Okay, we're going to get started with the next session. I'm Andrew Tai, Senior Biotech Analyst at Jefferies, and it's my pleasure to have the Rapport team with me to my direct left, Abe Ceesay, CEO, and to his left, Troy Ignelzi, CFO. Welcome, both of you.
Thank you.
Thank you, Sander.
Maybe spend a couple of minutes talking about the Rapport story for maybe those in the audience who are less familiar with the story. Talk about your platform, your overall approach, and then walk us through your milestones over the next six to 12 months.
Great. Thank you, Andrew, and thanks to the Jefferies team for hosting us this week. A little background on Rapport. Our vision at Rapport is to create the leading precision neuroscience company. We think that we're well positioned to do that, even though precision can be somewhat of a loosely used term in our industry. The reason we believe in that is our scientific foundation at the company, which are receptor-associated proteins. The science of receptor-associated proteins really drives two elements of our company. First is our lead program, RAP-219, which is an AMPA TARPγ8 modulator program. Utilizing a receptor-associated protein, it allows us to modulate AMPA receptors only in the areas of the brain, specifically for brain structures where focal seizures both originate as well as propagate.
By avoiding the modulation of AMPA receptors in the hindbrain, we believe, both through our preclinical experience, but also our clinical experience, is that we can mitigate some of the most burdensome AEs associated with anti-seizure medications, things such as sedation, somnolence, as well as motoric impairment or ataxia. The other aspect of receptor-associated proteins, in terms of our discovery efforts, allows us to uncover what were previously undruggable targets, leveraging receptor-associated proteins. The company was formed through a collaboration with Third Rock Ventures and Janssen to form this company. We created a company. Not only did we transition assets out of Janssen, but brought over key scientists that were working on these programs, both our lead program, RAP-219, as well as our discovery programs for over a decade at Janssen. So our institutional knowledge around our science at the company is pretty significant.
We can share a little bit of our upcoming milestones. We are currently executing a pretty innovative and important phase IIA proof of concept study with RAP-219 in focal epilepsy. We reported and updated this week that that study is fully enrolled with a sample size of 30, and we expect that data to be read out in September so r eally excited about that data. We think it's going to be very meaningful data, not only for the compound, but also for the field of epilepsy drug development, given the design of the study. In addition to that, we see RAP-219 as a pipeline in our product strategy. We are following where the biology takes us, but also where clinical precedence takes us with anti-seizure medications and are exploring the compound in two other indications, in addition to epilepsy, first being bipolar mania.
We look to initiate that phase IIA proof of concept study in the third quarter of this year, data expected in the first half of 2027. We're currently finalizing our plans to also go into peripheral neuropathic pain. The last aspect of the pipeline in the product strategy is the development of a long-acting injectable. RAP-219 has some unique characteristics that make it amenable to potentially being the first long-acting injectable for epilepsy. That would be transformational for patients. We're really pleased with the work that we've done thus far on feasibility and formulation work for LAI and look to bring that into development post the proof of concept data readout as well.
Great, thanks. You mentioned earlier that by being more selective, targeting certain brain regions, you think you can have cleaner safety with this product. As we think about other successful drugs in epilepsy, can you compare what you have that other drugs, these successful drugs, might have, such as the ease of use, convenience factor, aside from cleaner safety, which to me could be differentiating? Anything else you'd point out as a differentiating attribute?
Sure. When you look at the use of anti-seizure medications, not only is the clinical profile, efficacy and safety very important, but the other aspect that is very important is the overall dosing administration profile. There are a couple of reasons why that's important. First is really how patients are treated with focal epilepsy, and they're treated through polypharmacy. Physicians are constantly adding on medications to achieve additional seizure relief, ultimately trying to drive towards seizure freedom. When you think about that dynamic, you want a drug that can be easily added to polypharmacy. Some aspects that are important there are having no DDIs. Drug-drug interactions are really challenging to be able to basically modulate different doses of medications that patients are currently on. Second is the administration profile. We have with RAP-219, once daily dosing.
The other aspect of the compound is a long half-life. Why a long half-life is important is really two aspects. One is you think about the drug reaching therapeutic concentrations and receptor occupancy. You want to be able to get there in a moderated fashion that really allows you to mitigate some tolerability for anti-seizure medications. The other is really protecting patients. Patients often miss doses, and with drugs with short half-lives, when you miss a dose, you run the risk of having a breakthrough seizure. What's really important there in terms of the overall profile is when you think about adoption of anti-seizure medications in the market, you really, as you think about market opportunity, you want a profile that not only the epileptologist is comfortable utilizing, but also the general neurologist. That really is what defines broad utilization.
When we think about RAP-219, not only do we believe that the clinical profile is potentially best in class, but we also think that dosing and administration profile is differentiated and could be potentially best in class as well t hat would really drive that broad use utilization, but also be something that patients would really see as beneficial as they think about an additional medication.
Great, thank you. Maybe one question on the mechanism that's novel. Is it the truth , "truth" that seizures only originate in the hippocampus cortex where this drug is targeting, or are there other regions of the brain where you might not be targeting where seizures originate?
Yeah, what we know about focal seizures in terms of pathogenesis, seizure origination, and propagation is that they are occurring in forebrain structures. What we know through our PET imaging results is that our target is highly expressed in the forebrain regions, in the mesial temporal lobe, as well as the cerebral cortex. That is where seizures originate and propagate. They really have no role in hindbrain structures, areas such as the cerebellum, as well as the brainstem. What we know about that area of the brain is by modulating receptors in that area of the brain, that really drives things such as sedation, somnolence, as well as ataxia. There are vast majority of seizures are going to originate and propagate where we have the target expressed.
Great. Before we dig into the phase II expectations, where you have top line data in September 2025, heading into that event, what pieces of evidence from the phase I, you mentioned a PET study, but other phase I findings, maybe even preclinical findings that give you the confidence you do have something here on safety, efficacy, and so forth?
Yep. One of the benefits of epilepsy drug development is the high translation that exists preclinical to clinical, one of the highest in the industry, definitely in neuroscience as it relates to translation and really predicting probability of success preclinically to clinically. What we have seen in preclinical models, specifically the gold standard model, which is the corneal kindling model, is we've seen really robust activity of RAP-219 and complete suppression of seizures in that model. The other aspect of preclinical models is the kind of gold standard safety assay, and that is the Rotarod test. The Rotarod test is a safety assay that is evaluating tolerability issues such as sedation, motoric impairment, ataxia. What we see in that model is at the highest dose tested, we're not seeing any impact on the Rotarod. We're seeing that this drug is not sedating.
It is not inducing any motoric impairment as well. That's really kind of the first piece of evidence. There's been a whole other host of seizure models, preclinical seizure models that our compound and other compounds in this category have been tested in as well. Kind of the next step is really understanding what we see in early clinical development, and that is our phase I work. We've completed four phase I studies to date, a single ascending dose study, two multiple ascending dose studies, and one multiple dose PET receptor occupancy study. There's been 100 healthy volunteers that have been exposed to RAP-219. This week, what we are able to update on is our consolidated tolerability profile across the multiple ascending dose studies. That is a total of 64 healthy volunteers.
We've been very encouraged by the tolerability profile in our multiple ascending dose studies. This is a multiple ascending dose studies where patients or subjects all have been exposed out to 28 days, achieving receptor occupancies of up to 85%. We've seen what we believe is a very favorable tolerability profile, one that is highly differentiated from other anti-seizure medications. Consistent with the thesis on the biology, we have not seen sedation or motoric impairment show up in our phase I studies, and again, achieving very high levels of receptor occupancy, which we're really encouraged by.
Okay. Maybe you answered my next question is if the safety is that clean, which is unheard of, essentially, how do we know this drug is active and not a placebo?
Yeah, great question. We definitely see on-target pharmacology with this compound. Although the pharmacology is different from traditional anti-seizure medications, we're really confident that the drug is active. What we know about these compounds is that these compounds in preclinical models, as well as in clinical models, are actually different from traditional anti-seizure medications in that these compounds are actually somewhat activating. We know when we achieve on first dose very high levels of receptor occupancy, we're seeing on-target pharmacology. What we also know is when you have a more moderated approach in a multiple dose setting, you're able to mitigate that tolerability. That's really what we observed in our multiple ascending dose study.
In addition to that, not only have we done kind of single dose corneal kindling models, but we've done chronic dose corneal kindling models and saw that the drug continued to be active. No signs of tachyphylaxis either.
Great. Now shifting gears to the phase II study, you've over-enrolled 30 patients. Originally, it was planned for 20. It is a unique study design. Maybe walk us through this biomarker you're using and why you think it is useful, if not better, than the traditional way of capturing seizures, which is through diaries.
Yes. As Andrew mentioned, we're currently in a phase IIA proof of concept study. Important for us in this proof of concept study was to do a study 1 , in refractory focal epilepsy patients. T wo, being able to leverage a biomarker that we thought was highly objective and indicative of efficacy, and then three, have a data set that would allow us to rapidly progress into registrational trials. This study is done in a refractory focal epilepsy patient population. Demographically, these patients look very similar to your standard refractory focal epilepsy patient population. The difference is that they have an implantable device, an RNS device that is manufactured by a company by the name of NeuroPace. The device plays both a therapeutic role as well as a diagnostic role.
The therapeutic role, we're really not interested in, and we have made sure that we kind of manage for that therapeutic role to really understand the true effect of the drug. The diagnostic role, the device captures ongoing EEG activity. Specific EEG activity is a measurement called the long episode, which is Epileptiform activity that is highly correlated with both electrographic seizures as well as clinical seizures. Why we believe and why the community believes that this is such a great way to look at investigational drugs is that clinical seizure diaries, the way of standardly capturing efficacy in investigational trials, is wrought with error. Patients have to remember every seizure that they have. They have to record it. What we're leveraging is a highly objective biomarker that really is not prone to any human error.
This data has been really capturing a lot of attention in the community because the data is so objective, but also there is a high correlation with the reduction of long episodes and the reduction of clinical seizures. In our investor and analyst day on Monday, we are able to present the baseline characteristics of the patients enrolled in our trial. These patients, once again, we have confirmed that they are representative of refractory focal epilepsy patients. In addition to having the long episode count that we feel is meaningful, what we have also seen in these patients is that they have a baseline seizure frequency of about 10 clinical seizures.
We now are looking at this set of data, and we're confident that not only are we going to be able to detect a meaningful change in long episodes, but we will also have the clinical correlate along with that in clinical seizures as well.
Because you've enrolled a population that is essentially a refractory population, it kind of, in a sense, de- risks the next set of studies that you will be running, phase III studies. Is that fair to say?
It is fair. Once again, the reason that we are doing this study, when you think about other models that exist for proof of principle, proof of concept in focal epilepsy, you have models such as an external EEG model, which is the TMS model, or a photosensitive model. Neither of those models are done in the patient population that you're ultimately going to evaluate in registrational trials. This model and the study that we are doing is in refractory focal epilepsy patients. When we look at the results of this study, having an objective biomarker and then having the clinical seizures to go along with it, we think is going to be highly de-risking for the compound and highly translatable as we think about success in future registrational trials.
Makes sense. On, was it Monday during your analyst day, you shared the baseline characteristics on the first 14 patients. There are 30 patients enrolled. Do you plan to share the remaining 16 patients? Could that be during your Q2 EPS release in August?
Yeah, we will, given the window that we're working from today to September, we're going to just wait till we have the top line results to share the rest of our baseline characteristics of the remaining 16 patients enrolled in the study. We have no reason to believe that the baseline characteristics will change or have changed from the first 14 to the next 16. It was just a real artifact of us being able to capture the data, clean the data, QC the data for 14 patients. So we'll provide those baseline characteristics along with the top line results.
Makes sense. In that top line release, how I think about the study, it's interesting. There's a natural pretreatment baseline criteria. In my notes, is it an eight-week treatment phase?
Yep.
There is an eight-week follow-up phase. In the top line release, do you share data across all weeks or just up to the eight-week treatment phase without the follow-up?
Yep, we will. The design of the study is an eight-week retrospective period where we look at the patient's EEG activity to qualify for screening criteria. There's a four-week prospective period where we're continuing to look at EEG activity as well as capture clinical seizure diaries through that period, and then an eight-week treatment period, and then an eight-week washout period. For our top line results, we will share the efficacy data from that eight-week treatment period. In future meetings, whether that be medical meetings or any other corporate update, we'll share the eight-week follow-up period.
Thank you. Within this update on Monday, you confirmed you will share long episode data as well as clinical seizure data so we can make some nice correlations as well. What is going to be the go, no-go threshold for you to pursue to phase III?
Yep. Our expectations that we set on Monday are the following. First, we're going to be looking at two key endpoints. The first is our primary endpoint and then some key secondary endpoints. The primary endpoint and the way that this study was powered is on the reduction of long episodes. We're going to be looking at that as a responder rate. The responders' threshold is to achieve at least a 30% reduction in long episodes. Why that number is important is that is the threshold that correlates with at least a 50% clinical seizure reduction. That benchmark is important because that is kind of the clinically meaningful threshold as you think about clinical seizure reduction. Our expectation for that primary endpoint is at least 40% of patients will achieve at least a 30% reduction in long episodes. That responder rate of at least 40%.
In terms of our key secondary endpoint, as I mentioned, we'll be looking at clinical seizure reduction. The clinical seizure threshold is at least a 50% reduction in clinical seizures. Our expectation there is at least 40% of patients achieve a 50% or greater clinical seizure reduction. When we look at that data and we think about that threshold, that puts us well in line with highly effective anti-seizure medications. Having both the highly objective EEG marker coupled with the clinical seizure data, we think positions the data to be a pretty strong data set and again, one that really highly de- risk the compound moving into registrational trials.
Right. To be clear, this go, no-go threshold would be in line with essentially the best seizure medicines out there in terms of efficacy. Are you hoping you can go well above that?
Yeah. You know, the expectations that we set would definitely be in line with the most effective anti-seizure medications. We will look at the data. If we have a response, it's even greater than that, we would consider that a really nice scenario, and we'll see what the data says. I think the other way that we will look at this data, as you alluded to, Andrew, is the complete picture of this compound. When you look at efficacy at that level, coupled with a differentiated tolerability profile showing no or very low levels of sedation, motoric impairment, and then the overall administration profile, that complete kind of mosaic around the compound we think will start to set up a potentially best-in-class therapy.
Understood. If you do not show that threshold, you are below that, what do you do? Do you go up a dose in another phase IIA type study, or what would be that pathway?
Yeah. You know, we believe in the dosing that we have, and we don't believe that we have to push the dose higher. Our preclinical models, which again are highly translatable, had a maximum efficacy threshold in the 50%-70% receptor occupancy. Our dose in our phase IIA trial achieves a receptor occupancy between 80%-85%. So we really don't see a rationale to be able to push the dose further. If we were not to hit that threshold of response, we would continue to look at the entire data set. If you were to talk to the KOL community as an example, they think that we've set a pretty high bar for our data expectation.
Even a drug that had 30% responder rate on that long episode, if you were to talk to the KOL community, they still believe that's a highly effective drug, especially given the type of profile that RAP-219 has. We will look at the entire data set holistically once we have that phase IIA data.
Great. Moving to the safety, on Monday, we asked you, are you seeing any serious adverse events? When I think about other drugs out there, they're all pretty dirty. You confirmed there's no SAEs. What special AEs are you specifically looking for? I guess the second part of it is, what AEs can we expect?
Sure. It is a CNS active drug. With any CNS active drug, you are going to see CNS side effects in terms of the organ system classification. When you look at tolerability, those really are in the buckets of nervous system disorders as well as psychiatric disorders. For this compound specifically, the things that we will continue to keep our eye on and haven't shown up and we think are really key differentiators are no or very low levels of sedation, somnolence, as well as low or no impacts on ataxia or motor function. The things that we will look at in terms of the tolerability profile is you are going to see some level of nervous system disorders, whether that be low-grade headaches, whether that be some level of brain fog is often common with anti-seizure medications.
What we can say is in our phase 1 study, what we saw is no AEs greater than grade 2. The majority of AEs were actually grade 1, so mild AEs. All AEs were transient, resolved on their own. Those AEs that were nervous system related, such as headache, a few cases, I think we had five cases of brain fog as an example, all fit that category, grade 1 or grade 2, and as well as transient.
Perfect. Again, top line data, September 2025. When do you start the phase III studies? I think you plan to do two of them. How quickly could you start them? Could it actually make sense to do three with one as a backup, actually?
Sure. Do you want to start the timing?
Yeah. Yeah.
I would start those and I'll hit that.
Timing-wise, when we report, as we talked about, Andrew, we'll report on the eight weeks of drug treatment. We won't have the eight-week follow-up period yet. We have to wait for that. That'll then be put together with the end of phase 2 meeting package for the FDA. We'll give more specific guidance as we get through the trial. You can imagine this slipping into 2026. Again, we could get more specific later.
In terms of three phase III trials, one of the reasons we did this study the way that we did it is to give us data to really de-risk the program and only need to do the two registrational trials that we believe are required for NDA submission. Our base case plan, data dependent, will be to just run two parallel registrational trials.
I see. One of the advantages, though, that Abe often speaks to about our phase 3 execution is we're going to have more data on PK and PD on actual patients that you don't get in these other trial designs because we're going to have the long episode. We're seeing second by second, minute by minute, the response when the patient takes the dose because we're getting the long episode reading. We're going to have a great opportunity to effectively power the pivotal programs.
Makes sense. We're going to wait for that eight-week washout period. What would you expect to see in that period of time, e fficacy sustained? What would that even mean for the drug?
Yeah. It's another great benefit of this study design. As you think about a drug that has the half-life of our drug, which is 8 to 14 days, what we're going to be able to do is these patients will continue to have their data, their internal EEG data monitored. What we're going to be able to understand is from a PK perspective, PK/PD perspective, is how long through washout until you start to see that EEG activity return. We think that that is going to be really informative of the compound because, again, if you were to talk to patients and clinicians, what is one of the biggest fears living with epilepsy? That is missing a dose, having a breakthrough seizure, and having either significant morbidity and, in some cases, very sad mortality associated with that.
For us to be able to have a data set that really confirms the PK, the washout period, and the fact that the drug may continue to be on board, as an example, long after withdrawing from the drug or washing out from the drug, we think it's going to be a really helpful data set.
Great. I think that's all the time we have. Again, you have two other programs with the same drug starting up trials later this year. Thank you for your time. It's very helpful to walk through this expectation. Thanks, everyone, for listening.
Thanks, everyone.
Thanks, Andrew.