Everyone, and thank you for coming to Cantor's Healthcare Conference. I am delighted to be joined today by the team from Rapport. I'm Imogen Mansfield. I'm one of the biotechnology analysts here, and I'm joined by Rapport's CEO, Abe Ceesay, and CFO, Troy Ignelzi. Thank you for joining us. To start us off, could you give us a quick overview of Rapport today, a snapshot of the pipeline and what's coming up?
Sure. Well, Imogen, thank you so much for having us. Rapport Therapeutics is a company that is focused on precision neuroscience. We believe that although precision is a loosely used term sometimes in our industry and in neuroscience, we actually can bring that to life. We believe that based on our scientific foundation, which is receptor-associated proteins. The best way to think about receptor-associated proteins is through the lens of our lead program, RAP-219. RAP-219 is a TARP gamma-8 AMPA modulator. TARP gamma-8 is the receptor-associated protein or a member of a family of receptor-associated proteins associated with the AMPA receptor. And what it allows is with a small molecule to have a level of specificity that really hasn't been seen historically in neuroscience. This is a program where we released really unprecedented phase II results in September of last year in focal onset seizures.
We see it as an opportunity for a pipeline and a product, and we're coming up on the release of our bipolar data in the fourth quarter of this year in October. We also have plans to further extend this program with the formulation of a long-acting injectable. In addition to that, we have a fully integrated discovery pipeline that we believe gives the company an opportunity to really have a self-sustaining and regenerative pipeline. And we really bring that scientific foundation of receptor-associated proteins all the way through to our discovery pipeline as well.
Great. We're going to start with bipolar mania and then talk about focal seizures and then the long-acting injectable. But before we get there, what do you think investors are not giving you enough credit for?
Yeah. I actually think if you look at it from a stock perspective, investors are looking at Rapport like a late phase II focal onset seizure, start of phase III focal onset seizure company. If you look at our comps, you look at the market potential. I would say they're cautiously evaluating the potential in bipolar mania, which is, I think, where they should be looking at it. I don't think we have any really credit yet for the long-acting injectable, which according to our market research, could double the size of the opportunity in FOS as we move that forward. I think they're appropriately focused on the potential with the bipolar mania, but really grounding in the FOS.
So let's start with bipolar mania. This is a very large and very underserved market. Can you talk us through the biologic and mechanistic rationale for RAP-219 in this indication?
Sure. Admittedly, a neuropsych indication has less translatability preclinical to clinical, as, say, a neurology indication such as focal onset seizures. We knew that as we developed a strategy for our lead program and went into bipolar mania. There's also some real reasons to believe in this approach in bipolar mania. First is what we understand about the disease, and it is pretty well documented that one of the drivers in bipolar mania is excessive glutamate. What we know about RAP-219 is we are having an impact on glutamate through the modulation of the AMPA receptor via TARP gamma-8. The second is where that excessive glutamate is occurring kind of neuroanatomically, and what we understand and what the literature would say is that that is happening in the corticolimbic network. That exactly overlaps with the expression of TARP gamma-8 as well.
Then the third aspect is clinical precedence, and what we know is the anti-seizure medications that are used in this space, as well as another mainstay of therapy, which is lithium. Although those are somewhat dirty drugs that are having impacts across many different pathways, one of the common pathways is their impact indirectly or directly on glutamate, as well as AMPA receptors. So that was kind of the pieces of information we pulled together to really say, "You know what? This is worth the investment and the experiment for a bipolar mania trial."
We obviously took a lot of insight from what we gained in our focal onset seizure trial in terms of receptor occupancy, target engagement, and that has definitely increased our belief that at least going into this trial, we know that we have a dose that gets to therapeutic concentrations, that it's associated with the right receptor occupancy. At the end of the day, with all neuropsych trials, it comes down to how well can you execute these trials in a quality manner.
Therapies in this indication fall into sort of three broad categories of those addressing the acute mania, maintenance therapies targeted at the depressive symptoms. You're first going into the acute mania setting. Do you see a future going into maintenance?
Yep. So you're right. There's really three labeled indications in bipolar disease. First is acute mania, second is maintenance, and then third is depression. The reason we went into mania is, one, we believe that based on the structure that I walked through in the previous question, that this was the right indication to step into first. The reality in clinical practice, although maintenance is a labeled indication, in clinical practice, if a drug is effective as well as tolerated in a manic episode, clinical practice would tell you that patients should stay on that therapy. So although maintenance is a labeled indication, we don't necessarily believe that it needs to be a labeled indication to drive utilization and maintenance. With that said, we will assess maintenance based on if we had positive data in bipolar mania. Bipolar depression is another area that based on the data, we will assess.
Very different pole than mania, and also different considerations as you think about enrolling and executing those trials, but that's something that we will investigate. Mania on its own is a multibillion-dollar market opportunity. So we believe with positive data in mania as well as positive registrational studies and thinking forward to potential market opportunity there, that is an opportunity that somewhat matches the market opportunity that we see in focal onset seizures. Multibillion-dollar market opportunity.
And you mentioned enrollment, so could you tell us a bit more about the types of patients that you've enrolled and if you're enriching for any specific features like psychotic features or other—
Yep.
—aspects?
Yeah. So when you look at enrolling these trials, one of the things that you really want to do is you want to ensure that you are giving the drug the best chance of success. You are also trying to limit heterogeneity in the patient population, and then also that you are trying to enroll patients that aren't going to have self-resolution in their manic episode, and that pharmacologically, they really need a treatment to be able to have some improvement. So with all of that said, what that really drives you to is you want to ensure that you are truly enrolling an acutely manic patient. So some patients would have psychotic features, but one of the things that we are not looking to do is have a population with large mixed features, meaning both depression as well as mania, because we're really focused on that acutely manic patient.
And are the patients able to have been on another therapy for the current episode, or would this be the first therapy, and would it be an add-on or—
Yep.
Only the—
Yeah. So there's really two aspects to that question. The first is their history, and then the second is the actual protocol. In terms of their history, similar to the previous question, to ensure that you are enrolling patients that, one, are defined as truly acutely manic. What you don't want to do is enroll patients with their first manic episode. That could be driven by a whole host of things, recreational drug use, environmental factors, et cetera. So patients that are enrolled in our study, it is not their first manic episode. And then the second, in terms of their background medication, this is an inpatient monotherapy study. So all patients are washed out of any of their existing medications and background medications, and then enrolled into the study in a blinded fashion.
I will add that that's standard for phase IIs for bipolar mania. There's nothing unique about how we're conducting that.
Yep.
Yeah. Okay. Could you just tell us a little bit about the powering and the efficacy that you want to see to progress with the program?
Yeah. When you look at programs, really the clinically meaningful threshold is about a four-point placebo-adjusted difference in the YMRS, which is the primary endpoint in this study. We have powered the study to detect that four-point placebo-adjusted difference. We have discussed this, and we did make an adaptation to our protocol, where we decreased the alpha from 0.1 to 0.05, and modestly increased the sample size. The reason for doing that is based on what we are seeing in enrollment trends and the overall quality of the study. By decreasing the alpha as well as increasing the sample size just slightly, that puts us in a position that with positive data, this could meet the merits of confirmatory evidence on a go-forward basis as we think about potential registration.
That this study could be registrational?
This study could be registrational.
Okay.
Now, with that said, we always like to remind people that you're never going to know that until you submit the NDA.
Yeah.
But as you think about traditional approaches in neuropsychiatric indications, the mantra is do three studies to get two. So if you think about this development strategy and cadence, if this study were successful, we believe we have built in the right things to give it the best chance to be confirmatory evidence. And what we would do is do two additional—
Okay.
—phase III studies.
Yeah.
With, again, that strategy of do three studies for two positive.
Okay. And they would be a similar size?
They would be probably a bit larger, as you would just think about powering those studies. But in terms of design, that's one of the benefits as you think about bipolar mania. There's actually pretty high translatability from well-powered phase II studies to phase III studies. So the study design protocols overall would be pretty similar. Dosing arms may change a bit into phase III based on what we learn into phase II, but the overall study design would be very consistent.
And one more on bipolar, then we will move on to seizures. But for perampanel, which is also targeting the AMPA receptor, there's a box warning for psychiatric AEs of aggression and rage. Have you seen any signals or flags from blinded safety reviews of the bipolar study?
Yeah. So it's important to clarify a couple things. The first is the mechanistic differentiation between FYCOMPA and RAP-219. These are not the same compounds. These are also not the same mechanism. FYCOMPA, perampanel binds at the AMPA receptor, the allosteric site of the AMPA receptor. It is truly a sledgehammer, shutting down synaptic transmission via glutamate indiscriminately throughout the brain. RAP-219 is binding to the allosteric site of TARP gamma-8 and only interacting with AMPA receptors containing TARP gamma-8. So any other AMPA receptors that don't contain TARP gamma-8, RAP-219 is not binding to. The second important point of clarification is what the black box warning is for FYCOMPA, and that is for homicidal ideation. We have not seen homicidal ideation with treatment with RAP-219.
In terms of behavioral AEs and neuropsychiatric AEs, every anti-seizure medication will have some level of behavioral or neuropsychiatric AEs in their trial. Not only will you see it in the treatment arm, you'll actually see it in the placebo arm as well. So, we will see what we see in the bipolar mania data. What we can say is we had no AEs of special interest going into the study. We have a data safety monitoring committee that has been monitoring the study as it's been executed, and there have been no changes to how the study has been operating, and it's been straightforward.
Okay. Let's move on to focal seizures. We saw impressive efficacy on seizure reduction and on long episode reduction for patients who had the NeuroPace RNS device implanted. What are your key takeaways, and what gets you most excited about what we've seen so far in focal seizures?
Yeah. We are very excited about, one, the data we produced in the phase II study, but also the path forward in phase III, for a few reasons. The first is the trial design. This is a trial design that the epilepsy community has been wanting to do for years. The fact that we have produced data that has a highly objective biomarker in long episodes, which in our study, long episodes were electrographic seizures, to be able to corroborate every change that you see in clinical seizures. It is a very powerful set of data. The second is how robust the results were. We saw roughly a 77.8% reduction in clinical seizures. What we also saw was a 24% seizure freedom rate.
That 24% seizure freedom rate was a very conservative measurement of seizure freedom, truly from day one to day 56. What we know historically is that seizure freedom is really not impacted by placebo rates. It is in the 1%-3%. When we look at the objective biomarker, the overall reduction in seizure frequency, and then we also see the seizure freedom rate, we feel that, one, we have produced data that really starts to present RAP-219 as a potential best-in-class therapy. One also based on that line of evidence translates very well into a phase III study. In addition to that, we have produced more data around the half-life of the drug and the impact that that half-life may have in terms of additional efficacy or durable efficacy, I should say.
From a tolerability standpoint, we saw really highly differentiated tolerability and tolerability that we believe is consistent with the biology, meaning targeting AMPA receptors only in forebrain structures, not interacting with receptors in hindbrain structures. That really gets away from the most bothersome and burdensome AEs that are associated with traditional anti-seizure meds.
We've got some more data coming from the open label extension of the phase II. Can you tell us about how many patients have entered the OLE and what we could expect to see in that update?
Yeah. What we can say is the vast majority of patients have entered the open label extension study. That is ongoing. It's important to remember that this was not your traditional open label extension, meaning that patients rolled over directly from our phase II proof of concept into an open label extension. They were first washed off of treatment for eight weeks, then actually had a time in between that as well as rolling into the open label extension. These patients, although they were in our phase II study, they're somewhat new patients to us and to this open label extension study, just given the fact that a lot could have changed in their lives. With that said, we anticipate that in the fourth quarter when we do our initial data cut, that we'll have anywhere from four to six months of exposure.
We think that that is going to be very meaningful from a safety perspective.
That will be four to six months in a continuous stretch?
In a continuous stretch.
Okay, great. On the phase III, can you tell us a little bit more about the status there, how site activation is going, and if you can share any sort of estimates of how long you expect the studies to take?
Yeah. Both of those studies are off in earnest. We're really encouraged with what we're seeing in terms of engagement at the site level. We have now had interactions with the U.S. FDA, the Chinese FDA, EMA, as well as PMDA, which is the Japanese regulatory authority. All of those interactions has been very positive. As an example, we announced recently that our partner, Tenacia, who is our partner in China, has a green light on the Chinese IND, which will now allow us to include China in our global program. We haven't guided yet on timing for these studies in terms of overall enrollment. We think sometime next year we'll be in a position to do that.
We just want to get our feet underneath us a little bit, allow these other countries to come online, and that will give us a much better insight into overall enrollment projections. With that said, maybe Troy could comment on where our cash runway takes us, and we're really confident that we're going to be able to enroll these studies in time.
Yeah. We reported a little over $430 million in cash as of the end of Q2, and we reconfirmed the guidance that that takes us into the second half of 2029. Not explicitly stating, but we have said that it's sufficient to get us through our projections for the phase III timeline.
Great.
We also have a couple of bookends to look at with other companies. As fast as 18 months and as much as 38- 40 months, and we don't see any reason it will be on either end of those spectrum.
Okay.
The goal is to be efficient, but also be diligent on the patient enrollment.
You mentioned the Tenacia partnership, so that gives you access to patients in China as well. Can you tell us about if there's a cap on how many patients you will be enrolling from China or just any other regulatory considerations there with?
Yeah. First, this was a strategy that we had thinking about phase III enrollment. I have some history through our program at Cerevel. There has been a lot of other precedent programs, and you really have to think about where do you access these patients for enrollment. China was always a country that for various reasons was not able to be accessed. We are really excited about this collaboration. We think it is a true win-win collaboration ultimately for both organizations to actually see the development program through the same lens and have the same view of quality going into the study, given the fact that our global development program will feed the U.S. FDA registration package, but that same package will feed the Chinese FDA registration package. We did not cap, at this point, a priori, the percent of patients that would come from China.
What we can say is we are mindful of making sure, as with any development program, that the actual regional makeup of the study population is going to be supportive for FDA first. We, as well as our partner, Tenacia, see the world the same way in that regard.
Any impact that you are expecting on the baseline number of ASMs that patients are on with Chinese patients given the number of different available options?
No, not in our—
Okay.
—diligence. We don't see a significant difference there. Now, we will say that in our phase II study, 70% of the patients in our phase II study were on three to four medications in addition to the device.
Yep.
You can really think about that as four to five therapies.
We do not believe in our phase III study that patients will be that severe from a pharmacologic standpoint.
Yep.
That percentage is more in the two to three meds versus three to four meds.
And as we think about all the different background ASMs that these patients are on the safety side for the gait ataxia, dizziness, adverse events, what gives you confidence that you are not seeing those when patients are on a cocktail of other medicines?
Sure. The first is, one, we really believe in the target and the biology. The second piece is the preclinical evidence is very clear here. There is the gold standard model for focal onset seizures. Preclinical model is a corneal kindling model. There is an efficacy assay that is actually preventing seizures, and then there is a safety assay as part of that, which measures things such as sedation, somnolence, as well as gait impairment. And what we know about RAP-219, as well as other programs with the same mechanism, is that the therapeutic index is really unprecedented. So at highest doses, you are not seeing impacts on that safety assay, which is called the rotarod.
Then we play that forward, and we see what we see in our phase II study. Now, our phase II study, even in the worst interpretation, which is still a good interpretation, that you have to apply all AEs to the drug because there was no placebo arm, we still saw significantly lower levels of dizziness, gait impairment, et cetera. So we did not see the AE profile that is traditionally seen with anti-seizure medications. And again, that is being really conservative and putting all AEs on RAP-219 and not their other background medications. And as you said, they are on three to four background medications.
Yeah. I guess this gets us to the long-acting injectable, and it's very exciting that you're developing this. Tell us, why has no one else been able to pursue an ASM and—
Yeah.
—long-acting injectable?
We're very excited about the long-acting injectable. It was part of our strategy when we started the company and when we really understood the characteristics of RAP-219. RAP-219 has some inherent characteristics that are very unique as you think about anti-seizure medications. One, it has low solubility. Two, it's a very potent drug. What does that mean as you think about a long-acting injectable? That means that there's very low drug levels, and it already has, in the oral formulation, has an inherently long half-life, 22 days. When you package all of that up, as well as having no drug-drug interactions, you package all of that up, that makes a compound actually amenable to a long-acting injectable. When you look at other anti-seizure medications, they really do not have those characteristics. Many are not that potent, so you would have very large drug levels.
Many require titration schemas as well as have drug-drug interactions. You really just cannot formulate those into a LAI that could be practically used. We always believed in this, but we just received market research, and we now really understand that this would be transformational. Has the opportunity to double the market opportunity in epilepsy, but also would have the opportunity to apply to bipolar as well. We're currently in IND-enabling studies, and we expect that we'll be able to move into the clinic and produce our first human PK data in 2027, which, in terms of LAI drug development, that human PK data and really proof of formulation is the major de-risking step in LAI development.
And keep in mind, the utility of the long-acting injectable goes beyond just the patient component to it. It is creating this durability of revenue. So it extends the patent life. Historically, these were used as lifecycle management tools. In our case, we think the timing of it is such that we can make it more available to patients. But it takes a loss of exclusivity from the 2041 timeframe all the way to 2046, 2047.
And tell us about the development path there. Would you be able to show bioequivalence with the oral formulation, given that it has such a long half-life, or would that be an additional phase III study you would have to run?
Yeah, I think it is a little too early because we have not had the discussion with the FDA. There are two paths. One is to go and do a full efficacy study, and then the second is, as you mentioned, doing a bioequivalent study. Our baseline thinking is that we would do an efficacy study. That is all dependent on our conversations with the FDA after we have proof of formulation in our first human PK study and how we really build this into the overall development strategy for RAP-219 and FOS. The good thing is we have a lot of time.
Yeah.
We have a lot of time. We do not even think about this as part of the initial NDA package. This would be an SNDA. But the most important thing is we wanted to really confirm for ourselves, as well as investors, as well as the epilepsy community, that we can get this formulation right, and then we will take it from there.
Great. Well, that's all we have time for today, but thank you so much for joining me, Abe and Troy, and looking forward to seeing all of your updates.
Thank you.
Thanks for having us.