Rapport Therapeutics, Inc. ($RAPP)

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.