Awesome. Hi, everyone. Thank you for joining us at the 2026 TD Cowen Neuropsychiatry Summit. I'm Joe Thome, one of the senior biotech analysts here on the team at TD Cowen, and it is my pleasure to have with me today two members of the team from Rapport Therapeutics. We have CEO Abe Ceesay with us and CFO Troy Ignelzi. Thanks guys for tuning in. To the investors, if you do have any questions specifically for the management team, feel free to put them in your chat box, and we can help work those into the conversation.
But maybe just to start off, Abe and Troy, we'll obviously dive into the programs, but you had an analyst day yesterday, ahead of the bipolar data, but maybe just give a little bit of a top-down view of Rapport Therapeutics and what investors should be looking out for, as sort of a state of the business, and then we can go from there.
Sure. Thanks, Joe, for the opportunity, and good afternoon, everybody. Rapport Therapeutics is a company that we started through a collaboration between Third Rock and J&J, really to create what we hope to be the leading precision neuroscience company. We have a real scientific foundation that drives not only our lead program, RAP-219, but also our entire discovery focus, and that is the realization and the utilization of receptor-associated proteins. This allows us to have specificity with small molecules in neuroscience that we think is unprecedented. We think we've seen that play out with RAP-219. We're making significant effort across our discovery portfolio as well. We hope to continue to build that pipeline. Specifically, RAP-219 targets a specific receptor-associated protein, TARPγ-8, that is associated with the AMPA receptor. We presented and released unprecedented results in focal onset seizures September of last year.
We've continued to update that data set with a presentation at AAN this year that further elucidated the clinical utility of the drug. As you mentioned, Joe, we're on our way to potentially having some bipolar data here in the coming month.
Perfect. Maybe that'll be a good place to start, just given the theme of the day, but obviously expecting the data next month. Maybe what gave you the confidence or the interest in studying RAP-219 in bipolar mania? Maybe we'll start there on the profile. Then if you also just want to touch high level on the current unmet need and the indication, because I know there were some interesting takeaways from yesterday, too, on that.
Sure. Our approach when we started the company thinking about RAP-219 and the opportunity was always thinking about it as a pipeline and a target, a pipeline and a product potential. We really prioritized a set of indications where we felt the biology took us. First clearly was epilepsy, given what is known about the excitatory process driving seizures, but also the role of glutamate and the AMPA receptor. It was really kind of de-risk pass as we think about the opportunity and the path forward in epilepsy. Really next on the list was bipolar mania specifically. That was based on a few different points of evidence. One, the emerging literature was really supporting the role of glutamate in specific, the manic process.
Second was the region of the brain that functional MRI as well as other imaging was showing, which was that glutamate expression was focused in the corticolimbic network, which really overlapped with TARPγ-8 expression. Then the third was a long history of anti-seizure medications being effective therapies for bipolar disorder, both in terms of mania as well as mood stabilization. So it was always kind of a bet that we felt was the right experiment to run as we thought about the opportunity for RAP-219. We were buoyed as we saw the epilepsy results as well, because what we really understood from the epilepsy results is, one, we can confirm target engagement. Two, we felt that we had a tolerability profile that would be, along with efficacy, highly differentiated in bipolar disorder.
That really gets to your question around what is the unmet need in this patient population. The first I'll say is it's significant, and it's a large population. We're talking about roughly 1.6 million patients with bipolar I disorder. There has not been much innovation at all for these patients. As you think about the therapies that are available to them, they really are bucketed into three. One are atypical antipsychotics or the dopaminergic pathway. Two is lithium. Then three are a couple approved anti-seizure medications. When you think about this patient population, it's really a high-functioning patient population.
Although they do live with bipolar disorder, both in the manic side as well as the depressive side, the reality is they are looking to stay highly engaged in their lives, whether that is their family life, their social life, their work life, whatever it may be. The current available medications and the tolerability profile really takes them away from those things that they need to be engaged in. We really know what the tolerability limitations are of atypical antipsychotics. Those are the extrapyramidal symptoms, the weight gain, metabolic changes, et cetera. Then on the anti-seizure medication side, it is the sedation, somnolence, as well as gait impairment.
We saw a really nice opportunity that potentially bringing a novel MOA to bipolar disorder, and one that has a tolerability profile that would be much more appealing to patients and clinicians as they think about staying on a therapy long term.
Perfect. You've done some, I guess now several kind of phase I studies across both indications for RAP-219. The titration kind of protocol is a little bit different here than it is for epilepsy, I guess. You're looking at two different ones.
Even though at the end they're going to be one-to-one randomization. Can you just walk us through how you found the dose for bipolar and maybe why taking some of the adjustments on dose escalation versus what you saw in FOS patients?
Sure. Going into the bipolar study, we had the benefit of a lot of data as compared to going into our phase II study in epilepsy. Going into the phase II study with bipolar, we had the benefit of our human PET study. Clearly, all of our phase I studies, as you mentioned, Joe, which the PET study was one of them. We did not have the PET study when we went into our phase II study for epilepsy, the human PET study. We also had the phase II data from the epilepsy study as we considered dose selection going into the bipolar study. A couple of key aspects here and imperatives for us as we thought about dose selection going into the bipolar study. First was our understanding of receptor occupancy, and really informed by two things.
One, what was the maximal efficacy we saw in the corneal kindling model, which is a model of epilepsy, but also can be used as a model to inform bipolar mania, dose selection as well as efficacy. The second was thinking about how that receptor occupancy and PK lined up with a pharmacodynamic effect, and we really were able to glean that from our epilepsy study because we were able to leverage this novel biomarker, which is the long episode or that EEG electrographic data. What we really understood from all of this data is that with RAP-219, we are able to achieve a level of RO as well as a PD effect very early in dosing. In our epilepsy study, we saw that via the electrographic readings within two or three days of dosing.
When we thought about the dose that we take forward in bipolar, we knew what maintenance dose we needed to get to. We also understood by what time did we need to achieve that receptor occupancy. Basically what we did is looked at two titration schemas that are not that different from each other to understand if that had any differentiation in terms of tolerability. We did not go in with any tolerability concerns, but our feeling was any improvement that one can see in tolerability is always a benefit. That was really the rationale to look at those two tolerability, I am sorry, those two titration schemas.
Perfect. Neuropsychiatry studies are always, I guess notoriously maybe a little bit difficult to design and implement, and management of placebo controls, obviously-
top of mind. I think there were some really good takeaways from yesterday in terms of maybe things that Rapport along with the KOLs that designed the study are doing to make sure that you're enrolling the right patients and there is effective clinical trial conduct. Maybe if you want to touch on those, both from the enrolled patient population side of things, but then how are you monitoring patients to make sure that you're hitting a lot of the things that companies are usually a little scared of when they're running a trial?
Yeah, sure. It's something that we take as first priority here at Rapport as we think about clinical trial execution, and that is really quality execution as any biotech would. One of the things that we've really thought about here with the bipolar study is really listening to the experts and bringing the experts in as we thought about the overall trial design as well as the protocol.
In terms of the trial design, it's very standard, our bipolar study, as all bipolar mania trials are. They're three weeks in length with the primary endpoint being at week three, looking at that placebo-adjusted difference on the YMRS. The real innovation that comes in trials is really thinking about quality and also thinking about what are the methods that you're putting in place that can control variability, that ultimately allow you to have a better control of the placebo response as you think about these trials. That's where we brought in a lot of thought into this trial design, which we highlighted, as you mentioned, Joe, in our call yesterday with two key opinion leaders. A couple of key themes.
The first is, as you think about the type of patients you're enrolling into these trials, we really want to confirm that these are truly manic patients, and manic patients and their mania is driven by bipolar disorder. So looking at, one, it not being their first manic episode, two, that their mania was not caused by any environmental changes or drug-induced mania, as an example. Then we're also looking in the screening to baseline period to ensure that patients don't have a significant degree of self-resolution, because that would inform that these patients are going to resolve without any intervention. So that's just one example of some of the things that we've put together in the trial.
We have several quality metrics that we are looking at in a blinded fashion throughout the trial to ensure that we're seeing the right quality across sites as well as within sites. Also doing things such as the number of sites to decrease variability as well. We really feel like we have brought the best thinking into the trial design to give the drug, at the end of the day, the best chance for success.
Maybe we'll start on the efficacy outcome portion of what you'd like to see. Maybe what do you see as the bar here for what a successful study would look like on the YMRS? Obviously, stat sig-
but anything beyond that. The company did increase the size of the trial. Can you just walk us through that and whether you think now if you hit here, this could potentially be one of two pivotal registrational studies that you would need?
Sure. To look at the clinically meaningful threshold that has been defined as greater than four on the YMRS on a placebo-adjusted basis. When you think about that as it relates to trial success and also thinking about just commercial utilization of a drug, those are really two different things. When you think about commercial utilization, you see approved therapies that have anywhere from a four-seven point placebo-adjusted difference on the YMRS. Clinicians really aren't making decisions on one drug produces a four, one drug produces a six. What they're really making decisions on, is the drug effective and will the patient stay on the therapy? So that's a really, I think, important point just to hold onto as we think about market adoption. As we think about clinical trial success, we have powered the study to detect that four-point placebo-adjusted difference.
As you mentioned, we did adjust the alpha from 0.1- 0.05 partway through the trial. That was based on what we were observing in overall enrollment, quality of the trial, and our feeling was that by making that alpha change as well as doing the necessary increase in the sample size, it would position this program to be potentially confirmatory evidence. Our development strategy based on this data, if this data were to be positive, would to run two additional registrational trials with the old adage that do three to get two in neuropsychiatry program.
Perfect. Then maybe flipping to the tolerability side of things because I want to make sure we cover this. Obviously, there's been some news in investor discussion with the ASMs and trying to move into neuropsych and a tolerability profile. So I think it'd be good to just touch on it. I guess, what are you expecting to see maybe in the AE profile? What are some things that maybe in the bipolar mania population wouldn't surprise you
that you maybe would expect to see in both arms? What's your expectation for what the drug is going to do? Then maybe just in terms of real-world experience with approved drugs or label with approved drugs, just to help put that in context so that we're not surprised in terms of maybe some things that we're seeing when the top line comes.
Sure. So if you think about this patient population, a bipolar manic patient population or acutely manic patient population versus an FOS patient population, they are two very different patient populations living with a different set of comorbidities, but also different presentations. Specifically for the manic population, these patients are showing up in an acutely manic phase. It's an inpatient trial. Some of the reasons that they are defined as manic are things such as agitation, psychosis, aggression as an example. So the reality is, as in any trial, not every patient is going to improve on treatment.
We would not be surprised if some portion of patients had worsening mania symptoms as an example in the trial. To your point, we also believe that we will see that in placebo as well, and that's historically what you see in those trials. Another aspect of our trial is the use of rescue medications, which are benzodiazepines in mania trials are standard. It's standard to use benzodiazepines as rescue medications. Patients are washed out of all other treatments, but rescue medications are available for clinicians to use in acute mania trials. Those rescue medications are used based on the symptoms that the patients are presenting and the ability to maintain those patients in the trial as well as in the inpatient unit.
In the case of our trial, in order to use rescue medication or a benzodiazepine, the clinician had to identify an adverse event that they were trying to address based on the use of that benzodiazepine. That adverse event could be drug-related or non-drug related, but we expect to see that, as an example, if a patient had a certain symptom that a clinician felt needed to be addressed via a benzodiazepine, we assume that that's going to show up in the adverse event tables as well.
Okay, perfect. That's helpful. You touched a little bit on some patient numbers maybe at the beginning, but how large of an opportunity do you think bipolar mania could be for RAP-219? I know for FOS, you've indicated potentially a $2 billion drug on the oral side and a $2 billion on the LAI side. I guess, do you think bipolar mania could also be a blockbuster plus? How are you thinking about that?
Without a doubt. It is roughly the same size as the FOS patient population. FOS is roughly about 1.8 million patients in the U.S. The bipolar mania population is about 1.6 million. It's about 1.1 million patients that are either on second or third-line therapy, but it's a heavily treated patient population. We see a multibillion-dollar market opportunity that is here potentially for a novel agent like RAP-219. It has a really interesting place as physicians have provided us feedback through market research and the fact that it is non-dopaminergic, so that is a real class that both clinicians as well as patients understand the limitations with, but it's also not a traditional anti-seizure medication, and one that if it does provide efficacy, has a tolerability profile that would be really appealing for patients and clinicians.
The next is thinking about the availability of a long-acting injectable also for this patient population.
Okay, perfect. On that point, there is a lot that you can do here, LAI oral for both programs. Obviously, we would start a pivotal program upon positive data. Maybe over to Troy, can you just remind us of your current financing position? Obviously, you would have a lot of optionality if the data are good in terms of what you could do there. I guess, what does your current funding cover, and how are you thinking about expanding that timeline?
Yeah. The current cash would take us into the second half of 2029, and while we haven't given specific guidance on the timeline for our FOS phase III, we have indicated that that is sufficient to fund those two programs that are currently underway. It also will give us the opportunity to get through the long-acting injectable phase I work, which we expect phase I PK results next year, as well as advancing one of our discovery programs into and through the phase I's. Obviously, the bipolar mania is right around the corner. Those results, we would look to the markets for opportunities to fund that through the phase III. Interestingly, if we did see positive results, we would start the phase III in bipolar mania, call it nine months give or take. Those trials are more efficient, and they are smaller, excuse me, in time.
We would expect a time period where we could have four phase III's reading out in a very tight window. It could be an exciting opportunity for the company.
Perfect. In the last five minutes here, we will switch to the focal onset seizure program. Maybe if you want to just give an update. I know the phase III's are up and going. Maybe how are things progressing there? It seems like phase III programs for epilepsy have book-ended in terms of how quickly or how long it takes to enroll. I guess, what are your expectations or things that you will be looking for that might provide you an opportunity to narrow timeline guidance?
Yeah. The trials are both up and running. We have been really pleased with the start of the trials as well as the ongoing execution from our team. These are global trials in nature as you look at the history of development programs in FOS. As you mentioned, Joe, there are two bookends in terms of timing, think about length of trials. Our view here is that we do not believe we should be on either end of those bookends, there are reasons to believe why you should not, but also why you would not want to be on either bookends of those timelines.
We believe that there is a lot of wind in our sails, as we just think about the profile of RAP-219, the way that we have approached the study startup and the sites that we have gone to, but also we have done some new things in our trial, like the inclusion of China as a country via collaboration we have with a company by the name of Tenacia in China. Overall, we are really pleased with what we are seeing. We think we are going to probably be in a position middle of next year to provide actual guidance on completion of the studies once we have more enrollment under our belt. In addition to the ongoing phase III, the other aspect of the focal onset seizure program is the ongoing open label extension for patients that were in the phase II study.
The majority of patients that were in the phase II study have come over to the open label extension study. In the fourth quarter, we are on track to be able to release our initial set of data or initial cut from that open label extension study, and we think there is going to be, on an average, 6 months of exposure for those patients. So we think that that is going to be a really nice update to the program as well, particularly looking through the lens of longer-term safety.
Perfect. Maybe just last question, because I do think the LAI component here is probably underappreciated. Maybe what specifically about RAP-219 lends itself to LAI formulations? Maybe why haven't other drugs in epilepsy been able to be successful there?
The LAI would be transformational in epilepsy. We see in our market research, also just speaking to the community, that it has the potential to double the market opportunity for RAP-219. It's a huge unmet need in terms of that dosing convenience for this patient population, but also has applicability to the neuropsych patient population as well. The reason that there has not been an LAI in epilepsy is not based on the lack of need. It's really the limitations of other compounds. If you think about other compounds that might not be that potent, that really equates to larger drug levels that make it more difficult to have a subcu injection. Drugs or compounds that have high solubility, drugs and compounds that have longer titration schemas or the potential for drug-drug interactions, you're not able to formulate those types of compounds feasibly into long-acting injectable.
For RAP-219, it's a very unique compound in the fact that it's exquisitely selective and extremely potent. Our maintenance doses are up to 1.25mg , so that allows for really low drug levels. It has low solubility, and it has an inherently long half-life and no drug-drug interactions. We've made great progress with our formulations here at Rapport. We're currently in the back end of IND enabling work with the goal, and we're on track to be able to have our first human PK results for our initial formulation of an LAI in 2027.
Perfect. Awesome. Unfortunately, we're at time, but a lot to pay attention to here. So best of luck with the data next month, and thank you both for joining us.
Thanks, Joe.