All right. We're gonna go ahead and get started here. Thank you again for everybody for joining us this afternoon at the Citizens Life Sciences Conference. Really excited to be joined next by Rapport Therapeutics. Rapport is developing a novel drug for the treatment of epilepsy, really strong Phase 2 data last year and quickly moving into Phase 3. Joined by Abe Ceesay, CEO, and Troy Ignelzi, CFO. Welcome, Abe and Troy. Would maybe just ask you, Abe to give a quick 30-second overview of the company.
Sure. Jason, thank you so much for having us at the meeting. Rapport was created through a collaboration between Third Rock as well as J&J to create a precision neuroscience company. Precision is a term that's used a little bit loosely in our industry, specifically in neuroscience, but we believe that really the core technology and the core science that we're working from at Rapport can really bring that to life. Specifically, the real scientific premise behind Rapport are receptor-associated proteins. These are proteins that are associated with various ion channels, sensory neurons, that we believe through either understanding receptor-associated protein science or targeting receptor-associated proteins specifically, we can have real precision in terms of small molecules in neuroscience. Our lead program is the best way to understand that. Our lead program is RAP-219.
This is a TARP gamma-8 AMPA modulator program. TARP gamma-8, or TARP gamma-8 I should say, is the receptor-associated protein that is associated with the AMPA receptor. By targeting this receptor-associated protein, it allows us to only have activity in four brain structures. In the area of our lead indication, as well as our follow-on indication, our lead indication being focal onset seizures, follow-on indication being bipolar mania, having that four-brain focused selectivity is very important to be able to deliver efficacy while mitigating some of the most bothersome and troublesome adverse events that are associated with the anti-seizure medications as well as medications that are used to treat bipolar.
Maybe we'll start with mechanism because it as much as it's a truly novel mechanism through the receptor-associated protein, there is already validation of targeting AMPA in epilepsy. Just kind of walk us through the different components of the mechanism.
Yeah. AMPA is a validated target for epilepsy. We know that the AMPA receptor is extremely important in terms of synaptic transmission as well as glutamate transmission. We know by downregulating the AMPA receptor, you can have pretty effective control of seizures. The challenge is there's one drug that has been developed that is a pan-AMPA antagonist that is a drug by the name of Fycompa. That drug although it is effective, the challenge is when you are antagonizing AMPA receptors ubiquitously, you really have no therapeutic index. By interacting with AMPA receptors in hindbrain structures, you're seeing pretty significant adverse events that are tied to areas of the brain such as the brain stem and cerebellum. You're seeing gait disturbances, ataxia, sedation, and somnolence.
Now, that's actually understood pretty well with AMPA receptors, but it's actually the same concept for other mechanisms of action in with anti-seizure medications as well. Where with other mechanisms, whether it's calcium channel agents, potassium channel agents, you name it, if those drugs are interacting with those channels or receptors in the hindbrain, you're also going to see sedation, somnolence, et cetera. We're leveraging known biology, validated biology, but we're targeting that biology in a way that we know we can deliver efficacy while mitigating those side effects.
I think another important here is now we have, you know, clinical data in patients that really speaks to the safety profile. But before that, you had generated data both preclinically and in healthy volunteers showing the selectivity that really reinforces that the drug is targeted.
Yes.
Maybe just walk us through some of that imaging data.
Yeah, the great thing about developing drugs in epilepsy is the preclinical models are very translatable, both from an efficacy assay as well as a safety assay preclinically. The gold standard is a model that's called corneal kindling for focal onset seizures. We really saw unprecedented efficacy in that model, and potency, with RAP-219. Importantly, there's a safety assay which is called the rotarod test, and that is picking up tolerability issues such as sedation, somnolence, gait impairment. What we saw is at the highest doses of RAP-219, it was not inducing any failures on the rotarod. That is very unique. Most other anti-seizure medications, when you're achieving a therapeutic dose, you're actually seeing really no therapeutic index.
At the same level you're achieving efficacy or the same level you're starting to see those rotarod failures. That was kind of the first finding for RAP-219. The second is, you mentioned, Jason, is our observations through our human PET study to really confirm, one, the expression of the receptor-associated protein, and then two, kind of the receptor occupancy associated with RAP-219. What we've confirmed through those, a series of PET studies really around the target, is that this target is highly expressed in the areas you wanna be. Those areas for focal onset seizures are the mesial temporal lobe and the neocortex. Those are important because that's where the vast majority of focal onset seizures are both originating and propagating.
What we know about this receptor-associated protein is it's not expressed in high degrees in hindbrain structures. That was confirmatory. The last piece of confirmation, as you mentioned, has been our clinical experience. We have dosed over 100 subjects or roughly 100 subjects in our Phase 1 studies and really were able to confirm this wide therapeutic index through our observations of the tolerability of the drug, and then most importantly, our most recent Phase 2 proof of concept data in September of last year, where we really saw unprecedented efficacy as well as what we believe is a highly differentiated tolerability profile.
You ran a really novel Phase 2 study. I think the positive thing that now comes out of it is your clinical seizure reductions were so dramatic that a lot of the nuances behind that study, people don't really ask you about anymore. Maybe let me ask it from this perspective. You had a biomarker, long episodes. It's still a relatively small Phase 2 trial. How does the clinical seizure data marry with the biomarker data to really reinforce that you expect this result to be predictive of a positive Phase 3 outcome?
Yes. You know, we did take a little risk, and we were innovative in our proof of concept design. As you mentioned, we enrolled patients with an implantable neurostimulation device. Now, these patients are refractory focal epilepsy patients. When you look at their demographics, you look at their background medication, time living with the disease, as well as their baseline seizure count in our study, they look very similar, if not the same, as those patients that are traditionally enrolled in other trials. The difference is that they have this implantable device. This implantable device serves a therapeutic purpose, but in our study, it's really for the diagnostic purpose, and what it does is it constantly tracks electrographic activity. Specifically, you mentioned this concept of a long episode, which in the context of our study really is an electrographic seizure.
What we were trying to do in this study is to have an objective biomarker really validate the reductions we were seeing in clinical seizures. This is a study that ultimately the field really pushed us to. You know, we wanted to do this study, but the field was really driving towards we need more efficient trials and proof of concept to understand if novel anti-seizure medications are effective. By utilizing a novel biomarker, what we're able to do is we're able to enroll a much smaller study because the study is powered off of the biomarker, not clinical seizures. Clinical seizures just have natural variability and a placebo rate. If we were to do that study just on clinical seizures and proof of concept, we'd still be waiting for data.
Right.
By utilizing that novel biomarker, we're able to enroll a trial much more efficiently, and we believe with more objective results. In that study, we were able to see a 72% reduction in the biomarker, which are long episodes, and in our study, 92% of those long episodes were electrographic seizures, and we also observed a 78% median reduction in clinical seizures. To just remind people, our expectations for this study was to see a 30% reduction in long episodes and a 50% reduction in clinical seizures. We significantly surpassed our expectations in this study.
As you mentioned as well, the safety and tolerability profile looked fantastic too.
Yes. The safety and tolerability profile, we were really encouraged by. We thought it really supported the thesis around the biology. We saw a relatively low discontinuation rate with only 10% of patients discontinuing. We only presented data in the treatment period. We're going to be presenting data from the follow-up period here shortly. What we saw was all AEs were either mild to moderate, and the majority were mild. We observed no serious adverse events in the treatment period, so we were very encouraged with the tolerability.
You've been continuing to move quickly. You met with FDA at the end of last year. You were, you know. I think the positive is there is clear precedent on what a Phase 3 trial in epilepsy, focal onset epilepsy looks like. You were able to then move up your timelines to start that Phase 3 trial. Just kind of give us an overview of the trial design, yes, but more about how you think about trial design, trial execution, both making sure that placebo rate is mitigated, but also keeping the rate of enrollment, you know, at a pace that's on level with your targets.
Yep. Registration studies in focal onset seizures are really a well-trodden path. There's not a lot of innovation in terms of trial design. Most trial designs are going to look very similar, and really the nuance is going to be based on the profile of your drug. As you think about whether it's drug-drug interactions or titration schemas, whatever it may be, that's where the nuance is going to come in the design of the study. Given our drug and the benefits of our drug, our studies are very straightforward. Our drug is once daily dosing.
It will have a titration schema built into the trial, but a titration schema that is very easy as well as one that we think based on the feedback from the community is going to be accepted by the community, and we do not have any known drug-drug interactions. So that makes the trial as well as incomers to the trial pretty straightforward. We're going to be running two parallel studies. They're gonna be roughly 330 subjects in size. One study will be leveraging what we call a low-medium dose strategy, or low-mid dose, and then one study will be incorporating mid-high dose. Really if you think about the context of the two programs together anchored around that mid dose.
We'll be having a low dose of 0.25 milligrams, a mid dose of 0.75 milligrams, and then a high dose of 1.25 milligrams. These studies are large studies, as I mentioned. They're 300, roughly 330 patients, and they're global trials. That's just the necessity of enrolling these trials. We do believe we're in a position to enroll these trials relatively efficiently, compared to previous programs for a couple reasons. One is we think a lot of the competitive context should be out of the market by the time we're ramping up our trials. Two, there's a lot of excitement around our compound in the market, and we think it's going to be very appealing for investigators as well as patients.
Then three, as I mentioned, just the inherent nature of the trial design, the fact that we do not have any known drug-drug interactions, that's going to really widen the top of the funnel. The last thing is we are really excited with what we just announced this week, and that is a partnership and innovative partnership in China. China historically has not been a country that has been involved in large Phase III FOS trials.
We know there are a lot of patients in China, and we're really excited about the collaboration that we were able to execute with a company by the name of Tenacia, which is a Chinese-focused neuroscience company, that is going to be partnering with us not only to bring that drug to market in China, but most importantly, accelerate our global development by being able to add China as clinical trial sites in our Phase III program.
Great. Really relevant week to be talking about epilepsy. We saw really good results yesterday from another company, Xenon. Just talk to us about how you think about the market opportunity for a novel drug in focal onset patients, but also any learnings that you had from the Xenon trial experience and, for example, the predictive value of the Phase II data.
Mm-hmm
that really did translate for their
Yeah
Phase III program.
Yeah. When we started this company, we obviously knew that there were multiple drugs in development for focal onset seizures. What we are convinced by, and I think the community is convinced by, and we've done a lot of market research to support this, is that this is not a zero-sum game. There is a need for multiple innovative drugs for focal onset seizure patients. All patients, pretty much all patients are being managed via polypharmacy, so they're on multiple mechanisms to really try to achieve seizure freedom. When you look at what is really the immediate market opportunity, that is defined by the 30%-40% of patients that are considered refractory or treatment-resistant. That's 30%-40% of 1.8 million patients, so it's a large market.
From a dollarized perspective, when you think about that 30%-40% on branded, at a branded price, that's a $15 billion market. There is a lot of room for multiple medications, innovative medications, novel MOAs, in this space. We're continue to be very encouraged, again, as I said, with some market research that we've done where physicians clearly see RAP-219 as the potential best-in-class therapy. You mentioned some news this week, with Xenon's program. Very encouraging news. It's great for the space. As I said, it's great for patients. They need new medications. There are some things that we're really encouraged by. One, as you mentioned, Jason, the fact that there was no deterioration from Phase II to Phase III in terms of efficacy.
If anything, efficacy looked a little better in Phase III, both in terms of the placebo rate as well as the actual treatment effect on active drug. When we look at that data and we think about our Phase II data, we're really encouraged. We saw a 78% reduction in median reduction in clinical seizures. If we're able to maintain that efficacy in Phase III, that would be unprecedented, truly unprecedented efficacy.
Yep, for sure. You're also looking at the use of the potential for the drug and other indications. You have a Phase II study ongoing in bipolar mania, and you also recently announced the plans to move into Phase III in tonic-clonic seizures. Can you just kind of. Let's start with bipolar. What you know other anti-seizure medicines have been used in bipolar disorder. That gives some.
Yep
Validation there. Why did you pick bipolar as your second indication?
Yeah. There's a few reasons to get excited about bipolar. One thing that we, you know, continue to say is, unlike epilepsy, bipolar has no translation preclinical to clinical. You know, at the end of the day, you have to really believe in the biology, believe in the mechanism, and ultimately really test it in patients. When you think about the biology and the mechanism, there's a couple things to highlight. First, from a biology standpoint, what has started to be more appreciated is what neurotransmitter as well as what brain region is really excited in bipolar mania.
What has been seen through both MRIs as well as, you know, brain autopsy imaging, has been that glutamate is playing a very important role here in bipolar mania, and specifically in the corticolimbic circuit. We know very specifically that we are reducing glutamate transmission through our downregulation of the AMPA receptor in a very powerful way, and we also know that in terms of the enrichment of TARP gamma-8, it is in the corticolimbic circuit. We think right neurotransmitter, right, you know, circuitry in the brain and the right region. The last piece to think about is anti-seizure medications that have been effective and approved for bipolar, valproic acid as well as lamotrigine.
They have multimodal effects, but one thing we do know is one of their effects is through glutamate. We believe that that's another area that got us really excited. That trial's enrolling well. We're excited. We're guiding to early 2027, first half of 2027 for that data, and probably be in a position to update that guidance as we learn a little bit more on enrollment as we continue to progress through the year, but we're really encouraged with what we're seeing in enrollment.
The tonic-clonic opportunity?
Yes. The tonic-clonic opportunity is one where, you know, many sponsors have waited later in their development to start their program in primary generalized tonic-clonic seizures after you're seeing an effect in focal onset seizures. We accelerated that path, primarily based on the results that we saw in focal epilepsy. You know, given the robust result we saw in the Phase 2 study, given what we know about the involvement of the neocortex in primary generalized tonic-clonic seizures and also knowing that we did have some preclinical data that made us feel confident in the profile of the drug in primary generalized tonic-clonic seizures really put us in a position along with capital to really advance that program more rapidly.
It's the second-largest form of epilepsy or seizure type next to focal onset seizures, so we believe that, you know, really progressing that program, getting that program as close to the NDA on FOS in the form of an sNDA, we think is just going to continue to enhance the profile of the drug.
I wanna kinda come back and talk about the long-acting injectable, but I'll give you a break for a second and just ask Troy. Of all the things that are going on today, what's funded with the balance sheet that you have?
Yeah. We have announced that we have capital through the second half or into the second half of 2029, which would allow us, although we haven't given specific guidance, but it will allow us to complete the Phase 3 in focal onset seizures, both programs there. It will allow us to get through the Phase 2 in bipolar mania, coming in the first half of next year. It will also allow us to get through, and I think it's what you're gonna talk about next, a program around a long-acting injectable. IND-enabling activity is going on right now, and we'll have the first human models PK, Phase 1 results next year. We also have a discovery program based around alpha-6 beta-4. That's in IND-enabling.
We'll have those Phase 1 results again within that funding that we currently have.
Great. Thanks, Troy. This last topic, I think we could do a whole 25 minutes on in itself, but let me kind of broadly say. It's uncommon for an anti-seizure medication to have a, you know, focus on long-acting injectables, right? It's just. It doesn't happen. Why are you different? Why are you able to do that, and why are you prioritizing it now? Let me kind of like fold that into a bigger picture question. With this profile, this drug could be used very broadly, and that's epileptologists, it's general neurologists. Where do you think prior drugs have not been able to bridge that gap to more broad use?
Yeah
Tie that into why, you know, 219 is differentiated?
Yeah. I'll speak to kind of the considerations for the LAI, and then I'll ask Troy to speak to why we're so excited about this as we just think about the value of this program. A long-acting injectable. There's been a desire in the community for a long-acting injectable, so this is not something that we are forcing upon the community. This is something that the community really would like to see. The challenge is when you look at traditional ASMs, as well as ASMs that are currently in development outside of RAP-219, they're not amenable to a long-acting injectable. There's really kind of three things that you have to think about with the LAI. The first is the potency of the drug.
If you don't have a very potent drug, that means that ultimately when you formulate that into an injectable format, you're going to have a large volume of drug. You just have limitations on what is actually feasible to do from a depot standpoint. The second is the solubility of the drug. RAP-219 has an inherent low solubility, and I should also mention on that first point, RAP-219 is extremely potent. We're talking about maintenance doses of 0.25-1.25 milligrams. The volume of drug for an LAI is very low.
The last piece is the inherent half-life of the drug, and why this is important is when you think about formulation, trying to extend a drug's half-life is much more challenging than trying to just control the release characteristics of a drug. RAP-219 has an inherently long half-life, so we've reported a 14-day half-life. Really, we do not have to extend the half-life of the drug. What we really have to do is be able to formulate the drug to really be able to maintain release characteristics for an LAI. The drug has really set up well for a long-acting injectable. We're really excited about it. The community, we hear the word game-changing all of the time. The biggest fear for an epilepsy patient, an epilepsy patient's family, as well as the physician caring for them, is a missed dose.
If you miss a dose of current medication given short half-lives, there's a risk, a high morbidity risk, but there's also a mortality risk. I don't know, Troy, if you wanna touch on the value proposition here.
Yeah. I think the first and foremost is there are other drugs in development that we've talked about, but none of them can do this. They don't have the characteristics. No matter where we end up on the spectrum of efficacy, if we maintain the 78% and have this unprecedented results, or if we kinda normalize to something different, no one else can ever offer a long-acting injectable. What does that do? One, it extends your exclusivity from right what now is the early 2040s to the end of the 2040s. Durability of revenue makes it incredibly appealing. Again, differentiated there.
I think the other thing is as you start to think about even market share of the small molecule itself, if you're a patient or a physician who wants to be on a long-acting injectable, you don't start on one of these other mechanisms and then take the long-acting. You take the small molecule in order to get acclimated to the drug, and then you transition to the long-acting injectable. The first one we're looking at is probably a 30-day, but there are opportunities to take it from 30, 60, or even 90, which each one of those creates more exclusivity and creates a again, differentiation from the other programs that are available.
Great. Abe, Troy, really appreciate you being here this afternoon, and excited to watch the progress.
Thanks, Jason. Appreciate it.