To day one of the London Healthcare conference. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies, and it's my pleasure to have the Rapport team with me today. To my direct right is Abe Ceesay, CEO. To his right is Troy Ignelzi, CFO, and to Troy's right is Jeff Sevigny, CMO. Welcome, team.
Thanks, Andrew.
Maybe spend a couple of minutes for those who are less familiar with the Rapport story talking about what you're trying to achieve, what you're working on, what milestones we can look forward to over the next, say, one or two years.
Sure. Good morning, everybody, and Andrew, thank you so much for the invitation to the meeting and this opportunity. Rapport, we're a company focused on precision neuroscience. We know that precision is somewhat of a loosely used term in our industry, but we do believe our technology platform can really bring precision to life in neuroscience. That platform is receptor-associated proteins. The best way to think about receptor-associated proteins is through our lead program, RAP-219. RAP-219 is a TARPγ8 AMPA modulator program. The receptor-associated protein piece of that is TARPγ8. What RAP-219 is able to do is modulate AMPA receptors in a very precise manner, specifically in four brain regions, that being the mesial temporal lobe as well as the neocortex.
What that is translated to is really an unprecedented profile for an anti-seizure medication and ultimately a compound that we see a product in a pipeline opportunity for. We have just released recently in September our phase II proof of concept results that really showed a best-in-class profile in focal onset seizures, both in terms of efficacy as well as tolerability. Based on those results, we're well on our path to initiate our registrational studies. We will be meeting with the FDA here in the fourth quarter around our end of phase II meeting, and that will put us on a path for initiating our pivotal studies in 2026. In addition to our focal onset program, we're also evaluating this compound in bipolar mania. That study is ongoing. We're excited about the enrollment, and we expect that data in 2027.
We have a couple of other milestones over the course of next year where we'll be able to further elucidate our data from our phase II proof of concept study in epilepsy, both sharing our full trial results, both the treatment period as well as the follow-up period, as well as data from our open label extension study that was following this phase II study.
Okay. Congratulations on the robust dataset that you've generated. You mentioned the word unprecedented just now. Maybe talk us through what you mean by that in terms of efficacy and safety in terms of what you're seeing.
Sure. I'll open it, and then I'll turn it over to Jeff. When we say unprecedented, I think there's a few ways to think about what we observed with RAP-219. First was efficacy. We saw a robust response in clinical seizure reduction. We also in this study leveraged a novel biomarker, which is equivalent to an electrographic seizure called a long episode, that really corroborated that data in a very meaningful way. The other aspect is what we're able to do is really validate this precision mechanism. In addition to the efficacy, we saw a highly competitive tolerability profile, one that did not have the traditional AEs that are most burdensome to patients, those such as sedation, somnolence, as well as motor impairment and ataxia. I can turn it over to Jeff to provide some specifics on the results.
Yeah, thanks. You know, there are two things to look at. On the efficacy, first was the overall seizure reduction in this study, over 70%. There was over a 70% reduction over the eight-week period. The second bit was the responder, it was the results in the responder analysis. I'd point out perhaps the most relevant one for patients, and that is seizure freedom. Over the eight-week period, that's the entire treatment period, 24%, nearly one in four patients had complete seizure freedom, which I also think is an unprecedented result. In terms of safety and tolerability, I think Abe hit the highlights. RAP-219 was safe and well tolerated. Overall, adverse events did occur. They were mild or moderate. There were no severe or serious adverse events. That was on top of background ASMs.
Nearly 70% of patients in this study were on three or four background ASMs in addition to the device, the RNS device. I think that's a great result in the context of the population that was enrolled.
Very good. When we think about top-selling epilepsy drugs, there's strong efficacy, ideally clean safety, but there's also the tolerability or just ease of use, actually. Maybe talk about the eventual profile of what you think RAP-219 can achieve.
Yeah, it's a great question, Andrew. Quite frankly, that's probably one of the biggest shifts that we've had post this data is thinking about how this really evolves the market opportunity for a program like RAP-219. As you think about the market opportunity here, really the first way to frame the market opportunity is there's 1.8 million patients in the United States that live with focal onset seizures. 30%-40% of them are treatment resistant. What that means is that these patients have been on multiple anti-seizure medications or currently treated, but they're having breakthrough seizures. That in itself at a branded price is a $10 billion-$15 billion market. This is a very large market. The other dynamic is that all patients are really managed via polypharmacy, so are on multiple medications.
To frame the market opportunity specifically for RAP-219, the first thing that physicians are looking for is a novel mechanism of action. In the world of polypharmacy, they want to be able to add a novel MOA to provide additive efficacy to the current anti-seizure medication treatment regimen. In addition to that, they want a medication that is going to provide that additive efficacy, but be better tolerated than current medication. If your medication is providing efficacy, but it is also coming with the current AEs such as sedation as well as motor impairment, those are things that physicians and patients are not that keen in terms of just adding another medication that is driving those same types of AEs. The third element is the dosing and administration profile. As you think about the world of polypharmacy, one of the most important aspects is drug-drug interactions.
The ability to add a medication without having to adjust other medications that can be really bothersome for the patient can risk patients missing doses and have breakthrough seizures. The other aspects that come with RAP-219 are simple once-daily dosing as well as a very long half-life, 18+ days. Based on that half-life, it may be able to protect patients from breakthrough seizures if they're able to miss a medication. You put all of that together, and really what our work has shown us is that translates into a multi-billion dollar opportunity.
Really the way that you get there is that this is a drug that through our market research is confirmed that it will be used by not only the epileptologists, but also the general neurologists, both in third line, second line, as well as interest in using the drug first line given its overall profile. We are really excited about that. That, as I said, has been supported by some recent market research. The last aspect that we are working on, which we believe would be transformational for patients, is a long-acting injectable. Currently, there are no long-acting injectables available for epilepsy patients. That is not based on the lack of need. That is based on the limitations of current anti-seizure medications.
If you have a medication that has a large dose, if you have a medication that has drug-drug interactions or a medication that has to be dosed more than once a day, that just does not make an anti-seizure medication amenable to a long-acting injectable. For us, we have an extremely potent drug. We're talking about therapeutic doses anywhere from 0.25 mg up to 1.25 mg, a drug with a built-in long half-life, no DDIs. We've made great strides in our feasibility work and are well on our way to developing a long-acting injectable. In addition to that base market opportunity, we think that the long-acting injectable, as I said, would be transformational, but also would be significant in terms of market opportunity.
Very clear. Now you have the phase II data on hand. There typically is an AES, the AES conference in December. What can we expect you to share at that conference?
Yeah, so we aren't providing the details on our presentations just because we want to make sure that that doesn't get in the way of acceptance at AES. We are really interrogating this phase II data. The dataset is extremely rich given the fact that we leveraged this novel biomarker. You can expect some pretty interesting and insightful analyses that we think will be really additive to the understanding of our compound, but also the efficacy and tolerability that was seen in the phase II study.
Okay, very good. Now you're meeting with the FDA in Q4. When can we expect to hear back after the meeting? What exactly will you be asking the FDA?
Yeah, I can talk about guidance in terms of when we hear back from the FDA, and then I'll have Jeff walk through kind of our approach to the end of phase II meeting. So we had guided to having that end of phase II meeting in the fourth quarter. As we know, there's only about five weeks left in the fourth quarter. So we can say we are on track and we are scheduled to have that meeting with the FDA. We'll be in a position early next year to talk a little bit about our exact path forward initiation of our phase III studies. We've guided that we will start those by the third quarter of next year, but we'll do everything we can to accelerate those. I'll turn it over to Jeff to talk specifically about our approach at end of phase II.
Yeah, so we feel very confident we're well positioned to start our phase III studies, that we are fully enabled. We've completed the necessary phase II study. We've completed the necessary toxicology and CMC studies. Much of this end of phase II meeting will be to ensure that we are aligned with what an NDA submission would need to look like. It's really in anticipation for the NDA. Of course, the FDA may have questions or comments about the phase III study design, but that's not really what the end of phase II meeting is about. It's really about preparing for the NDA.
I see. Can you give us a teaser what kind of phase III design then you want to pursue? Is it the typical phase III traditional design? Maybe walk us through how many patients, how many drug arms, duration of treatment, so forth.
Yeah, so we haven't disclosed the exact phase III design, but what I can say, it will be fairly standard, not as innovative as the phase II design. I think if you look for precedents, you could look at ongoing or recently completed phase III study designs. The endpoint, of course, will be the same endpoint. It'll be seizure reduction or a responder analysis, depending if it's U.S. or ex-U.S. The population will be very similar to what's typically enrolled in the phase III. In fact, quite similar to what we enrolled in phase II, except they won't be required to have this RNS device. We'll be exploring a few doses, but we haven't disclosed what those doses are yet.
Okay, multiple doses, however. Okay. And then this phase II was technically an open label trial. Phase III obviously has to be placebo-controlled. How are you expecting the absolute seizure reduction to change, if at all, from phase II to phase III?
Yeah, so I feel very confident the results from the phase II will translate faithfully into phase III. There are a few reasons for that. Let's start off with the phase II results. Again, the effect on seizure reduction really is unprecedented. It was open label. Of course, it wasn't placebo-controlled, so one can naturally criticize the study and say, maybe there's a placebo effect. The study was designed around this RNS device and this outcome measure called long episodes. A long episode is the equivalent of electrographic seizure. It's an objective measure that's detected by this device. It's not influenced by the patient. It's not influenced by the physician or the investigator. The results of what we had predicted would be came to fruition.
We had predicted there would be a certain degree of decrease in long episodes, and this would translate into a lowering in clinical seizures. That prediction came to fruition both in the phase II with respect to long episode reduction and clinical seizure reduction. Based on these two pieces, the long episodes corroborating the clinical results, we feel that the results will faithfully translate. In terms of the patient population, the phase II population was quite representative of what's typically enrolled in phase III. The only real difference is that the phase II population had this RNS device. Apart from that, when you look at the other characteristics, it's quite similar. For example, the amount of seizure activity at baseline was similar to what's seen in phase III.
In the phase II, we had these patients had 10 seizures per 28 days, right in the middle of what you would expect in a phase III study for baseline. The other, I'd say, small difference would be that the patients in the phase II study were heavily treated. 70%, as I mentioned before, were on three or four background ASMs. In addition to this, of course, they had the RNS device. They're on four or five treatments. They're highly resistant, and these are the most difficult patients to treat. Overall, I think these results will faithfully translate into phase III.
Makes sense. Base case, start the phase III, two of them in Q3. Can you give us a bookend of how long it would take to enroll however many patients you need to enroll?
Yeah, so as you know, Andrew, there's really kind of two ends of the spectrum here. One end of the spectrum is taking a pretty significant length of time, call it 2.5+ years, and then another end of the spectrum where sponsors are at least guiding to enrolling those trials in 12-18 months. Our feeling is that we don't want to be on either end of the spectrum, and we don't believe we will be on either end of the spectrum. We think that 12-18 months, based on all of our work and our team's work, who have a lot of experience in this space, one really has to consider quality of enrollment. And then on the outer end, there's a lot of dynamics that we think really drove the length of that type of enrollment.
When you think about the competitive nature of starting trials, when we believe we're going to start trials, we think a lot of the competition in terms of enrollment should be washed out of the marketplace. It is the overall profile of the drug as well. We believe we have a very exciting profile, one that investigators are really excited about as well. We're not in the position yet where we're going to guide, but as I said, we don't believe we're going to be on either ends of those spectrums. Once we kind of get into next year, get these studies off the ground, we'll be in a better position to guide on length.
Yep. Within the phase II, eight weeks, there's also another eight week of follow-up where patients are washed out of the drug. I think you'll be sharing that dataset in first half 2026. What exactly do you want to see with that data cut? Do you want to see sustained efficacy? Is that needed? If you do see sustained efficacy, what does that mean exactly for your phase III and real-world use case?
Yeah, I'll share my views, and then I'll ask Jeff and Troy to share theirs as well. I think there's a couple of important aspects here. One is the power of the patients we enrolled in the design of the study. Jeff mentioned that these patients have continuous EEG recording through their RNS device. As I mentioned, this drug has a very long half-life. One of the benefits that we could derive from that eight-week follow-up period is having that continuous EEG recording, given the half-life of the drug, to understand basically when EEG recordings start to come back.
That will give us a really good perspective on kind of that PK to PD relationship that we think is going to be really insightful and also really differentiating with the drug because we know drugs with shorter half-lives, the risk of rebound seizures, truly the day, if you miss a medication that day is there. We think that that could be really informative. I do not know, Jeff, if you have anything.
Yeah, I think it's a durability of effect. I think one of the theses of this program is a patient could miss a day or several days and still have therapeutic benefit. I think we would predict that that will bear out in the washout period where patients will go, we'll see, but they could go several days or weeks and still have a reduction in seizures and long episodes.
Very good. You will have another data cut, actually, second half, I believe, for the open label phase, patients who've transitioned from the phase II blinded portion. How many patients' worth of data do you think you'll share in second half? Would it be fair to assume it's one year of additional follow-up?
Yeah, so there is an open label portion to this study that's just being operationalized now. The reason why it wasn't contiguous is because we didn't have the tox coverage at the time of the start of the phase II study. Now we do. It's all in place. Patients are just starting now, sites are just getting the protocol approved, and patients are just starting to enroll into it. We don't know what the actual number will be, whether it will be the full 30 or less. It'll probably be fewer than 30. We would predict that the majority of them will enroll anytime in Q4 to Q1 of next year. It really depends on how quickly the sites can get the protocol approved.
Okay, so maybe at least six months of data.
Correct.
Okay. You spoke about the LAI program. You're starting that program up too. Is it 2026? Maybe talk us through what the phase I design would be, what you're trying to achieve. Would it be in actual patients or healthy volunteers?
Yeah, so we have nominated a candidate for a long-acting injectable formulation. The next steps with that candidate would be to take it into human phase I studies. We have not yet finalized the study design for phase I. What we can say is that it will be a PK study. It will be a straightforward phase I PK study looking at the LAI, but in terms of patients, healthy volunteers, that's something that we're going to have to continue to assess based on not only the design of that study, but feedback with the FDA and also how we may integrate that into our overall kind of global development plan. In terms of expectations, we're looking to have that phase I PK data in 2027.
Got it. What do you think is the dosing profile of this long-acting injectable? Is it once monthly or something longer?
Yeah, we believe we have a lot of flexibility here. We need to learn, obviously, through our human PK work. We think that anything from once monthly, maybe it's once quarterly, we think that our feasibility work has really afforded us a pretty wide window. We will take that formulation into human PK work, also talk to the community to understand what they believe the best profile is. I think where we stand today, we feel excited given the fact that the compound in the formulation is providing us those options as we move it forward.
By the time your phase III program's done, how far along would you be with the long-acting injectable? Could it be side by side in terms of program development?
Yeah, great question. What we can confidently say is we will have phase I human PK results in 2027. Your next question then, Andrew, is how do you take that formulation into your overall global development plan? Would you make it a portion of your original NDA, or would it be kind of a follow-on via an SNDA? We have not made that decision yet. I think that will be highly influenced by what we see in the human PK results, but also our conversations with the regulatory agencies as well in terms of what evidence they want to see to support approval for an LAI.
Understood. In the last couple of minutes, you do have another dataset with the bipolar program reading out in the first half of 2027. If an investor were to ask you, what exactly is the read-through here? Because when we think about epilepsy drugs, there are not that many also approved for bipolar. What would you say to that?
Yeah, there was some reasonable read-through. Let's start off with RAP-219. I mean, there was a very important read-through that the doses that were used in the phase II study for epilepsy obviously get into the brain, they hit the target, there's a pharmacodynamic effect, and there's a clinical effect. That read-through applies to bipolar disorder, acute mania and bipolar. That's particularly relevant because acute mania is driven by glutamate excess. You see these hypermetabolic pathways or circuits, particularly driven through the mesial temporal lobe and the hippocampus. That's precisely where the target TARPγ8 is expressed. We know we're hitting the target, and we know the target's in the right place to treat acute mania and bipolar disorder. Of course, there's a little bit of read-through from other medications that are used to treat epilepsy and bipolar disorder.
That includes valproic acid and lamotrigine and lithium. Part of that read-through comes from the fact that those treatments are effective and their effects are mediated through targeting the glutamate in the AMPA system, exactly the way RAP-219 is re-proposed would be a treatment for acute mania.
Okay, I think we'll wrap it up there, but congratulations on all the progress. Look forward to more milestones over the coming next two years. Thank you, everyone.
Thank you.
Thanks, Andrew.