Go ahead and get started here. Thank you again for joining us this afternoon at the Citizens Life Science Conference. Excited to be joined next by Rapport Therapeutics. Rapport is a company focused on developing precision neuroscience therapeutics. Lead program RAP-219 is being developed for Focal Epilepsy, and we also think there is a pipeline and a product potential here as well, as well as a really exciting platform that the compound, the lead compound, came out of. Joined this afternoon by Troy Ignelzi, the company's CFO, and Will Motley, who is the program lead for RAP-219, the lead program and the focus for our conversation today. Welcome both of you, and maybe Troy, just hand it over to you to give a quick 30-second overview of the.
Yeah, you did a good job there, but thanks for having us. Appreciate it, and thanks for those that are attending. We'll get into the science and the background of that with Will's discussion, but in a nutshell, Rapport was spun out of technology that, through a genesis of work done by our scientific founder, Dr. David Bredt, came back from his days at UCSF, through his time at Eli Lilly as the head of R&D, discovery R&D in CNS, and then to J&J . J&J , along with JJDC and Third Rock, spun out the company a couple of years ago around this receptor-associated protein technology that allows us to hone in on where a drug actually targets, as opposed to ubiquitously across the brain.
Again, we'll spend some time talking about the technology, but the idea is that by being more precise, we can address, in the case of the lead, focal onset seizures, focal epilepsy, and then other indications. We took the company public in June of last year. We just had our Q come out this morning, ended the year with about $285 million. You can tell when the CFO is doing this versus the CEO. I'm getting all this stuff out of the way in case I don't get a question that I can actually address. The idea here is that we've got enough cash to get through at least the end of next year.
We've got a very important readout coming in Q3, our phase II in focal onset patients will read out, and from there we'll have a cadence, we believe, of value inflection points for the company, clinically driven by the second indication, which will also kick off a bipolar mania trial in third quarter of this year, with that data reading out in early 2027.
Great. Thanks, Troy. I promise we'll ask some questions later that are suited, but we're going to jump straight in and go to Will and just maybe say, what is a receptor-associated protein and just what's the goal here of focusing on the receptor-associated protein versus the receptor itself?
Yeah, that's a great question. I think we see a host of super compelling neurotransmitter receptors that make excellent drug targets, where identifying the appropriate receptor-associated protein either gives you a new approach to targeting that receptor-associated protein or facilitates drug discovery where drug discovery has not been possible. A great example of that is our lead program, RAP-219, where we're targeting AMPA receptors, and it's a negative allosteric modulator of AMPA receptors, but only those AMPA receptors that are bound by the accessory protein, gamma-8 TARP. By binding at the interface, if you screen in the absence of gamma-8 TARP, the pocket isn't there. When you do screen with gamma-8 TARP present in the native complex, you have unleashed a tremendous opportunity for small molecule drug discovery.
Let's move straight into the mechanism then. You mentioned it's AMPA receptor targeted. Just give us the background of AMPA receptors in epilepsy and why they're validated.
Yeah, of course. AMPA receptors, AMPA is a primary excitatory neurotransmitter for glutamatergic signaling in the brain, and it has been non-selectively targeted with perampanel. It is a validated mechanism in focal onset seizures. By targeting it through the accessory protein, we're only targeting it in the forebrain. We feel we have likely dialed out a lot of the tolerability challenges which come from non-selective targeting in the hindbrain.
We see that on the perampanel label specifically. There are meaningful side effects, but it is an effective drug.
Yeah, that's exactly right. I think it's even a highly effective drug in patients that are able to tolerate appropriate concentrations. That's just really hard.
I guess looking preclinically, are you able to see that targeting the RAP versus targeting the receptor has the same impact on the downstream pathways?
Yeah, so that's a great question, and I think that's super clear. The approach preclinically, where the corneal kindling model has so consistently been a model that has effectively translated to the clinic, and the way that tolerability has tended to be assessed in preclinical models is through rotor rod testing, which is if an animal falls off the rotor rod, you don't know why, because you need lots of systems to be working, but when an animal stays on, you know that all those systems are working. The therapeutic index between improvement in corneal kindling and failure in rotor rod is very narrow with perampanel and is completely opened by targeting the RAP.
Okay. So you have a lot of preclinical data supporting this, but you also have phase I data. One of the aspects of the phase I data I'd like to just spend a couple of seconds on is what you just said about where the receptor, where the RAP is expressed. Can you just walk us through that imaging data that you've generated in phase I?
Yeah. Maybe one thing with that, though, is before we move on that, you might want to talk about in those animal models how we identified the receptor occupancy that we were targeting for that, because I think that then translates to where we're at in the clinic, what we've seen from a TEAE perspective, but also the opportunity that lies before us as far as from dosing flexibility. Talk about that.
Yeah, that's a nice add. Preclinically, we had established a receptor occupancy and concentration relationship across three different species, and they tracked really nicely together. We went into the clinic with a high degree of confidence that you achieve therapeutic receptor occupancies in single-digit nanogram per milliliter concentrations. It is a very potent molecule. We did, though, despite that degree of confidence, because we had looked across three preclinical species, want to do this in humans. We did a PET receptor occupancy study. It was a multi-dose study where we dosed patients for 14 days, and we did see that at low single-digit nanogram per milliliter concentrations, you see nice concentrations that are in the therapeutic range.
Our target has always been 50%-70% receptor occupancy, and at the dose that we're taking forward in our two-way study, we exceed 80% receptor occupancy. We're extremely confident that we're achieving appropriate target engagement.
That PET study also confirmed that you were only seeing expression in human in the right place.
Yes.
Signs in the right place.
Exactly. Yeah. So the baseline scans where we use the tracer, which is in the same compound series as our molecule, very accurately and granularly looks at the distribution of the target in the brain, saw a nice expression in the cortex, enrichment in the mesial temporal lobes, and an absence of expression in the cerebellum and brainstem.
We were talking about this before, so I'll ask the same question you brought up. How do you know that you're not too targeted, right? How do you know that you're in all of the areas of the brain that you need to be?
Yeah, I think it's just from an understanding of where seizures originate and in understanding, in looking at the literature, the big body of literature around understanding the origin of focal seizures. It is really, there's a predominance of seizures originating in the mesial temporal lobes, where we have particularly robust expression, and most of the others originate in the cortex and often propagate through the mesial temporal lobes.
You're running now, as Troy said, a phase II trial with data coming in 3Q. Troy, this is one for you. Can you just talk? We think it's a really differentiated, novel, innovative trial design. Just strategically, what did this approach allow you to do? I know there's other stuff that scientifically and clinically we're going to learn, but just from a drug development strategy perspective, why was this trial design so appealing?
There'll be a couple of things, and Will is actually the architect of this, so I'll want him to weigh in on it as well. It came to us from the community, and the current methodology for doing proof of concept in epilepsy is really an induced model that tracks patients with a seizure diary or they're looking for electrographic signaling. What was happening is they weren't doing it necessarily in patients, and it takes an extended amount of time. Xenon, for example, did their phase II trial, took over two years. We're going to get in less than 12 months. We're going to get long-episode data, which long-episode is a predictor to electrographic seizures, and electrographic obviously has a tight correlation to ultimately clinical seizures, which is what the phase III endpoint would be, the pivotal.
It would just be this phase II for us, very efficient in a patient population. We're also going to be able to see a PK/PD relationship because these electrographic seizures, the long-episode, are being tracked. We're going to know what the dose was. We're going to know how the seizures responded, the long-episodes respond, day one, day two, hour 37. It's going to be tracked longitudinally. We're going to get a really good understanding of how this drug works in patients, which is not common with some of the other methods. We do believe that this is something others will end up doing. I said it was brought to us by the community. Abe talks about there's three constituencies for the data. One is the community. They brought this to us. They get it. Two would be potential strategics.
They absolutely get this as a drug development tool and the correlation. The third is Wall Street. Right now we're working on making sure that Wall Street appreciates this because it is unique, and it's not something that investors have been able to index against previously. We've done a lot of work tracking the patients. We're close partners with the device manufacturer. These patients, and we'll get into the details of this, it's using an RNS device. These patients have it implanted. It's an approved therapeutic, but it has this capability of tracking these long episodes, which is what we're going to correlate to a reduction ultimately, and there's literature around that.
Will, do you want to talk a little bit more about the trial design? Like you said, you're enrolling patients that already have this implanted, FDA-approved implanted device. The device is approved both for treatment but also for diagnostic. Just walk us through the trial design.
Yeah, absolutely. That was a great intro. I think, and just this came from the community because as physicians who manage patients with RNS started effective therapeutics, they noted movement in these biomarkers. It is from that experience and from collective data aggregating that experience gave us confidence in this paradigm. Yeah, the participants in the trial come in for evaluation and screening, and we're able to look back at how they've been doing based on their RNS data and look back eight weeks. They come in and start an eight-week prospective baseline period if they are eligible, and then dose for eight weeks and have follow-up and washout for eight weeks after that.
By establishing a 12-week baseline of biomarker data, we really feel as though we're establishing a very solid understanding of how these participants are doing and that if we see changes during the treatment period, they are clearly attributable to the drug.
You mentioned the biomarker is long episodes. Just at a relatively high level, what is a long episode?
Yeah, so the device is constantly monitoring for epileptic activity, and when that epileptic activity persists for a certain duration of time, it's determined to be a long episode. What's important in our study is that we've selected participants where more often than not those long episodes are electrographic seizures. We're trying to come as close as possible to a study of electrographic seizures and changes in electrographic seizures as a sign in early development that we have a highly active compound.
I think one of the points here is that this is an extremely clearly defined endpoint, right? There is no opportunity. We will compare and contrast to patient diaries where a patient may forget or not input data. This is something where, A, there is no patient input per se.
Yeah, it's truly objective. The device is counting these and timestamping events constantly for the entire duration of the study.
It also avoids any type of placebo response because you're not going to change electrographic by just the fact that you're participating in a trial. It makes it more efficient. It also makes it, we believe, more predictable. I think in the KOL community, they've suggested 70% of them think it's going to be more predictive than the models that they've used historically, and the other 30% said it's going to be at least as predictive. Nobody believes that the results we're going to get are going to be inferior to what they've worked with really for their entire careers.
Right. The obvious question that comes out of it is how validated it is. Can you just walk us through? There has been data published as recently as AES, there was a good amount of data. Just walk us through the data that establishes that impacting long episodes is going to have an impact on clinical seizures.
Yeah, that's a great question. I think it's our group and other groups, including NeuroPace themselves, the device maker, and a group at Yale, have really dug into the data from NeuroPace's post-approval study where they were tracking clinical seizure diary data and selected participants that had stable device settings for the appropriate chunk of time. During that period, looked at participants where new effective marketed drugs were added. They asked the question of when you see clinical benefit, what is the change in long episodes that best correlates with a 50% improvement in clinical seizures, which has so uniformly been used as the definition of clinical benefit in seizure diary data? The best correlated proportion is a 30% decrease in long episode frequency, really nicely correlates with a 50% decrease in clinical seizure frequency.
In terms of anticipating how we will look at the data and interpret it, we're really going to focus on looking for participants that did experience that 30% decrease in this electrographic objective biomarker and look at the proportion of patients that achieve that.
What would you view as a successful outcome? What kind of proportion of patients do you want to see meet that threshold?
The way we've benchmarked this is we want a high degree of confidence that we have a dataset that portends success in pivotal studies. When you look at the proportion of patients that receive that degree of clinical benefit in phase III, we have set a bar of approximately 40% or greater proportion of responders would be success.
I always try to make sure I put a point on this because there's 30s, there's 40s, there's 50s. 50 is the goal for the clinical seizure diary, the phase IIIs. That's what you'd be shooting for. The long episode, what good looks like to us, what we think success is, is again, I know you said this, but I always make sure because we've had some confusion. 30% reduction is considered a responder, and we're hoping to have 40% or more of the trial participants in that responder rate. That portends to, as you said, a successful pivotal trial, which will be done just like everyone else is doing them. It's not going to be anything unique. It's going to likely be a global. There's likely to be two of them running in staggered parallel, that kind of thing.
Yep. Okay. You're also looking at clinical seizure data, diary data in this study. Just tell us how we should interpret those data. You'll be able to, in some ways, validate your own correlation hopefully as well.
Yeah, exactly. I think that's right. We do care a lot about clinical seizure diary data. We understand that it is influenced by placebo. That's obviously been well documented. We do see that the power of our dataset will be in the combination of clinical seizure diary data and an objective electrographic biomarker.
You say speak to the power of the dataset. I think one thing that's important, but also important for investors to understand why you're so confident. You mentioned the Xenon study, Troy, and I know they looked at a couple of doses there, but that was a 250-patient study, essentially. This is a 20-patient study. Just reinforce to us why you're so confident that 20 patients is the right number to give us that predictive confidence in a phase III program.
I think first I'll let Will get into the powering assumptions coming, but it's really important to know we have at least 15 months of data back on these patients. They've been on the device for at least 15 months. We have access and have been working with NeuroPace across the entire data. There's over 6,500 patients on this device in the U.S. right now. We have a very large set of data in addition to the analysis that was done for the AES publication by us and others. 20 is the target. We actually think it's going to end up going over that number. That's the minimum available. That has to do with, as Will outlined, the trial design. There's a four-week period where we're doing the prospective analysis before the patient actually gets dosed. We want to make sure there's 20 available.
There's going to be patients that are in that four weeks. We're not just going to pull the rug out from under them. There's likely to end up more than 20, but we still expect the data again in Q3. I don't know if you want to talk about why 20.
Yeah, why 20? A few things. One was a series of powering calculations focused on responder proportion that we talked about, which is consistent with what we talked about in terms of setting a bar for success. The second was also just asking the most thoughtful people about how many patients they thought they would want to see to have a super high degree of confidence in the activity we observed. Independent and without having seen those power calculations, that is very, it's the number they came up with as well. I do think that speaks not just to looking at it across a group, which is what the statistical considerations were, but also the individual case studies and how confident, when you start an effective drug, how confident you can be in the changes you observe.
Just to tie it back into what Troy said about the pivotal study, as much as this is an innovative phase II trial and something you've been in dialogue with regulators, I'm sure you're not changing anything versus what we consider a typical phase III registration program. You also, and I know you get this question a lot, you're not looking at long episodes as an endpoint in the phase III.
Correct. Yes. We do believe, and I think we don't want to go down the discussion here, but I think the FDA does see this as a potential path as well. It's way too premature because we're on the cutting edge of it. There's a lot of reason, like I said, the community, the drug development world see this as highly predictive. That's why, 20, you have to think about these long episodes. Patients might be having 10, 20, or 100 of them, but you've got these activities. We had one of our KOLs think of it as a bunch of little sparks that sometimes they turn into a full-blown seizure, which, as he said, was the flame.
He said, you've got these little sparks, and if you can see very early and very quickly reductions in those, just you're going to have enough as opposed to a seizure diary where I can't remember in phase IIIs, but patients have to have somewhere between four. It takes so much longer and your numbers are so much. We're going to have multiple of these. These patients have to have at least eight seizures, and they're going to have more than that, we believe, when you look at the data that's been generated historically. We expect to have more data points, which allows you to plot a reduction.
Last quick point here. We've talked about this before. This is a defined patient population because they have the implanted device, but there's nothing different about this patient population than the population you'd enroll in phase III. I think it's fair to assume that they're likely a refractory population as well, just the kind of patient that would go and be willing to get the device implanted.
Yeah, that's exactly right. When we put the characteristics of the RNS patients next to the patients that participate in pivotal studies, recent pivotal studies, the characteristics, demographic characteristics, how many years they've had epilepsy, how many drugs they're on is very similar.
That did make me think of something. We should have talked a little bit about the patient, the focal epilepsy patient. There are about 1.8 million patients with focal epilepsy. About 40% of those are still experiencing seizures. It is a very large market opportunity here. That is why we think that there is certainly an opportunity for new drug entrance into the space with mechanistic rationale, kind of a precedent, and also a differentiated tolerability profile because of the lack of activity in the other regions of the brain. We think it is a very large opportunity for patients.
I mentioned at the beginning, we see there's a pipeline and a product potential here. You're initiating a phase II study in bipolar disorder as well. Just the rationale for bipolar and yeah.
Yeah, absolutely. I think in bipolar and pain, you have seen historically that anti-seizure medications can be really effective in those areas. We see tremendous unmet need in those areas. In terms of why this mechanism, that is one thing. I think why this mechanism in bipolar acute mania, there is very clearly defined hyperactivity in the limbic system. That is exactly where our drug and our target is most enriched. By dampening down that hyperactivity in the limbic system, we hope that we will appreciate a therapeutic benefit. I think the second thing is that when you look at carbamazepine and valproate among the anti-seizure medications, they are not pure or clean mechanisms for AMPA, but there are ways in which carbamazepine is modulating glutamate. Valproate does have a link to AMPA in the hippocampus in terms of its hypothesized mechanism in bipolar.
Fantastic. Will, Troy, really appreciate you being here. Obviously, a very important data point coming up in 3Q, so excited to watch.
Thank you. Thanks, everybody. Appreciate it.