All righty, I think we're gonna go ahead and get started. Thank you everyone for joining us on day two in the room and online for the 2026 46th annual TD Cowen Healthcare Conference. I'm Joe Thome, one of the Senior Biotech Analysts here on the team at TD Cowen. It is my pleasure to have with me today the management team from Rapport Therapeutics. With me today, we have Abe Ceesay , who's the CEO. Joining us in a moment will be Troy Ignelzi, CFO. Maybe we'll just kick things off before we dive into the individual programs, obviously a lot of progress over the past 12 months.
If you wanna kinda hit the highlights of, you know, the big things that happened in 2025 and early 2026 and what investors should be looking for maybe for the duration of this year, and then we can kinda dive into the programs.
Great. Thanks, Joe. Thanks for having us here at the meeting. Yes, 2025 was truly a transformational year for Rapport. It really allowed us, we think, to really show data that we think is really confirmatory of our approach with the receptor-associated proteins and precision neuroscience, and that really being led by our lead program, RAP-219, in focal-onset seizures. In September of 2025, we released our proof-of-concept data in focal-onset seizures. This was a study that was in a refractory focal-onset seizure patient population. Specifically, this patient population had an implantable neurostimulation device by the name of the RNS System. We leveraged that device to be able to utilize a novel biomarker.
Through the use of that novel biomarker, we were able to really conduct a very efficient trial, and in our opinion, and I think in the opinion of the community, a best-in-class design for proof-of-concept as well. Specifically in that trial, what we saw was a significant reduction in the biomarker, which is a long episode or an electrographic seizure. Statistically significant reduction, a reduction of 72% from baseline. Also in that trial, as a key secondary endpoint, we were able to capture clinical seizures through traditional patient diaries, and what we saw was a 78% reduction in clinical seizures, which again, was really a kind of an unprecedented result.
In addition to the overall median reduction in clinical seizures, we saw a 24% seizure freedom rate that we're also very encouraged by given the fact that we know seizure freedom isn't typically impacted by placebo rates. That put us in a position that we were able to progress the program into registrational studies. We ended 2025 by having an interaction with the FDA that went very well and very efficiently. That put us in a position to accelerate our phase III program. We'll be initiating our phase III program in the 2nd quarter of 2026. We originally guided to the 3rd quarter, but based on that great interaction with the FDA, we're going to accelerate to that to the 2nd quarter.
Great. Excellent. Maybe what remains to be done to start the pivotal program, maybe can you hit the high points of what the pivotal studies are going to be looking like?
Sure. Our pivotal studies are going to be traditional in nature. As you think about the current trials that are occurring and underway in focal-onset seizures, our trial design will look very similar to those. We'll be re-recruiting and enrolling refractory focal-onset seizure patients. These are patients that are currently on medication but having breakthrough seizures. We'll be running two trials. Those trials will be done in parallel. Our specific design of our trial is going to explore three dose levels. We'll have one trial that will be a low-mid dose trial, and then a second trial that will be a mid-high dose trial. Really, we're anchoring on that mid dose, which is 0.75 milligrams.
The high dose is 1.25 milligrams, and the low dose is 0.25 milligrams. We're able to select those doses based on really some key insights from our understanding of receptor occupancy, but also some real great insights that we're able to derive from this phase II study that put us in a place where we're very confident that we're bringing forward three doses, that we believe will be efficacious.
Right. Obviously, you took a interesting approach to the signal generation study and the proof-of-concept study using the RNS device. Can you talk a little bit about the types of patients that were enrolled in that study, given that they were, you know, implanted with the RNS, and maybe contrast that with what you expect the patient population would look like in a phase III?
It's a question we often get because this was a novel study, our proof-of-concept study, enrolling patients with the RNS device. Although these patients had the RNS device, when you look at them demographically, they actually look and are very similar from a demographic standpoint to those refractory focal epilepsy patients that are enrolled in studies without the device. When you look at the time that they've lived with the disease, their number of baseline seizures, we saw baseline seizures over a 28-day prospective period of 10. That's very similar to the baseline seizure count that you're seeing in other phase III studies. If anything, the patients that we enrolled in this study, in the proof-of-concept study, are probably more refractory than the patients that are being enrolled in other studies.
Specifically, 70% of the patients enrolled in our study, in our proof-of-concept study, were on three-four medications in addition to the device. What you see traditionally is more in the two-three range in terms of background medications. These patients were highly refractory, and we were still able to see that magnitude of effect with RAP-219. We feel like the data is highly translatable. We feel that we have the opportunity to really drive and deliver best-in-class profile in our phase III studies as well.
Right. What do you think is the current sort of bar for placebo-adjusted seizure reduction that you think would be clinically meaningful? Obviously, you tie that in with the overall profile and, you know, safety and everything like that. I guess, what are you looking for? What are you hearing from your KOLs?
Yeah. I think on a placebo-adjusted basis, you know, I think the bar is in the, you know, 30%-35% placebo-adjusted reduction in seizures. The placebo rate, as you well know, Joe, is in kind of the 20% range, so you're looking at a non-placebo adjusted reduction in the 50%-55% range. I think what's really important, though, with that, and I think where the community is really driving sponsors is not only is it about efficacy, but it's how you deliver that efficacy, and that comes to the tolerability profile and also the dosing and administration. What we know about patients that are living with focal-onset seizures is these patients are on multiple medications.
They're treated via polypharmacy, and many of the current antiseizure medications have pretty significant tolerability issues, things such as sedation, somnolence, gait impairment. If you are delivering efficacy, but you are exacerbating those current AEs that a patient is suffering from on their current antiseizure medications, that's not as attractive as a profile. The other element is dosing and administration, and this becomes really important as you think about utilization patterns in the market. Utilization patterns in the market to really drive disproportionate share utilization and ultimately revenue, the drug has to be used by the general neurologist. What does the general neurologist want in a profile? They want efficacy and tolerability, but they also want a drug that they can add easily.
A drug that is dosed once daily, a drug that does not have drug-drug interactions is really what they are looking for. When we look at RAP-219, we believe that it really has those components, and we just did some recent market research that we think confirms kind of that profile that could drive broad-based adoption.
Maybe on the efficacy or the safety profile that you saw in the proof of concept study, I guess, you know, what were you seeing? I think there were some patients that had some signs of anxiety, which obviously, you know, triggered some investors given the non-selective Fycompa version and some of those aggression. I guess, what have you heard from KOLs that, you know, aggression is very distinct from the anxiety signal maybe that you saw in some of the patients in your trial?
Yeah, sure. What we saw in our phase II study, we believe is a differentiated tolerability profile and still really matches up to a potentially best-in-class tolerability profile for an anti-seizure medication. First, all of the AEs that we saw were mild to moderate. We did not see any severe AEs in our phase II study. When you look at the AE profile, it was mild to moderate AEs, what we also know is those AEs arise early in treatment and often mitigate throughout long-term use or long-term treatment. Specifically, we did see some psychiatric AEs as you mentioned, Joe, in terms of anxiety. What we know about these patients is these patients have psychiatric comorbid conditions.
Even when you look at placebo arms in focal onset seizure trials, you often see rates anywhere from 10%-1 5% in various MedDRA terms that ultimately layer up to psychiatric disorders. To believe that you're going to have a trial in refractory focal onset seizure patients with no psychiatric AEs is really just not feasible. You're going to see this in this patient population. What you asked specifically, Joe Thome, is this distinction between a psychiatric AE such as anxiety and what has been observed with a drug like Fycompa, which is a pan-AMPA antagonist, a really kind of a sledgehammer for an AMPA drug that is really non-selective in nature, and that drug has historically seen some aggression that has been associated with that drug.
What should also be understood is probably the most frequent aggression is seen with the most utilized drug in this space, and that's Keppra. Again, this is something that is seen in patients. We did not see aggression in our phase II study, and really the anxiety that we observed was actually preexisting anxiety in the patient that reported that as an AE. We do believe that the selective nature and the way that we modulate AMPA via receptor-associated protein should avoid some of those behavioral issues that have been seen with other mechanisms.
The company continues to do work on sort of the overall market opportunity here. I guess how large of a drug do you think, 219 can be in focal-onset seizures?
Yeah. One of the things that we've been, I think really excited about is the market opportunity and how that has evolved, based on our phase II data. As I mentioned earlier, we just completed a large set of market research with over 100 neurologists and epileptologists. We looked at our profile, and we also looked at blinded profiles of other novel agents that are in development. What we learned in that market research is that, clearly RAP-219 is seen as a best-in-class agent across all dynamics: efficacy, tolerability, as well as dosing and administration.
We see roughly a $2.5 billion market opportunity. That's pretty easy to get to as you think about the current refractory population for focal-onset seizures, which is 30%-40% of 1.8 million patients. At a branded price, that's a $15 billion market. We clearly see an opportunity for a multi-billion dollar market opportunity here with RAP-219. The other aspect of RAP-219 that we're actively working on is a long-acting injectable, which would be the first of its kind in epilepsy and really unique and distinct for RAP-219.
In addition to that base case market opportunity, we see additional growth with a long-acting injectable, but also from a revenue perspective, that's an extension to IP, and that just makes a much more durable and long-term revenue path for the asset.
Maybe we'll pick up on the long-acting injectable. I guess, what have you heard from KOLs as to how that would be implemented? Maybe why do they want one, given that there hasn't really been much traction in long-acting injectables? Where would that fit in? I think you're supposed to see some PK data maybe next year. What would you be looking for in that?
Yeah. This is one of the things that we are most excited about. KOLs tell us and the community tells us that a long-acting injectable for focal-onset seizures, as well as primary generalized tonic-clonic seizures, would be absolutely transformational for patients. If you think about patients, their caregivers, their families, as well as their clinicians, the biggest concern is patients missing a dose. Given the half-lives of current Anti-Seizure Medications, if you miss one dose, you have the risk of a breakthrough seizure, which has morbidity and in some cases mortality. To have an option of a long-acting injectable that allows you to be able to always have drug on board for a significant period of time would be transformational.
The reason that there hasn't been a long-acting injectable in epilepsy is not based on the lack of need, it's the limitations of other or current anti-seizure medications. You really kind of have to think about really kind of three domains. The first is the potency of the drug, because potency equals dose, and if you don't have a highly potent compound, that means you're going to have a lot of drug level. You're just not able to do a LAI with high drug levels. The second is thinking about just the inherent half-life of the parent compound. With short half-life drugs, you're just going to have to do a lot of formulation to extend that half-life. What we know about RAP-219 is in the parent compound, we have an extended half-life. The third, I'm sorry, is solubility.
We have a low solubility compound. You couldn't really design a compound better for an LAI. We've identified our development candidates. We're currently in IND-enabling work, and we expect to have our first human PK results in 2027.
When we talk about enrollment rates, maybe we'll touch on that for a little bit because obviously that's been an area of focus for investors and companies over the past couple of years. We've seen a lot of very interesting targets come through, which may also kind of extend the enrollment timelines for pivotal studies. I guess, how are you thinking about how long a pivotal program would take to enroll, and what can the company do to balance obviously a reasonable timeline to data, but making sure you're getting the right patients in?
Yeah. It's been a real dynamic in ongoing focal-onset seizure trials. You really have kind of two ends of the pole here. You have, you know, one end of the pole where, you know, it's taken sponsors, you know, anywhere from three-four years to complete these trials. You have an other end of the pole, which we'll see, continue to see how this plays out, but, you know, call it more in the, you know, two-year kind of horizon to complete these trials. I think we still have to see how that actually plays out, as I said. The key for us is really control what we can control, and a few things that we think are really important. The first is the excitement in the community.
You know, physicians and patients are selective about trials they enter. They want to enter trials that give them hope of, you know, ultimately getting a medication that's really gonna benefit them. We think there's a lot of excitement around a novel MOA like RAP-219, especially on the heels of the results that we had in September. The second aspect is you have to think about kind of the top of the funnel when you are recruiting patients. As soon as you have a drug that has things such as drug-drug interactions, limitations of other therapies patients can be on, you really narrow the top of the funnel pretty quickly, which limits your ability to recruit patients in a timely manner.
The last aspect is we're fortunate that, you know, a lot of the ongoing trials are going to be kind of wrapping up as we start to ramp up. We think that we're going to be in an advantageous position to have a bit of a more wider, wide open playing field as we think about recruiting patients globally. We believe that we can do these trials, you know, more efficiently. We haven't guided on timelines. We'll be in a better position once we get some enrollment under our belt. We think we have the right kind of tailwinds, but we also think that we have the right profile to be able to drive more efficient timelines.
Great. Maybe we'll jump over to the next data set that's coming in bipolar mania. Maybe if you could just touch a little bit on why the mechanism for 219 makes sense for bipolar mania. Why is this the first neuropsych indication that you're going after?
Yep. Bipolar mania inherently is a lower PTS indication than epilepsy. Epilepsy, you have a lot of preclinical models that have high translation that you can leverage. Bipolar and other neuropsych indications, quite frankly, you just don't have that. With all of that said, we do believe that there's strong rationale for one, bringing RAP-219 forward, and really thinking about the potential to show efficacy in bipolar mania. There's really three aspects. The first is the biology.
What we understand and what the field understands about bipolar mania is, from a biology perspective, there's really kind of a glutamate theory here, that when you look at both MRI as well as autopsies of patients with bipolar mania, is that there seems to be excessive glutamate that is really part of this disease. The second aspect is the circuit that is really implicated in that excessive glutamate, and that is the cortical limbic circuit. What we understand about the expression of TARP gamma-8 is that is specifically where TARP gamma-8 is expressed. What we also know about the AMPA receptor is the AMPA receptor has the ability through antagonism to lower glutamate transmission.
The third aspect of this is looking at the medications that are currently available for bipolar mania. When you look at two ASMs, both Valproate as well as Lamotrigine, and then you look at a drug such as lithium, all are kind of mainstays of treatment. These drugs are effective through kind of a multimodal approach. What we do know is one of the impacts that all of these drugs have is reducing glutamate. We really feel like the biology is right, we're in the right area of the brain, and again, there is some clinical precedence here with other medications that are impacting glutamate.
The company did some additional dose finding or, you know, titration work between the focal-onset seizure population and the bipolar population. I guess, can you kind of walk through why a different titration protocol might be more applicable for this population than seizures, and what did that data show?
What's important in mania is, First, it's an acute condition. These patients have acute manic episodes. In the context of this study, they're actually inpatient. These patients are being hospitalized. It's a short trial, as one would imagine. This is an acute episode that you're trying to get under control. The endpoint is anywhere from three- four weeks, sometimes five weeks, depending on the trial. The point is that what you need to be able to do is get to a receptor occupancy and a therapeutic dose relatively rapidly in order to be able to show that effect by week three.
What we really had to understand, both from our receptor occupancy work, as well as insights from our phase II study, is at what concentrations do we believe and by what time do we believe we can achieve those concentrations and the associated receptor occupancy that we believe is going to drive an effect. We're confident that 0.75 as a maintenance dose will achieve that. What we've really tried to do is optimize the titration period. We're looking at two different titration schemas up to 0.75 in this bipolar mania trial to really see what is the most tolerated path to get to 0.75, in a relatively short order, to be able to drive efficacy but also balance tolerability. In epilepsy, you have a longer time.
You have a longer time to achieve therapeutic concentrations in epilepsy studies.
What will you be looking for in the readout of this study? Maybe how is it powered and the primaries, the YMRS, I guess, what's the you know, compelling benefit on that scale that would give you confidence to move this into a pivotal program?
Yeah. As you mentioned, the primary endpoint is the Young Mania Rating Scale, the YMRS. In terms of our inclusion criteria, patients need to have a baseline YMRS at greater to or equal to 25. These are acutely manic patients. It's a little bit higher than what's been seen in traditional studies. What we believe is a meaningful effect would be to see a four-point placebo-adjusted change from baseline. We hope for something greater than that, but four-point change, as I said, placebo-adjusted, would be a meaningful effect.
Great. Maybe we'll jump over to the pain programs. You were pursuing RAP-219 also in pain. You know, the FDA put a little IND hold on there, but you've cleared that and then decided to kinda go forward with the nicotinic acetylcholine receptor program. Can you kinda walk us through why this target might be more applicable or I guess more warrant your resources?
You know, it was great to get the hold lifted on 219 . As we had talked to everyone about this, you know, it was really some protocol changes that the FDA wanted to see mainly, and given just the capacity of the team and as well as our compelling phase II results from epilepsy allowed us to submit to the FDA, get the IND hold lifted. As you said, Joe, we have decided to focus our next program in kind of our overall focus in pain and our strategy there. We think that the nicotinic program is better placed. This nicotinic program is a program that was really key to founding the company and starting the company.
This program has a level of genetic validation, the specific nicotinic receptor, but also a level of clinical experience. Company about 20 years ago by the name of Targacept was ultimately acquired by Abbott before they were AbbVie. Abbott had a very promising program here, one that showed a pretty robust level of efficacy in neuropathic pain. However, the program was really held back based on some tolerability, and this was a pan-nicotinic agonist or a very non-selective nicotinic agonist. What the scientists at Rapport have been able to do is through receptor-associated proteins, really understand what are the subunits that are responsible for analgesia, and if you can be specific to those subunits, then can you have a more specific agent than dials out some of the tolerability?
We believe that we have done that, both through what we know about the biology, but also most importantly, what we see in our preclinical models. This is a program where we've done some preclinical work in both areas of neuropathic pain and inflammatory pain, as well as migraine. A program we're very excited about. We're currently in IND enablement, and we look to be in the clinic on the backside of that, and we'll be in a better position to guide on that in terms of timing into the clinic later this year.
Great. Obviously, after the focal-onset seizure data, had access to more capital and kinda top that off, I guess, where does your current runway get you when we think about the three programs that we just kinda touched on, what milestones will we get through for those in your current runway?
Yeah, Joe. We're now funded into the second half of 2029. While Abe said we haven't guided to the completion of our phase III, we think that gives us sufficient runway to complete the phase III in focal onset. It'll also allow us to complete the phase II, obviously, in bipolar. Then we will be able to do the phase I PK results from the long-acting injectable. We should be able to finish up the phase I work in the α6β4 program. One thing I know you mentioned that bipolar was the next. We will have some data later this year. We'll have two, actually, I think, important data points. In the second quarter, we'll read out the eight-week washout period.
Remember, with the long half-life of RAP-219, there's reason to believe that we provide protection from the long episode as well as the clinical seizures well into that eight-week period of the washout. In the second half of this year, we'll have an open label extension, which will be patients from the phase II that went back on drug after this washout period. We'll have four- six-month data being able to show safety of longer exposures, but also still tracking long episodes in that population.
Great. The company can have a lot going on here very, very soon with, you know, epilepsy and bipolar mania and pain and migraine, and hopefully all of these go well. I guess, do you wanna keep all of these programs? I guess, is there any appetite for, you know, BD seeking a partner to help you on any of these targets, or kinda how are you thinking about that?
Yeah. I'll start, and then I'll ask Troy to add some comments as well. You know, we've built the company and financed the company in a manner that we can really control our own destiny. As we think about all of our initiatives with RAP-219, epilepsy, bipolar mania, the long-acting injectable, and then we think about our pipeline programs, we're in a position where we can execute those on our own. We think we're in a really great position to do that. We know not all of our peers are. Sometimes you have to make partnering decisions based on capital constraints, but also sometimes partnering decisions are the right thing to do to bring in the capabilities that are needed to execute those programs.
Given where we are today and, you know, the great team that we've had assembled at Rapport, we think we're in a good position to, you know, really do it on our own.
I think the only thing I would add is certainly we intend to be focused on the U.S. markets. If opportunities present themselves ex-U.S., doing it in such a way as not to compromise the overall program, but certainly something we would consider.
Great. Awesome. Well, congrats on the progress, and thank you for the conversation.
Thanks, Joe.
Thanks, everyone.