Good morning, we're going to get started with our session. I'm Andrew, it's I, Senior Biotic Analyst at Jefferies, and it's my pleasure to have the Rapport team with me today. To my direct left, H.C. Say, CEO, and to his left, Troy Ignolzi, CFO. Welcome, both of you.

Thanks, Andrew. So, as usual, some people may not be as familiar with the Rapport story, so would you mind level setting what you're working on, you know overall strategy platform milestones over the next six to 12 months that could be very helpful sure so rapport we're a company that is focused on precision neuroscience our foundational technology and scientific foundation is based on receptor-associated proteins we'll talk a little bit more specifically about why receptor-associated proteins are important in terms of a potential drug target in the context of RAP219. Our lead program, RAP219, is a program that targets a specific receptor-associated protein associated with the AMPA receptor, which is called TARP gamma-8. This is a receptor-associated protein with the AMPA receptor that has very specific neuroanatomical distribution, which makes it really an ideal target for our lead indication, focal epilepsy but also other indications that we're pursuing with this compound we released last year in september really meaningful phase two data for our lead indication in focal onset seizures and we're currently advancing that program into phase three studies which are truly getting up and running as we speak and then in terms of additional milestones we have recently re-guided to bring in our bipolar mania readout with RAP219 to the fourth quarter of this year we'll also on track to be able to release our first cut of open label extension data and focal onset seizures with RAP219 in the fourth quarter of this year and then another program that we're very excited about is the LAI formulation with RAP219, which we think could be transformational for epilepsy as well as bipolar with RAP219. We are currently in IND enabling activities and look to have that human PK data for the long-acting injectable in 2027.

Wonderful. And so maybe to start with the focal epilepsy program with RAP219, congratulations on a really great data set in October of last year. Maybe walk us through big picture, what kind of attributes are we talking about that makes your compound superior to what's out there? Why does this have blockbuster potential?

Yeah, I think the best way to understand the potential value of RAP219, and as you mentioned, Andrew, kind of the blockbuster potential of RAP219 is really to think about it through the context of what clinicians and patients are looking for in new treatments in focal onset seizures. So this is a field that has had over 30 drugs approved and available for the treatment of focal onset seizures, but the patient population continues to have significant unmet need. There's 1.8 million patients in the United States and roughly 30 to 40 percent of those patients are treatment resistant meaning they're currently managed and treated with multiple anti-seizure medications but they continue to have breakthrough seizures so what patients and clinicians are looking for first and foremost is a novel MOA an MOA that can be added to polypharmacy and really provide additive efficacy as well as a a drug that is better tolerated. Most all anti-seizure medications that are currently available are interacting with receptors kind of in a ubiquitous nature in the brain. And what that is causing is, although you're seeing some level of efficacy, pretty significant tolerability issues associated with those anti-seizure medications. What we see with RAP219 is given the fact that we are targeting TARP gamma-8, which is a receptor-associated protein associated with the AMPA receptor that is primarily expressed in forebrain structures, both the mesial temporal lobe as well as the neocortex, we're able to drive efficacy where focal seizures both originate and propagate, but by targeting those receptors only in the forebrain were able to really mitigate some of those most bothersome AEs that are associated with other anti-seizure medications. And what we saw in our phase two results is really unprecedented efficacy. We saw a 77.8 median percent reduction in clinical seizures. That was accompanied by a meaningful reduction, a 71 percent reduction in a biomarker that that we assessed, which is a long episode, or in the terms of our study, an electrographic seizure. And then when you look at that efficacy, we also saw a really appealing tolerability profile. And the drug also has attributes that are ideal for an anti-seizure medication. It is extremely potent, so that leads to a low dose. It has a 22-day half-life, and also has a profile in terms of drug-drug interactions that we don't think will be a culprit or at risk for a DDI, which is very important as you think about adding it to polypharmacy.

And then QD dosing as well as novel mechanism and no titration essentially too. So that's good. And then after that data set, then at AAN this year in April, you shared some washout data.

So I think you alluded to it with your 22-day half-life, but maybe speak to the significance so these the same patients from the phase two wash out of their drug and you shared data at AAN so speak to the significance what do other drugs maybe show as well sure so in our phase two trial design we had an eight week treatment period and then we had an eight week washout period and what you're alluding to Andrew is at the AAN presentation we are able to share our data form that from that washout period and what we were really encouraged by is given the half-life of the drug which is approximately 22 days what we saw is really continued efficacy through that washout period given the fact that drug is still on board even though these patients come off therapy due to the half-life so specifically as I mentioned in our primary endpoint, or I'm sorry, our secondary endpoint around clinical seizure reduction, at eight weeks, we saw a 77.8% median reduction in clinical seizures. That actually increased to 90% at week 12. So why is that important? That's really important because when you look forward to our phase three trial and all other phase three trials, those are 12-week treatment durations. so this gave us a lot of confidence in terms of the effect that we could potentially see at 12 weeks as we move into phase three the other aspect of this that you mentioned Andrew is the half-life most other anti-seizure medications have very short half-lives and that's a huge risk for patients living with focal onset seizures one of the biggest fears for patients their caregivers as well as clinicians is a missed dose. Missed dose in this patient population has the risk of breakthrough seizures. Breakthrough seizures have the risk of significant morbidity and in some cases mortality. So when you look at a drug that has the type of coverage that we have with a 22 day half life that's a big benefit for patients. No one would ever encourage missing a half, missing a dose but the reality is that happens in a chronic condition and having that extended half-life could really provide a lot of protection for patients right and maybe it gives you also you have some confidence in your la program which we can touch on a little bit later too yes yeah and and so those same patients then now go back to being treated i think there are 27 patients in the washout how many have actually went back to the open label extension where you'll share data in q4 yep so we have an open label extension that that was available for these patients that were involved in our phase two study. That open label extension had a gap period, so patients did not directly roll over into the open label extension study, and that was really due to us just enabling the open label extension due to long-term talks that has now obviously been completed. Now patients are enrolling into that open label extension study. So we haven't guided specifically on how many patients have enrolled, and that continues to occur. But what we can say is we're really encouraged by what we're seeing in that enrollment. So those patients are actively enrolling. They're going to be kind of reinitiated on RAP219, and we expect to be able to share an initial cut of that data in the fourth quarter. We look at this data really primarily from a safety perspective. We think that that is the most informative as we think about this data set, the fact that patients will have longer exposures on RAP-219. And that's very important as clinicians really think about the profile of novel anti-seizure medications to understand long-term safety.

Understood on safety. Is it fair to assume, sure, there's a gap period, but they resume that efficacy could be similar to what you saw in the original eight weeks of 78 percent? Like, should we expect that or not necessarily?

Yeah, it's hard to say right now, and we're not setting, you know, expectations around efficacy, you know, for a couple reasons. You know, the first is that these patients did have a gap period. So we know that through that gap period, things in their medical history could have changed as well as their background anti-seizure medications could have changed. So the patients are rebaselined going into that open label extension period. So we will have a new baseline period. So we will be able to derive efficacy from this study. It's just not going to be a direct comparison to what we saw in that initial eight-week treatment period. So there will be some efficacy information, but it's hard to compare one-to-one, just given the nature, again, of how these patients ultimately came into the open label extension period.

Okay, great. And so I guess one more is the open label cut, do you think it could be like three or six months of follow-up? And then secondly, it's just the existing patients, there are no de novo patients, to be clear, in this open label extension.

Yes, and I think kind of your time frame is kind of directionally right in terms of the level of exposures that patients will have going into that fourth quarter data release and yes this this initial open label extension study will just be the patients from the 201 study our phase two study now we are opening other open label extension studies associated with our phase three program so there will be open label extension study for patients in our two phase three studies our focus one and focus two study that will be able to enroll into an open label extension study and then there's another part of that open label extension study that will also capture de novo patients that ultimately will be able to allow us to achieve our appropriate safety exposures.

Great and speaking of the phase three focus one based on clinical trials I think started dose or a site maybe started up in late May but anyway it's starting up now basically Yes, it is in earnest.

So as we speak about those sites are being initiated and you know, we're actively looking to screen patients as well.

Right and as we think about phase two to phase three translation, how much do you think efficacy that you saw in phase two could degrade from the 78% at week eight? I know you mentioned now we have a week 12 more treatment.

So how are you thinking about absolute efficacy for the drug by week 12 in these trials as well as how placebo might perform and what kind of placebo adjusted separation are you thinking yeah so we look at the phase two study and we believe that it is highly translatable going into phase three in terms of efficacy we believe that the way that we ran the phase two study and given the fact that all clinical seizure reduction is corroborated by a highly objective biomarker really gives us a lot of conviction in terms of the efficacy that we can see in phase three. So as we think about the results for phase three we are not necessarily taking a discount in efficacy for phase three. Now I want to be really clear on that versus how one may think about powering a phase three study because what the phase three studies don't do is we did not power the study based on the results and the treatment effect that we saw in phase two. And there's a couple reasons for doing that. One is I think in drug development you always want to be thoughtful about the powering of your phase three studies. The second is as you think about an indication like focal onset seizures there is the requirement for a safety database so we want to be one thoughtful about the powering the study and then two also having sample sizes that allow us to fulfill those safety exposures so as we think about kind of the powering and overall kind of separation from placebo you know very similar to what contemporary studies have done whether you look at the xenon program or previous programs that kind of separation from placebo are powering is it's somewhat similar to that I see it maybe maybe around 15 to 20 percent or

something placebo just Delta yeah yeah in that range okay thank you and then um so the two trials focus one of first focus to technically have I think different dosing levels so for the studies to succeed do both dose levels in each study need to hit stat sig versus placebo or can the top dose only beat placebo stat sig and you're good to go yeah so a couple things prior to just addressing the question directly I want to just provide some context so the first question is why why have we chose multiple doses in phase three we think

that given the profile of the drug it is really a differentiating factor for us to bring forward multiple doses that could be efficacious from a prescriber's perspective. That is information that we've received from the community, and we think bringing forward multiple doses as you think about ultimate prescribing information could be highly valuable. So when we designed the studies, we looked at three doses that based on our understanding of the PK of the drug, insights from our phase two study will really provide shots at efficacy across three dose levels. So in one study, we have what is called mid-high, and then the other study, we have low-mid. From a statistical standpoint, really everything is anchored around that mid-dose because that is the common dose across two studies. So, really that is where the anchor point is. So we have had dialogue with the FDA through our end of phase two, and we feel confident that the design of these studies will really give us a shot to have a successful study based on that mid-dose, then followed by the high dose, and then following from a statistical priority the low dose.

Oh, super helpful. And then in terms of data timing, I know there's no guidance, but can you give us a bookend of other recent studies? You mentioned Xenon. I can think of Praxis, which reported some data earlier this week. There's Biohaven. I guess Praxis, the point being, Praxis and Biohaven was pretty fast. Xenon was on the slower end. So remind us how many years it took those studies and where do you think you could fall?

So you've kind of laid out the spectrum. Andrew so on the on the long end you have Xenon's program now I want to just say you know I think the Xenon team has done a remarkable job and did a remarkable job in their development program the reality is when they started that development program it's one of the most challenging times to do a focal onset seizure studies both in terms of the competition for recruitment but also you had COVID and other dynamics so that's kind of one end of the spectrum the The other end of the spectrum is some other sponsors that you had mentioned, which have either guided to or delivered data in a much more rapid fashion. As we kind of look at the landscape, quite frankly, we do not want to be on either end of that spectrum. We don't want to be as aggressive as certain sponsors. When we look at overall trial conduct and ultimately how we believe a program should be run, we think that going too rapid really starts to really have an impact on patient quality in terms of enrollment. And also we think that there's certain things that are tailwinds for us that won't make our program as long as Xenon. So what we have kind of mapped out is roughly a three year timeline to data. But what I can say is, you know, we'll continue to monitor our enrollment and I think, you know, give us a year into this program or so, we'll be in a much better place to really put a more finer line on the delivery of data.

Yes, great, and so thank you. And then maybe shifting a little bit to the LAI program where there's phase one data in 2027. Bigger picture, which epilepsy drugs have an LAI formulation and then how does it boost the appeal of RAP2 and 219 if you did have one successfully in the real world? Why is this important?

So there are currently no available long acting injectables for focal onset seizures or epilepsy. We believe, and this is supported by the feedback that we received from the community, that a long-acting injectable would be transformational for patients. Going back again to the comment that I made around the fear of missing a dose for patients, clinicians, as well as their caregivers, a long-acting injectable would really be a solution for that. So it would be a real differentiating aspect for RAP219 if you think about the overall profile of the drug. The drug has some inherent qualities that make it amenable to a long-acting injectable, which other anti-sigure medications don't. One, low solubility. Two, is the inherent half-life of the drug. And then three is the potency. So all three of those aspects really allow this drug and RAP219 to be the only anti-seizure medication that really has a straightforward path to a long-acting injectable. The other dynamic that we think is somewhat underappreciated is how that would change the overall market dynamics for RAP219 as a commercial asset. The reality is, in order to be able to access a long-acting injectable, you would first have to be exposed to the oral formulation. So we think that that will really drive uptake and share to RAP219. The second is, as you think about the terminal value of RAP219, it's a complete game changer. What long-acting injectable formulation does is roughly extend the IP runway for the asset for another decade. So as we think about a $2-plus billion market opportunity on the oral formulation alone, that really markedly changes the overall terminal value of the asset as well. Got it, got it. and so phase one data again in 2027 will this be in healthy volunteers and what exactly are you see do you want to see in the phase one data set is it like high receptor occupancy for a long duration yeah so really what we're looking at in this first phase one study is pk so that's really what you're looking to confirm we already know ro and RO and concentration relationship based on our oral formulation so really what we're looking for here in this initial study is to really have proof of formulation. The fact that we have a formulation that can achieve that PK profile and then you're also looking at certain aspects of the LAI that you want to ensure meet certain safety criteria So looking at injection site reactions, as an example, and also looking at the profile of the PK to ensure that you don't have a burst profile or any other PK profile that might make you have to go back to the drawing board on formulation. What we can say is based on the inherent qualities of RAP219, as I've already mentioned, and as well as our previous formulation work, we're really confident with what we see and that human PK data would be kind of the next de-risking event.

Got it. And what kind of dosing frequency are we talking about? Is it like every month or is it every six months?

Yeah, so our first formulation is looking at an every monthly profile, but what we're currently working on and will continue to work on are extended profiles beyond the monthly.

Got it. And after the phase one, let's just say you liked what you saw, what would be the next steps? Do you actually go to phase two or can you jump to phase three? How does this work?

Yeah, so that's still undefined, and we'd have to have those conversations with the agency. You know, there's been, you know, multiple long-acting injectables in other disease areas, and there's a little bit of variability based on the disease area, but, you know, once we have that human PK, those human PK results, we'll talk to the agency, and we'll figure out kind of what that path looks like in terms of, you know, including that as, you know, part of an SNDA with the RAP219 oral formulation, which would be the base of the NDA.

Got it, got it. And then shifting to other programs you're pursuing with the same drug, PGTCS, which is primary generalized chronic seizures, you're starting a phase three in 2027. And any color when data could be and maybe confidence why you want to pursue this indication?

Yeah, so you know the confidence really was driven by our Results that we saw in our phase 2 study in FOS As you think about this seizure type There's a lot of reasons to believe both based on our preclinical experience in certain animal models As well as the distribution of the target and then also as you look at the phase 2 results in FOS to really believe that this drug could have an impact in primary generalized tonic-clonic seizures. The reason that we're starting this program as early as we are is that these trials do take longer to recruit. It's just a harder patient population to recruit, but it is also the second largest form of epilepsy behind focal onset seizures and has a very similar profile in terms of the unmet need with roughly 30 to 40% of those patients also being refractory.

So our belief here is given the length and time it takes to recruit these studies, we wanted to get going on this program earlier because we think having that labeled indication as close to our indication in FOS would be another differentiating factor and really just expand the clinical utility of RAP219. perfect and then in the meantime as we wait for these programs to evolve you also have a bipolar phase two to hit a readout in Q4 also for the same asset so it is a placebo-controlled readout I think they'll be meaningful bottom line when I think bipolar mania I think antipsychotics remind us what the

antipsychotics show on the young mania score is that kind of the bar to beat here yes so a program that we're excited about you know one that you know I think everyone is aware that neuropsych indications quite frankly have a lower probability of success versus a condition like epilepsy just given the fact that there is low preclinical to clinical translation but there's many reasons to believe in this experiment with RAP219 based on what we know about Bipolar mania the role of glutamate the distribution of the target and why you know wrap 219 could be a really interesting mechanism and compound here In terms of the current standard of care You mentioned atypical antipsychotics There are other anti-seizure medications that have been approved in bipolar mania both in terms of acute mania as well as maintenance therapy and the real Well, the true efficacy measure is the YMRS, the Young's Mania Rating Scale. And when you look at approved drugs, there's anywhere from a four to seven point placebo-adjusted difference. We have powered our studies to detect a four-point change. And when you think about really kind of that four to seven-point range, What's important is to think about the totality of the picture of the drug So these current treatments that are available for bipolar mania may deliver some level of efficacy But the reality is the top the tolerability profile is really not ideal for patients living with bipolar When you think about atypical antipsychotics You have EPS symptoms you have weight gain and other issues.

What we see with wrap to a nine is the ability to have a mechanism that drives efficacy but is non dopaminergic and does not produce sedation or some of those EPS right and then maybe one more question in the last minute is just I think personally I think the safety looking at the safety could be important to a long Long story short, you know, FICOMPA, another AMPA, does have a black box for, like, aggression behavior and so forth. So is it fair? Would you agree that this fourth quarter readout could be a double whammy in terms of it could also help you de-risk further that you do not have that kind of signal that FICOMPA might show kind of thing?

Yeah, we would agree that we think that this fourth quarter readout with bipolar is going to be informative in two forms as you mentioned one is you know having an efficacious drug in bipolar mania would really increase the opportunity with wrap 219 regardless of the efficacy readout we're going to have another 125 patients that are exposed to wrap 219 these are acutely manic patients and having that level of safety data in addition to the data that we've already produced across all of our phase one studies, our phase two study, as well as the open label extension study, we think is going to be a really robust safety data set.

Okay. I think that's all the time we have, but thank you for walking us through your story and congratulations on all the progress. Thanks, Andrew. Thank you, everyone.