We're going to go ahead and get started. For those of you that do not know, we're hosting this here, but we're also live webcast. Formally, I'm Troy Ignelzi, the Chief Financial Officer of Rapport Therapeutics. Myself and the rest of the team are really pleased to invite you to our inaugural Investor and Analyst Day. Thank you for coming out. Like I said, we're hosted here. Appreciate the NASDAQ letting us use their facilities. We do have this being live webcast for those that could not attend in person. Before we get going, I want to remind everybody that we will be talking about some or looking at some forward-looking statements. Please note that we have our safe harbor both up here, but also on our website. These slides are available on our website. We did just put out a press release with the content that's going to be included today as well. Others are seeing this as we get going. We have a very full agenda. It will be focused almost exclusively on RAP- 219 in epilepsy. We've got Abe, who's going to walk us through some background on the company, overview, the pipeline. We're going to spend time, as I mentioned, on the lead candidate, RAP- 219, with some historical phase one foundational science, preclinical data. We're going to spend a fair amount of time talking about the design and what we know so far on the characteristics of our ongoing phase two trial in focal onset seizure patients. We're also thrilled to have Jackie French here today with us. Many of you know that Jackie is a professor of neurology at NYU Langone School. She is also a PI for our ongoing phase two trial. She is also the Epilepsy Study Consortium Chair and Founder. Jackie, thanks for joining us today. She will join Jeff on stage, our Chief Medical Officer, and walk through a fireside chat. I think that will be really informative because I know many of you had questions about the trial itself. Jackie's insight should be really helpful there. We will have various points throughout the day for you to ask questions. We ask that you hold them in the middle of the presentations because we will do a recap at the end of the foundational science in phase one. We will do a recap after Jackie's presentation. We will do a final recap at the end. There will be several opportunities for you to ask some questions, and the team can engage. With that, I'd like to have the members of the management team that are here from Rapport stand up and give a brief introduction before Abe kicks us off. Good afternoon, everyone. I'm Cheryl Gault, the Chief Operating Officer here at Rapport. Good afternoon, everyone. Nice to see you all. Swami Yeleswaram, Chief Development Officer. Thank you. I'm William Motley. I'm program leader for the RAP- 219 program. Very nice to meet you. Great to see a full house. I'm David Bredt, founder and Chief Scientific Officer. Good afternoon, Jeff Sevigny, Chief Medical Officer. Abe. Great. Welcome to everybody in the room. I want to thank everybody for making the time to be with us here today, but also for those folks that are joining us on the webcast as well. This is a very exciting day for Rapport. As Troy mentioned, this is our first Investor and Analyst Day. Our goals today are to, one, update you and provide a background on RAP- 219, the science that really drives RAP- 219. Two, is to give you insight, further insight into the phase 2A proof of concept study in focal onset epilepsy. Third, as Troy mentioned, we're honored to have Dr. Jackie French with us today to provide perspectives on the unmet need in focal epilepsy, the science, her perspective on the science driving RAP- 219, but also her perspective on our own ongoing trial as well. We've been very fortunate to have Dr. French as a partner in helping us design this trial. As Troy mentioned, she is also the PI of the study as well. You've heard from our management team in terms of their introductions. I'd just like to reinforce how intentionally built this management team has been. We spent a lot of time thinking about how we were going to build the team here at Rapport. As we thought about the type of company we were looking to create, this team is a team that has deep experience in neuroscience, drug discovery, drug development, and most importantly, getting products over the finish line and approved to patients. In addition to the management team that you see here today, we have a dedicated team in both Boston and San Diego, a fully integrated company across both drug discovery as well as drug development. The same goes for that team. This is a team that is intentionally built, deep experience, not only in our science, but in the broader neuroscience fields. You'll see a mention of our board of directors on the slide as well. We have spent a lot of time really informing the build of our board. Importantly, we wanted to make sure that our board was representative of true leaders in the biotech industry, those that have had experience in creating companies, building companies, getting products to patients, and also creating significant value for shareholders. Our board is chaired by Steve Paul, who many of you know. Steve is a true luminary in neuroscience company creation as well as neuroscience company leadership and is also a co-founder of the company. Our vision at Rapport is to create the leading precision neuroscience company. We recognize that the word precision is somewhat of a loosely used term in our industry and also loosely used in neuroscience. We believe the foundational science that we're working on at Rapport, which are receptor-associated proteins, has the opportunity to bring precision to life with small molecules in neuroscience. This company was formed on a unique partnership between Third Rock and Janssen. We often refer to this as a company creation effort. That is purposeful in terms of the use of that language because not only did we transition assets out of Janssen, but most importantly, we brought over people from Janssen. These were the key scientists that were working under our founder's leadership, David Brett, biologists all the way to medicinal chemists that were working on these programs for over a decade. The level of institutional knowledge that we have on our science is significant at Rapport. We have a fully enabled pipeline that crosses across both discovery as well as development. Our pipeline, and you'll see it on the next slide, is anchored by RAP- 219. This is a TARP gamma-8 AMPA modulator program. We believe, and you'll see from the data both through our preclinical experience as well as our clinical experience, is starting to believe what we see as a potentially best-in-class profile for focal epilepsy. In addition to that, we have a fully enabled discovery program. We have two late-stage discovery programs that are nearing the development candidate stage, with the next stage ultimately getting those programs into IND enablement and then into the clinic. RAP- 219, we see as a pipeline and a product. I'll share more on that. Our whole strategy as we launched this company was to ensure that given the novel mechanism, given the biology, but also given the clinical precedent where anti-seizure medications are effective in other indications, is to really enable that. We financed the company as we've built the company. That has been our strategy from the start. We're well on our way. We anticipate our results for the focal epilepsy trial in September. That is an update that we've had today. We've now fully enrolled that trial. Great milestone for the company as well as the community. There's a significant amount of excitement around this study. This trial is fully enrolled. We expect those top-line results in September. In addition to that, we're looking to initiate our phase 2A proof of concept in bipolar this year in the third quarter with data expected in 2027. We're currently finalizing our plans for our peripheral neuropathic pain program. About a year ago, as I'm sure everyone is aware, we did IPO the company. We were able to capitalize the company and really allow us to invest in all of these programs. As of March 31, we had $285 million on the balance sheet, which allows us to continue to pursue our operations through the end of 2026. As you think about our vision and our approach here at Rapport, it's really to create that leading precision neuroscience company. We think that the approach with receptor-associated proteins is really starting to tackle some of the biggest challenges with conventional small molecules in neuroscience. One of those challenges is the lack of precision that exists with traditional small molecules. Most small molecules are interacting with receptors that are ubiquitous throughout the brain and the body. That is causing pretty significant issues. One of those issues is many patients are not able to maintain themselves on their most efficacious dose due to the narrow therapeutic index and the tolerability issues associated with traditional therapies. The second aspect, which was really uncovered by our scientific founder, David, was that by using traditional approaches, it really limits the amount of targets that you can uncover as you think about novel targets for indications with high unmet need. When you think about the opportunity for receptor-associated proteins, we think it plays out in really kind of two forms. This is a very simplistic way, but a direct way to think about it. First is the example of our lead program, RAP-2 19. By utilizing receptor-associated proteins, we're able to have precision with small molecules. That is by modulating AMPA receptors only in the region of the brain which we think are important for given conditions. That's by targeting the receptor-associated protein versus targeting the receptor ubiquitously. The second is, as we apply receptor-associated protein science to drug discovery, it allows us to unlock targets that were previously undruggable. We're seeing that starting to play out in our discovery pipeline as well. Here is a snapshot of our pipeline. As I mentioned, anchored by RAP- 219, first with focal epilepsy. As I said, the trial is fully enrolled. We expect results in September of this year. Bipolar mania, we're looking to initiate Q3 of this year with data expected in the first half of 2027 and finalizing our approaches for diabetic peripheral neuropathic pain. Our discovery programs are noted here are two late-stage discovery programs. Both of these are looking at nicotinic receptors, alpha 6 for chronic pain, and alpha 9 and alpha 10 for hearing disorders. Both of these, as I mentioned, are late-stage discovery programs, with the next stage being the nomination of a development candidate. When we think about the pipeline and a product opportunity for RAP- 219, there's a couple of important aspects that we've thought about as we develop this strategy for RAP- 219. First, as we think about these indications, we believe that these indications, focal epilepsy, bipolar mania, as well as peripheral neuropathic pain, are large markets with significant unmet need. The second is really following where the biology takes us, but also where clinical precedence takes us with anti-seizure medications. Bipolar disorder, as well as peripheral neuropathic pain, have been indications where anti-seizure medications have been effective and have become really the gold standards of therapy for some of these conditions. The last aspect is when we think about this product profile for RAP- 219, what's emerging both through our preclinical experience as well as our clinical experience, we believe that it can be a best-in-class profile for all indications. Once daily dosing, a differentiated tolerability profile based on its precision mechanism, as well as no drug-drug interactions, really starts to form what we believe, as I said, a best-in-class profile for all of those indications. The last aspect of our pipeline and a product strategy is the development of a long-acting injectable. You'll hear more from David on the unique characteristics of RAP- 219, really the optimized characteristics of RAP- 219. We believe that this affords the opportunity for a long-acting injectable with RAP- 219. This would be the first long-acting injectable for focal epilepsy. Based on our discussions with the community, what we hear is that that would be transformational for epilepsy patients, epilepsy patients along with many other chronic conditions. Sometimes you forget your dose. Sometimes you miss a dose. Having the convenience of a long-acting injectable would really be helpful for patients as well as clinicians as they manage their disease. A long-acting injectable hasn't been available in focal epilepsy, not based on the lack of need, but based on the limitations of current therapies. When you think of less potent molecules that really lead to larger drug levels on board, when you think to the risk of drug-drug interactions, when you think about really complicated titration schemas, the reality is traditional anti-seizure medications have not been amenable to a long-acting injectable. We believe that RAP- 219 is. A long-acting injectable would also be important for all other indications we're seeking and also would really be a nice opportunity for an IP extension as we think about the long-term value of the asset. I want to spend just a moment on focal epilepsy. You're going to hear a lot more around the unmet need from Dr. French, but I'd just like to frame a couple of concepts. First, focal epilepsy is a large market, 1.8 million patients in the United States. The real unmet need in this patient population is that 30%-40% of patients are drug resistant, meaning they're currently on medication, but they continue to have breakthrough seizures as well as significant seizure burden. We think that that is based on the limitations of currently available anti-seizure medications. Although there are over 20 approved medications available for these patients, the reality is we have not seen much innovation in this space in a long time, innovation primarily around mechanism of action. The mainstay of treatment for these patients is polypharmacy. If you're not providing novel mechanism of action in the world of polypharmacy, your ability to achieve a greater degree of efficacy is somewhat limited. We also see with currently available anti-seizure medications, there's pretty significant tolerability issues. We believe that's by the ubiquitous nature of these compounds, the most bothersome being sedation, ataxia, as well as cognitive problems. There's the potential for serious adverse events with some treatments. There's also the risk of breakthrough seizures given the PK profiles of some drugs. Finally, one aspect and criteria that often goes overlooked is the administration profile. When you have drugs that have long titration schemas, drug-drug interactions, the requirement for lab monitoring, what you often see in the community is that limits the uptakes of certain drugs, primarily based on the fact that general neurologists might not be as comfortable utilizing those drugs versus the epileptologist. When we think about RAP- 219, we believe RAP- 219 is addressing all of these characteristics and, again, starting to create a potentially best-in-class profile in focal epilepsy. With that, I'd like to turn it over to David, who is our co-founder of the company, our Chief Scientific Officer, to really lead you through the science driving RAP- 219. All right. Thanks so much. I'm super excited to tell you guys about this. My mother told me when you give a lecture and you're super excited, look at someone in the back of the room and speak slowly. I'm going to try to do those. I'm so super excited about this. It's 10 years of research that my former colleagues at Janssen did on the underlying biology, science, and creating the specific molecule RAP- 219. As Abe said, it was the product of dozens and dozens of biologists, chemists, translational scientists. As he explained, our drug is targeting the AMPA receptors at the end of the day. AMPA receptors are like the most important proteins in your brain. They mediate by binding to glutamate most all aspects of excitatory synaptic transmission in the brain. They're present in essentially every neuron. There is a drug, only one, that very potently and selectively targets AMPA receptors. It's Fycompa, perampanel. It's a complete blocker of all AMPA receptors everywhere in the brain and throughout the body. It's a very powerful inhibitory mechanism. Predictably, it's a very powerful anti-seizure medicine. Also predictably, it's wrought with lots of side effects. Blocking AMPA receptors, which mediate most all excitatory transmission in the brain, is associated with side effects, significant side effects of sedation, motor impairments, cognitive impairments. The science that Janssen and now Rapport is pursuing was fantasizing, well, could you block AMPA receptors, but only in specific brain regions that are involved in certain diseases? Epilepsy, many of you will know, almost always begins focal onset seizures in the mesial temporal lobe and cerebral cortices, shown in yellow and red on the right. Most all focal onset seizures start there. All of them amplify through there. Could you somehow block AMPA receptors in those brain regions, but spare the cerebellum, the brainstem, where epilepsies don't begin? That was made possible by the discovery 22 years ago now of a family of receptor-associated proteins of AMPA receptors that have differential distributions throughout the mammalian, including human, brain. A cryoelectron micrograph on the left shows that structure. The red, white, and blue proteins are the AMPA receptor subunits that perampanel binds to. There is a TARP, transmembrane AMPA receptor regulatory protein, the number eight, which is good-looking Chinese. My wife's Chinese. It is shown there on the left. Our drug binds at the interface between the gamma-8 TARP and the AMPA receptor. The reason that this is valuable is because the hippocampus and the cerebral cortex express gamma-8 TARP protein at high levels. You can see that in the western blot in the middle. A PET tracer, the very one that Jeff is going to tell you about in a bit, demonstrates the distribution of the TARP gamma-8 protein on the right. High levels of this protein are in the mesial temporal lobe, the hippocampus, the cerebral cortex. You will see this probe and our drug have minimal to any activities in the cerebellum or the brainstem, which is not shown in this PET tracer because the binding site is not abundantly present there. The compound that came out of these 20 years of research is shown here. It is a spectacular molecule, really optimized over 10 years of research at Janssen. These are data, much of which was generated at Rapport. The compound has fabulous potency, potency of about 100 picomolar, thousands of times selective against AMPA receptors with other TARPs or any other TARP that we have looked at. It has super optimized pharmacokinetic properties, fully bioavailable in all the preclinical species we had explored, not subject to transporters out of the brain, so high brain-to-plasma ratios. Really importantly for epilepsies and many neurological diseases that are treated with polypharmacy, it was designed not to be a victim or perpetrator of drug-drug interactions. It does not bind to cytochromes at levels anywhere near as potently as it does to its target. It is not metabolized by cytochromes. It receives receptor occupancies that I will show you are associated with efficacy, at least in preclinical models, at low nanograms per mL levels. That is a few percent of the plasma levels of typical anti-seizure medicines. That is achieved at micrograms per kilogram dosing in animals versus the milligrams per kilogram dosing you are typically familiar with in animal models. In our IND enabling studies, it was viewed as non-adverse at levels at the top dose levels, hundreds of times above its efficacious exposures. It was not sedating at any exposures in preclinical species. Something really exciting to explore in preclinical models, which I'm going to show you here in the gold standard focal onset seizure model of efficacy in animals. This is the corneal kindling model where animals are first given non-epileptogenic stimuli. Over a course of about two weeks, those non-epileptogenic stimuli become convulsive. Animals are fully kindled, so to speak. That resembles the pathophysiology of human epilepsy. The hyper-excitability actually manifests in the mesial temporal lobe in this model. You can see at that third green triangle, the one where you see about 85% protection, that is occurring at 20 micrograms per kilogram dosing in these mice or just three or four nanograms per mL plasma exposures, really low exposures, really effective. Just as impressive, this compound, even at its highest exposures, hundreds of times higher than where you are seeing efficacy in this model, is not impairing on the rotor rod. That is the preclinical model that is most predictive of sedation and motor impairments that thwart the activity of most other anti-seizure medicines. This graph, if you were to compare it to perampanel and many other anti-seizure medicines, would look very different. For perampanel, for example, the green line would be shifted about two orders of magnitude to the right because our drug is about 100 times more potent than perampanel. Also, the red line would parallel the green line at the very same exposures of perampanel where it shows efficacy in preclinical models of epilepsy. It causes falls on rotor rod. It's not just perampanel. It's most essentially all other anti-seizure medicines will perform more poorly than RAP- 219 in this gold standard ratio. Here, this is all work done by the same group, the Epilepsy Therapy Screening Program, an NIH-funded group who's evaluated 40,000 anti-seizure drugs over 40 years. These are approved medicines like these, experimental medicines from companies like Rapport, academic compounds. Ours is unparalleled in terms of its safety in this preclinical therapeutic index. That is, you can see RAP- 219 far on the left and other molecules on the right. If you compare ours to different classes of drugs, for example, KV7 drugs that are being developed, ezogabine would be an example of that, about a tenfold ratio on this toxicity to efficacy ratio. GABA drugs like clobazam give about a fivefold ratio. Sodium channel drugs tend to do very poorly on this. You can see topiramate has almost no margin. Perampanel would have no margin. It would have a value of one. This gives us a lot of confidence that our compound will avoid the motor and sedating properties that are ubiquitous with anti-seizure medicines. Our compound does not only work in kindling models, but also in a raft. Compounds in this class work in a raft of other anti-seizure mechanisms preclinically. The PTZ model is a generalized epilepsy model. It is chemically induced. Our compound works in that model. Compounds in this class also work fabulously in kindling models, not just corneal kindling, but mesial temporal lobe-induced kindlings in the amygdala, the hippocampus. Also, in genetic models, there's an audiogenic seizure model. There's AMPS on septal link, so generalized models. This class of compounds shows a broad efficacy spectrum. It's worth noting that one model, the maximal electroshock model, which people have recognized over the years as perfectly predictive, especially in focal onset seizures, drugs like levetiracetam are not active, and several other anti-seizure medicines like 219 are not active in this model. Seeing this kind of broad efficacy across a broad array of models is unlike in other neuroscience indications where the translational probability at this stage in the midst of a phase 2A study might not be so high. But Jackie French, who's going to speak with you in a bit, has observed that the majority of molecules that are well tolerated, that are achieving their receptor occupancies in phase one, that work in this array of preclinical species and models can get all the way across the finish line. With that, I'm going to introduce Jeff or let Jeff take the stage to tell you about phase one. All right. Thank you, David. I'd like to thank each of you for joining us today. It's great to see such a high level of interest in what we're doing. I'm going to cover the phase one program and a little bit about the phase two program. Let's get started with phase one. We've completed four phase one studies, starting on the left, a single ascending dose study, followed by two multiple ascending dose studies and one multiple dose PET receptor occupancy study. Overall, that's 100 healthy volunteers exposed to RAP- 219 at single doses of up to 3 milligrams and multiple doses of up to 1.75 milligrams. RAP- 219 has been safe and well tolerated across all of our clinical studies. On the left is a table of our aggregated TEAEs from the multiple dose studies. Here, we're showing TEAEs occurring at an incidence of three or more, which is approximately 5% or greater. I would point out the most common TEAEs include headache, dry mouth, brain fog, which also occurred in the placebo group, and fatigue. As you look down the rest of the column, I would point out that most of the other TEAEs are actually non-CNS related. Regarding severity, most TEAEs were grade one, that is mild, with the remainder being grade two. All TEAEs were grade two or less. They tended to occur early in the course of treatment and self-resolve. There were no SAEs or clinically significant laboratory vital signs or ECG abnormalities. There are three discontinuations, which is less than 5%. As I mentioned, we completed a human PET study, which confirmed that TARP gamma-8 is highly expressed in the neocortex and the mesial temporal lobe. These are precisely the areas of the brain where focal onset seizures originate. You can see this nicely in the figure on the right, which shows the parametric PET images superimposed on MRIs. Here you see the neocortex lit in bright yellow and the mesial temporal lobes lit in bright red. This is signifying high TARP gamma-8 expression. I'd also point out that there is relatively low expression in other areas of the brain like the cerebellum, the brainstem, and the thalamus. We believe this differential pattern of expression of TARP gamma-8 supports a potentially favorable and differentiated benefit-risk profile compared to other ASMs that are either on the market or in current development. The PET study also taught us the dose-exposure receptor occupancy relationship. Recall from David that the preclinical models demonstrated a maximal seizure protection at a receptor occupancy of 50%-70%. That's our target. We learned from the PET study in the phase one PK that this target receptor occupancy is achieved at lower exposures than we had predicted from the animal models. I'll draw your attention to the figure on the right again. In this green curve, which is our phase one dose of 0.75 milligrams times five days, followed by 1.25 milligrams for the remainder of the 23 days, achieves a receptor occupancy in the mid-80% range. This is well above the target receptor occupancy of 50%-70%. Below that, you see a curve of multiple doses of 0.75 milligrams, which achieves a receptor occupancy of approximately 80%. The lower curve shows multiple doses of 0.25 milligrams, ultimately achieving a receptor occupancy of 50%. These results give us great confidence that the dose selected in our phase two study is going to achieve its effect and also provides support for potentially using lower doses in our future studies. Overall, RAP- 219 is a very promising, highly promising molecule that has been generally well tolerated with a relatively low incidence of TEAEs and, in particular, low incidence or no incidence of TEAEs such as somnolence, sedation, dizziness, or other motor adverse events. TARP gamma-8, the target of RAP- 219, is highly expressed in the neocortex and mesial temporal lobe, precisely the areas of the brain where focal onset seizures originate, with relatively low expression in other parts of the brain. RAP- 219 achieves a clinically efficacious exposure at doses as low as 0.25 milligrams and has excellent pharmaceutical properties, including no drug-drug or SIB interactions and is suitable for once-a-day dosing. With that, I'm going to move to our phase two proof of concept study. Now, Will and the team at Rapport, with the help or guidance of Dr. French, designed a truly innovative and, more importantly, a scientifically robust study to test RAP- 219's effect using an objective biomarker of epileptiform activity, specifically long episodes. To accomplish this, the study enrolls patients with refractory focal onset epilepsy who have a device called the NeuroPace RNS system implanted in their brains. What is this RNS system? The RNS is comprised of two probes implanted into the regions of the brain known to have epileptiform activity. Typically, one of the probes is implanted deep in the brain. In this case, this linear probe is implanted into the mesial temporal lobe. The other probe can also be deeply implanted or can be superficially implanted. Here, you see a probe that is lying along the neocortex. These probes continuously monitor, detect, and record epileptiform activity, including long episodes. Based on its programming, can stimulate the region to attenuate seizure activity. Now, the treatment effect is not something that we're concerned with with our clinical study, but what we exploit is this device's ability to monitor real-time, all the time, epileptiform activity and to record it. To walk you through what this would look like, on the upper row, you see an EEG. This is what would typically, how an EEG would typically look with a scalp electrode. Electrographic seizures are comprised of things called epileptiform discharges. Here, a classic spike wave that increase in amplitude or spread and have a duration to meet the definition of a clinical, of an electrographic seizure, which you see in the middle panel here. The clinical correlate of the electrographic seizure is a clinical seizure, and this is recorded using a clinical diary. On the row below it, you see what the RNS detects. It detects also epileptiform activity, but the waveforms do look different. Here, you see epileptiform activity increasing in amplitude and the duration of it from one to two seconds. That triggers something that is defined as an episode start. When this is detected, the device can trigger an electrical stimulation, but it also records the event. This is the blue part of the wave here. In the next panel, you see a similar activity, but in this case, the epileptiform activity is increasing in amplitude and lasting 30 seconds or more, which is the definition of a long episode. I would point out that not all epileptiform discharges become electrographic seizures, and not all electrographic seizures become clinical seizures. Likewise, not all episode starts become long episodes, and not all long episodes become clinical seizures. However, and this is a very important point, the majority of long episodes are considered electrographic seizures. This is very important for our clinical study, and we have criteria specifically around this. Now, the idea of using the RNS system to assess the effects, the clinical effects of an ASM is not a new one. In fact, in ScarPass in 2018 and Qureshi in 2020, both published articles demonstrating that the RNS system provides rapid and objective measure of epileptiform activity and can provide an early signal of a clinical response to an ASM. Both publications underscore the value specifically about long episodes. I'll point your attention to the quote on the right. This is from Qureshi, the authors, stating, "It could be argued that long episodes are an even better therapeutic target than reported clinical seizures." Our rationale for selecting long episodes as a primary endpoint is based on these findings. That is the well-established relationship between long episodes and clinical seizures. In addition, we did our own research, and this is presented by Arnold Gametoni, who reviewed patients that have an RNS device implanted who started a new marketed ASM. What he found was that ASMs resulting in a 30% or greater reduction in long episodes were associated with a 50% or greater reduction in clinical seizures. It was data like this that served as the foundation for the clinical design of our proof of concept study. Now, here is the design of the study, which enrolls patients with medically refractory focal epilepsy who've had an RNS device implanted in their brain for at least 15 months. They must have stable RNS settings and must be on stable background ASMs. They must have at least 16 long episodes and at least one clinical seizure for the preceding eight-week period. There must be at least a greater than 50% concordance between long episodes and electrographic seizures. Patients who meet these criteria are enrolled into a four-week baseline period and then start an eight-week open-label study in which they begin taking RAP- 219 at a dose of 0.75 milligrams for five days, followed by a dose of 1.25 milligrams for the remainder of the treatment period. I'll point out again or remind you that this is associated with a receptor occupancy of over 80%. Following the eight-week open-label period, they then enroll into an eight-week follow-up period. On the bottom of the slide, you see the key endpoints. Our study was designed and is powered around long episode reduction. That will be our key endpoint, and we'll be assessing that two different ways, both conventional ways, including the proportion of patients with a greater than 30% reduction compared to baseline, as well as a median percent change from baseline. The second key endpoint will be clinical seizure reduction that will also be assessed as both by the proportion of patients meeting greater than 50% reduction and the median percent change from baseline. Will, who will be speaking in a bit, will go into a bit more details about this. As Abe mentioned at the beginning of this talk, we have completed enrollment. In fact, we've enrolled 30 patients into this clinical study. The study was originally designed to enroll approximately 20 subjects, but we had such high enthusiasm from the patient community and from sites that we had several people in screening once we hit the 20 patients. We thought it would be better to permit those who were still in screening to enroll into the study so long as they met the inclusion criteria. Hence, the enrollment of approximately 30 patients. Finally, I'd like to share with you some really new and exciting data for us that demonstrates that the patients that have enrolled into our study are representative of patients that typically enroll in phase three studies. This dataset comes from the first 14 subjects that have enrolled into our phase two study. These are subjects where we've been able to clean their data. I would point out the column on the right, which I think is probably most meaningful, starting with the long episode frequency of 51, followed by the concordance between long episodes and electrographic seizures of 92%. This, as I mentioned earlier, is a very key metric for us because these long episodes reflect electrographic seizures. The top row shows the frequency of clinical seizures per 28-day period, and that is the median is 10. Again, representative and reflective of what is typically seen in phase three studies. The median number of background medications in this population is three. In addition to these three medications, they also have the RNS device. This is, for us, a great outcome because not only is it representative of phase three population, but it also gives us a great chance to see efficacy vis-à-vis long episodes and clinical seizures. With that, I think we'll take some questions. Abe, do you want to moderate? Great. Thank you, Jeff and David. What we'd like to do is, before we go to our section with Dr. French, just open it up for questions given the amount of information that we've covered, preclinical, clinical data, as well as some of the background on the phase two result. I think I saw Joe first and then Paul. We'll start with you, Joe, and then we'll go to Paul. Hi, Joe from TD Cowen. Joe Thorne from TD Cowen. I guess on that proportion of patients that see over the 30% reduction in long episodes, is the company targeting a certain metric on that? Is there any reason why the second half of the patients enrolled in the trial would look any different than the first half that you presented today? Yep. I'll answer the second part of your question first. We're confident that given the screening criteria, as well as our observations of the trial, the remaining enrolled patients should not have any material difference in their baseline characteristics. Will, right after the fireside chat with Dr. French and Jeff, will be sharing more around the specific metrics that we're anchoring to and expectations around the endpoints, both in terms of long episodes as well as clinical seizures. Thanks. Paul Matisse from Stifel. Good to see how high the concordance rate is between long episodes and electrographic seizures. I was curious what the team thinks is the concordance rate between electrographic and diary seizures. That is one. Two, I believe patients to participate in this study need to have at least one lead in the hippocampus. What have you learned from enrolling this study in terms of what% of patients in FOS have a hippocampal lead? Maybe give us some perspective on how that might impact the extrapolatability of these results into a non-EEG selected phase three population. Yep. In terms of the concordance and the distinction between concordance of long episodes and electrographic seizures, and then the concordance of long episodes and clinical seizures, I'll provide some perspective and then ask Will to add in. The first is we know this, right? We know that many patients, and based on the literature, and I'm sure Dr. French can give a great perspective on this, is that clinical seizure diaries are an inaccurate art, clearly. Patients do not recall all of their seizures. Patients can have seizures while they're sleeping. Patients can be amnestic. There are many reasons for why clinical seizure diaries are not a full representation of a patient's disease burden. I think as we talked to Dr. French and many members of the community, that was really the value of this study. This study allows, we believe, a true insight into the burden of disease of these patients and measures a highly objective endpoint through long episodes and electrographic seizures. We also have the clinical seizure data to be able to support that. We really believe we're kind of bringing together kind of the best of both worlds. Will, I don't know if you want to add anything there. Yeah, no, I think that was a great perspective. I think we're really impressed by the degree of electrographic burden of disease and clinical burden of disease. While every patient has a unique concordance in connecting those two things, across the group, we're really impressed by the burden of disease and think it's a perfect population for proof of concept and for our study. Will or Jeff, do you want to add a perspective on kind of the translatability of this patient population in terms of where the probes are set and then how we think that this is representative of the broader, call it the non-EEG refractory focal epilepsy patient population? Yeah, I think when we look at we selected patients with hippocampal leads partly because we wanted a homogenous patient population where we could achieve proof of concept. I think it has been a traditionally difficult patient population to treat. They have tended to be a highly refractory patient population. And we're really thrilled to have had so many patients enroll with electrodes there. In terms of the translation, we see distribution of the target in all areas of the brain where focal onset seizures are expected to originate. We do expect really strong translatability as we broaden the population. Did you see a lot of patients who didn't have a hippocampal lead when you were trying to enroll in the study? Like, I feel like there's just not good data out there on how big that population is in FOS. There is good data in the NeuroPace patient population. And in the NeuroPace patient population, it's about 50/50. 50/50. 50% do not have one at all. 50% have seizure onset zones outside the hippocampus. They still have a hippocampal lead or not? They don't. They don't. Yeah. Okay. All right. Thank you. Andrew Tsai, thanks from Jefferies. Noticing the disclosures today, three concomitant AEDs for these patients. I'm curious how many AEDs they've previously failed because we know efficacy can do better for patients who have less prior therapies. Secondly, how often does the DMC meet on safety? Can you confirm you're not seeing any special AEs? Because when we think about Fycompa, there have been some weird AEs with that compound. Yep. Let me answer the second question in terms of AEs. We have ongoing safety monitoring of the trial as any kind of good clinical practice. We have not disclosed, obviously, the AEs in our phase two study. We will report tolerability with the final results of the study. What we can speak about today is that we have not seen any serious adverse events. That is consistent with our phase one experience as well. As soon as I was saying that, I knew I was going to forget your first question. What was your first question? All the AEDs of that. Oh, yes. Yeah. So, Will, can I add to this? I'm not sure if we know all of the medications patients have been historically on over the course of their disease, if we have that amount of historic data. I would point you to the demographic data. These patients, on average, have had the device implanted for how long? Fifteen months. I think our median was in several years. This is a highly refractory population. I think our median is above where other trials and later stage trials have tended to be. I think we're really confident that if we see an effect in this patient population, it's highly predictive success. Yeah. I think generally, when we think about this study, this is where the innovators here. We're the first to do a prospective study in this patient population. We're really confident in the design of the study. With that, there isn't precedent. I think what we step back and we think about today, as we've discussed with the baseline characteristics, is we think that this study is highly representative of refractory focal epilepsy patients. If you look at all of the aspects of the baseline characteristics, the number of background AEDs they're on, their clinical seizure burden, the concordance between long episodes and electrographic seizures, their time living with the disease, we don't question at all that these patients are representatives of those patients that would be enrolled in a phase three trial outside of the fact that they have the RNS system. We will, after Jeff and Jackie's session, have an opportunity for Q&A with that. We will have another Q&A right at the very end. I am sure things will come up. As we were planning for this, we wanted to make sure that questions did not just continue to build and we could not get them all at the end. We are going to bring in the chairs and have Jackie and Jeff take the stage. Very relieved when I saw the chairs. I thought. You're going to stand the whole time. Make me stand the whole time. All right. First of all, Dr. French, thank you for joining us today. It's a. My pleasure. It's a pleasure for us to have you as the leading guru of epilepsy and treatments for epilepsy. Why don't we first start with talking about things like the unmet need and how treatments have evolved over the course of your career treating these patients? How has the unmet need changed? What is the current unmet need? The unmet need, sadly, is the same as when I started in 1989, 1990. The number, as probably many of you know, the number of treatment-resistant people have not really changed. The number of seizures that they're having has probably gone down, which is good. It makes recruiting for clinical trials a little harder. It is overall much better for the patients to have a lower seizure frequency. Seizure freedom is what we're looking for. In that regard, the number of people has not changed. What has changed is the number of options that people have. They have many, many, many options of anti-seizure medicines. They also now have options of the vagus nerve stimulator, the responsive neurostimulator, the deep brain stimulator, which were not available in the 1990s, the early 2000s. You would think with all of that that things would have changed for them a little more. Another big change in what I see in the community is an overwhelming use of levetiracetam or Keppra for a large proportion of people, particularly those who do not make it to an epilepsy center where we have a tendency to be a little more generous with the number of anti-seizure medicines that we try. The reason that levetiracetam has become so ubiquitous is because you can start it without titration. You do not have to worry about drug interactions. In comparison, the other drugs start to look more difficult. On top of that, the drugs that we have to offer often have issues for women who want to bear children, whether it be an issue with the drug causing birth defects or even before that, interactions with oral contraceptives and other forms of contraception that make it very difficult for people to manage medications before and during pregnancy. Also, interactions with other medications that people take, side effects that we have already heard about. Even though there are many, many, many options for people, there are shockingly not that many options that are good options for people. We need more good options for people and maybe less options as a whole, ones that work, that are easy to handle, that have a low side effect burden. Great. In your practice, what percentage of patients are not well controlled? Or still looking for treatment? I work in an epilepsy center. In an epilepsy center, the majority are not well controlled. Hopefully, as we I actually just submitted a paper on 200 people who were treatment-resistant who were enrolled in a multi-center trial. Fortunately, over time, seizure control does get better. We actually published decades ago that the treatment-resistant population in general, with all of the options available to them, continued manipulation of medication, surgery, device implantation, have a likelihood of becoming seizure-free of 5% per year. That is, if you come in with treatment-resistant epilepsy, which is pretty dismal, I would say, 5% per year, no matter how hard we try with all the available therapies. I mean, I think of treatments that there's three components to a treatment. One is the efficacy. The other is the safety and tolerability. And the third is ease of use. How would you weigh the relevance of each one of those in your practice with really refractory patients? And how do you think a generalist would weigh it? We start when somebody has newly diagnosed. First of all, I have a slide that sort of represents this. When people come in, they may be old, young, short, tall, fat, thin, male, female. As far as their response to any given mechanism of anti-seizure medicine, they all look the same. We can't say, this mechanism goes with this person because they have this type of epileptic discharge on their EEG or that one goes with that person. Here you have this group of people. You have this group of drugs. What are you going to do? You're going to try the safest ones and the best tolerated ones first because why would you not when you have no other way of knowing who's going to respond and who isn't? You are going to work your way through from the safest to the less and less and less and more and more and more problematic drugs. Unfortunately, after somebody has failed seven, eight, nine drugs, you are going to give them the next drug, which either is the newest drug on the block. It is good if you have got one of those, like Cenobamate, for example. If not, you are going to say, I am going to try this. It might cause peripheral visual field defects, or it might make you very sleepy, or it might cause problems for your unborn child. It becomes more and more problematic. It is like, I do not want to give you this drug, but I have to. We talk about risk-benefit. When you are talking about somebody with very treatment-resistant epilepsy, they incur risk every single day of their lives. We know that the risk of sudden unexplained death is about 1 in 200 per year. You put on 10 years, you're getting to 1 in 20 people are going to die. We don't think of epilepsy as a disease that is deadly or has high mortality. In fact, looking at the number of life years lost, it is only second, only counting for sudden unexplained death, not even counting for accidental death and drowning and other things. It is number two after stroke as the highest number of life years lost to any neurologic disease. Do you think this, going back to the approach of selecting ASMs, do you think the approach that you've enumerated is similar to the approach that a generalist would do, like a general neurologist? Unfortunately, the general neurologist doesn't feel comfortable using most of the drugs because they may cycle through one or two or three. If the person is fortunate, that general neurologist has an epilepsy center to refer to. Most general neurologists will not even attempt the more complicated drugs. Even though there's a nice instruction manual that tells you exactly how to do it. In some cases, I'm going to take Cenobamate, for example. It's not dangerous as long as you use it properly. If you're not comfortable using it, if you haven't used it on a lot of people, you don't have that level of comfort with it, then it's going to seem dangerous. It's going to seem difficult, more dangerous and more difficult than perhaps it is. I see. Okay. Okay, great. I was thinking of shifting gears a little bit and talking about study design. My favorite topic. Your favorite topic. You're instrumental in this design. Maybe talk a little bit about the ways of demonstrating proof of concept and the models, the study design models that have been used historically, like TMS and photostimulation compared to this one. Maybe talk a little bit about the history and then why you think this one is important. I would be happy to because to this audience, because you guys are all driving all of this because you're not going to open up your pocketbooks and give more money to these poor companies until they show you, until they de-risk, right? It's always about de-risking and when you de-risk and how you de-risk. Clearly, we don't have a good biomarker per se. Clearly, something that says the drug gets into the brain, the drug affects epileptic activity in the brain is a good starting place. Certainly, the reason that photosensitivity has probably become, and I'm like probably one of the people who have raised it to prominence, but only because I am aware that these companies need some funding and they need it early. The idea that you can give a single dose of an anti-seizure medicine, get some information that the drug actually gets into the brain and has an effect on epileptic activity is enough to get some funding there. It is not the answer to the question. That is why I like photosensitivity because you can do it with a single dose. You can also figure out the duration of effect. In some cases, if you know the mechanism and you know what that mechanism has done in photosensitivity, you can say, all right, are you at least as good as other drugs in that class? We know those other drugs work. The problem with photosensitivity is twofold, two big problems. Number one is that it is essentially a model of not focal activity, but generalized spike and wave activity. Generalized spike and wave activity, 95% of the time, comes from a whole different kind of epilepsy. These people do not have focal epilepsy. They have something called idiopathic generalized epilepsy. Some very, very prominent and well-loved anti-seizure medicines that work very well in focal epilepsy do not happen to work in generalized epilepsy and do not happen to suppress generalized spike and wave. You can get a false negative, not a false positive as far as we know, but a false negative. The drug can do nothing in photosensitivity and be a very, very good drug for focal epilepsy. That is why to me, knowing the mechanism and that that mechanism has already succeeded in photosensitivity gives you at least some indication that this drug might work. Otherwise, you are sort of shooting in the dark. I always tell companies, get excited if it's positive, but you shouldn't kill the drug if it's negative. Of course, if you're depending on funding from that, investors are going to get all crazy when there's a negative outcome. I don't like it for that reason. It doesn't really reflect, like a lot of people get the false impression that you're then going to go treat photosensitive epilepsy. That's not the point, right? You really don't know what's going to happen to seizures. You only know what's going to happen to perhaps epileptic discharges and not even the epileptic discharges that you're worried about. It's there. It was the only thing that was available. Yeah, go do it because you have no other options. I like TMS even less because it's not even epileptic activity. You have no idea. It's in people that don't have epilepsy. You don't even have any idea of what that means. Do you think the new paradigm for developing ASMs in the future will be to use something like this RNS device to measure electrographic activity of these implants? The good news is, perhaps the good news is that in addition, I mean, it's fascinating because as you mentioned, the RNS is there to treat. It was interesting because I might say that early on, there was not a great appetite to look at the epileptiform activity that was coming from the RNS. It's turned out to be clinically very useful to look at it. If you were the company that was developing the RNS, the last thing you would want people to be like squarely looking at is the epileptic activity that continues to go on. There was sort of a look away, look away, let's just look at the seizure reduction. Now that we're looking at it, it is very clinically useful. The good news is that it wasn't initially intended for diagnostics. It was intended for therapeutics. Now, there are devices that are intended for diagnostics. Just in the last month, there was a device called the Epiminder, which can be implanted in an outpatient office instead of putting people at great risk for bleeding in the brain and other things. That is a small but perceptible risk, infection and other things in the brain. These actually are subscalp. They do not go into the brain, but they do continuously record with much better precision epileptic activity. They can see long episodes and spikes and other activity. A lot more people are probably going to be walking around with those. After it starts to get, and there is also the UNEEG and more coming. As people are wearing these chronic devices, and then there are also external devices that because you're obviously not going to implant somebody for the purpose of a trial, they may get implanted just for their chronic care. There are also external continually recording devices. As the diagnostics get better and better and better, there's going to be a much greater opportunity to use those for proof of concept rather than relying on just a single dose. Super. So, you're instrumental in helping design the study. When doing this, what did you envision success looking like? I mean, when we, I mentioned before, and I think it's really important that we didn't think of the RNS being implanted for diagnostic purposes or therapy other than what is the device going to do to reduce your seizures. As we have more and more people, as you saw 65,000 people who have these things implanted, we realized that they actually are extremely useful. We also talked about the fact that people are not very good at tracking their seizures. It is a way for us to see whether therapies are getting better or getting people better or not getting people better or possibly getting people worse. We have, as clinicians, come to use the devices for that purpose. I have a strongly held belief. To me, it's more than a belief, but I'll say a strongly held belief that what I see coming out of the RNS tells me how a human being is doing. If I see that those long episodes and electrographic seizures going down, I am believing that that person is better, maybe even more so than, and you saw the quote too, maybe even more so than the person telling me I'm better or worse because people telling you they're better or worse can have to do with a lot of different things like the seizures now. I have a famous story about a guy who was seizure-free for years. One day, his wife, this is a patient of mine, one day his wife came like frantically into the office saying, "You've got to do something. All of a sudden, he's having multiple seizures every day. It's like terrible. He's like doing so much worse. The guy was not doing worse. She had shifted from the night shift to the day shift. There are a lot of things that can make people believe that they're better or worse. This is objective evidence that they're better or worse. If I see long episodes getting better, in my mind, that means people are getting better. Super. Great. Shall we open it up for questions from the audience? Who's—I'm seeing—me? I saw Paul pop up first. Yeah. I'll go to the back. Hoping to get my name out there. Thanks for the presentation. Yeah, Dr. French, appreciate it. I guess if you were us, how would you interpret data from this study if we saw a robust reduction in long episodes, but the clinical diary seizure data were uninterpretable? I’d love if you would opine on my question from before. If these data look excellent and you were in our seat, how would you think about the probability of that translating into a non-RNS selected population in phase three? Yeah, I mean, to me, that's a no-brainer, so to speak. I answered the question already, but you don't want to listen to the answer really. The answer is, you posited to me, what if the RNS gets better and the person doesn't? I'm going to posit to you that if the RNS gets better and the data does not support an improvement in clinical seizures, that probably means that you just don't have the power in 30 people to demonstrate that. It doesn't mean that people aren't getting better. I already told you that fundamentally I believe if the RNS is getting better, people are getting better. I don't see how the long episodes get better and people don't get better. The other way around, I can see. I can see the RNS not getting better and people getting better. I'm just going to throw that out there to you because what can, and somebody's going to ask the question, so I'm going to answer it for you. Why is the reduction not the same in long episodes? Yeah, everybody's nodding. Was there somebody going to ask that question? Okay. Just imagine that an anti-seizure medicine can do one of two things, right? The electrographic seizure that comprises most of the long episodes means that you have 30 seconds of electrographic discharge. You also know that when we look at people that we're going to do epilepsy surgery on, they have a lot of these electrographic seizures that they are completely not aware of, right? They have the same exact discharge, and then it goes on for two minutes or three minutes, and then it's a seizure and they're aware of it, their family's aware of it, et cetera. One of two things can happen, right? What happens when you give an effective anti-seizure medicine is it starts to shrink the seizure down, and then eventually it eliminates it entirely, right? If some of them are eliminated entirely, you get no long episode. What about the ones that are just shrunk down to the point where you only have an electrographic seizure now, right? The person may be better because they're not having that three-minute clinical seizure, but you may still have the long episode. That's why you're not going to get necessarily a one-to-one correlation. You still have to look at clinical seizures. If you can get rid of that electrographic seizure entirely and now you see fewer of those long episodes, how can that not mean that the person is getting better? The seizure still has to start, and it still has to be some duration for the person to have a clinical event. Paul, did we get to the questions? Second question was just around this RNS population that hit a Campbell lead and how to extrapolate that to a phase three FLS population that's not recruited the same way. What I love about this study and this approach is that, I mean, why would you not be thrilled about the fact that these people, most of them have two leads or three leads, and many of them have one lead in the hippocampus and one lead not in the hippocampus? You've got almost your own study going on there. You can look at the impact of the hippocampal lead, and you can look at the impact of the extrahippocampal lead, right? Beautiful. Right? Joe Thorne from TD Cowen. A lot of the conversation focused on neurologists, general neurologists versus epileptologists. I guess what's the bar for a general neurologist to be comfortable with a new ASM if something like 219 with the existing safety profile that we saw in the phase one came along with obviously good efficacy later on? Do you think this would be a candidate that would be adopted? Or kind of how do you think the general neurologist would adopt new therapies? Jackie, before you answer, not only the safety profile, but the ease of use with once-a-day dosing and no drug-drug or CYP interactions. First of all, I am going to go back to what Abe said, and I'm going to double it and triple it. You said, well, people want a long-acting formulation because it'll be easier. Uh-uh. People, I want a long-acting formulation because I want everybody in this audience to imagine that you have a disease that if you miss one pill, I had a patient who I was following for a decade. She had terrible seizures. We were working really hard and finally found this combination that kept her seizure free. For 10 years, she would come and see me, and we would have a lovely conversation about her kids going to college and all that kind of stuff. After 10 years, I got a frantic call from her husband that she was on her way to the emergency room with two tonic-clonic seizures. It turned out when he looked in her pill box, for the first time in 10 years, there were pills in the pill box. The first time in 10 years. How can anybody be expected? I mean, I would ask everybody, first of all, I would ask everybody in this audience who takes medication, do you have any idea how many pills you missed? Most people don't, right? I would ask, has anybody been 100% adherent with the medication they take? Anyone? I Anyone? I want to see a hand. Does anybody in this room think they've been 100% adherent with medication that they take? Not seeing any takers on that. Imagine that burden of knowing that you just have to slip up once and you could lose your driver's license or lose your life. That is an enormous burden. Having some sort of long-acting formulation, that's why it's a game changer. It's not because it's easier. It's because it's life-saving. If doctors had that option, that changes the game. That absolutely changes the game, particularly if it was well tolerated. Hi, thanks. Justin Walsh from Jones Trading. Given that you're looking at sort of the most refractory patient population, is there any concern that you could see a failure of the drug to have an effect here, but it might actually benefit the broader population? Oh, that's the other way around. Everybody here is worried that the population is not refractory enough, but you're worried that it's too refractory. Let me tell you an interesting thing. Actually, UCB did this study with Lacosamide, post-hoc, I should say. They did a pooled analysis looking at people who had a VNS or surgery. At that time, there was no RNS, but a VNS or surgery versus people who had not to see whether the efficacy was different, which is pretty cool. What they found was that the efficacy was identical. What was different was the placebo rate. The placebo rate was much higher in people who did not have a VNS or surgery and was only 3% in people who did. That's why I'm not worried. If the drug works, it's going to work. Thank you, Dr. French, for this. Earlier in the fireside chat, it sounded as if you highly value safety and tolerability. In this upcoming readout, if the drug is truly safer, much cleaner, what kind of long-episode threshold or clinical seizure reduction do you want to see for this to be still considered best in class? It's a good question. I'm going to say that it's up to Rapport to decide what kind of risk they want to take at that point. You want to know what kind of risk to take with your money. That's the thing. One of two things could happen. You could have a modest reduction in everybody, but even if you had a really substantial reduction in a few people, that would be good enough for me. Rapport has to make that decision for themselves. And you. Hi, Doug Tsao, H.C. Wainwright. Just a quick question. I'm just curious. It sounds like you feel comfortable in terms of sort of the representation of the population that has the RNS device, but I'm just curious about the types of patients that choose to get the device and how they may be sort of totally representative and that it is just, you never know, or are there certain types of patients that might ultimately choose to get this versus just sort of proceeding with living without one? Because obviously, there seems to be some risk. There is some sort of added sort of involvement with it. I think that at least in my center, people get an RNS when they've started down the surgical path. They have to be severe enough to want surgery. Seizures certainly have to be impacting their lives enough that they want to take the risk of surgery. They usually get implanted for resective surgery, and then resective surgery is not possible for them. At that point, they're desperate to have something, and then they get offered the RNS sort of as a consolation prize almost. You could say people who actually ultimately get surgery, which is, by the way, a lot of people right now with mesial temporal lobe epilepsy will have resective surgery, they do not end up with an RNS. Maybe a little more diffuse disease because if it's very well localized, maybe they'll have that resection. Remember that the vast majority, I'm always shocked at how few surgeries are done in the U.S. every year. I mean, most people with treatment-resistant epilepsy don't get surgery. I think it's 2,000 a year. You saw the numbers of people with treatment-resistant epilepsy. I think there is plenty of people to go around. More questions? Hi. My question is, given the psychiatric side effect that you see in Fycompa, did not really show up until later phase three studies, kind of larger longer treatment. With this 28-day phase 2A study, let's say they come out with no side effect in the psychiatric domain, would that be enough for you to feel comfortable that targeting the associate protein is avoiding the problem with Fycompa? I personally, I would probably want a little more data, but as an investigator, I can't tell you, obviously. As an investigator, I would probably know because there's that, and by the way, I'm going to start off with, in my mind, levetiracetam is no better than Fycompa. Levetiracetam makes people want to crawl out of their skin too. I don't know why Fycompa got such a bad name and levetiracetam didn't. If you listen to the population, as I do, because you heard I'm the medical director of the Epilepsy Foundation, so I talk to a lot of people in the community. Most of them will say to me that the worst time in their life was after getting levetiracetam. Now, not as many people get Fycompa, obviously. But there's a lot of drugs that cause psychiatric problems out there, is all I'm saying. Apparently, being easy to use sort of makes up for all of that, or so you would think looking at how people get treated. Great. And just a small correction. The study is eight weeks, not 28 days, so extra four weeks. Okay. Great. Thank you, Dr. French. It's a pleasure to have you. Dr. French will be here if you have other questions. Will Project Leader is going to be talking about what expectations for our patients. Great. Thank you, Jeff. I'm really excited to have the opportunity to share with this group and talk to you about the data we expect to gather from the study and how we plan to share it in September. The goal of the study has always been to generate more than 20 participants' worth of data showing a convincing reduction in both long episodes and clinical seizures to support the advancement of the program into registrational studies. As we spoke about earlier, we're thrilled that we over-enrolled and we have 30 participants moving through the study. It is a true reflection of the enthusiasm from sites and a push to get more patients into this study. First, I'd really like to take a moment to orient everyone to the types of data that the device generates and why we're so excited about the paradigm. On the right side of the slide, you'll see episode starts on the top and long episodes, which Jeff helped clarify. This participant or this patient was having 400 long—this is not a participant from our study, I apologize. This patient from retrospective data set was having 400 long episodes per day. Each of those bars is a day in the life of the events recorded on the RNS device. On the bottom, you see the same patient was having between 10 and 20 long episodes per day. Along the x-axis, you see the progression in months. In our study, we have three months of baseline data. We have a deep understanding of how patients have been doing before starting RAP- 219 and are able to make a direct comparison between how patients are doing in that long baseline to how they do on RAP- 219. In the case of this patient, in mid-October, they started a titration scheme for an approved and highly effective ASM. You see when they finished that titration scheme at the end of December, you see a nice pharmacodynamic improvement in both episode starts and long episodes. The depth of the response does matter. You can see this is a very striking and impressive response. It was in reviewing data like these and in speaking to investigators and thought leaders about the RNS device that gave us a great deal of confidence in the experimental paradigm and really made us feel confident that an open-label study could deliver excellent proof of concept without exposing these highly refractory patients to placebo. As Jeff noted earlier, we see this clear association in the retrospective data between a 30% improvement in long episode frequency and a 50% improvement in clinical seizure frequency. As we've thought about benchmarking success in our study, we've looked to non-placebo adjusted proportions of patients that achieve that clinical seizure frequency threshold of improvement in later stages of development in pipeline and approved products. What you see in the data are that between 25%-55% of patients achieve that clinical seizure frequency threshold. Because of our belief in the connectivity between that clinical seizure frequency threshold and our long episode frequency improvement threshold, we have set a goal for both at 40%. We believe that this puts us squarely in the category of highly effective anti-seizure medications and that it would be very highly predictive of success in later stages. Our target responder rate will be greater than or equal to 40%. To review the key data points that we intend to share in September, we have long episode focused data points and clinical seizure frequency data points. Again, reiterating the connectivity between this 30% reduction in long episodes and the 50% improvement in clinical seizure frequencies, we are setting exactly the same target, which is a greater than 40% proportion of patients. As you'd expect, when you set this as a target, the median% changes would be expected to be very close to the cut points we've designated. We will also plan to share our TEAE incidence and grade. Great. We are really excited to aggregate and analyze and share the data in September. Troy? All right. Before we get to our final Q&A session and then a wrap-up from Abe, I wanted to provide a few highlights and remind everyone of some upcoming catalysts. Let's start with the market opportunity that we've spent a little bit of time talking about. Obviously, we've spent most of our time on the 1.8 million patients with focal epilepsy. We learned that despite all of the available medications and patients failing at least two, there's still 30%-40% of those patients, very large market opportunity in and of itself with patients with focal onset seizures. Secondly, we look at the bipolar. We didn't spend, again, much time. We are going to start that trial in Q3 in bipolar mania with the data reading out in the first half of 2027. Again, we're pretty excited about the start of that. The next one is the peripheral neuropathic pain. Again, we'll provide further guidance and update on that later this year. These are large populations of patients with significant unmet need. Part of that need, we think, is highlighted by the fact that these precision targeting drugs that work novel mechanisms could really become very important and meaningful clinical impact for patients. RAP- 219's differentiated pharmacology positions us well to deliver across those. While we haven't talked about this yet, while we don't expect a direct read-through from RAP- 219 of focal onset, a couple of things we can feel good about is if positive data there, we know that we're getting the receptor occupancy. Again, we've talked about the 50%-70%, and it also is going to give us a very nice profile on the safety and tolerability. Second, I want to get into a little bit here is the cash runway. As we mentioned, $285 million as of the end of the quarter. What that does is allow us to deliver on several meaningful value inflection points for the company through the end of 2026. Most importantly, will be the phase 2A focal onset readout in Q3, again, refined to September of this year. We'll also be starting, as I mentioned, the bipolar mania trial in the third quarter. We'll also come back again with further information on the planned trial in diabetic peripheral neuropathic pain. We'll also, again, on the heels of positive data, we'll be providing specific guidance on the pivotal program for RAP- 219 and focal onset, but expect it to be a very similar approach to the other ASMs that have been approved here when they go through their pivotal program. Combined, I think we feel that these milestones will guide our deployment of capital over the next several months and into next year. With that, we'll have another Q&A session here before Abe comes back with a wrap-up. Timing-wise, we're doing really well. Abe, take it over. Great. I would like to open it up for more questions from the group. Joe? Sorry. Joe Thorne from TD Cowen. Maybe can you just remind us, as the study is open label, how frequently you get reports from the ongoing study in terms of how patients are doing from a clinical efficacy standpoint? Is this something that you can monitor, or is it kind of once the cards are flipped at the end, you see everything? Yeah. There is a group within the organization that is actively monitoring the study. It is blinded to several folks, but there is a group that is actively monitoring the study. Thanks. Thanks Thanks again, Abe. Can you just talk about if this study works? What is the preliminary thinking on the design of your phase 3 studies? Is it definite you'd go right to multiple phase 3s, consider a phase 2B? What are the different scenarios? Yep. Interestingly, when we started designing this study with Dr. French and other folks within the KOL community, our strategy, as we were thinking about assessing the various proof of concept models, was we wanted a model that would allow us to do what you said, Paul, which is rapidly go into two parallel phase 3 trials. We think that this study affords us the ability to do that. Our strategy based on positive results would be evaluate the results, get in front of the FDA for an end of phase 2 meeting, and then look to our base case would be look to run two parallel registrational trials. Thanks. Just a really quick question. Are you able to share what the discontinuations were in the phase 1 study? Sure, we can. We're happy to share those. As Jeff mentioned and as the slide said, we saw three discontinuations, relatively low discontinuation rate. Jeff, do you want to share a little bit more on that? Yeah. There were three discontinuations. Two of them, one was related to excessive rumination, one was anxiety, and the third was bowel movement irregularities. Grade 1, grade 2? I don't recall the grades. Definitely not grade 3 or? Definitely not grade 3. Yep. Nothing. No AEs were greater than grade 2. Julie back there. Thanks. Hi, Imogen Mansfield from Cantor. I don't cover the stock, but still have a question. On the long-acting injectable, could you talk about your plans there and how you would think about taking that forward? Would that be in the first line setting and how attractive is that? How would that work commercially? Sure. Maybe I can just open it up, and then I'll ask Swami, our Chief Development Officer, to provide some perspective. Our thinking with the long-acting injectable is to really ensure that we have proof of concept data with RAP- 219 and its oral formulation before we actively pursue a formulation in the clinic. One of the things that we do want to reinforce is that we have done our early feasibility and formulation work, and we're really confident with what we see. Our strategy would be to pursue a path in development alongside, not sure if it will be parallel, but alongside with our ongoing phase 3 development programs. Swami, you want to share more? Yeah. I think, Abe, you captured most of it. We are really excited about the feasibility here based on the work we have done so far. What is really important here is to notice the properties of the molecule in terms of the low dose, because the lower the dose, better the probability of success, as you want to put the load for the whole month or two months, right? The long half-life, which allows this as well. Consistent with those expectations, we have some interesting options to pursue, and we have a subteam now formed to look into exactly when to introduce this long-acting injectable into the clinic, into a phase 1 study. As Abe mentioned, how to kind of space this in relation to the oral program, that's being worked out. At a high level, we are really excited about the possibility of the LAI. Jack's out with a follow-up on that. I think you sort of alluded to it in your answer. Just in terms of your target profile for the long-acting, would it be a one-month, two-month, or, I mean, I know there are three-month in the schizophrenia market, there are three-month injectables. Yeah. I think it's a little too early to guide exactly what that profile might be. Our minimum requirement is once a month. We'll see as we get further in profiling the long-acting injectable, as we go into a phase 1 study, we could guide you better on exactly what the possibilities are. It is definitely feasible to think of once in two months. We need more data. Okay. Great. Thank you. Jeff, do you want to spend one second, though? Because I think obviously the LAI is important to think about, but the characteristics of the once a day, Jackie shared her story about a single missed dose with the long half-life, that we're somewhat shielded from that. I don't know if you. Yeah. The current formulation has a half-life of days. I think it's two weeks. Two weeks. Two or two weeks. There is sort of the benefit of, of course, we do not want people to miss doses, but missing a dose or two is less likely to have a detrimental effect than a drug that has a short half-life or has to be taken more than once a day. It is not quite a long-acting injectable, but it is on that end of the spectrum. Any other questions? Okay. I'll wrap this up here. First of all, I want to just say thank you again for everyone in the room, as well as everybody joining us on the webcast. We are very excited to be able to share the updates that we were today, and we really appreciate you taking the time, investing the time to, again, learn more about Rapport, more about the science driving RAP- 219, and also hearing from Dr. French, the unmet need, but also the potential for a novel agent such as RAP- 219 in the treatment of refractory focal epilepsy. We believe, as I said at the beginning of the discussion today, that we are developing a potentially best-in-class therapy for focal epilepsy. We think the robust data that supports our preclinical package, the emerging clinical profile really starts to support this thesis of the opportunity to have a precision medicine that is really focused on interrogating AMPA receptors only in the region of the brain that are needed in focal epilepsy. In addition to that, our phase 2A proof of concept study, we believe, is the optimal design for proof of concept studies. We believe that this is data in refractory focal epilepsy patients first. Second, that the data that's going to be generated from this study, looking at both an objective biomarker such as long episodes, coupled with the clinical seizure data, is going to be highly translatable as we think of the proof of concept data, but also thinking about the probability of success for future registrational studies. This is a pipeline and a product strategy. We're leaning into that strategy. We're invested in that programs, and we look forward to getting those programs off the ground as well. Finally, we're very encouraged by the tolerability profile that's emerging with RAP- 219. We believe that given the multiple ascending dose experience that we've had with the phase 1 study, seeing that exposure in healthy volunteers out to 28 days, a tolerability profile that we think, one, supports the biology, and then, two, really differentiates it from other anti-seizure medications, again, not seeing the bothersome side effects such as sedation as well as motoric impairment, coupled with the potential efficacy from the phase 2A study, will really make this program potentially stand out in overall anti-seizure medication drug development. Thank you so much again for your attendance today. I want to thank Dr. French for being here as well and spending some time with us. We will welcome any other follow-up questions post the close of the formal session. Thank you so much.