Thanks very much. It's my pleasure to moderate this chat with Abe Ceesay, CEO of Rapport Therapeutics. Maybe I'll have Abe just kick it off and give a quick overview of the company, and then we'll do Q&A. Thank you. Great. Thanks, Paul. Thanks, as always, for having us at the meeting. Just a quick background on Rapport Therapeutics. We're a company that is focused on precision neuroscience. We realize that precision is somewhat of a loosely used term in our industry, but we do believe we have the technology to bring precision to life at Rapport. That is by leveraging receptor-associated proteins. Receptor-associated proteins via small molecules really allow a level of precision at both specific receptors as well as sensory neurons, which we believe can be truly transformational for patients, both in terms of efficacy and improved tolerability. The best way to think about receptor-associated proteins, where I'm sure we'll spend most of our time today, is our lead program, RAP-219. This is a TARP gamma-8 AMPA modulator. The program let me just break down those words: TARP gamma-8 being the receptor-associated protein, the AMPA receptor being the main receptor that we're modulating. This is a program that has shown really promising results in a proof-of-concept study in epilepsy. We see it as a real program portfolio within a target opportunity with an ongoing program in bipolar mania, as well as the ability to develop a long-acting injectable, which we think would be transformational for patients as well. Great. What are the next steps now with engaging the FDA? As we think about a phase three program, is it sort of safe to say you're copying the playbook of others or any other nuance to that? Yeah. So, as you're well aware, we took a pretty innovative approach to proof of concept. We're not taking an innovative approach to our phase three studies. These will be very standard studies. This is a well-trodden path in focal epilepsy. I think, as it relates to the protocol, every protocol has its specifics based on the nature of the compound that's going into studies. Overall, you should expect a pretty standard protocol as we approach our registrational studies. Our strategy is to run two parallel registrational studies. We're financed to do that. Really, the next steps for us, based on this proof-of-concept data, are that we're on track to meet with the FDA by the end of the year at our end-of-phase-two meeting. Then, based on that, we expect alignment that will allow us to proceed with our phase three studies. We've guided to start those studies by the third quarter of 2026. "By" is an important term because we are going to do everything we can to accelerate these programs. We really want to respect the standard timeline from proof-of-concept results to the end of phase two, ultimately leading to the start of a study. Great. Great. Can you take a step back and review the biological thesis here? From the safety perspective, one of the main questions still pending from some investors is that we now have data that looks really encouraging, but how will the safety hold up in a larger sample? Maybe discuss the biological thesis, compare it to FICOMPA, and your thoughts on the safety profile going forward. Yeah. The biological thesis here is straightforward. Epilepsy is primarily an excitatory process within the brain. Glutamate plays a major role in that. The main glutamate-type receptor is the AMPA receptor. Antagonizing the AMPA receptor is a validated approach, as evidenced by the drug you just mentioned, Paul FICOMPA a pan-AMPA antagonist. It is a blunt instrument, antagonizing AMPA receptors throughout the brain. What we are doing is targeting a receptor-associated protein linked to the AMPA receptor. That is how we modulate the AMPA receptor as well as glutamate trafficking. TARP gamma-8, the receptor-associated protein, is only expressed in four brain structures, primarily the mesial temporal lobe and the neocortex. That is exactly where you want to target both the origination and propagation of focal seizures. The thesis has always been that by doing this, you can achieve efficacy while sparing the hindbrain, mitigating many of the most bothersome adverse events (AEs) for patients sedation, somnolence, motor impairment, and ataxia associated with hindbrain structures such as the brainstem and cerebellum. We have observed this from our preclinical models through our phase two data, which we believe strongly supports this hypothesis. We are encouraged by the tolerability profile in the phase two study, with most AEs being mild to moderate. We only had a 10% discontinuation rate. That is really kind of best-in-class tolerability as you think about anti-seizure medications. We have received questions given some of the AE profiles of parenthenol. Do we expect to see those in larger patient populations? One thing that I think has to be considered is the nature of this patient population. This patient population has baseline psychiatric and mood disorders. Across all trials with all mechanisms and medications, you will see some level of psychiatric disorders as AEs. There is a specific AE regarding aggression and homicidal ideation that is associated with parenthenol. Quite frankly, all of the work that has been done, no one has really been able to detect. Do we have an idea of what brain area that could be emanating from? No. There has been a lot of work there. What we can confidently say is we have not seen that in any of our trials. The other aspect is when you talk to clinicians in the field, this is not their concern with FICOMPA. The reason they do not use FICOMPA is the dose-limiting toxicity is really around sedation as well as gait impairment. That is why they are not using it. Quite frankly, the drug with the highest prevalence of psychiatric disorders and aggression is Keppra. Keppra is the most widely used ASM. This is not something that we really are concerned about. As I said, we have not seen it in our trials. We are really encouraged by the tolerability profile that has been presented thus far. Yep. OK, great. On the efficacy side, could you discuss the phase 2A data? The challenging part is that we observed a 78% seizure reduction. Since it was a small open-label study, most people expect the reduction will not be 78% in phase three. How do you approach this to manage expectations and give confidence that efficacy will hold up with a reasonable margin for success? Yep. There's a couple of things that we think about. As Paul mentioned, we saw very robust efficacy in our proof of concept study. We saw a 78% median reduction in clinical seizure frequency. In addition to that, across all of the meaningful thresholds, 50% reduction, 75% reduction, we saw statistically significant change. Importantly, we saw a 24% seizure freedom rate, which is the highest that has been seen with an anti-seizure medication. We measured that in a very conservative manner, weeks one through eight, the entire trial period. We think that that data is very strong. The first place I'll start is actually with that data. As you know, Paul, there really is no placebo rate in seizure freedom. It's very low in controlled trials. It's in the 1%-2% range. Seeing a 24% seizure freedom rate really, for us, gives us a lot of faith here that we are seeing a really robust drug effect. If we step back to the median seizure reduction of 78%, I just want to remind everyone the type of trial that we did. We did a trial in patients that have an RNS device. We utilized a biomarker that reads EEG activity, which is called the long episode. You should think of those as electrographic seizures. What's really important is the association with the reduction of EEG activity and the reduction that we're seeing in clinical seizures. We're seeing that really tight correlation. When we look at the data, we really believe that that 78% number is real. That's a real reduction given the tight correlation that we are seeing with the electrographic data. Now, as you think forward to phase three, will there be a decrement in efficacy? We can say we're not walking into that study thinking or designing the study with an intention that there will be a decrement in efficacy. What we do know in studies is that these inherently have greater variability because you have a larger number of patients, you have a larger number of sites. Will there be more variability in the response and the efficacy? Yes, one can assume that. Do we believe that there should be a significant reduction in efficacy in terms of median response? We don't believe so. The data will show. We're not walking into those studies either guiding to or expecting a significant reduction in efficacy. Makes sense. Can I ask you the patient selection question for the 20% time? Sure. Yeah. Yeah. I mean, I do think it's interesting, right, because I could see this both ways. On the one hand, this RNS population is averaged probably much sicker than your phase three population, higher bar. On the other hand, right, we've talked about this forever, right? The mechanism of 219 is not only but more central to the hippocampus. Patients in this study needed to have one electrode in the mesial temporal lobe, which contains the hippocampus, right? I think I've asked you this before. Is this a more enriched population to respond to the drug versus a phase three population that is not selected based on these criteria? How would you kind of make sense of all that? Yep. You're right. There really are two sides of this that you have to understand. The first is if you look at the demographics of these patients in our proof of concept study. Demographically, as you think about the time that they've lived with this disease, their overall disease burden defined by clinical seizure frequency, they look very similar to the patients that are enrolled in registrational trials. Interestingly, though, these patients, we do believe, are a bit more refractory, so a higher bar. 70% of the patients in our study were on three or four anti-seizure medications, including the RNS system. This is a highly refractory patient population. We were able to achieve these robust efficacy results. In terms of the foci of their disease, yes, an inclusion criteria for our study was that one of the two probes had to be in the mesial temporal structure. That is where RAP-219 is expressed. We should also just remind everyone that RAP-219 is also highly expressed in the neocortex. When you think about both where focal seizures originate as well as propagate, those are the two structures of the brain. There is really very limited—we are talking about case reports—where seizures originate outside of those structures. We believe that the target is exactly where it needs to be. Additionally, five patients in our study had that second probe outside of the mesial temporal structure. All five of those patients were clinical seizure responders. When we look at kind of the totality of data, we really believe that, one, the data is representative for the broader patient population. We have an efficacy signal that we think will translate very well into the phase three patient population. OK. Makes sense, Abe. As it relates to timelines, it's actually in FOS, maybe more variation across companies in how long these studies have taken to execute. By the way, I don't know if faster is better. I think we'll find out. It's not necessarily better in MDD, that's for sure. What do you think is a reasonable base case for how long the pivotals might take? Yep. So you're right. There's really kind of two ends of the pole. There is an end of a pole which is 2 and 1/2 years plus as you think about certain sponsors. And then there's another end of the pole that is 12-18 months. What we say is we don't want to be on either end of the pole. That is our approach. And there's reasons why that is important. First is if you think about why it takes certain sponsors so long to enroll the trial, one, you have to think about when they started the trial. Starting a trial during COVID, starting a trial during probably the most competitive time in this space with multiple therapies under investigation, it ultimately took some sponsors a long time to enroll their trials. Other sponsors have enrolled very rapid. I still have never seen in neuroscience rapid actually equal in quality. I think you always have to think about quality of enrolled patients. For us, as I said, we do not believe we are going to be on either end of the pole. We have not guided specifically to length yet. Once we get out of our end of phase two meeting, I think we will be in a better place to talk about that. A couple of things that we think about. First, why do physicians or investigators and patients want to enroll in trials? First is they are looking for a novel mechanism of action. Patients that enroll in these trials are refractory patients. They want a novel MOA. They want the chance to achieve greater seizure relief. Second, you want a drug that has a limited DDI or no DDI profile. As soon as you have a DDI, you have narrowed your patient population significantly because you can't enroll those patients that primarily through SIP induction, those drugs that are on board could be affected. The third is, quite frankly, the excitement in the community around your drug. What we hear about our drug, given the results, is that this is a drug that will be very attractive to sites. The last point is how you run your trial. These are global trials in nature. We will be running a global phase three trial to really leverage where patients can be recruited and where quality data can be ensured. Makes sense. Maybe we can talk a little bit about bipolar. I think I'd love you to comment on this in a couple of ways. I know, one, there's this preclinical model that's got predictiveness working in epilepsy at all is somewhat predictive. On the other hand, is there anything we can learn from just other AMPA approaches out there? An AMPA agonist looks like it might actually be an effective antidepressant. Does that have good implications or any implications for 219? Has FICOMPA ever been studied in psychiatric populations? I wonder if there's any clinical experience too we can touch upon. Yep. AMPA and its role both on dampening the excitatory process and then potentially upregulating the excitatory process has been a target that has been of significant interest in the community for a very long time. This is not a target from both bipolar mania standpoint and then on the other side of the pole, depression, that hasn't had a lot of interest. What is the reason to really believe here as you think about RAP-219 and bipolar? To your point, Paul, admittedly, this is not an area of high translation as you think about psychiatric disorders. Some experts do point to the corneal kindling model as being an informative preclinical model for bipolar mania. Again, it's not by any means the level of translation that exists in epilepsy. There are some reasons to believe 219 in bipolar. The first is when you look at bipolar, a lot of the data points to a clear excitatory process in the limbic structure in bipolar patients. One, we know that that is driven by glutamate. Is this target expressed there? Yes. Yep. In the limbic structure, we know that TARP gamma-8 is expressed there, primarily expressed there in the hippocampus. What we also know is that glutamate plays a major role in that excitatory process. What we also know is that other anti-seizure medications have been effective in treating bipolar. Some of those anti-seizure mechanisms work through the glutamatergic system, now, albeit indirectly. We have a direct approach. We believe that if there is a drug that has a line of sight in bipolar, this is the drug. It is going to be empirically driven as we see the data. We are really encouraged with the enrollment of the trial. The enrollment of the trial is going extremely well. We are on track to deliver that data in 2027. OK. OK. Great. Any questions from anyone hanging out here? OK. How are you thinking about other indications as well? Yeah. One of the strategic pillars we have at Rapport right now is given the data that we've seen with RAP-219 in this proof of concept study is to really interrogate the biology and really understand where could the biology take us. First is bipolar. The second, as we think about epilepsy, is primary generalized tonic-clonic seizures. That is an area that we're going to continue to assess as well. As we know, we also have thought about this mechanism in pain. That pain program is on clinical hold with the FDA, very division-specific. We're working to clarify some protocol changes with the FDA regarding that. We will continue, as I said, to kind of interrogate the biology and really take this to where we think it makes the most sense. What we're really encouraged by and excited by is what we see as kind of a re-envisioned market opportunity with RAP-219. When we look at the data that we produced in the proof of concept study in epilepsy, we see this as a multi-billion dollar opportunity. The feedback that we've received from the community, as well as the work that we've done on our own via primary market research, really shows that utilization of RAP-219 is really starting to show up Keppra-like, which really translates into a multi-billion dollar opportunity with a drug that can be widely used by both general neurologists as well as epileptologists. What are the cadence of updates from Rapport that we should expect over the next, say, six to nine months? Sure. So for us, as we think about the end of this year, end of 2025, as I mentioned earlier, we're going to execute our end of phase two meeting with the FDA. We also are going to have a meaningful presence at AES in December with additional data analyses that we think are going to be very insightful from our phase 2A proof of concept study. As you look into 2026, we also believe that that's going to be a busy year. We look to initiate our phase three studies. We also will have the complete data set from our phase 2A proof of concept study. What we reported this year was just the treatment period. But the study also had an eight-week follow-up period. So we'll be able to report on that full data set in 2026. Finally, in 2026, we will be in a position that we will be able to update on our open label extension study. Patients that were in the phase 2A proof of concept study have the ability to roll into open label extension study, which we think will be informative to long-term safety. Also, given the fact that these patients have the RNS device, we'll still be able to assess efficacy vis-a-vis the electrographic readings. As you look into 2027, we're on track to be able to deliver our bipolar data. Also, we believe that we'll be in a position to have our human PK data on our long-acting injectable formulation, which we're very excited about. Great. Cash runway, Abe? Yep. With our latest raise, that put us in a position that we have cash through 2029 that will allow us to complete our pivotal studies in FOS, as well as complete our bipolar study, continue to move our long-acting injectable program forward, and support our discovery efforts. We ended the third quarter with a little over $500 million in cash.