To the next session. I'm Marc Goodman, one of the biopharma analysts at Leerink, and we appreciate everybody being here for the week in the conference. We're lucky to have Rapport Therapeutics with us next. Thank you, Abraham Ceesay, who's the CEO, and Troy Ignelzi, who's the CFO. Great interesting company and having real nice success and here things are going really well. Working on a different mechanism than other people are working on. Maybe start by just describing a little bit of, you know, what you're doing and how it's a little bit different from what other people are doing.
Sure. Marc, thank you to you and the rest of the Leerink team for having us, this week, and the opportunity to talk about the program and the broader story with Rapport. Rapport Therapeutics, a company that's focused in precision neuroscience, a term that's somewhat, loosely used, in our industry. I think as we explain and answer your 1st question there, Marc, it will really bring kind of precision to life in terms of how we're approaching things. We focus on receptor-associated proteins. In the case of our lead program, this is an auxiliary protein that is associated with a AMPA receptor.
What's important around this receptor-associated protein, which is TARP gamma 8, is that it is discretely expressed in regions of the brain that we believe, and we think that the biology supports this, that are the regions of the brain that are very important in both the origination and propagation of focal-onset seizures. Those are 4 brain structures, both the mesial temporal lobe as well as the neocortex. Importantly, there's low to no expression in hindbrain regions. Why that's important is when you think about most anti-seizure medications, they're ubiquitous in nature, so they're interacting with receptors and channels throughout the brain.
What the issue is there, traditionally with anti-seizure medications, is you have a very low therapeutic index, meaning at the same concentrations, receptor occupancy that you are driving efficacy are the same concentrations and ROs that you're ultimately seeing pretty significant tolerability issues. What we've seen with RAP-219 all the way from our preclinical experiences to our clinical, early phase I clinical experience, and now our proof of concepts data, is we're really able to achieve unprecedented efficacy, but we're able to see a very differentiated tolerability profile, primarily in the areas of sedation and somnolence, as well as gait impairment.
Talk about the mechanism a little bit.
Yeah.
Yeah.
Specifically, we are targeting the AMPA receptor through this receptor-associated protein. The AMPA receptor is a validated target in epilepsy. It is important for synaptic transmission, specifically neurotransmitter glutamate. We know through you know previous mechanisms, but also validated preclinical models, that by reducing glutamate, you're able to reduce the excitatory process in the brain and really have a significant impact on the reduction of seizures.
The selectivity aspect, how is that? You know, I guess selectivity of the target improves the risk-benefit versus just all the products that are out there, like basically. I mean, is that what you're seeing?
Yeah. We believe that, and we've seen that in our preclinical models. By being highly selective in those 4 brain structures, again, the mesial temporal lobe as well as the neocortex, we know that's where focal seizures originate and propagate. The reality is, you don't need to be working in the rest of the brain in focal-onset seizures. The risk-benefit profile here is, you know, very strong for RAP-219. Again, we see kind of that unprecedented therapeutic index as compared to other anti-seizure medications and other mechanisms.
Okay. Let's talk about data. Kinda take us through, you know, what you worked on, and then obviously the phase II.
Sure. We just reported our data in September of last year, and this was our proof of concept study in focal-onset seizures. We employed a pretty unique and innovative trial design where we enrolled refractory focal-onset seizure patients. These patients demographically look very similar to the patients that are enrolled in other proof of concept or registrational studies. The difference is, though, that these patients had an implantable neurostimulation device by the name of the RNS System, manufactured by a company by the name of NeuroPace. Why that's important is the NeuroPace system is a therapeutic device, but in the context of our study, it's a diagnostic device. It's able to continuously record electrographic activity. There's a specific electrographic measurement, which is referred to as a long episode.
In the context of our study, long episodes were electrographic seizures that the device is constantly recording. What was seen in the literature, and really what the KOL community brought to us, is that that was a biomarker that was heavily correlated with the actual clinical measure, which is the reduction of clinical seizures. Through this study, we're able to leverage a biomarker that is highly correlated with clinical seizures. We saw in our study a 72% reduction in these long episodes or electrographic seizures, and we also saw a 78% median reduction in clinical seizures. 1, the biomarker was highly correlated as we expected, with clinical seizures. The 2nd is we really saw an unprecedented reduction in clinical seizures.
In addition to that, we observed a 24% seizure freedom rate, which was a very conservative measure of seizure freedom, truly day 1 to day 56 in our trial.
Oh, amazing data. What made you use that device, and why is no one else using it?
Well, I think what you will see is this will in our opinion and also in the opinion of many KOLs become the gold standard for proof of concept studies in focal onset seizures. The reason that we did this study and the reason the community brought us this concept is that when you look at focal onset seizure studies, there's inherent variability in patients capturing clinical seizures in diaries. There's just inherent variability. Ultimately, you're relying on a patient with refractory focal epilepsy to remember all of their seizures.
Right
Which is a hard thing to do. What the biomarker does is it allows you to have a much smaller and efficient study because ultimately, you're powering your study on the biomarker, you're not powering your study on clinical seizures. By doing that, we are able to do a relatively small study, 30 patients in our sample size, and we were able to get to data within a year. If we were doing a traditional study that was only focused on clinical seizures, that would be a 200+ subject study. We'd still be waiting for data. 1, it allows you to get to data much more efficiently, and 2, the objectivity of the data really allows you to understand everything that you're seeing in clinical seizure reduction is supported by the objective biomarker.
How many patients have been exposed to your product, I guess overall, like in the phase I program and all of that?
Yeah.
Just give us a sense of like.
Yeah. Well into the hundreds at this point. You know, we had 100 subjects that were exposed to the drug in our phase I traditional SAD/MAD studies. We had 30 subjects that were exposed in our proof of concept study, and we've had additional pharmacology studies that have been ongoing, you know, as we've continued the development program.
A few extras there. Maybe 140 to 150, whatever it is.
Yeah.
Talk about what kind of side effects are we seeing, what are, you know, kind of on target, what are some. You know, just give us a sense of what we should be expecting also, you know, kind of.
Yeah. I think the best way to think about the tolerability profile is ultimately what you observe in patients. That's the most important.
Yeah.
We, you know, crossed the chasm of both the SAD and MAD studies to really understand, you know, is there an MTD? We didn't see an MTD in our phase I studies.
How high did you go up in dose?
We went pretty high in dose. Our target receptor occupancy from our preclinical work is in the 50% to 70% range.
Mm-hmm.
These are in, we were talking before, Marc, highly translatable models in focal epilepsy. We were in the 80% to 85% range of RO. We're able to dose this drug very high, and what we're seeing is a very well-tolerated drug. If you look specifically at our phase II experience, what we were able to see is that, you know, for the AEs were all mild to moderate. What we saw were common AEs that are associated with anti-seizure medications, dizziness, headache, as an example. We only observed a 10% discontinuation rate, which is relatively low for focal epilepsy trials. We're really confident with the tolerability profile.
In terms of what is known to be on target with this mechanism, what we believe is it's really Cmax driven versus tmax driven.
Mm-hmm.
If you are to give a patient or a subject, in the case of our phase I studies, a real whopping dose on 1st dose that gets them to, you know, 70% RO on dose 1, you're going to see on target pharmacology. What we saw in terms of the phase I study is the subjects, this mechanism is actually activating versus sedating.
Mm-hmm.
Patients would say, you know, "I feel like I've had too much coffee. I need to get up and walk around," as an example. Interestingly enough, when you have a more moderated approach to that target RO, and when I say moderated, it's not over the course of weeks, it's really over the course of a few days.
Mm-hmm
Y ou're really able to mitigate those AEs. Why I say it's Cmax versus tmax driven is we're able to achieve over time 80+% RO, and the drug is extremely well-tolerated.
Okay. Right. Will there be like a slow titration, do you think, here?
Yeah.
for your product as you move forward?
We are evaluating some titration schemas in our phase III study. We finished our phase II study. We met with the FDA.
Yeah, let's talk about that.
Yeah, we had-
Okay
an interaction with the FDA, I should say, at the end of last year. It went extremely well, which put us in a position to really accelerate our phase III program. We're looking to initiate those phase III studies, 2 parallel phase III studies in the Q2 of this year. In those studies we're going to be exploring 3 dose levels. 1 study will be leveraging what we call a low mid dose strategy. That low mid dose will be 0.25 at the low, mid would be 0.75. The 2nd study or the other study will be employing a mid high strategy, so 0.75 and 1.25. Really, the program itself is really anchored on that 0.75 dose overall.
In terms of the titration schema, each dose will have a level of titration, and it will be a titration that at the longest would be over the course of anywhere from, I think, 7 to 9 days at the high dose. You know, a very, you know, in terms of-
Pretty short.
It's very for neural.
Grand scheme of things. Yeah.
For the grand scheme of things.
Yeah
for a chronic condition, this is a.
Yeah
a very efficient titration scheme.
Yeah. Very interesting. Okay, that's going to be the 2 pivotal, you're saying, starting next quarter. How many patients and how long do you think it'll take to kind of do the recruitment?
These are global studies, you know, in the, call it 320 to 330 subject range or sample size range for each study.
Right.
We're not guiding on the length of the studies right now. We wanna get a little bit of experience under our belt before we provide guidance on the length of those trials. With all of that said, there are some things that either we have done to put ourselves in a great position to execute these trials, or from a macro perspective, we think is gonna be really supportive of the enrollment of the trials. On a macro perspective, one of the things that you have to think about in enrolling these trials is, what does the kind of competitive context look like in the market? One of the things that we think we have going for us is that a lot of the trials are kind of ramping down-
Yeah
versus ramping up as we think about, you know, the other competitive trials. I think we're gonna be in a good position there. The 2nd is there is extreme excitement around our compound-
Yeah
In the community based on our phase II results. We think that that is going to be very supportive enrolling the trials. The 3rd is you always have to think about the top of the funnel as you enroll these studies. If you have a compound that has, you know, not the best benefit risk profile, very long titration schema, drug-drug interactions as an example, you start to really narrow the funnel. We have no DDIs. We have a phenomenal benefit risk profile. We think we're gonna have a pretty wide top of the funnel to recruit these trials. The last thing is, we've been really strategic about how we think about enrolling these trials. These are global trials. You will never enroll a phase III epilepsy trial in the U.S. only.
If you look at, you know, some of the most recent examples, you're looking at anywhere from 40% to 60% of the sites being outside of the US. One of the things we announced this week was, we just executed a partnership in China, with a company by the name of Tenacia, a neuroscience only focused company in Tenacia. We did that strategic collaboration to focus on not only moving this program forward in China, but also we have aligned interests. Meaning at the same time they are looking to think about their Chinese development, they're actually supporting our global phase III. Now we have opened up China as a country for recruitment of patients in our phase III. Historically, China has not been accessible, and we think that that's gonna be really beneficial as we think about the enrollment of our trials.
Since you mentioned the deal, we'll come back to the phase III in a second, but just finish up with the deal. What does the deal entail? What are the economics?
Yep. The economics are really favorable. I think it, you know, validates kind of what we're working on. It's a $20 million upfront deal for rights to RAP219 in the Greater China territories. About $308 million biobucks on the back end as well as royalties included.
Let me just add, I think importantly.
Yeah
They'll also pay for all of the development in China.
Uh-huh.
It's not like we have to pay for the global phase III. We can do that minus the China stuff.
China part
'Cause they fund that themselves.
The China part.
Those dollars don't get.
I think 10% or 20% of the
Yes. Whatever percentage.
Whatever.
It's saving us, if you will, not only time.
Right
the investment to conduct either in China or some other region.
Have they done these type of studies before?
They have, yes. They have been developing drugs in epilepsy in China.
That's what I mean, epilepsy.
Yeah.
Yeah.
Yep. In epilepsy specifically. They have additional partnerships, so we are very confident with them.
Yeah.
as a partner.
It's a good partner.
Yeah.
Yeah, it's a really interesting deal. Let's just go back to the phase III and how we should be kind of thinking about expectations for efficacy.
Mm-hmm.
First of all, the type of study that you did in phase II was very different than everybody else. Perfectly makes sense to me. I get it, and it was fantastic. I mean, how do we expect 77% lowering in phase III? Like, that's. I mean.
Yeah
That would be unprecedented.
Yeah, it would be unprecedented.
I mean, you know, to be frank, we believe we have an unprecedented compound.
Yeah.
We do. Every piece of data and experience that we've had with RAP-219 supports that. You know, yes, if we maintained 77% to 78% median reduction in clinical seizures into phase III, that would be clearly a best in class therapy.
Yeah.
Never been seen in terms of that level of efficacy in focal-onset seizures. We are not going into the phase III study believing we will have a deterioration of efficacy but at the same time, we did not power the studies around that level of efficacy.
Yeah.
There's a reason for that. You know, you usually want to be thoughtful about designing and powering your studies, but also we need to think about the number of exposures we need to gain over the course of development as we think about ICH guidance. However, you know, there's been a couple pieces of information that we think are really supportive. You know, if you look at the data that was just released this week from Xenon was able to not only maintain their efficacy, if not improve their efficacy from phase II to phase III. That is something we've always believed that there is the opportunity to do that. We're confident going into these phase III studies.
We believe, whether it's maintaining the efficacy we had in phase II, or even if we saw a slight decrement in efficacy, we still believe we have the opportunity to have best-in-class efficacy here.
Let's go back to the phase II for a second. Open label-
Yes
attached to it. What have you learned?
Yep. We reported in September there was really 2 aspects of the study. There is an 8-week treatment period and then an 8-week follow-up period, and then patients have the opportunity to roll into an open label extension study. We reported data on the 8-week treatment period. The first is what we're going to report here in the Q2 for the 8-week follow-up period. We believe this is going to be really interesting data. Remember, our drug, RAP-219, has a long half-life, 14 days. We actually have more data coming out on that, which we'll update at an upcoming medical meeting.
The point being is, with that half-life, one of the things that we're really interested in in the redesign of this study is when you think about that follow-up period, how long, given the exposures and the half-life of this compound, how long will patients continue to receive benefit as they're washed out from the drug? Given the fact that we can leverage this electrographic biomarker, we're able to see that in real time from the electrographic readings. That's going to not only be informative of kind of that half-life and that ongoing protection, but it's also going to help us to have, like, real insight on the PK to PD relationship. As patients wash out, we understand their exposures, their receptor occupancy. When do we start to see those electrographic biomarkers return? When do we start to see clinical seizures return?
Which will help us really be even more confident in the dose selection for our phase III study. That will be what's reported in the Q2 . In the H2 of this year, in the Q4, we'll report on our open label extension study. This will be those same patients who are in the phase II, have the opportunity to go into an open label extension study. This will be looking at long-term exposures, primarily looking at, you know, long-term safety. Again, given that these patients have this RNS System, we'll also have insights on efficacy. We're going to continue to track this electrographic biomarker as well as clinical seizures for long-term kind of durability.
You mentioned the half-life, which is a little bit unique to your molecule. Talk about this LAI opportunity that you were
Yeah. I'll start maybe on the technical side, and then I'll ask Troy to speak to-
Yeah
kind of why we believe it's so valuable.
Yeah
As you think about just the value of this asset. There has never been a long-acting injectable in epilepsy. If you were to talk to the community, that is definitely not based on the lack of need. It's based on the limitations of available ASMs. Most anti-seizure medications aren't that potent. When you don't have a very potent drug, that means you have large doses. Converting that to a long-acting injectable isn't really feasible just because of drug volume. The 2nd thing is most ASMs have very complicated titration schemas or have some level of drug-drug interactions. That also is an impediment to a long-acting injectable. The last is just the inherent half-life of drugs. Most anti-seizure medications have very short half-lives.
When you think about RAP-219, 1st, the drug has very low solubility. 2nd, the drug is extremely potent. We're talking about maintenance doses of 0.25 milligrams up to 1.25 milligrams, and we have a 14-day half-life. The drug does not have drug-drug interactions. We have a compound that is ideally suited for a long-acting injectable. We have nominated our development candidate for formulation. It's currently in IND-enabling studies, and we expect to have our first human PK results for the LAI formulation in 2027. This would be transformational for patients. If you think about patients' biggest fear is missing a dose. Patients, clinicians, caregivers. Biggest fear in epilepsy is do I miss a dose? Do I have a breakthrough seizure? There's morbidity, but there's also mortality associated with that.
To have a LAI that basically gives patients background protection and drug on board for 30 days, 45, 60, 90, and we're going to be thinking about all of those, our initial target is 30 days, we think and we hear from the community would be transformational.
Very-
Maybe, Troy, you can talk about the value a little bit.
Yeah. You know, our base composition of matter plus PTE expires in 2041. With an LAI, because the patent clock starts differently on the formulation, you've got a composition of matter on the LAI that it would take us to the end of the 2040, so 2048, 2049. The durability of the revenue-
Yeah
extends almost another decade, and that's just for the 30 days. If you extend to 45 or 60, you're starting that clock all over again.
Yeah.
That's from a durability. From a demand perspective, for those patients and clinicians that are looking for a long-acting injectable, the way it would work is you would first start on the small molecule daily. You would, you know, acclimate to the drug, go through the short titration and become stabilized, and then you would transition. If you walk in and say, "Hey, I would like that LAI," or as a doctor you say, "I have an active patient, I don't want them to have the risk of that, I'm gonna try to target you to the LAI." Now all of a sudden you're getting demand for utilization-
Yeah
of the small molecule early on because you wanna transition to the long-acting. Each one of those steps along the way also allows for premium pricing. You know, 'cause an LAI is typically have a premium price over-
Exactly.
There are a lot of the patient benefits that Abe alluded to, but from a business, you've got durability of revenue and more significant demand, and it is a clear differentiation factor to RAP-219.
Very much so. How long are you thinking you might be able to get out to? Like once a month or even.
I mean.
once every other 2 months?
The attributes of the drug lend themselves to, you know, certainly 60 or 90, but maybe even longer.
Wow.
We do have to do some research because while we sit here and think, "Oh, it'd be great to only go once a year," but these patients have other things they're doing anyways, so to go to the doctor and talk to them every 3 months. There's some work that we have to do. I think the drug characteristics lend themselves to up to a half year or more.
Do you have this technology in-house to make it long-acting, or are you working with an external company?
All of our formulation work is in-house in terms of the formulation strategy, and then we work with CDMOs to, you know, manufacture the drug.
Right. It's an in-house technology.
In-house formulation strategy, and what we should say is, you know, from excipients that are being used and things like that, very thoughtful to ensure that we're using things that have, you know, established safety, as we think about just tox and regulatory phasing.
Yeah. Good. Let's talk about potential other indications.
Yes.
What else are you thinking about?
Yep. W e've always thought about RAP219 as a pipeline and a product strategy. The next indication that we're pursuing in epilepsy is primary generalized tonic-clonic seizures. That is the 2nd largest form of epilepsy next to focal-onset seizures. We started that development program early based on the robust results we saw in phase II. We really want to have the broadest epilepsy label as we think about moving this program to market. That program will be started in 2027. The program that is ongoing is a study in bipolar mania. There is reason to believe as you think about not only the biology around bipolar, but also the mechanistic rationale. What has been known about bipolar is that it's a disorder that could be driven in part by glutamate.
What we understand is not only is it driven by glutamate, but also the circuitry of the brain and the location of where that excessive glutamate is occurring, and that is in the corticolimbic structure. What we know about AMPA is downregulating AMPA is going to lower glutamate transmission, and we also know that RAP219, the target of RAP219, TARP γ8, is highly expressed in those cortical regions. We believe right neurotransmitter, right biology, right location of the brain, and we think we have a shot here in bipolar. That trial's enrolling well, and we expect that data in the H1 of 2027. As we get some more enrollment under our belt, we'll be in a place later this year to guide more specifically on that.
In our last couple of minutes, what have we missed? What else should we talk about?
Going back to the bipolar because.
Okay
It is a huge unmet need in bipolar. Right now, the most commonly used drugs outside of lithium are ASMs.
Yeah
who have, you know, some of the side effects that we've been talking about,
Yeah
as it relates to somnolence and sedation. The other most utilized class, they're atypical antipsychotics, which have weight gain. Remember, this is a high functioning bipolar population, so the weight gain, the movement disorders that come along with that are a real bothersome to that. There's a huge need. What I would say is that if you look at where Rapport is trading today and you look at, as Abe mentioned, Xenon, we're actually below where they were after their phase II. Right now, there's really no upside on the bipolar built in. I think you'll start to see more people doing work, trying to understand this mechanism.
Yeah.
The other thing that we didn't mention was PGTCs, primary generalized tonic-clonic seizures.
Yeah.
That is the 2nd largest group of epilepsy patients. We'll start the phase III on that.
Good
Next year. We believe because of the robust efficacy and the mechanism, we've got a great shot in that population. From a cash runway perspective, we've got money into the H2 of 2029.
Mm-hmm.
Which allows us to finish the phase III and focal-onset, the phase II and bipolar, the PK phase I results from the long-acting injectable, and it allows us to do work on the phase I in a discovery asset, alpha, which obviously we've run out of time to talk about.
Yeah.
Very exciting target in pain and migraine. It also will allow us to start the PGTCs trial next year.
Just quickly on the pain, the migraine you were talking about, that's gonna start when do you think?
It's actually I am enabling activities.
It is right now.
on one right now, so we expect.
Right now.
phase I for that next year.
Yeah.
And the reason-
Wow
We think it's exciting, it's clinically and genetically validated target going way back to the Targacept Abbott days. I'm sure, Marc, you've
I do remember.
Probably seen those. They're. Yes. We think it's a very exciting target, and using our science of receptor-associated proteins, we think we've found a way to achieve the efficacy-
Yeah
that was seen, but dial out the bothersome side and safety concerns as well.
Yeah, yeah.
Yeah.
We need to talk more about that.
Yes.
Targacept, I remember that. I mean.
Yeah
It was really promising.
Yeah.
Thank you. Thanks for joining us. Really appreciate it.
Yeah. Thank you, Marc.
That was fun. Yeah.
Appreciate it.
Great.
Thank s.