] Your first question comes from the line of Salveen Richter of Goldman Sachs.

Congrats on the data. Can you just square the 3-point improvement on the YMRS with prior historically successful trial outcomes, particularly in the context of the tightened statistical bar here and the potential Phase III study design?

Yes. Great, Salveen. Thank you for the question. So as you think about this 3.1 placebo-adjusted difference, I'm going to have Jeff provide some perspective as well as Gary, Dr. Sachs provide some perspective as well.

From our standpoint, the data clearly meets a threshold of clinical meaningfulness. Importantly, not only that placebo-adjusted difference hitting statistical significance, but that being corroborated by the secondary endpoint as statistical significance as well as the individual measures in the YMRS.

Historically, you have seen programs that have had a placebo-adjusted difference in the 2s, in the 3s, and ultimately in the 4s and the 5s as they go across clinical development. So we're really confident in this result and also feel like this result is very meaningful.

I'll turn it over to Jeff for additional comments, but also to Dr. Sachs, so he can provide a perspective on these results, but also how clinicians may make treatment decisions.

Yes. I think of this at 3 different levels. The first question, is this a real signal? And the answer is unequivocally yes. We saw a consistent effect on the outcome measures at all time points, and the effect was growing. The second speaking -- getting to your specific question, is it meaningful? And there, I would say unequivocally, yes, this view is validated by really 3 points. The first is the absolute delta on the YMRS was 15.4 points. This is consistent and in line with what other approved therapies have observed.

The second is that this effect is validated by the statistically significant effect on the CGI, which is a global scale and interpretation of how the patient is doing by the clinician. And the second bit is where are the effects being observed. The effects are being observed in the domains of the YMRS that are most meaningful to the patients and to physicians, particularly irritability and aggressive behavior. So it's treating the core underlying disabling effect with bipolar mania.

In regards to what we can do next, the question is can we get a better effect? And there, the answer is also yes. I believe in this proof-of-concept study, we left efficacy on the table, testing a dose of 0.75 milligram. We intend to get that extra efficacy by increasing the dose to 1.25 milligrams in the Phase III study.

Dr. Sachs, do you have any perspectives on these results, but also how that might inform kind of how physicians look at the meaningfulness of this?

Yes. I agree with how Jeff laid this out. But I would also add the idea that you can simply compare the drug-placebo difference across trials is clearly not supported by the data. For instance, if you look at the studies that have the greatest drug placebo difference, you might see it for risperidone. But then you'd also see that it's a drug that also has one of the smallest in a different study.

So the idea that we'll learn more in a Phase III set of studies, I think, is exciting. But I wouldn't make a lot of the difference being a point or 2 different from another study that may have had different entry criteria, been done in a different region with different placebo response. So really good results. And as Jeff said, the statistical significance speaks for itself.

Next question, operator?

Your next question comes from the line of Marc Goodman of Leerink Partners.

Dr. Sachs, can you talk about the AEs in the context of the drugs that you're using today for bipolar mania and how you think this drug fits in? And then just for the company, can you talk about the rescue meds with lorazepam and just put that in perspective for us?

Sure. The kinds of problems that you see reported from these clinical trials really do carry over in practice where you'll have patients who will have most commonly sedation, weight gain, headaches. Those are the kinds of side effects that are associated with discontinuation. And I find the results here really encouraging. This is the first non-sedating antimanic drug suggesting that, that mechanism-driven idea behind RAP-219 may really have some truth here that this is much more specific to what the illness is about and will be ultimately a better tolerated treatment.

And then, Jeff, maybe you can provide some perspective on the rescue medication use and maybe also a perspective on previous trials as much as we know.

Yes. So rescue lorazepam was permitted in the study. Recall that this was a monotherapy study. Many patients were on medications for their bipolar disorder and on anxiolytics and hypnotics prior to entering the study, all of that has to be washed out.

During the treatment period, rescue lorazepam was permitted. Its use was a bit more than 50% in both arms and similar in both arms. When you compare that historically, across other studies, the use of rescue lorazepam is on the low end. It's been typically reported to be between 60% and 80% up.

Your next question comes from the line of Paul Matteis of Stifel.

Congrats on the data. Maybe taking a step back here, I know you guys set the study up as a pivotal trial, but do you feel comfortable that the FDA might recognize this as a pivotal considering that the p-value is 0.045. And then to that point, is the base case here for risk mitigation to do 2 additional pivotal studies? And what might you do in those studies to try to mitigate a large placebo response from repeating itself?

Yes. Thanks, Paul. So the answer is yes. We continue to believe this data support confirmatory evidence. As Dr. Sachs said, statistical significance is statistical significance. And the strategy has always been to do 2 additional trials with the kind of conventional adage in neuropsychiatry do 3 to get 2. So our plan will be to meet with the FDA, as Jeff said, within our end-of-Phase II meeting and then run 2 parallel Phase III trials based on the outcomes of those -- that end-of-Phase II meeting. But we really are confident in this data.

And again, just bring it back to the point that Dr. Sachs highlighted as well as Jeff highlighted, the statistical significance on the primary is obviously hierarchically number one. What you have to look at number two is the statistical significance on the secondary and then the corroboration of effect through the secondary as well as the core items on the YMRS. So maybe, Jeff, you could talk through a little bit of kind of how we're thinking about Phase III. I know you highlighted some of those things in your prepared remarks, but we can discuss those as well.

Yes. So we believe there are ways to improve the placebo effect overall. The Phase II study was a well-conducted study, but it was conducted exclusively in the U.S. And studies in the U.S. in this indication are notorious in the sense that they have a lower signal-to-noise ratio and a higher placebo effect.

Studies that -- if you look across other programs, they often run their Phase III programs in the U.S. and ex U.S. geographies, including Eastern Europe and others. And in those other geographies, there tends to be a greater signal, and that is believed to be in part because many of the patients that are enrolled in those other geographies come from an inpatient setting already, as opposed to the U.S., where most of the patients come from an outpatient setting and are recruited to an inpatient setting. So that's believed to be one of the reasons why the better signals are detected in some of these ex U.S. geographies.

Your next question comes from the line of Joseph Thome of TD Cowen.

Congrats on the data. Maybe as the benefit does look to continue to widen with time, can you just talk about any thoughts you're having on the Phase III and sort of the timing of assessment of the primary endpoint? Would you look to maybe extend that at all, especially given any potential changes to the titration regimen if you do go to the higher dose?

And then maybe just on the discontinuations in the study related to withdrawal of consent. Can you just go into a little bit more detail as to kind of what's included in that? Why do patients withdraw consent and were these numbers expected?

Okay. Yes. Thank you for the question. Yes, regarding the efficacy, as you point out, the efficacy grew over time, and that is a really important observation. What else increased over time is the drug exposure or the blood levels of the drug. So as the exposure was increasing, the efficacy was increasing. This study went to week 3. Conventionally, Phase II and Phase III studies in this indication go to week 3 or week 4. So that will certainly be one of our considerations when designing the Phase III study. Do we increase the duration of the study to week 4 because we believe that the effect at week 4 will be greater than week 3? So that is an important consideration. There is precedent for it, and it's something that we'll be considering in designing the Phase III study.

In terms of the discontinuations, the most common reason for discontinuation was withdrawal of consent. It turns out that withdrawal of consent is the most common reason for discontinuation historically in bipolar mania studies. This has been acknowledged by both the FDA and other sponsors. And the rate of withdrawal of consent tends to be in the mid-teens. So in our study, the withdrawal of consent was in the mid-teens. So that is consistent with the historical fact. In the placebo arm, it was lower.

Specifically, why it was unusually low in the placebo arm, I don't know. I can say we've explored potential reasons and one of which is, for example, were people doing worse in the active arm and therefore, discontinued. And in fact, that's not the case. We do have data from the last YMRS, the patients completed prior to discontinuing. And it turns out people in the placebo arm were doing worse and people in the RAP-219 arm were doing better. So a plausible explanation is people are getting better and they no longer want to be in the inpatient setting.

Your next question comes from the line of Andrew Tsai of Jefferies.

Congrats on the data. This is John on for Andrew. So on efficacy, how much do you think you can reasonably improve the YMRS placebo-adjusted efficacy delta in the next Phase III studies? If you do wind up making the tweaks like pushing the dose, expanding ex U.S. and maybe even extending the study for longer, maybe even making it outpatient?

And then secondly, how much do you think you could potentially even reduce the placebo response on some of the measures you mentioned earlier?

Yes. So I'll let Jeff get into the details of that. But I want to -- we want to really make sure we continue to reinforce that this was a positive response. So although there are opportunities in the Phase III study to work on both ends, as you said, the treatment effect, the absolute treatment effect of RAP-219 as well as controlling for placebo response, we will do that, but this trial was successful.

And as you look historically at drugs in development in bipolar mania, I think Dr. Sachs pointed this out is you have drugs that have had as low as a 2 in a least square mean difference and have been able to grow the effect over time. So we see this trial clearly achieving success. But as you said, we will continue to look to ways to improve as one always does going from Phase II to Phase III.

Yes. I would be speculating with regard to what effect we think we would see with a higher dose other than to say that I firmly believe that a greater effect will be observed at a higher dose as there is going to be greater exposure.

With regard to the placebo response, I would say and our goal is to get it at 10 or less. We observed about 12 in the study. And historically, I think a placebo response of 10 or less would be a good outcome. So that would be a reasonable goal.

Yes. Let me just add another bit of color commentary there. The placebo response observed here is not so far out of line with other U.S.-based studies. However, this study has an additional element to it with that novel mechanism. And novel mechanisms raise expectation, expectation drives true placebo response. And I think as we go forward, instead of imagining that we don't have to do anything to mitigate placebo response, we will use some of the training techniques to help site staff lessen that expectation-driven placebo response.

Congrats again.

Yes. Thank you for the question. Operator, next question?

Our next question comes from the line of Myles Minter of William Blair.

Congrats on the data. First one is just on -- was there any sort of material differences you saw in the 2 different titration cohorts? They seem pretty minimal differences to me. And in the past, I think you've expected that they performed pretty similarly. But anything different there? And as you're thinking about putting that 1.25 mg dose into the Phase III, what titration you'd use? That's the first one.

And then the second is just given the importance on keeping patients on therapy as highlighted by Dr. Sachs, what's your plan for generating maintenance data in your Phase III program?

Thank you for the question. Regarding the titration, it was basically a subexperiment within the main experiment to determine whether the 4-day titration would be better tolerated than the 2-day titration. But in fact, the 2-day titration was so well tolerated. There was not really any room for improvement. So what we learned is if we were to run the study, the identical study a second time, we would not use the 4-day titration. Now in the Phase III study, we still have to decide whether we use the titration at all. So I don't want to tip our hand yet regarding what we will or will not do regarding titration other than to say what we learned was there was no real reason or benefit to doing a 4-day versus a 2-day titration.

I'm sorry, Myles. What was the second part of your question -- maintenance. Thank you. So maintenance is a really important consideration here. We will provide a perspective, but this is another point that I'd like Dr. Sachs to comment on. So there are 3 indications in bipolar, that is mania, maintenance as well as depression. However, indications do not necessarily drive clinical care. And what our understanding is, is that clinical care is really determined by is the drug effective and tolerated in the acute phase and then patients maintain themselves or clinicians keep patients on that drug in a maintenance setting. So we don't necessarily believe that a maintenance study is required for registration. However, part of our Phase III program will be the inclusion of an open-label extension study, which will give some insight into longer treatment duration on RAP-219 in that setting.

But Dr. Sachs, would love to hear your thoughts on this as well.

I'll tell you the thing that comes to mind about long-term treatment was the improvement seen on the irritability item. When we look at the data set from STEP-BD, we can see over time that irritability tends to be among the residual symptoms that patients have at the end of 1 episode. They may have only mild symptoms, but irritability drives the experience of the patient, their family members, their employers, et cetera, and is often present at the beginning of the next episode. So a treatment that can effectively reduce that would be very attractive for long-term management of bipolar patients. And I'm hoping that we'll be able to get to a point where we have that kind of data because this is a promising mechanism for that reason.

Your next question comes from the line of Kambiz Yazdi of U.S. Bancorp.

Congrats on the data for the Rapport team, how do you think about RAP-219 mechanism potentially in conjunction with other antimanic agents?

And then a second question for Dr. Sachs. The absence of sedation in the 219 data is notable given the lack of somnolence. How do you think about the clinical implications of the non-sedating profile differently in the acute hospitalized patient setting versus a potential outpatient setting long-term?

Yes. On the thinking around polypharmacy with RAP-219, we're very encouraged based on everything we know around the mechanism and similar to how we think about it in epilepsy, given the metabolism of this drug that is not CYP-mediated, we feel that it carries a low to no risk of drug-drug interactions and one that could be added in a rational way to polypharmacy. So we think that those same benefits really apply to bipolar as they do in epilepsy.

Dr. Sachs, I'm not sure if you heard the second part of the question.

Yes. No, I got that and really appreciate that question because it's important to understand the way clinical management works. And we've used terms like irritability and disruptive aggressive behavior as items on the YMRS in an abstract way. In truth, when the patients are there at the hospital, these are things that cause it to be an emergency. And I'm not concerned about whether I get efficacy on day 1 by producing too much sedation. That might be okay in the hospital on day 1 and 2.

And so I imagine that we will either learn that RAP-219 is effective at higher doses early even without sedation or that we need these sedative treatments early on and that we will peel them away and leave patients on this more specific longer-term treatment after that hyperacute phase is over. So the idea that it might play well with other treatments is really encouraging. Let's see what happens in the real world.

Your next question comes from the line of Danielle Brill of Truist Securities.

Congrats on the outcome here. Two from me. So you guys noted that the RAP-219 patients who withdrew were generally improving at their last assessment. I'm wondering if you could discuss how the primary endpoint held up across key sensitivity analyses for the missing week 3 data?

And then also, wondering if you could share the YMRS response and remission rates by arm and whether those showed a similar separation or more clear separation than the mean change analysis?

Right. So the statistical model used for the primary for all the analyses we presented was an MMRM. This is a robust model. It's the model that we would use in Phase III. The population used in that model was anyone who was randomized and received a dose of RAP-219. And in this case, that's everybody. So the model includes data from all patients that were randomized into the study. The model handles missing data implicitly. That's a device that the model has built in. And we assume that any data missing was missing at random. So all data that has been generated is included in the analysis.

With respect to response and remission, yes, in both cases, it favors RAP-219. The response rate at the greater than 50% responder rate was close to becoming statistically significant, but didn't quite reach the 0.05 threshold, but certainly favored RAP-219, and the remission rate also favored RAP-219. Those were not primary or secondary endpoints. Those were exploratory. So we're very pleased with those outcomes as well.

Your next question comes from the line of Benjamin Burnett of Wells Fargo.

And I'll add my congrats on the data. I just wanted to go to the model PK data that you have or the analysis that you have there. Just looking at that, it looks like the drug concentration is not expected to -- or it's expected to continue to build within the sort of the 3-week time frame that you have here. I just wondering if you could maybe speak to your level of confidence in just being able to maintain a good therapeutic window as you dose higher?

Yes. That's a great observation. So unlike other small molecules that reach steady state usually after a couple of days, steady state with RAP-219 is not achieved until several weeks. In fact, some are likely between week 12 to week 16. So of course, it's not -- the exposures are not growing linearly. They're approaching an asymptote, but they do continue to grow over the course at any dose level, whether it's 0.75 or 1.25. So the exposures grow. And again, as I mentioned earlier, at each time point, we saw greater efficacy and with each time point, there's greater exposure. So that really sets up a nice exposure-efficacy relationship.

The higher dose achieved these exposures earlier, so we can left shift the -- we believe we can left shift the response, the clinical response. And of course, with greater doses, it gets greater exposures, and we believe that we'll get a greater clinical effect. Those data are from 1.25 are based and modeled from the data from our -- we have a great data set from our Phase I studies. We have a data set from our Phase II proof-of-concept study in focal onset seizures. And we have -- we understand receptor occupancy because we have a PET ligand. So we have a great -- we're able to work with a great model to model out this dose-exposure-receptor occupancy relationship.

Your next question comes from the line of Tiago Fauth of Raymond James.

Congrats on the data. Just a quick one on my end. For the AEs that were deemed drug-related, again, not a high absolute rate, but just curious if there's anything there that was noteworthy in terms of them clustering after dosing or after titration? Just trying to see if there's anything else that can be understood from the reported rates and if there's any mechanistic tie to how the trial is being conducted or the exposure that patients had at the time they experienced the ease.

Yes. Yes. Thank you for the question. The adverse events that were considered related by the investigator, particularly the psychiatric adverse events really are too small a number to draw any conclusion. The numbers are just too small. I'd say in general, for example, agitation tended to occur early and mostly in the first week of treatment. But apart from that, I don't think we can draw any conclusions other than really the drug was well tolerated.

Your next question comes from the line of [ Delma Caiati ] of Guggenheim.

Congrats on the very good data. So I wanted to ask about the broader [indiscernible] profile because I think it could be one of the most differentiating part of the story. So we know that many current mania drugs risk tipping patients into depression. So I'm curious what did you see on the depressive side? How did the Mania score and the CGI Depression scale move on treatment versus placebo and if you may, including the 8-week follow-up?

Yes. I'm very sorry, but I think your line is not clear, and we cannot hear your question. I don't know if there's -- operator, if there's a way to move on to the next person in the queue and maybe have that question typed out and you could read it back to us, but we're not going to be able to take that question because we can't hear it.

Your next question comes from the line of Joon Lee from UBS.

Congrats on the data. Hope you can hear me. A question for Dr. Sachs. What is the typical duration of therapy for bipolar mania? And are there any risks associated with treating the patient for longer than the symptom manifestation? And part 2, how accurate or specific is the typical clinical diagnosis of bipolar mania from bipolar depression? And does the company -- do you guys have any plans to study RAP-219 in the context of bipolar depression just to explore the safety of 219 in that setting?

Let me start with your second question first because that's an interesting point that you're making. Everybody should realize that the idea of mania as distinct from depression, these pure episodes are relatively uncommon and patients usually experience a certain degree of mixed features. And it will really be interesting to see how that plays out ultimately. It looks promising from what we've seen, but we'll need to look more carefully for the mixed feature type patients.

The other question that you asked about the duration of treatment. The average duration of a manic episode is somewhere between 8 and 12 weeks. And treatment would continue throughout that period. Why? Because as you've seen here, you have patients coming in with an average YMRS score in the mid-30s. We improve it by 15 points, and we get down to, let's say, an average score of roughly 20. Some of the acute mania trials that have been done have used that as an entry score. So after 3 weeks, there are still plenty of symptoms that need treatment. And on average, what you would see the clinicians do is maintain that treatment until there were a sustained period of recovery, usually 8 consecutive weeks. And to get out that far, we'd probably be talking about between 6 and 12 months.

Thank you. Operator, I think we have time for one more question.

Your next question comes from the line of Douglas Tsao of H.C. Wainwright.

I'm just curious, did you take PK -- or do you get -- collect PK data from each individual patient? And I'm curious if you got insight in terms of the PK/PD and an expectation that when you go to the higher dose, not just that you would get ultimately a higher effect size if you move to week 4, but we could perhaps see separation earlier because it looks like the biggest effect really took place between weeks 2 and 3?

Yes. Thank you for the question. Yes, blood levels of RAP-219 are taken on a weekly basis. Because there's only a single dose level, it's really -- it's very difficult to do a proper dose response relationship because there's only one dose level. So that hasn't been done.

But you can look at this question another way, and that is if you look at exposures over time, what is clear is that at each week when we test the blood levels, the drug levels are increased, and that fits with the model I showed you on the slide. And what is also clear is as those exposures increase, so does the efficacy. So in that respect, there is an association with exposure and efficacy.

Well, Jeff, I guess as a follow-on because I think that was sort of my question or sort of my observation is that it did seem to -- as we saw the drug levels increase. And I'm just curious from a receptor occupancy standpoint, to put it another way, did you kind of see a tipping point where patients started to separate? And I understand that it's only a Phase II and not huge numbers, but just from an observation standpoint, was there anything noteworthy to you?

Yes. We haven't done that any formal analysis to look at that. Going back to epilepsy, for example, we had a really good animal model that suggested a 50% receptor occupancy was a tipping point to get efficacy. And we believe that really translated well in the clinical study. Unfortunately, we don't have a model for bipolar mania, but we don't have an idea of where that tipping point, if there is one is. So we haven't done that. I'm not sure if this data will provide any -- shed further light on that question though.

Thanks, Doug. Okay. Great. Well, thank you, everybody, for your time today. As we close, I really want to take this opportunity to thank patients, investigators as well as clinical teams who made this study possible as well as the outcome possible. We're encouraged by what these data mean for patients living with bipolar mania, and we're excited about the milestones ahead for RAP-219 as well as the company overall. I want to have a special thank you to our employees for their dedication, and thank you all for joining us today as well. Operator?

Thank you for attending today's call. You may now disconnect. Goodbye.

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.