30 seconds, I think. Oh, and actually, we're starting. Okay, we're going to get started on the next session. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies. Thanks for tuning in. Next up is Rapport Therapeutics, to my direct right, Abe Ceesay, CEO, and to his right, Troy Ignelzi, CFO. Welcome, both of you. Yeah, thanks for having us, Andrew. For those in the audience who may be less familiar with the story, you did just IPO. Maybe just give a couple minutes, spend a couple minutes talking about Rapport and what you're working on and what kind of milestones we can look forward to. Sure. So thank you, Andrew, and the Jefferies team for having us. So Abe Ceesay, CEO of Rapport. Maybe I can give a little background on the company, both the history, the formation, and really what our vision is. So Rapport, a company that is really focused on building the leading precision neuroscience company. We realize that precision is a word that's used somewhat loosely in our industry, but we do believe our scientific foundation, which is receptor-associated proteins, really allows us to bring precision to life with small molecules in neuroscience. The formation of the company is based on a partnership between venture and large pharma to realize the formation of Rapport. That is with Third Rock and J&J. So we licensed in assets from J&J, as well as a discovery platform. When I say company creation, the reason I say that is this is more than just assets. We were able to bring over core members of the scientific team at J&J that were working on our lead program, but also scientific platform of receptor-associated proteins. Our lead program is RAP-219. This is a gamma-8 TARP AMPA modulator program. It specifically modulates AMPA receptors in a very precise manner, only in the forebrain, so not modulating AMPA receptors in the hindbrain, which we believe starts to show a profile of best-in-class potential for focal epilepsy, but also the ability to develop a pipeline and a product in areas such as neuropathic pain, bipolar mania, as well as the opportunity to potentially develop a long-acting injectable, which would be the first of its kind in epilepsy. Beyond that, we have an active discovery program that is focused on our same scientific platform of receptor-associated proteins with two late-stage programs that are both in late-stage discovery, with their next stage gate being nomination of a development candidate. Wonderful. And it sounds like you will have a presence at AES this year. So what can we expect there as well? We will have a presence at AES. So that gives us the opportunity to highlight some of the phase 1 work that has been done with RAP-219 to date. But the other aspect that we're focused on is really continuing to shed light on our unique trial design for RAP-219, our proof of concept study in focal epilepsy. That study is using a biomarker that is called a long episode. It's a biomarker that is gaining a lot of attention and appreciation in the epilepsy community, given its objective nature and its ability to really predict and correlate to a reduction in clinical seizures. So we've been partnering with the manufacturer of the device that diagnostically is able to read these long episodes, and we'll be presenting some data there that we think even further strengthens the correlation between long episodes and the reduction in clinical seizures. Got it. And just big picture to help level set things, what kind of profile are we talking about in focal epilepsy at the end of the day? Maybe talk about the potential differentiating attributes you think you can offer. Sure. So first of all, focal epilepsy is a large market, 1.8 million patients in the United States. The key aspect of this market, and really the patient population, is although there's over 20 anti-epileptics that are available for patients with focal epilepsy, 40% of patients still have breakthrough seizures, so they're refractory. These patients are being treated. The issue that has been seen in epilepsy drug development is, although there has been a lot of products that have been developed, the issue remains that most anti-epileptics are interacting with receptors that are ubiquitous throughout the brain. So you may receive efficacy with these drugs, but there's a pretty significant tolerability trade-off that patients have. So with RAP-219, what we have seen in our preclinical, as well as our clinical work today, is the potential for an unprecedented therapeutic index. What that means is the ability to achieve upwards of 80% receptor occupancy in our preclinical work that is completely suppressing seizures with no impact on sedation or ataxia or motoric impairment. We see that as a best-in-class profile from a therapeutic index standpoint, but also a compound that has really an ideal administration profile, once-daily dosing, a long half-life that allows for the patient to not be concerned about a rebound for a missed dose, as well as the lack of DDIs based on the metabolism of the drug. And pretty novel mechanism. And how about rapid acting, do you think? Yeah, so what we know about our compound is that it has a long half-life, as I mentioned, and what we also know is in terms of getting to therapeutic concentrations, you want to take a very kind of moderated approach to that, so in terms of our dosing profile, we do not have a complex titration scheme. What we have is a patient starting or dosing schema in our trials where patients start on 0.75 milligrams for five days and then stepping up to 1.25 milligrams for more chronic treatment, and what we see there is, one, the ability to achieve a therapeutic concentration in the seven- to 10-day range, but also by moderating that approach to therapeutic exposure, Cmax, and ultimately steady state, we're able to mitigate almost all AEs. And you've went through preclinical phase 1, and you're about to start phase, maybe actually you started phase 2. So we're getting data mid-2025. But backtrack to the preclinical side, as we kind of compile all the data points that can get you confident why this upcoming phase 2 will show a very strong signal. What did you see preclinically that made you move to phase 1 to begin with? Yep. So RAP-219 and compounds in this category have been assessed in multiple preclinical models. One of the things that we really benefit from in epilepsy drug development is the strong translation that exists from preclinical to clinical. It's one of the highest in terms of probability of success in our industry and definitely in neuroscience. Specifically in what is considered the gold standard of efficacy assays and preclinical assays for efficacy in epilepsy drug development, the corneal kindling model, we were able to see complete seizure suppression with RAP-219 at pretty low therapeutic concentrations given the potency of the drug. So we're talking about concentrations of three nanograms-seven nanograms per ml, and that's associated with about 50%-70% receptor occupancy. And in that same work, kind of the safety assay is what is referred to as the Rotarod. And this is a safety assay that is able to assess common side effects with anti-seizure medications such as sedation and motoric impairment, and at no doses does RAP-219 impact the Rotarod. So that's where kind of that real unprecedented therapeutic index really comes from. And what we know from other anti-seizure medications is they have very narrow therapeutic indices. Basically, at the same dose, you're able to achieve efficacy in, say, a corneal kindling model. It's the same dose you're going to start to see Rotarod failures based on the sedative properties of those medications. And then in the phase 1, we're talking about doses in 1.25 milligrams, basically. And so when I think about other epilepsy drugs, their dose 500-1,000 mg. So what exactly did you see in phase 1 to make you stop at that dose? Why not push it higher, basically? Yeah. So So great question. And what Andrew is referring to is really the potency of the compound and the specificity of the compound allows for very low drug levels on board. So as I mentioned, a starting dose of 0.75, stepping up to 0.75 milligrams, stepping up to 1.25 milligrams. So in our SAD and MAD experience, first in the SAD experience, what we were able to observe in our SAD experience is when you push the dose high in that first dose and achieve rapid exposure, and that is in the 2-3 milligram range, and that is associated with about a 50%-60% receptor occupancy, we see on-target pharmacology. So on-target pharmacology for this compound, and this on-target clinical pharmacology is consistent with what we saw in the non-clinical setting, is these compounds are actually activating, which is somewhat unique. Most anti-seizure medications are sedating. So activating, how does that present itself in human subjects? Basically, patients report that they felt like they've had too much coffee, they need to walk around. And what goes along with that, and what we saw with that, was transient tachycardia. The tachycardia is not symptomatic. Patients aren't even aware. The way we were able to pick that up is basically Holter monitoring. And this is kind of a constellation of on-target pharmacology that is observed. All of these were no greater than grade two. So these were not severe adverse events, and all were transient and resolved on their own. Interestingly, and this is known about this compound and really was kind of behind the design of 219, is if you can approach Cmax, target exposure, steady state in a more moderated fashion, you can mitigate those AEs. So that's what we learned through our MAD setting, which again, I said is 0.75 starting, stepping up to 1.25. That constellation of AEs was really mitigated completely in our multiple ascending dose experience. You maybe hinted at it, but if I were to play devil's advocate, maybe someone would say, "Wow, the safety is clean. How do we know this drug is active? Could it be a placebo at the end of the day? Yep. Great question. Something that we asked ourselves, quite frankly, because when we saw the fifth cohort of the MAD study, we were very encouraged based on what we saw as kind of an unprecedented type of picture for an anti-seizure medication. The first thing that gives us a lot of encouragement is the fact that in the SAD setting, we're able to see on-target pharmacology. That's consistent with what we saw in the non-clinical setting. So we know that this drug is active, obviously from a single dose, and we were getting to those same exposures, significantly higher exposures in the multiple ascending dose setting. The other aspect is what we did is we repeated really that gold standard preclinical model with RAP-219, which is the corneal kindling model. So we repeated that study. Not only did we have that for one day, but we looked at that for chronic dosing over seven days. And what we saw with RAP-219 is not only were we able to maintain that efficacy over seven days, but if anything, the curves were shifted to the left, and the drug actually looked to be more potent over chronic dosing. So that gave us some real confidence that this approach that we're taking and kind of the PK of the drug really has the opportunity to deliver that benefit, but at the same time, be able to moderate and mitigate those AEs. Thanks. And before the phase 2 data reads out in mid-2025, you are, based on my understanding, working on either MRI or receptor occupancy in a separate study. Can you talk about what you're working on to help further de-risk their approach? Yeah. So we have two ongoing phase 1 studies. First, as Andrew mentioned, is a PET receptor occupancy study in humans. That PET receptor occupancy study, we really see as a confirmatory study. There was extensive work done at J&J on receptor occupancy, both in rodents and non-human primates. The actual tracer that we are utilizing is a tracer that was developed by J&J that we have access to. So that PET data for us is confirmatory. As I said, we're very confident in our projected receptor occupancy at peak. What this PET study will allow us to do is not only confirm that, but also really define that PET kind of curve for us. So as we think about various concentrations that we will be at as patients slowly accumulate this drug, what is the associated receptor occupancy? We think that that's going to give us a real nice line of sight as we think about multiple dosing arms going into a phase three study or doses that we take forward in other indications. The other study that is currently ongoing in the phase one setting is our second MAD study. Our second MAD study has an objective looking to even pull that therapeutic concentration even earlier. The reason for that is to inform bipolar planning. We're looking at our lead indication in bipolar being bipolar mania. Those trials are pretty short in duration. What you want to do is try to achieve therapeutic concentrations as rapid as possible given the needs of the patient, but also given the length of trials. So both of those studies are ongoing, are nearing completion, and we're looking to report out that data in the first quarter of 2025. Great. And now let's move on to the phase 2 study. How many patients' worth of data in mid-2025? How long of a treatment duration? And you did mention LE being the biomarker you're pursuing. Why go that route instead of the traditional seizure reduction endpoint? Sure. So we chose to move forward with a proof of concept study, which is in a patient population, an RNS patient population. So just step back and understand why we chose to do that. Our objective here with RAP-219 was to think about the most efficient development path, but also a development path that each part along the way was confirming the thesis around the compound, but also highly de-risking. So this RNS patient population is a focal epilepsy patient population. So unlike models such as photosensitive epilepsy or, say, an external EEG TMS model, which are not in focal epilepsy patients, our proof of concept study will be in focal epilepsy patients. Demographically, these patients look exactly the same to what patients would be enrolled in a phase 3 trial. If you look at the time of living with the disease, their clinical seizure burden, the number of background medications they're on, these patients look demographically the same as the patients that were enrolled in Cenobamate trials, but also being enrolled in, say, a Xenon trial. The difference is that these patients have an implantable Neurostimulation device. This Neurostimulation device plays two roles, a therapeutic role and a diagnostic role. We're leveraging the diagnostic portion of that. We're measuring what are called these long episodes, as I talked about before. Long episodes are a biomarker that are gaining a lot of appreciation in the community given how objective they are. These are long EEG recordings that are predictive of both electrographic seizures as well as clinical seizures. What the literature has told us is that if you are able to reduce long episodes by 30%-40%, that is predictive of a reduction in clinical seizures of at least 50%. By doing this type of trial, it allows us to get to a clinical readout in patients much more efficiently than other models. In our study, we'll be enrolling 20 patients. We're going to have a treatment period of eight weeks. The study itself is 20 weeks in length with a four-week pretreatment baseline period, an eight-week treatment period, and then an eight-week follow-up period. What we'll be assessing in the eight-week treatment period, we'll be looking at that long episode reduction for the last four weeks compared to baseline. So you mentioned patients who achieve 30% reduction and 30%-40% in LE seizures should be a responder on the traditional seizure reduction endpoint of 50% reduction in seizures. So what is good data to you? I mean, I've analyzed what other drugs show. It seems as if the responder rates for the approved drugs can be as high as 50%. Do you think you want to show higher because you have a smaller patient sample as well as it being an open label? Yep. So we've really looked at this study as a signal detection study. So we haven't really anchored in on exactly what we believe should be the right responder rate. What we do believe is there is going to be kind of a mosaic of data that we're going to produce here in terms of not only the amount or the degree of reduction in long episodes, but also that associated responder rate. So we haven't really anchored in on that exact percentage for a responder rate yet. I think the other thing that we'll be closely looking at is beyond just the efficacy is the tolerability profile. So if you were to talk to the community, clearly efficacy is important. And as you mentioned, Andrew, there is kind of an emerging threshold that is being reinforced through drug development in the space now. But the other aspect is what is the trade-off that you have for safety? Because being able to achieve that, efficacy sometimes comes with significant liabilities on tolerability. So in addition to the responder rate, we're going to really look at that safety and see what type of profile there. And we are hopeful that we're going to be able to pull through that same kind of unprecedented therapeutic index, best-in-class profile in terms of safety and efficacy. Yeah, that makes sense. I think you because every drug out there is kind of dirty. So if you can have cleaner tolerability, that changes the therapeutic index. Makes sense. And so why do an open label study in the first place? Why not a placebo-controlled? This is, at the end of the day, still eight weeks long. So why not make it a placebo-controlled to make it "more robust"? Yeah. So we evaluated that. Our view was this proof of concept study one is a signal detection study. We wanted to get to an answer as rapidly as possible. But also, I think what drove our decision in terms of the design of the study was the feasibility work that we did on this patient population and ultimately the data that supports it. So as I mentioned, the device is manufactured by a company by the name of NeuroPace. We have a direct relationship with NeuroPace. And part of our study is actually doing a retrospective look back on every patient that's enrolled. So as soon as the device is implanted, NeuroPace starts to record data. So as an example, in our study, each patient that's screened has to meet a specific set of inclusion criteria. And that's based on an eight-week look back of their data. They have to have a minimum threshold of long episodes. They have to have at least one clinical seizure. We have to understand the medications that they're currently on. Once they screen and they have met screening criteria, they go into a four-week prospective baseline period where all of those things are locked. So if you think about this patient population, they serve as their own control. This is a very objective biomarker, one that cannot be manipulated in any way. The device settings are closed, they're locked, their medications that they're on are locked, and then the introduction of RAP-219. So as we went through the NeuroPace data, we gained a lot of confidence on how objective the biomarker is, but also how sensitive the biomarker is to new drug starts. From a feasibility perspective, we felt getting to an answer, but also having some confidence in the objective nature of the biomarker really got us comfortable with doing this in an open label setting. Very clear. I was going to ask, I guess in terms of next steps, should this study meet your go, no-go threshold? What would be the next set of studies? How many more studies would you want to do? Yeah. So the next set of studies for us, given again the model that we've chose to do our proof of concept study in patients, would be to go into, we believe, will set us up for registrational studies. Now, typically, you would need two registrational studies for approval in focal epilepsy. So that is our plan. We believe this is going to be totally data-driven, as one would expect. But we believe, given the design of this study, it will set us up to consider parallel registrational studies, which we think would be very efficient. That is also going to be based on dialogue with the FDA at the end of phase two meeting. But we would step into our next study being registrational in nature. What I wanted to ask was actually going back to the phase two, will you also capture traditional seizure reduction? We will. So we will capture clinical seizures in our proof of concept study. We remind people that we have powered the study for long episode frequency reduction. But we know that these patients continue to have clinical seizures. They have a minimum threshold of having at least one. So we will capture clinical seizures via seizure diaries in the traditional form. And we hope to be able to see a nice trend there, but we're not powered to detect a signal there. Understood. And maybe last 15 seconds, just remind us the next steps for your other two programs for RAP-219 in the meantime. Yep. So I'll hit on one point, and then I'll ask Troy to share and close. So our next two programs with RAP-219 are neuropathic pain and bipolar mania, as well as ongoing work for a long-acting injectable that we think would be transformational, would be the first of its kind in epilepsy. We look to initiate our neuropathic pain trial as soon as possible. Troy can hit on some feedback that we've received for the FDA on the neuropathic pain trial. And then bipolar is on track to initiate in 2026. Yeah. So many of you might have seen we reported in our queue that the clinical trial was put on hold by the FDA. I think important to note, same package, different division within the FDA, no impact to the enrolling phase two POC and focal onset patients. That's neurology. The pain division asked for some clarifications on the protocol, and we're going to be working with them to get that trial back on track as soon as possible. Okay, well, that's all the time we have, but thank you so much for the updates, and thanks everyone for tuning in. Thanks, Andrew.