Rapport Therapeutics Stifel 2026 Healthcare Conference

Phase 3 studies, FOCUS-1 and FOCUS-2, both have roughly about 320 patients that are looked to be enrolled in each study. As you know, Paul, these— all of the FOS Phase 3 programs are global in nature. And to your point, they do take a while to enroll, just based on kind of the stringent approach one takes to really screening baseline characteristics, et cetera. For us, we believe there's a few reasons why we can execute these trials in a quality manner as well as do it efficiently. The first and foremost is quality. We believe we have brought kind of the best kind of thinking forward, partnering with groups such as the Epilepsy Study Consortium to really understand that patients are screened appropriately, patients are trained the right way in terms of how they count seizures. And then from a timing perspective, we've done a couple of things. One is we partnered with a company in China to open up China as a country to enroll. Historically, China has not been accessed in Phase 3 programs. Company is a company by the name of Tenacia, which is 100% neuroscience-focused in China. The other aspect is really the qualities of the asset as well are super important as you think about enrollment.

As it relates to RAP219, this is a drug that doesn't have drug-drug interactions. We're not competing with any other mechanisms outside of any overlapping AMPA modulators, but that's not a really big issue for us as we think about enrollment. So the whole point here is the top of the funnel is much wider than other programs. We're not guiding on delivery of data yet, but we think probably middle of next year we'll be in a position to guide. Okay, that's great. I mean, the Phase 1 Phase 1B data is, I mean, it's unquestionable, the effect size and the cooperation with the long episodes.

I think the only question we think about when we sort of extrapolate to the Phase 3 is how similar is that Phase 3 population? Is it more heterogeneous? Could that cost some efficacy? What's your perspective overall there? Yeah, so I think there's no doubt that the population in Phase 3 will be more heterogeneous.

I mean, that's just the nature of going to a broader population. The heterogeneity, I think, is more defined by the fact that this patient population will not have, or the majority of patients will not have, it'll be probably, if any, a small number of patients would have the RNS device.

So you don't have the corroboration in a Phase 3 trial of the electrographic seizure or long episode biomarker. But one of the things that we look at in the Phase 2 data is a few things. One is this patient was highly refractory. patient in our Phase 2 study. The majority of patients were on 3 or 4 to 5 medications, including— and I'm including the RNS device in that— Their baseline seizure count was around 10, which is very similar to Phase 3 trials. And when you look at the overall profile of these patients, if anything, we think the Phase 3 patient population won't be as refractory.

So we think that there's a really high likelihood that the results that we saw in Phase 2 will translate very well into Phase 3. Yep. Okay, great. And then on the safety side, do you want to just at this point now talk about the totality of the data you have, not just in epilepsy, but also in bipolar disorder?

Sure. So we have roughly 250 subjects now that have been exposed to RAP219. That is across all of our programs, both epilepsy, as you said, Paul, as well as bipolar. We believe, and we have always felt, that we have a really good understanding of the safety of RAP219, the tolerability profile of RAP219 as well. The drug, one, is consistent with the target biology. So by avoiding hindbrain structures, we're not seeing the most bothersome and burdensome AEs that are associated with anti-seizure medications, but also associated with atypical antipsychotics, as you think about bipolar mania. So we're not seeing sedation, we're not seeing somnolence. We're also not seeing any of the AEs that are associated with the dopaminergic pathways, such as metabolic changes, akathisia, extrapyramidal symptoms. So that's very compelling and differentiating. In terms of what people think about, given the somewhat similar approach in terms of AMPA modulation. We're doing it very differently by targeting a receptor-associated protein. But what's in people's minds is, the Fycompa experience, and will this drug induce any behavioral type of AEs? And what we've been really encouraged by is we have not seen those types of behavioral AEs. And those behavioral AEs are hostility, as well as homicidal ideation, which are very different from, say, agitation or anxiety.

And importantly, when you look at our bipolar data, the most improvement that we saw in the drug was actually on those domains, was on hostility, as well as irritability. Patients improved on treatment as compared to placebo in a significant manner. Yep, yep, yep. Okay, makes sense. Certainly the bipolar data, I think, is helping, like, you know, assuage that, that risk there.

Do we understand, like, are you guys— has anyone furthered the understanding of like Fycompa and like why it has that problem? You know, the whole regional selectivity thesis on RAP209, we always found super appealing. But then it's always hard in neurology to really like point to a brain area and say this is causing that. It is. Outside of we know what is really driven by engagement in the hindbrain because You see that across the board for anti-seizure medications, you know, if you're interacting with receptors in the hindbrain that are causing kind of sedation, somnolence, as well as gait impairment.

The behavioral aspect, it's really not well understood, but what's really important here is, you know, if you look at the rates of these behavioral rage type of AEs, with Fycompa, it's extremely low.

We're talking about like 2%. Sometimes if you look at the data, it could even be 1%. The drug that is the most widely used anti-seizure medication has the highest rates of aggression. Levetiracetam. Levetiracetam. Yeah. It has the highest rates of aggression as well as what is called Keppra rage. So maybe help people understand then, like, why Fycompa is a commercial flop, if not that. Yeah. Fycompa is not Actually, the commercial viability of Fycompa has not really been impacted by this concern of behavioral AEs. The dose-limiting toxicity for Fycompa is really sedation, as well as gait impairment. Patients cannot tolerate effective doses. They are completely snowed by the drug. It puts them to sleep, and they have significant gait impairment. And that has been the issue and the reason why clinicians as well as patients— patients can't tolerate it, and that's the reason why clinicians have not used the drug. If you were to talk to clinicians, they would tell you that they never have seen the rage associated with Fycompa.

Interesting. Okay. On the bipolar side, I mean, again, I thought the, the PSYCH-AE data, like the subcomponent domain, I mean, all that was like super encouraging.

I think the one data point some investors fixated on was dropout rates and difference between drug and placebo and how to make sense of that being discordant from the AE data. What would you say to that? Sure. So there was an imbalance in discontinuations between the treatment group as well as the placebo group.

Interesting, when you look at the overall discontinuation rate in kind of that low 20-ish percent, That is really consistent with all other previous trials. The real difference here was that the placebo rate was a bit lower, I think in roughly the 11-ish percent range, was lower than historic trials. The main reason for discontinuation was withdrawal of consent. It was not AEs, though the discontinuation rate to AEs was pretty low and low compared to other trials. Withdrawal of consent is an interesting one. It was, you know, to family reasons or patients ultimately just wanted to leave the unit. And this is an inpatient study. And ultimately were no longer a part of the study. We have analyzed that data. And we think we have a good understanding of the data. On a high level, what we saw in the placebo group is those patients that discontinued were either at where they were at baseline or worsening, and the patients in the treatment group were either at baseline or actually improving.