Good morning, and welcome to the Rapport Therapeutics Bipolar Program Update Call. Following the prepared remarks, we will hold a brief question-and-answer session. As a reminder, this webcast is being recorded today, October 20th, 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 plans 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 Massachusetts 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 and 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 is 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 would 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 two key themes. First, a 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 is 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, anti-seizure 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 would 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. Seven core symptoms, of which three 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 Jeff will share, I would encourage you to keep two 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 domain 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 will turn it over to Jeff.
Okay, great. Thank you, Abe. Good morning, and thank you for joining us this morning. I am 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 three, 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 mania score, which demonstrated a statistically significant improvement of 0.4 points at week three. In a pre-specified exploratory analysis, all 11 items on the YMRS numerically favored the RAP-219 treatment arm, with four 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 two groups. Lastly, adverse events commonly reported with atypical antipsychotics such as somnolence, dizziness, akathisia, and other extrapyramidal symptoms were not reported or occurred at very low rates in this 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 two or four-day titration to the 0.75 mg or to placebo, and then followed in an inpatient setting for a three-week treatment period. After completing the three-week treatment period, patients entered an eight-week safety follow-up period.
I would point out that this was a monotherapy study, so patients were required to wash out of any treatments used for bipolar disorder and any anxiolytics or hypnotics prior to enrollment. A protocol-defined rescue lorazepam was permitted during the screening and treatment periods. 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 three. Today, we are presenting the results from the three-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 three-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 will 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. Those adverse events were agitation, one patient in each arm. 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 two 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 three.
As shown in the figure, the placebo-adjusted effect continued to grow over the three-week dosing period, the lines never touching, never crossing. The absolute treatment effect of the YMRS at week three was -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 pre-specified single-item score analysis of the YMRS, and all scores numerically improved and favored RAP-219 over placebo at week three. The four items showing the greatest improvement were irritability, thought content, disruptive and aggressive behavior, and sexual interest, and these were nominally significant at week three. The improvements in the irritability and disruptive aggressive behavior items were also nominally significant at week two.
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 three. Mirroring the effect I described of the YMRS, the placebo-adjusted effect on the CGI continued to grow over the three-week dosing period, with the lines never touching and never crossing. As a reminder, the CGI Bipolar Mania Severity Scale is a clinician-rated seven-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. Therefore, these results provide 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 two 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 two times 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 two 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 truly or 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. 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 mg.
Both the primary and the 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 studies, including testing a higher dose of 1.25 mg. As a reminder, 1.25 mg 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 mg dose used in the phase II study. This is the orange line. With what 1.25 mg would achieve, this is the green line. As you can see, a higher exposure receptor occupancy is achieved with 1.25 mg at week three, and we believe this higher exposure may confer greater clinical efficacy. Moreover, 1.25 mg achieves receptor occupancy more quickly than did 0.75 mg. For example, the receptor occupancy of 1.25 mg at day seven is approximately equivalent to the receptor occupancy achieved with 0.75 mg 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 II study design and conduct. I am 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 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-BD 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 is 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 anti-manic 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 non-specific sedative effects. 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 are 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 have seen.
This may offer a user-friendly option for long-term treatment. Said another way, all approved treatments for acute mania demonstrate efficacy in clinical trials. T he 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. RAP-219 has real promise to lessen that efficacy effectiveness gap that is so problematic for patients and their families. I will stop there.
Thank you for those 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 from 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 five phase III trials underway, two in focal onset seizures, two in bipolar mania, and one 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 end 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 two multi-billion-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?
Thank you. We are now opening the floor for question-and-answer session. If you would like to ask a question, please press star followed by one on your telephone keypad. That's star followed by one on your telephone keypad. Your first question comes from the line of Salveen Richter of Goldman Sachs. Your line is now open.
Congrats on the data, and thanks so much for taking our question. Could you maybe just square the 3-point improvement on the YMRS with prior historically successful trial outcomes, particularly in the context of the tightened statistical bars here and the potential phase III study design? Thanks so much.
Salveen, thank you for the question. As you think about this 3.1 placebo-adjusted difference, I'm going to have Jeff provide some perspective as well as 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 twos, in the threes, and ultimately in the fours and the fives as they go across clinical development. 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.
I think of this at three 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, getting to your specific question is it meaningful? T here, 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. 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 patient and to our physicians, particularly irritability and aggressive behavior. I t's treating the core underlying disabling effects of 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 mg. We intend to get that extra efficacy by increasing the dose to 1.25 mg in the phase III study.
Dr. Sachs, do you have any perspectives on these results, but also how that might inform how physicians look at the meaningfulness of this?
Yeah. I agree with how Jeff laid this out. 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 looked 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. T he 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 two different from another study that may have had different entry criteria, been done in a different region with different placebo response. R eally 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. Your line is now open.
G ood morning. 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? Then just for the company, can you talk about the rescue meds with lorazepam and just put that in perspective for us? Thank you.
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. I find the results here really encouraging. This is the first non-sedating anti-manic drug, suggesting 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.
Jeff, maybe you can provide some perspective on the rescue medication use and maybe also perspective on previous trials as much as we know.
Yeah, r escue lorazepam was permitted in this 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 that had 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% though.
Thanks.
Your next question comes from the line of Paul Matteis of Stifel. Your line is now open.
Good morning. Thank you and congrats on the data. Maybe taking a step back here, I know you guys set this 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? Then to that point, is the base case here for risk mitigation to do two additional pivotal studies? What might you do in those studies to try to mitigate a large placebo response from repeating itself? Thank you.
Yeah. Thanks, Paul. The answer is yes. We continue to believe this data support confirmatory evidence. As Dr. Sachs said, statistical significance is statistical significance. The strategy has always been to do two additional trials with the kind of conventional adage in neuropsychiatry, do three to get two. Our plan will be to meet with the FDA, as Jeff said, within our end of phase II meeting and then run two parallel phase III trials based on the outcomes of that end of phase II meeting. W e really are confident in this data.
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, but 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. M aybe, Jeff, you could talk through a little bit 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.
Yeah, 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. S tudies 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.
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. T hat's believed to be one of the reasons why the better signals are detected in some of these ex-U.S. geographies.
Thanks, Paul. Next question, operator?
Your next question comes from the line of Joseph Thome of TD Cowen. Your line is now open.
Good morning. Thank you for taking my questions, and congrats on the data. Maybe as the benefit does look to continue to widen with time, can you 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? 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 what's included with that? Why do patients withdraw consent, and were these numbers expected? Thank you very much.
Okay. Thank you for the question. Yeah, 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. As the exposure was increasing, the efficacy was increasing. This study went to week three. Conventionally, phase II and phase III studies in this indication go to week three or week four. T hat will certainly be one of our considerations when designing the phase III study. Do we increase the duration of the study to week four because we believe that the effect at week four will be greater than week three? T hat is an important consideration. There is precedence for it, and it's something that we'll be considering when 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. The rate of withdrawal of consent tends to be in the mid-teens. I n 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? In fact, that's not the case. We do have data from the last YMRS that the patients completed prior to discontinuing.
It turns out people in the placebo arm were doing worse, and people in the RAP-219 arm were doing better. A plausible explanation is people are getting better, and they no longer want to be in the inpatient setting.
Great. Very helpful, thank you.
Thank you, Joe.
Your next-
Sorry, operator. Go ahead.
Your next question comes from the line of Andrew Tsai of Jefferies. Your line is now open.
Hey, guys. Congrats on the data. This is John on for Andrew. 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? Secondly, how much do you think you could potentially even reduce the placebo response on some of the measures you mentioned earlier? Thanks.
Yeah, I'll let Jeff get into the details of that. I want to really make sure we continue to reinforce that this was a positive response. Although there are opportunities in the phase III study to work on both ends, as you said, the absolute treatment effect of RAP-219, as well as controlling for placebo response. We will do that, but this trial was successful. 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. W e see this trial clearly achieving success. A s you said, we will continue to look to ways to improve, as one always does, going from phase II to phase III.
Yeah, I would be speculating with regard to what effects 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 because there is going to be greater exposure. With regard to the placebo response, I would say and our goal would be to get it at 10 or less. We observed about 12 in this study. Historically, I think a placebo response of 10 or less would be a good outcome. T hat would be a reasonable goal.
Yeah, 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. Novel mechanisms raise expectation drives true placebo response. 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.
Thank you, Dr. Sachs.
Thank you guys so much, and congrats again.
Yeah, thank you for the question. Operator, next question?
Our next question comes from the line of Myles Minter of William Blair. Your line is now open.
Thanks for taking the questions, and congrats on the data. First one's just on, was there any sort of material differences you saw in the two different titration cohorts? They seem pretty minimal differences to me, and in the past, I think you've expected that they'd perform pretty similarly. 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. 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? Thanks very much.
Yeah, thank you for the question. Regarding the titration, it was basically a sub-experiment within the main experiment to determine whether the four-day titration would be better tolerated than the two-day titration. I n fact, the two-day titration was so well-tolerated, there was not really any room for improvement. W hat we learned is if we were to run the identical study a second time, we would not use the four-day titration. Now, in the phase III study, we still have to decide whether we use a titration at all. 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 to or benefit to doing the four-day versus the two-day titration.
I'm sorry, Myles. What was the second part of ? M aintenance, thank you.
Just the plan for maintenance.
Yeah, 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. There are three indications in bipolar. That is mania, maintenance, as well as depression. However, indications do not necessarily drive clinical care. What our understanding is that clinical care is really determined by, is a drug effective and tolerated in the acute phase? Then patients maintain themselves, or clinicians keep patients on that drug in a maintenance setting. 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. Dr. Sachs, would love to hear your thoughts on this as well.
Yeah. 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 one episode. They may have only mild symptoms, but irritability drives the experience of the patient, their family members, their employers, etc, and is often present at the beginning of the next episode. A treatment that can effectively reduce that would be very attractive for long-term management of bipolar patients. 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.
Next question, o perator, please.
Your next question comes from the line of Kambiz Yazdi of U.S. Bancorp. Please go ahead.
Good morning, Rapport team. Congrats on the data. For the Rapport team, how do you think about RAP-219's mechanism, potentially in conjunction with other antimanic agents? 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 a non-sedating profile differently in the acute hospitalized patient setting versus a potential outpatient setting long term? Thank you.
Yeah, 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 interactions. O ne that could be added in a rational way to polypharmacy. 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.
Yeah, no, I got that and really appreciate that question because it's important to understand the way clinical management works. W e'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. I'm not concerned about whether I get efficacy on day one by producing too much sedation. That might be okay in the hospital on day one and two.
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 hyper-acute phase is over. The idea that it might play well with other treatments is really encouraging, let's see what happens in the real world.
Thank you so much.
Next question?
Your next question comes from the line of Danielle Brill of Truist Securities. Your line is now open.
Good morning. Congrats on the outcome here, and thanks so much for the questions. Two from me. You guys noted that the RAP-219 patients who withdrew were generally improving at their last assessment. I am wondering if you could discuss how the primary endpoint held up across key sensitivity analyses for the missing week three data. Also, I am wondering if you could share the YMRS response and remission rates by arm and whether those showed a similar separation or more clear separation in the mean change analysis. Thank you.
The statistical model used for the primary primary analysis we presented was a MMRM. This is a robust model. It is 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 is everybody. The model includes data from all patients that were randomized into the study. The model handles missing data implicitly. That is a device that the model has built in, and we assume that any data missing was missing at random.
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, that is a greater than 50% responder rate, was close to becoming statistically significant but did not quite reach the 0.05 threshold, but certainly favored RAP-219. The remission rate also favored RAP-219. Those were not primary or secondary endpoints. Those were exploratory. We are very pleased with those outcomes as well.
Next question, o perator?
Your next question comes from the line of Benjamin Burnett of Wells Fargo. Your line is now open.
T hank you, and I will 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 is expected to continue to build within the three-week timeframe that you have here. I was 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.
Yeah, that is a great observation. 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, it is somewhere likely between week 12 to week 16. Of course, the exposures are not growing linearly. They are approaching an asymptote, but they do continue to grow over the course at any dose level, whether it is 0.75 or 1.25. The exposures grow, and again, as I mentioned earlier, at each time point, we saw greater efficacy, and with each time point, there is greater exposure. That really sets up a nice exposure-efficacy relationship. The higher dose achieves these exposures at earlier, so we believe we can left shift the clinical response. Of course, with greater doses, it gets greater exposures, and we believe that we will get a greater clinical effect.
Those data from 1.25 are based and modeled from the data from our great data set from our phase I studies. We have a data set from our phase II proof of concept studies in focal onset seizures. We understand receptor occupancies because we have a PET ligand. We are able to work with a great model to model out this dose exposure receptor occupancy relationship.
Thank you. Operator, next question.
Your next question comes from the line of Tiago Fauth of Raymond James. Your line is now open.
Hi. Congrats on the data, Jeff. Thanks for taking the question. 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 is anything there that was noteworthy in terms of them clustering after dosing or after titration. Just trying to see if there is anything else that can be understood from the reported rates, and if there is any mechanistic tie to how the trial is being conducted or the exposure that patients had at the time they experienced the AEs. Thank you.
Yeah, 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 conclusions. The numbers are just too small. I would say in general, for example, agitation tended to occur early, mostly in the first week of treatment. Apart from that, I do not think we can draw any conclusions other than really the drug was well-tolerated.
F air enough. All right, thanks.
Your next question comes from the line of Delma Caiati of Guggenheim. Your line is now open.
Hi. Congrats on the very good data, and thank you for taking my question. I wanted to ask about the broader mood profile, because I think it could be one of the most differentiating parts of the story. We know that many current mania drugs carry a risk of tipping patients into depression. I am curious, what did you see on the depressive side? How did the MADRS score and the CGI-BP depression scale move on treatment versus placebo? If you may, including the eight-week follow-up. Thank you.
Yeah. I am very sorry, but I think your line is not clear, and we cannot hear your question. I do not know if, operator, if there is 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 are not going to be able to take that question because we cannot hear it.
Your next question comes from the line of Joon Lee from UBS. Your line is now open.
Hi, guys. Congrats on the data, and thanks for taking our questions. 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? Part two, how accurate or specific is the typical clinical diagnosis of bipolar mania from bipolar depression? Do you guys have any plans to study RAP-219 in the context of bipolar depression just to explore the safety of RAP-219 in that setting? Thank you so much.
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. It'll 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 eight and 12 weeks. 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. A fter three weeks, there are still plenty of symptoms that need treatment. On average, what you would see the clinicians do is maintain that treatment until there were a sustained period of recovery, usually eight consecutive weeks. To get out that far, we'd probably be talking about between six and 12 months.
Thank you.
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. Your line is now open.
Hi. Good morning, thanks for taking the questions. I am just curious, did you collect PK data from each individual patient? I am 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 four, but we could perhaps see separation earlier. It looks like the biggest effect really took place between weeks two and three. Thank you.
Yeah, 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 very difficult to do a proper dose-response relationship because there's only one dose level. That hasn't been done. Y ou 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. What is also clear is as those exposures increase, so does the efficacy. In that respect, there is an association with exposure and efficacy.
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? I understand that it's only a phase II and not huge numbers, but just from a observation standpoint, was there anything noteworthy to you? Thank you.
Yeah. 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 the tipping point to get efficacy. We believe that really translated well in the clinical study. Unfortunately, we don't have a model for bipolar mania, so we don't have an idea of where that tipping point, if there is one, is. We haven't done that. I'm not sure this data will provide any, shed further light on that question, no.
Okay, great. Thank you.
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 of 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.