All right. Thanks very much. It's my pleasure to introduce Abe Ceesay, CEO of Rapport Therapeutics, a CNS-focused company with programs in epilepsy, bipolar, and pain. I'm going to have Abe do a quick overview of the company, and then we'll do Q&A, so thanks so much.
Great. Thank you, Paul. And thanks for having us here today. And thanks to the Stifel team for having us here as well. So background on Rapport Therapeutics, we're a company that is looking to build the leading precision neuroscience company. We realize that the word precision can be used somewhat loosely in our industry and also in neuroscience, but we do believe that our scientific foundation, which is receptor-associated proteins, has the opportunity to bring neuroscience precision to life in neuroscience. Our pipeline is really anchored off of our lead program, which is RAP-219. This is a gamma-8 TARP AMPA modulator program. We see this program as having a potential best-in-class profile for focal epilepsy, but also a pipeline and a product opportunity with indications in areas such as neuropathic pain as well as bipolar disorder.
Beyond RAP-219, we also have a fully integrated discovery platform that leverages receptor-associated protein science. Two of our programs are in late-stage discovery, really with the next stage gate being the nomination of development candidates. Well-financed company. We have cash to the end of 2026 and through 2026, completed a $174 million IPO in June of 2024.
Great. Do you want to talk a little bit about the history of the science here? So there's literature on RAPs or TARPs that has been around for a while, but only recently was Rapport incorporated. So where did all this kind of come from, and what was the breakthrough?
Yep. So I'd like to say that the history of receptor-associated proteins and our program, RAP-219, is really where biology and chemistry have ultimately caught up to one another. So the biology, to your point, has been pretty well understood for a while now. So the biology actually was identified by our scientific founder, a gentleman by the name of David Bredt, while he was a professor at UCSF, where he discovered the TARPs, the receptor-associated proteins associated with the AMPA receptors. That discovery was really novel in the fact that AMPA receptors have receptor-associated proteins that are core to their function, and that these receptor-associated proteins are uniquely distributed in various brain regions. So if you can drug the receptor-associated protein versus the AMPA receptor, that would allow you to basically modulate AMPA receptors only in the brain region of interest.
Post David's academic career, that took him into industry. He was actually recruited out of UCSF into Eli Lilly by Steve Paul to run neuroscience drug discovery. Ultimately, he went to J&J to run neuroscience drug discovery, where this program really started to come together, and that's where kind of the chemistry caught up, so compounds were developed at J&J, really optimized over time. J&J ultimately decided that the best way to realize the potential of RAP-219, but also the platform overall, was externalized versus within the four walls of J&J, which really led to the creation of Rapport, which was a partnership between, at that time, Third Rock Ventures as well as J&J to create our company.
Great. So the lead drug 219 targets TARPγ8 . Can you talk a little bit about the biological rationale for that target in epilepsy specifically?
Sure. So what we know is that AMPA modulation and AMPA receptors are glutamate-type receptors, very important role in synaptic transmission overall. And what we know about AMPA receptors is we know that antagonizing AMPA receptors has been validated clinically in reducing seizures. That's via a drug by the name of Fycompa. But just like all anti-seizure medications, Fycompa is interacting with AMPA receptors indiscriminately, so all AMPA receptors throughout the brain. And what you're seeing with a drug like Fycompa is, although it is a very effective anti-seizure medication, it basically has no therapeutic index. So what does that mean? That means that the same doses that are efficacious in reducing seizures, you're seeing pretty significant tolerability issues, tolerability issues such as sedation, ataxia. And those are really driven by interacting with AMPA receptors in the hindbrain. So what does our lead program really offer?
What we have the opportunity to do with RAP-219 is modulate AMPA receptors only in the forebrain, in the areas such as the hippocampus, the prefrontal cortex, as well as the amygdala. We believe by doing that, you can provide the efficacy of AMPA modulation, which is clinically validated, but by avoiding the receptors in the hindbrain, we think we can mitigate a lot of those troublesome tolerability issues such as sedation as well as ataxia that is really not just an issue for Fycompa, but really an issue for almost all anti-seizure medications.
Yep. Makes sense. So I feel like the million-dollar question with this approach has been, is selectively blocking AMPA potently in the hippocampus or predominantly the hippocampus enough? I know it's kind of a weighted question, but how did you get comfortable that this all just sort of makes sense?
Yeah. One of the things that I think we benefit from in epilepsy drug development is the strong translation that exists from preclinical to clinical. It's one of the, as you know, Paul, one of the very rare areas in neuroscience where you can actually believe in the preclinical data and translate that into probability of success in the clinic. So when we looked at the profile of our program, RAP-219, but also looked at the profile of other compounds that were created in this category, what we became really encouraged by is the number of preclinical models we saw efficacy with our compound, and those were models all the way from generalized epilepsy to very specific models that have high translation into focal epilepsy, such as a corneal kindling model.
What that did is really gave us a belief that really where you wanted to be in terms of modulating receptors was in the forebrain structure. The other piece of data that we're encouraged by is where seizures originate, focal seizures originate. Seizures originate in forebrain structures. About 50% of seizures originate and their focus is in the hippocampus. That's where gamma-8 TARP is mostly enriched. But other seizures are usually emanating from other forebrain structures, prefrontal cortex as an example, and have some hippocampal involvement. gamma-8 TARP is also expressed in those other forebrain structures, such as the prefrontal cortex and the amygdala. I think when we think about the biology, the pathophysiology, but then finally the preclinical models, that gave us a lot of confidence that this targeted approach will be able to address the majority of patients.
On the preclinical side, I'm not trying to nitpick for the sake of it, but there's one model that this mechanism didn't work in, mouse electroshock. There's another company. Look, there's other companies that weigh things differently, but I have heard some companies weigh that model pretty heavily. How did you kind of make sense of that in the context of everything else?
Yep. So when you look at historically the models that have had the highest validation of translation, preclinical to clinical, you really have had two models that have risen to the top. One is the Corneal Kindling model, and the other is the MES model. For some reason, compounds in this category do not show efficacy in the MES model. The biology and the mechanistic rationale behind that are really not well understood. But we also know that a drug like levetiracetam, which is a really effective anti-seizure medication, is also not effective in the MES model. So I think we don't know why it's not effective in the MES model, but we do look at all the other models where we do see efficacy with 219 and other compounds in this category.
The other aspect of this that I think we were really encouraged by is a lot of the preclinical work that was done with these compounds was done by the Epilepsy Research Group, which is an NIH-funded group, really does all of the preclinical research for investigational antiepileptic drugs, and they've started to publish more and more and really lean into the Corneal Kindling model being the model that they lean into and they believe is the most translatable, so the data is going to tell us all, but I think when we look at the whole kind of mosaic of information, we really believe that the Corneal Kindling model is highly supportive of translation into the clinic.
Okay. Great. So maybe set the stage and talk about the phase IIa RNS study, the rationale behind it, and then I can pepper away with some follow-ups.
Yeah. So we are entering and we're currently enrolling in our phase IIa proof of concept study with RAP-219. And as Paul mentioned, that is in a patient population that is referred to as the RNS patient population. This is a focal epilepsy patient population, a refractory focal epilepsy patient population. Demographically, these patients look very similar to those patients that would be ultimately enrolled in a registration trial in focal epilepsy, outside of the fact that they have an implantable neurostimulation device. This neurostimulation device really does two things. First is a therapeutic, and then the second is a diagnostic. In the context of our trial, we're really leaning on this device as a diagnostic. Let me explain a little bit why.
There's been some emerging literature and real movement in the community to identify a biomarker that is more objective and a more efficient way to understand efficacy for investigational drugs or new drug starts in this patient population, and the biomarker that has really risen to the top is what is referred to as a long episode. These are long EEG recordings that are really seen as subclinical seizures, and the RNS device detects these, so what we're going to be measuring is the reduction of those long episodes. What the data has shown is that a reduction of 30% to 40% in long episode frequency is predictive of at least a 50% reduction in clinical seizure frequency, and that's, we believe, a clinically meaningful threshold in terms of that clinical seizure reduction, so we've gotten really excited about this trial design. The community is highly supportive of this design.
We will continue to execute and expect data in mid-2025.
Is there any concern that this might be like a more refractory than average population? I think by the time you get an RNS device, you'd have tried a bunch of drugs.
Yeah. So we did. It's a great question. We did a lot of feasibility work before we started this trial to really understand this patient population, also understand what are the endpoints we should be looking at. And when you look at this patient population, it's interesting that this patient population isn't more refractory. And people ask the question, well, why? Why does a patient elect for this implantable neurostimulation device? Well, for many patients that get the RNS device, they may not be surgical candidates for actual resection. So they look at this device as a potential additional therapeutic that is taking the place of an actual resection that they might have via another surgery. The other reason is, as we know, antiepileptic drugs and your path to getting relief on antiepileptic drugs is a long journey.
So when you present a patient that has failed multiple drugs and you're asking them to go on another drug that could have a very long titration period, it could have sedation, it could have ataxia, those are all things that really interrupt with the patient's lives. They look at this device as a way that can provide them some relief, but may not come with the tolerability issues associated with pharmaceutical agents. The last reason, and this is really the emerging reason, is the diagnostic aspect of this. So historically, when patients start a new antiepileptic drug, the way to find out if this drug is working for the patient is patient started on a drug, very long titration period, physician follows up with the drug, how's the drug working for you? It's really based on patient recall.
That could be months based on the titration schema and what type of drug they have started. With this RNS device, given this biomarker, its objective nature, its sensitivity, you can know within weeks if a drug is working for this patient based on the reduction of a long episode, so what we're seeing more in the community is physicians really thinking about this device for that diagnostic purpose, and it lets them make better decisions, but also helps the patient make better decisions as well.
Makes sense. So in looking at a couple of the publications that you pointed us to and others, we found that, not surprisingly, in someone who gets an RNS, that their baseline seizure frequency clinical seizures is pretty high, right? I mean, why otherwise would you get it? So I would think in this trial, even though you're not enriching for it, that you're going to have patients with some meaningful level of seizure burden at baseline. Is that fair? How analyzable will the seizure diary data be from this study?
Yep. So you mentioned clinical seizure reduction, which ultimately will be our registrational endpoint. That is the registrational endpoint for the FDA. However, for a proof of concept study, our primary endpoint is off of long episode frequency reduction. So we will capture clinical seizures. For our study, a patient has to have at least one clinical seizure in the screening period. But to your point, our belief is that patients are going to have a range of clinical seizures. So we will be capturing clinical seizures via paper diaries, the traditional way, and we will look at those. We keep on telling people that and guiding people that that will be directional in nature. And we've powered the study to long episodes given the predictive value of long episodes.
But if clinical seizures corroborate it, I'm sure you'd feel considerably more confident.
Yeah. It would definitely be helpful data.
Any reason to think that the RNS population is or isn't perfectly generalizable to a focal epilepsy population in phase IIIa? I know there's one question related to where the lead is in the brain, and you have one lead at least in the hippocampus. Do you think that matters? Said another way, do you think this population in terms of the biological driver of their seizures is consistent with the average focal epilepsy patient in a study where you're not acatually doing anything anatomical in screening?
We do. We do. When you look at the demographics of these patients and you think about the imaging that these patients have that is consistent with the imaging that other focal epilepsy patients have, really there's not a difference in this patient population. The leads are placed where the focus of the seizure or the initiation point of the seizure. So what we know with the biology of this disease is that 50% of those are in the hippocampus. So a lot of these patients with the RNS device have at least one lead in the hippocampus, but some will also have another lead in other forebrain structures.
Okay. Do you think if these data are positive, you'd go right into phase III?
That is our strategy. We believe that utilizing another driver for doing this study is we are in focal epilepsy patients. We're using a biomarker that is highly predictive of the endpoint that ultimately will be used in registration studies, so we believe we're going to be positioned to go into registration studies based on the data from this study.
Okay. And do you think, I mean, maybe this is putting the cart before the horse, but do you think you just do both phase IIIs at that point, right, versus staggering them?
It will be totally data-driven. We'll also make sure we have the appropriate dialogue with the FDA from an end of phase II standpoint, but what I can confidently say today is we are setting ourselves up to be able to run parallel studies. We think that this data will allow us and put us in the position to do that, assuming everything else lines up, FDA discussions, et cetera.
Right. Okay. So maybe let's talk about safety for a minute. We know Fycompa is a super dirty drug. Can you talk about your phase I data and just what we know, what we don't know, any lingering risks from that data set?
Yeah. So we've completed our SAD-MAD study with RAP-219. We were really encouraged by that data for a few reasons. The first is we really wanted to see if we could pull through the therapeutic index hypothesis and the precision hypothesis in human subjects similar to what we saw in the preclinical models. And then the second is we wanted to see if we could achieve a projected receptor occupancy that we think would really give us the best chance of success as we went into our phase IIa study. So specifically in our SAD study, what we saw in that SAD study is, in a single-dose setting, in kind of ranges of two to three micrograms, when you achieve receptor occupancy in the projected range of 50%-60%, we're definitely seeing on-target pharmacology that was consistent with our preclinical experience.
For some reason, this mechanism in this category of drugs, unlike other antiseizure medications, is somewhat activating. So what the preclinical and clinical experience tell you is that preclinically, dogs would kind of pace around the cage a little bit, and in human subjects, they say, "Hey, it feels like I drank a little bit too much coffee." So that gave us a little confirmation that, one, we had on-target pharmacology in the SAD study, and two, it was consistent with our preclinical experience. What has been always known about this compound and what really has been optimized through the work that Janssen did is you want to approach Cmax, and you want to approach your projected receptor occupancy in a more moderated fashion.
In our MAD study, what we observed is rather than starting a patient on a 2 microgram dose, starting patients on, say, 0.75 for five days, and then stepping them up to 1.25, we're able to achieve and significantly exceed those same concentrations, get to levels of projected receptor occupancy of 80%, and we're not seeing any of those tolerability issues.
Do you want to talk briefly about the rationale in pain and bipolar?
Sure. So as I mentioned earlier, we do see this as a pipeline and a product opportunity with RAP-219. There's a couple of reasons to believe here. One is where the biology takes you, and then two is where clinical precedent takes you with antiseizure medications. From a clinical precedent standpoint, antiseizure medications have been shown to be efficacious in both neuropathic pain as well as bipolar. Specifically with bipolar, you see drugs such as Depakote, Lamictal, Lamotrigine. These are drugs that have been shown to have efficacy from anti-mania agents as well as mood stabilization agents. The rationale and the reason mechanistically for why is not really well understood because we don't know that much about bipolar, but it is pointing to some level of hyperexcitability in the hippocampus.
So we believe with our drug and the profile of 219, we have an opportunity to really have a best-in-class type of profile because our drug does not have the sedative effects. It does not have the motoric impairment effects of other previous compounds. In terms of neuropathic pain, there's both clinical precedent as well as biology. From a biology standpoint, the other expression of AMPA and gamma-8 TARP containing AMPA receptors are actually in the dorsal horn of the spinal cord, which is really well understood in terms of nociception as you think about pain inputs. So we've done some preclinical work that we are really excited about looking at RAP-219 in neuropathic pain models. And also on the clinical precedent side, what we know is drugs like gabapentin started off as an antiseizure medication, ultimately showed efficacy in neuropathic pain and are widely used drugs.
Again, we see this opportunity for a best-in-class type of profile given the efficacy we might be able to deliver without the sedation as well as motoric impairment.
Okay. Great. Anything else you'd like to highlight, Abe?
The only other thing I'll highlight is we did recently receive feedback from the FDA on our neuropathic pain program. We submitted an IND to initiate our proof of concept study. That study and IND is with a separate division. It's with the pain division versus the neurology division that reviews a program for FOS. We were placed on clinical hold for the neuropathic pain program. This is a protocol-related hold feedback. So we're currently working with the FDA and will be working with the FDA to resolve those issues. It's not something that we think is unsurmountable, nor is it based on any new information. The same set of information went to neurology that was able to support our FOS program. So we'll continue to work through that.
Okay. And cash runway?
Cash runway to the end of 2026, which allows us to meaningfully get on the other side of our proof of concept data for FOS and be in the position to initiate our other programs in neuropathic pain as well as bipolar. We also have an ongoing development program for a long-acting injectable. We think could be transformational in this space. It would be the first long-acting injectable for epilepsy.
Great. Awesome. Thank you, Abe. Appreciate it.
Thanks, Paul.
Thanks.