All right, I think we're going to go ahead and get started. Hello, everyone. Thank you for joining us in the room and online at TD Cowen's 45th Annual Healthcare Conference. I'm Joe Thoma, one of the Senior Biotech Analysts here on the team at Cowen, and it is my pleasure to have with us today the team from Rapport Therapeutics. We have CEO Abraham Ceesay and CFO Troy Ignelzi here for a fireside chat. Maybe just to kick things off, we'll dive into the specific programs. Maybe, Abe and Troy, if you want to, at a high level, give us a brief state of the company and maybe what investors should be looking at for the next kind of 12 months here.
Sure. Joe and the rest of the Cowen team, thank you so much for having us at the meeting. It's been a great meeting so far. Rapport Therapeutics, we're a company that is focused in building the leading precision neuroscience company. We believe we can bring that to life through the use of receptor-associated proteins. We'll talk a little bit more about that and the application of that for our lead program in RAP-219. We've given a couple of updates over the course of the year. We're currently in a phase 2A proof of concept study with our lead program, RAP-219, in focal onset seizures. That study is progressing very well. We're on the cusp of data in the third quarter of this year.
We also guided at the beginning of this meeting that we will be initiating our bipolar program in 2025 as well with RAP-219, with the hopes of data in early 2027. We also appointed a new Chief Medical Officer who we're really excited about, Jeff Sevigny. Jeff comes to us from Eli Lilly as a Senior Vice President of neuroscience. He came to that role through Lilly's acquisition of Prevail Therapeutics, where he was the inaugural CMO.
Perfect. Maybe just to start at the beginning, obviously the lead compound, RAP-219, is the targeted AMPA receptor inhibitor. Can you talk a little bit about these assets that come from J&J? Maybe how did you get them in-house and maybe why was J&J not necessarily focusing on continued development in-house here?
Yeah, this company is really due to the partnership between Johnson & Johnson and Third Rock. It was really a company creation model versus an asset transaction model. I say that for a few reasons. First, the company was created not only on our lead program, RAP-219, but also based on the application of receptor-associated proteins to discovery efforts. Not only did we bring out a lead program, but we brought out an entire discovery platform. In addition to that, we brought seven of the core scientists from Johnson & Johnson that were really prosecuting this effort for over a decade. This is everything from biology up to the medicinal chemistry. The last aspect is Johnson & Johnson is an investor in the company. They participated both in the Series A as well as the Series B financing for the company. True company creation effort.
In terms of why did J&J look to partner these assets and create this company? When you talk to J&J, they talk about it in the context of strategic externalization. What they believe is that they can progress programs as rapidly through this type of company creation model as they can through a large organization. Truly for them, they still have belief in this target, still have a lot of belief in the program, but they feel that the most efficient path was to create a company like Rapport.
The ownership is through JJDC, through the equity side, and there is a modest economic obligation back to JJ or to J&J, $116 million in development milestones and then mid to high single-digit royalties.
Perfect. Can you go into a little bit about the mechanism and sort of the targeted nature? Obviously looking at TARP gamma-8, AMPA-associated receptor targeting with this therapy. Why specifically the TARP gamma-8 in terms of localization in the brain?
Yeah, so we're leveraging what is known biology as well as a validated mechanism in epilepsy, which is AMPA modulation. We're doing that in a very different manner. We're targeting a receptor-associated protein, which is the TARP gamma-8. This family of RAPs, receptor-associated proteins, are unique in the fact that they have localization throughout the brain. The gamma-8 version of that receptor-associated protein is expressed in forebrain structures, mainly in the mesial temporal structures as well as other cortical structures. Importantly, it's completely absent from the hindbrain. Why that is important is we're able to modulate AMPA receptors, and we're able to do that in both our preclinical models, but also our emerging clinical profile with an unprecedented therapeutic index.
Because by avoiding AMPA receptors in the hindbrain, what we're able to do is not see things such as sedation, somnolence, or motoric impairment, which is really an unprecedented profile for an anti-seizure medication.
Maybe what have we learned by the initial phase 1 exposure data that you've seen so far before entering focal onset seizures? Maybe if it's related to that, how is 219 maybe differentiated either preclinically or in the early experience from some others like ES Pharma's drug as well?
Sure. Today we have completed four phase I trials, a single ascending dose study, two multiple ascending dose studies, as well as our human PET receptor occupancy study. We're really encouraged by all of the data that we've generated from those studies, kind of the mosaic as we think about this program, we think is really continuing to kind of present this real unprecedented profile. In terms of our human PET study, a couple of observations from that study. First is we were able to reconfirm the localization of TARP gamma-8 to forebrain structures. What we're also able to do is really confirm the receptor occupancy curve, but also confirm the receptor occupancy of the dose that we have brought forward in our phase II study. For example, that dose that we're currently utilizing in our phase IIa study achieves roughly 80-85% receptor occupancy.
Linking that back to our preclinical data, and preclinical data in epilepsy is highly validated, high translation between preclinical and clinical. Our target receptor occupancy was 50-70%. We are bringing a highly, we believe, bringing a highly efficacious dose forward in our phase 2A study. In our multiple ascending dose studies, as well as our single ascending dose study, we are able to really tease out what we know about this compound. I think that gets to the second part of your question in terms of how is this compound differentiated from earlier compounds in this category. What is known about this compound and compounds in this category, as well as its biology, is that what you want to do is have a more moderated approach to therapeutic concentrations and a more moderated approach to CMAX.
What we have with RAP-219 is a compound that has a very long half-life, 8-14 days. What that does is it allows the drug to slowly accumulate and achieve therapeutic concentrations in a more moderated fashion. Why that's important is what was learned in our single ascending dose study, as well as previous compounds in this category, is if you achieve really rapid CMAX with single dose, you will see on-target pharmacology and some tolerability findings. That's what we learned in our single ascending dose study. We looked at doses up to 2 and 3 mg. Those doses were tolerated, but we did see some on-target pharmacology when we did a dosing regimen of looking at multiple dosing of 0.75 mg for five days, stepping up to 1.25 mg for 23 days, so 28 days of exposure.
What we saw is we were able to mitigate mostly all of those adverse events and then achieve exposures, as I said, of roughly 80-85% receptor occupancy, and the drug is very well tolerated.
Perfect. For the initial indication, you are looking at epilepsy, and we are going to see the initial data in the third quarter of this year. You are taking a little bit of an innovative approach to trial design. Maybe it would be helpful to kind of slowly break it down into component parts because it is taking some time for investors to kind of get a handle. You are using the RNS device to measure long episodes. I guess maybe just to start, what is the RNS device and what is a long episode?
Important for us as we thought about a proof of concept study in epilepsy, what we wanted to do is ensure that we had data that gave us the most definitive data set to allow us to understand, one, do we have a drug, and then two, how rapidly could we get into registration trials. Our thinking was the way to do that is to do a proof of concept study in the same patient population that you're ultimately going to assess in registration trials. The choices that we had in front of us were to do a traditional photosensitive epilepsy study. Also, there's external EEG studies. Both of those studies, while interesting and provide you some pharmacodynamic data, they are not in focal epilepsy patients. What we chose to do is do a study in refractory focal epilepsy patients.
The difference, as Joe noted, in this patient population is these patients have an implantable neurostimulation device. This neurostimulation device is both a therapeutic device, but in our case, it's a diagnostic device. The data from this device has caught a lot of attention in the epilepsy community because it reads a biomarker, which is epileptiform activity, which is called a long episode, that is a defined precursor of an electrographic seizure and a clinical seizure. What the community has done through research around this data, independent of us, but we have produced our own data here, is that they've really confirmed the association of this biomarker and reduction of long episodes with a clinically meaningful reduction in clinical seizures. That threshold is about 30%.
A 30% reduction in long episodes has defined a greater than 50% reduction in clinical seizures, which is really the clinically meaningful endpoint as you think about phase 3 trials.
Perfect. I know that presentation was announced at AES last year. I guess how does that 30% reduction in long episodes and the correlation to clinical seizure activity play out in what you would be looking for in the third quarter? I guess either what level of reduction in the overall population in long episodes will you be looking for, or if that's not the way to think about it, how should we think about it?
Yeah. Our study is looking to enroll roughly 20 patients. There is both a retrospective as well as a prospective baseline period and then an eight-week treatment period followed by an eight-week washout period. What we'll be looking at specifically in our trial for a primary endpoint is the reduction of long episodes, and the threshold that we're looking at is that 30% reduction of long episodes. We believe the best way to look at that is through a responder analysis. We think that a 30-50% responder rate is a pretty good responder rate because that would get you to roughly 30-50% of patients having a potential for a 50% reduction in clinical seizures. When you look at that range, that's a pretty meaningful range as you looked at other previous anti-seizure medication trials.
We will be looking at it in terms of that responder rate with a 30% reduction in long episodes as being the threshold.
Perfect. It seems like through your partnership with NeuroPace, you're able to have access to a lot of different types of information when this trial does read out. I guess outside of long episodes, is there anything else that you're going to be looking at? I believe patients do need to have a certain level of baseline clinical seizures and baseline to even enroll. Will we be able to get any sort of read on clinical seizures as well?
Yeah. First, these patients, when you look at their demographics, are very similar to the patients that have been enrolled in previous anti-seizure medication registration trials. We feel like this patient population is highly representative of what would be translated into a phase 3 trial. With that said, when we think about collecting data from these patients, we're focused on long episodes and the electrographic readings. However, we are going to be capturing clinical seizures as well. Clinical seizure diaries will start in that 28-day prospective baseline period, and then patients will continue to capture their clinical seizures on treatment through that eight-week treatment period. We will and are prepared to really present that full set of data all the way from electrographic readings through clinical seizure diary data readings as well.
If I could, I want to put a point on something that Abe said, both from the patient, but also from a finance perspective. This will be the first time that we'll get phase 2 proof of concept data in the patient population. The translatability into the phase 3, we're also doing this in about a year. If you look at most proof of concept trials that are run, they're 24-36 months. The efficiency that we've gained as a company, we think it gives us predictive data in about a year that's going to allow us to move into our pivotals will end up being the same design as everybody else. That's the way we're planning for those with the diaries, but it gets us there a lot faster and more efficiently from an investment perspective.
Can you talk a little bit about enrollment? Because enrollment's always a topic of conversation with epilepsy studies. Maybe what does the benefit of the RNS device provide you? Do you know everyone that has this? You can kind of just call them up and say, "Hey, we have a study ongoing.
Yeah. You alluded to our partnership with NeuroPace, and that has been just critical in the design of the study, but also the execution of the study. NeuroPace owns the data on every patient that has been implanted with the device. There are 6,500 patients in the United States with this device. Importantly, what NeuroPace can do is understand what are the demographics of that patient population, what is the current disease burden electrographically of these patients. What we're able to do is we're able to take that data, understand that data in a de-identified way, and actually understand where those patients are relative to our investigators and our sites. It has been a really collaborative effort. We've been really pleased with the quality of sites first that we're partnering with.
We are truly partnering with the premier epilepsy sites in the country. Also, we've been very pleased with the demographics of the patients that we've been able to enroll and really ensure, or put us in the best position, that we can detect a clinically meaningful change.
Perfect. You alluded to this a little bit at the beginning, I think, in the overall discussion of the mechanism, but can you just touch a little bit on the unmet need in epilepsy and how big you think this drug could potentially be?
Yeah. Epilepsy is a large market, 1.8 million patients in the United States. Really, one of the key defining factors of epilepsy, which really defines the unmet need, is that 40% of these patients are treatment resistant, meaning these patients are currently on anti-seizure medications, but they're having breakthrough seizures. The standard of care for all epilepsy, refractory focal epilepsy patients, all focal epilepsy patients is polypharmacy. These patients are treated with multiple compounds, multiple mechanisms of action to really try to provide as much relief and potentially get patients to seizure freedom. With our mechanism, why I think the community is so excited about the mechanism is first, it's a novel mechanism of action.
If your patient has failed on a gabapentin drug, a sodium channel drug, calcium channel drug, you name it, you don't have to really be concerned about that with our compound because it's a novel mechanism of action. The second aspect is what is the profile of a drug that really allows for broad utilization in this patient population and in the community. What you need there is you need a compound that, one, is efficacious, but also is very well tolerated and doesn't have the risk of a serious adverse event. That's the case for our drug. Also, administration is really important in this patient population, given the fact that they are on polypharmacy. What we're really buoyed by is our compound is not metabolized via cytochromes.
It has a very low potential for DDIs, both being the perpetrator or at risk of drug-drug interaction, which we think is an ideal profile in the world of polypharmacy.
Perfect. Maybe we'll come back to some additional indications. Maybe moving on to bipolar. You did release some initial or additional, I guess, MAD data earlier this year, kind of looking at different dose titration ramps. Can you kind of highlight why you might need to hit a different level of exposure earlier or later, depending on the indication and what you saw in that?
Yep. Bipolar mania trials are relatively standard trials. They are three to five weeks in duration. Given that duration, the need in those trials, both from just a trial conduct standpoint, but also just from an ethics standpoint, these are inpatient trials. These are patients that are having a manic episode. You really need to be able to achieve a therapeutic exposure and efficacy within a week. What we really wanted to understand, not only through a multiple ascending dose trial, but through our PET study, is do we have a compound that can do that and also be well tolerated? We were able to confirm that. We are confident that we have a dosing regimen that can get there in three to five days and really get to that level of exposure needed to enable a bipolar study.
Perfect. We did have the experience with Fycompa to kind of de-risk the epilepsy side of things a little bit. Can you go into the rationale for bipolar with the RAP-219 mechanism?
Yeah. Bipolar, in terms of preclinical to clinical translation, is definitely not as strong as epilepsy. It is one of those indications where ultimately you have to look at a whole bunch of information and kind of a mosaic of information to get yourself comfortable that you have a compound that might be effective there. For us, there is high clinical precedence with anti-seizure medications being effective therapies in bipolar mania. There are three approved products, both as anti-mania agents, but also as mood stabilization agents. The biology that we really look at is the hyperexcitability that has been shown in imaging in manic patients is really focused in the hippocampus. We have a drug and have a target that has broad forebrain exposure, but primarily we have a lot of concentration in the hippocampus.
We think with some of that neuroimaging data, knowing that hyperexcitability in the hippocampus is a key factor of bipolar mania. And knowing that we are hitting kind of a glutamate-type receptor that really is driving or responsible for excitability, we think we have a chance here with bipolar.
Perfect. You indicated this week that you're going to start the study in the third quarter of this year. Maybe what's left between now and then? Do you need any additional FDA sign-off or meetings, or is it just kind of blocking and tackling to get the study going?
Yeah, it's really blocking and tackling to get the study going. We will submit the IND to the Neuropsych division in the coming months, and then we will execute the protocol. The team is actively kind of leaning into all of study preparations as we speak.
Obviously, with the epilepsy study, you did do a little bit more of a unique design. What will a bipolar study look like if you can comment? Will it be more traditional than what we've seen before, or are you going to do something else exciting?
We like to innovate, but we're not going to innovate on everything. Bipolar studies are very straightforward. You can look at almost all bipolar programs having pretty similar characteristics in terms of study design. Key to bipolar, as with other psychiatry indications, it's really about trial conduct where you're looking to ensure that you are enrolling the right patients, sites have the right training, raters have the right training, and you're really looking to reduce variability. Our focus will be on that, is really the conduct of the trial, the execution of the trial to really minimize any placebo effect and also to really minimize variability in the study.
You indicated earlier that the mechanism would likely play well with other mechanisms in epilepsy. Obviously, in neuropsychiatry, there's a lot of overlapping mechanisms. Will this be seen largely as a monotherapy drug, or are you going to study it as an adjunctive treatment? Kind of how are you thinking about that?
It will most likely be in the adjunctive setting for bipolar. That is kind of also another indication and treatment paradigm that is really defined by polypharmacy. Importantly, for our compound, when you look at the needs in bipolar, it is very similar to epilepsy. The current agents that are available for patients with bipolar are heavily, heavily sedating agents. Although they might provide some relief for patients, the tolerability profile of those drugs really is not conducive for patients really maintaining themselves on the most efficacious dose or feeling comfortable having kind of that mood stabilization agent on board. We believe that if we can provide efficacy, but also have this tolerability profile, it could be a really transformational therapy for patients.
Perfect. The last indication that you've highlighted for 219 is pain. Can you talk a little bit about why the mechanism lends itself to pain and kind of what are you seeing about the pain space recently? Obviously, it's gotten a lot of attention through Vertex and some others. What are your thoughts there?
Yeah. The biology leads us in the direction of pain. The only other location of AMPA receptors containing gamma-8 TARP are actually in the dorsal horn of the spinal cord. There is some really interesting biology that leads you there. We have also done some preclinical work looking at models in neuropathic pain with our compound and compounds in this category. The results are really promising. As we all know, there is a huge unmet need in neuropathic pain. It is an area of growing prevalence, but also just really not many effective therapies available for patients. Finally, when you look at anti-seizure medications, one of the most widely used drugs for neuropathic pain, maybe not the most effective, is gabapentin. There are a lot of places to kind of point to why we believe that that could be an opportunity with this compound.
We have submitted our IND for neuropathic pain. We did hear back from the DAAP division, the pain division at the FDA. They did put our program on clinical hold at the DAAP division. Importantly, that has no relevance to what we're doing in epilepsy, nor do we believe has any relevance to what we're doing in bipolar. It was really a division-specific set of feedback that related to the protocol. We are looking to refine some elements of that protocol and hopefully be in a position to enable that program in the near term.
Maybe just one question on that process. Is it clear based on the FDA what you might need to do in order to remove the hold, or kind of when do you think you might be in a position to update the street on that?
Yeah, I think we'll be in a position to update the street probably later this year.
Yeah. You do have a couple of earlier stage portfolio candidates focused on nicotinic receptors. Maybe how do you think about that? You obviously have a lot on your hands with the three indications with 219. How do you prioritize kind of earlier stage advancement as well?
Yeah, you know our vision for this company was always to have a company that had the opportunity to have a self-sustaining or regenerative pipeline. We are actively investing in our discovery efforts. We have a fully enabled discovery team that is based in San Diego. The foundation of that team was the team that came and joined us from Johnson & Johnson. What we're focused on are receptor-associated proteins, but applying those to other ion channels. In this case, we're looking at nicotinic receptors. For us, our lead program is a program that is looking at a nicotinic receptor that actually has really strong biological precedent in neuropathic pain, but also some clinical precedent based on a program that was done by Abbott before they were AbbVie. We are excited about that program.
That program continues to make progress, and we should be in a position to update on that program this year and into next year.
Perfect. You did successfully complete the IPO process last year. As of the end of the third quarter, you had over $300 million in cash. Kind of how do you feel about your runway? Where does that get you through in terms of a clinical milestone perspective? I know based on timelines, it was kind of to the end of 2026. Is that still the case?
It allows us to get through the end of 2026. That importantly gets us through the phase two proof of concept, which we think is going to be transformational for the company because it is a program that's needed. It's a disease state that there's a lot of opportunity to help patients. As Abe alluded to, it's a very large market. We have enough to get through that, and then we'll move things forward from there.
Perfect. Awesome. With that, we're just about out of time. Thank you both for taking the time today. We appreciate it.
Thanks, Joe.