Thank you all for joining today's fireside chat. My name is Justin Walsh, covering healthcare analyst here at Jones Trading. Any viewers should feel free to send me questions via email at jwalsh@jonestrading.com. We'll try to get to these if they come in and time permits. We can kick things off with you guys introducing yourselves, your role at Rapport, and a little on your background.
Great. Troy, do you want to kick off?
Sure. Thanks, Justin, for having us. Appreciate the opportunity to share the story about Rapport. I'm Troy Ignelzi, the Chief Financial Officer here about a year and a half. We took the company public in June of last year. Coming up on our one-year anniversary, Abe will talk a little bit about the data. Prior to Rapport, I spent the last 25 years helping companies in finance, business development, operations, raise close to $5 billion for what are now eight approved products. Most recently, I was the CFO at Karuna Therapeutics. Thanks again, Justin. Appreciate the time.
Great. Justin, yes, thank you so much for having us and allowing us to share the Rapport story. My name is Abe Ceesay. I'm the CEO here at Rapport. I've been with the organization since we launched the company in early 2023. I've got over 20 years of experience in the greater Boston biotech community. Most recently, I was the president of Cerevel Therapeutics. I had a great experience there building a standalone neuroscience company, that being in the form of a partnership with Bain Capital and Pfizer. We believe that we have the opportunity to do something even greater here at Rapport, given the foundational science that we're working on.
We will talk more about that and really the opportunity to build the leading precision neuroscience company and build a self-sustaining and regenerative pipeline in neuroscience, which has been a very challenging thing to do in the biotech sector. We think we have a real shot at doing that here at Rapport. I look forward to sharing more about the Rapport story.
Great. Thank you both again for joining. You mentioned that foundational science. Maybe we could just start with quickly, what are receptor-associated proteins and why could targeting RAPs lead to improved clinical profiles?
Great. I'll talk a little bit about receptor-associated proteins broadly, and then I'll spend maybe a minute or so on how it's realized both in our lead program as well as the rest of our discovery pipeline. Receptor-associated proteins are proteins that interact directly with specific cell surface receptors. RAPs themselves, or receptor-associated proteins, play critical roles in regulating receptor function, trafficking, as well as signal transduction. If you think specifically for Rapport and how we're leveraging receptor-associated proteins, it's really two ways. First is through, and I think the best example is through our lead program, RAP-219. This is leveraging a receptor-associated protein associated with an AMPA receptor. Our lead program specifically is a TARPγ 8 AMPA modulator. AMPA being kind of that main receptor, TARPγ 8 being the receptor-associated protein.
In this context, what we are doing is we are modulating the AMPA receptor through engagement of the receptor-associated protein. By doing that, what we're able to do is have a level of specificity and precision with a small molecule that's really unprecedented. We're able to only modulate those AMPA receptors that express TARPγ 8 or that receptor-associated protein. We're also leveraging receptor-associated proteins similar to what we're doing with RAP-219 and the AMPA receptor in other areas of our discovery portfolio. What the founding scientific team here at Rapport also discovered was the ability to utilize receptor-associated proteins to actually help express certain subunits as well as novel targets with specific ion channels. That really unlocks a whole host of opportunities as we think about novel drug targets, specifically thinking about ion channels is where we're currently focused.
Got it. You kind of preempted my next question here about what is your lead asset, RAP-219 target. I think you alluded to a little bit here how it could be differentiated from competitor drugs of relevance given kind of the specificity you cited. Is there anything more you'd like to talk about on kind of that expectation of differentiation?
Sure. One of the significant limitations with neuromedicines and specifically anti-seizure medications is that they are interacting with receptors ubiquitously, whether that be in the brain or in the periphery. Some of the limitations we see specifically with anti-seizure medications is they have a very narrow therapeutic index. What we mean by that is at the same level drugs are achieving efficacy are the same levels that you're starting to see a level of toxicity or really bothersome adverse events. Specifically for anti-seizure medications, two real bothersome adverse events for patients are sedation or somnolence as well as motoric impairment or ataxia. When you really kind of follow the biology through, that's because many of these anti-seizure medications are interacting with receptors that are in the hindbrain, so areas such as the cerebellum as well as the brainstem.
RAP-219, through leveraging receptor-associated proteins, we are only engaging receptors in the forebrain and specifically in areas of the forebrain that are known for both where seizures originate, but also propagate. By doing that, what we're able to see in our preclinical models is that we're able to achieve significant seizure suppression in validated preclinical models with really no observations of sedation or motoric impairment, which really starts to present this, what we consider kind of an unprecedented therapeutic index for an anti-seizure medication. Importantly, with this program, the target is validated. The AMPA being the target, a glutamate-type receptor that has been validated through approved drug by the name of Fycompa, which is a pan-AMPA antagonist. We really know that the pathway and the target is validated.
Now for us, we're approaching that in a unique way by only modulating those AMPA receptors in the forebrain.
Got it. You mentioned preclinical evidence. Obviously, we have kind of a drug comp here. How would you summarize, I guess, the evidence supporting the use of RAP-219 in focal epilepsy?
Yeah. RAP-219, as well as compounds in this category, have been tested in a whole host of preclinical models. One of the things that we really benefit from in epilepsy drug development is the fact that actually in epilepsy, preclinical to clinical translation is extremely high, probably one of the highest therapeutic areas in the industry in terms of probability of success, preclinical to clinical, and that translation of efficacy and safety. What we see across models both that are more akin to focal epilepsy, such as the corneal kindling model, but other models that are more akin to generalized epilepsy as well as genetic forms of epilepsy, we see a significant degree of efficacy with RAP-219, but also other compounds in this category.
Within that, the consistency is both across all of these preclinical models as well as our preclinical tox program is kind of this common theme that we are not seeing sedation that is really common with many anti-seizure medications.
Got it. Thanks. Now we can talk a little bit more about the clinical work that you guys are doing. Maybe to start off there, can you tell us what an RNS device is and how you're leveraging it in your phase II-A trial of RAP-219 in focal epilepsy?
Sure. Today we've completed a pretty comprehensive phase I program. We've completed three multiple dosing studies, which include two MAD studies as well as our human PET receptor occupancy study. We've also completed our Single Ascending Dose study. We have a really good understanding of kind of the overall characterization of this compound. For us, as we thought about going into a proof of concept study, there were a couple of things that were really important to us. The first is we wanted to make sure we had a clear signal of efficacy as well as an understanding of the tolerability profile in patients. That was the most important aspect. The second is making sure the data that we generated from our proof of concept investment would allow us to move rapidly into phase II-B3 registration studies.
What we are doing is we are leveraging a device. That device, as you mentioned, Justin, is the RNS device. This is a device that is implanted in focal epilepsy patients. The device serves both a therapeutic rationale and a diagnostic rationale. For our study, we're leveraging the diagnostic rationale. What's really interesting about this device is that this device is constantly reading epileptiform activity in the patient's brain. These patients are refractory focal epilepsy patients. When you look at their demographics outside of the device being implanted, they look very similar to those patients that are ultimately enrolled in a phase II-B3 study. Specifically, this device is measuring a biomarker by the name of a long episode. A long episode is a precursor to both an electrographic seizure as well as a clinical seizure.
The biomarker has really received a lot of attention in the community because it is a much more objective way to measure efficacy of anti-seizure medications than clinical seizure diaries. Clinical seizure diaries really require the patient to recall a reduction or a change in their clinical seizures. What we are measuring here, in addition to clinical seizures, we are measuring those, but our primary endpoint is measuring this highly objective electrographic activity that is defined as a subclinical seizure and a precursor to a clinical seizure.
Got it. I'm assuming that this sort of objectivity is an aspect of this, but maybe you could just expand upon why you decided to design the trial using RNS patients instead of more of a traditional proof of concept trial design that uses something like photosensitivity.
Yeah. Great question. When you look at the traditional models that have been used, they've been used because that's what's been available to the community. A model like photosensitive epilepsy is really a model of pharmacodynamic activity. When you look at the actual results of photosensitivity, there are some false positives, meaning some of the data you generate does not always translate into clinical success as you look at phase II and phase III settings. That's because you're not measuring efficacy in your intended patient population. Photosensitive models are not refractory focal epilepsy patients. For us, we wanted, as I said, to be in the patient population. The second aspect of this is there's been a lot of data and a lot of analysis around this epileptiform activities, these long episodes.
What the community has really come to is that these long episodes are not only a highly objective marker of efficacy, but they also are a very predictive marker of clinical seizure reduction. We think we're getting kind of the best of both worlds in this study. We're able to have a highly objective measurement, but we're also having a measurement that we believe that this output will help us predict our ultimate success in a phase II-B3 setting. We will be measuring clinical seizures. Our study is not powered for clinical seizure detection, but we are measuring that. We think that dataset ultimately is going to put us in a much better position than historically would be if we use something like a photosensitive model.
Got it. What feedback have you gotten? Oh, yeah, go ahead, Troy. Yeah.
Is we'll get these proof of concept results in less than a year from start of the trial to top-line readout, which is also very unique in this space where diary trials, whether it's a phase II or pivotals, can take two to three years. It is a faster, and we think, and I think the community as well as potential BD development partners that we've spoken with see this as a very reliable way to predict use in phase III's.
Got it. Yeah. I'm wondering if that's, I think you just mentioned this, but how KOLs have, what feedback they've given you on this trial design. I imagine that it's generated a bit of interest.
It's generated a significant amount of interest. First, the study came to us through our partnership with the community. We had the opportunity to be at a research roundtable with the Epilepsy Study Consortium where this concept really came to life and was discussed. That was the community really searching for, as Troy mentioned, a more efficient way to think about proof of concept with investigational anti-seizure medications, but also to have a much more objective measurement of efficacy. What we have seen both through that initial engagement, but also over the past 12-18 months is the community has really taken a high degree of attention to our study design, high degree of interest. I think that is based on the fact that, one, we will have results that we think will really build a lot of efficiency as we think about overall drug development.
I think the community also sees this as a step forward in terms of drug development with investigational products in epilepsy.
Got it. You guys did have some posters recently presented at the 2025 American Academy of Neurology meeting. Were there some key takeaways from that?
There are. What we've continued to do is work with the community and also work with the manufacturer of the device, which is NeuroPace, to continue to assess kind of the predictability of this biomarker in predicting long-term clinical efficacy with anti-seizure medications defined by the reduction of clinical seizures, which is important because that is the phase II-B3 endpoint as you think about registration trials in focal epilepsy. What we highlighted during our AAN meeting and the poster, as well as the data that we presented at last year's AES, was that correlation. What we were able to do is define at what thresholds in long episode reduction do they predict a threshold in clinical seizure response.
Interestingly, not only have we produced that data, but we've seen that data now be produced by other people independent of us, other researchers independent of Rapport, that this 30% reduction in long episodes predicts at least a 50% reduction in clinical seizures. That's really important because that 50% reduction in clinical seizures is really the clinically meaningful threshold as you think about the percent of patients that can achieve that in a phase II-B3 study. We produced that data. It was really helpful to, I think, to see that data and the community has really been interested in that data, not only for that cut point, but the fact when you look at other cut points, there's a very strong linear relationship with the increase in long episode reduction being tied to an increase in clinical seizure reduction.
Got it. I think that sets a kind of a nice baseline on expectations here, but maybe we can talk a little bit about, first off, confirming our expectations for timing for the RAP-219 top-line readout in focal epilepsy. And then what should we actually be looking for or expecting in that readout?
Yep. We have guided to the third quarter of this year for our readout in our phase II study. We're on track for that. We're feeling really great about what we're seeing with the study in terms of enrollment, ongoing dosing for the study, and just overall operations of the study. In terms of expectations for the study, we're going to be looking at the data in a holistic manner. Our primary endpoint is the reduction of long episodes. We're going to be looking at that through the lens of a responder analysis with that cut point being a 30% reduction in long episodes. That's the first kind of set or anchor of the data, is that responder analysis. We'll also be looking at clinical seizures as well.
We are capturing clinical seizures through a 28-day prospective baseline period where patients are keeping a clinical seizure diary, and then they're keeping that clinical seizure diary as they go on to RAP-219 treatment, which is an eight-week treatment period. We will also be capturing tolerability as with any study. I just want to reinforce what's beautiful about this study is, again, these patients are refractory focal epilepsy patients. In a proof of concept model, we're really able to see kind of that additive efficacy in a refractory patient population that are currently on anti-seizure medications. We're going to be looking at that both objectively through the biomarker and epileptiform activity, but also capturing clinical seizure diary data.
Got it. In terms of key benchmarks, that 50% reduction is kind of what we're keeping an eye out for, right? And then the, I guess, the 30% in the long episodes. Are there any other benchmarks? That's kind of.
I think you got it. You know, the 30% threshold, response threshold for long episodes, which correlates to at least a 50% reduction in clinical seizures. When you look historically at what proportion of patients ultimately achieve a 50% reduction in clinical seizures, there's a lot of 30s and 50s going on here. That, when you look at historic trials, it's about 30%-50% of the population achieves that. We will be looking at the data, as I mentioned, holistically. We feel that, again, this data should be highly representative of what we think we can achieve in a phase II-B3 setting.
Got it. What are your next steps if the data are positive? Is there a possibility that you could go right into a registrational trial?
That's our plan. That is the reason we're doing this study, as we think it creates the efficiency to do just that. We are going to be on the heels of this data, we'll have our end of phase II meeting with the FDA. Our current baseline plan is to be running two parallel phase II-B3 studies concurrently. Those would be registrational trials.
Got it. Would you expect to use an RNS device in those as well?
No, we don't. We don't expect to use the RNS device. We see the RNS device as a really great proof of concept model for us. As we look at the phase II-B3 population, that will be your standard refractory focal epilepsy population that has been used in previous investigational drug trials. Importantly, demographically, these patients, as I mentioned early, look very similar. Outside of the device, when you look at their age, time living with the device, their number of background medications, demographically, these patients are going to be very similar to what we see in a phase II-B3 setting.
Got it. We have about one minute left here. I'm just wondering if there's anything else that you'd like to highlight for either RAP-219 or sort of your broader pipeline.
Sure. We have always envisioned that RAP-219 really can serve as a pipeline and a product. That is given the biology, but also given clinical precedence where anti-seizure medications have shown efficacy. Given our specificity, we think we have an even kind of better opportunity to really bring kind of a transformational therapy to many patient populations. With that said, we are also going to be getting our bipolar mania program off the ground this year. We are on track to start that study in the third quarter of 2025, data expected in early 2027. We are also working through the finalization of our neuropathic pain program with RAP-219 as well. We will end up guiding on the initiation of that program at some point in this year. We are really excited about both of those programs. We think there is high unmet need.
We also think the profile of this compound is going to be a great fit for both of those indications in addition to epilepsy.
Great. We are out of time now. I want to thank you again for taking the time and speaking to us about what you guys are doing over at Rapport Therapeutics. Have a great day.
All right, Justin. Thank you.
Take care.
Bye.