We're going to get started with our next session. I'm Andrew Tsai, Senior Biotech Analyst here at Jefferies. Thanks for joining us. It's my pleasure to have the Bright Minds team with me today. To my direct right is Ian McDonald, CEO, and to his right, Stephen Collins, CMO. Welcome, both of you. Okay. Maybe just to help level set things, a brief overview of Bright Minds, what you're trying to achieve, the programs you're working on, milestones over the next six to 12 months would be helpful. Yeah, sure. We're a company focused on serotonin. We have a few different programs here at Bright Minds. Our most advanced is a 5-HT2C highly selective agonist called BMB-101, which we had taken forward in a phase II study, which we announced results on early this year in both treatment-resistant absence seizures, as well as treatment-resistant developmental epileptic encephalopathies. We are also advancing a Prader-Willi syndrome program. That program is in phase II right now. We have a separate 5-HT2C highly selective agonist, which we're moving forward into a phase I program shortly, with data on that coming in the next several months. We also have a number of 5-HT2A assets in our portfolio we would consider potentially best in class. Those assets are all pre-clinical at the moment, but once a decision is made to move forward with those, we could have them potentially in clinic within a matter of months. Okay, very good. Again, congratulations on the data set from earlier this year. Maybe to help us summarize what kind of efficacy safety you showed, and how does that compare to current drugs approved or in development right now in both broad DEEs and absence? Let me just start off with absence. In absence, we have a couple of drugs out there, ethosuximide, first approved in 1957, Depakote in the '70s. Ethosuximide can be helpful, particularly for children who have perhaps a more easily treated absence problem. As you age, people start having different reasons for the absence. You have so-called childhood absence, juvenile absence, et cetera. Unfortunately, while ethosuximide works in a number of those subjects, it doesn't work so well in the majority of them. Depakote would be the next drug, unfortunately, while it has some efficacy, it has numerous problems, three black boxes, teratogenicity, et cetera. Not a great drug. This is the only drug in development at this time for absence seizures, and it would be for seizures so that a sales rep could go in and rep to a doctor for a patient of any epilepsy type who had absence seizures. What we saw there, using an extremely robust endpoint that is EEG, ambulatory EEGs, which we took two 24-hour ambulatory EEGs in baseline and two in maintenance, we demonstrated a 73.2% decrease in the number of those seizures. We also looked at all the seizures in a day, sort of an area under the curve, and we demonstrated. Pardon me. 74% reduction, and it was independent of the length of the seizures, whether they were shorter or longer, we had a robust effect. In this refractory population, who on average had failed multiple medications and came in on multiple medications, this was quite a robust signal. In DEE, we also had a very refractory population, more refractory than any of the recent studies based on the number of medications they were allowed to be on and the number of failed medications. There we had approximately 63% reduction in the number of major motor seizures. They ranged. The most spectacular result was in a subject with Rett syndrome, and she had 100% reduction of seizures at a middle dose in the study, and that seizure freedom actually lasted for several months. Quite a spectacular result for someone who had 15 seizures a day at baseline. The Lennox-Gastaut subjects, who were the majority of the rest of the study, had a range of responses, and so call it average 70% or 80% response. We had one Dravet subject who came in, and while actually by exclusion criteria should not have had a prior experience with fenfluramine, this patient had actually failed fenfluramine in the past on an efficacy basis. That patient, at the very first dose level, attained a 50% decrease of seizures. Really robust findings. The adverse events in the phase II are very similar. In fact, I'd argue better than the phase I study. Pardon me. We had a series of mostly mild to moderate adverse events, usually transitory, a couple of sedations, and a couple of nausea, a couple of diarrhea, but in a long-term study, not unusual. Certainly not that you might expect from some other drugs in the class who are bedeviled with these problems, because they have very fast uptake, very high Cmaxes, and rapid elimination. Our drug has a slower uptake, slower elimination, extremely specific to the 5-HT2C receptor. We don't have the issues of older, sort of first-generation drugs like fenfluramine, which as people are pretty well understanding, has binding at the 5-HT2B receptor, and therefore the risk for cardiac valvulopathy, routine cardiac monitoring, and most importantly, a weight gain cap so that patients who are above about 40 kg simply can't take the medication. That's a high level of that. Majority of the patients continue in open label and are doing well. We have two patients who the investigators have dropped concurrent drugs. This, based with the underlying biology which we understood and the prior older generation drugs like fenfluramine or bexicaserin, allows us to enter into regulatory studies. Got it. You're talking to the FDA now and starting phase IIIs, sounds like later this year. Is it Q3 timing, or? Yes. It's later this year. Later this year. Okay. We've had discussions, that is pre-IND meetings in both DEE and absence, and I would characterize them as extremely useful. The agency came back and agreed with the design endpoints, titrations, and dosages. That's what we're looking for in those interactions. Next will be to file the INDs, which, as I say, will be later this year, and beginning those studies. DEE, we presume will be global, so the efforts will be United States, Europe, and Australia. In absence, solely due to the fact that there are so many of these patients, we can restrict the studies to the United States. I see. Big picture, let's just say you made it through the goal line approved. Help us frame the market opportunity, actually, first and foremost. How many patients for each different patient type? What kind of pricing power do you think you can get? For each indication, they're roughly around the same amount of patients. Ballpark quarter of a million, potentially up to 300,000 you could argue for both absence as well as DEE. It depends on where you price the drug. You've seen some pricing in the mid hundreds of thousands for these orphan epilepsy indications. If you simply multiply that, let's say a $250, 000 times 300,000 patients, you start to get some very big numbers very fast in terms of overall market potential. We would expect our compound to be priced on the higher side if it can hold up its efficacy and safety profile. You have FINTEPLA, which is a weight-based dose in. Their list price is around $96,000 a year. However, if you look at their average patient, it's probably closer to $200,000 for that drug. I think, a very large number of patients who are treatment refractory, unfortunately, in these indications, and a strong rationale for pricing with a quality, safe drug like the one it appears we have. Right. Let's dig into the broad DEE first. How does the 63% absolute efficacy that you saw compare to, you mentioned fenfluramine, even bexicaserin in their original phase I and IIs. Help us frame the competitiveness, all while appreciating, I believe the line of therapy for your patient group was 15 prior lines or something like that. Help us compare on the efficacy front. 5-HT2C really seems to be king in terms of small molecules treating developmental epileptic encephalopathies. I'll give you some other numbers. You have compounds like ganaxolone, which are showing, call it 20%, 25%, 30% in that range of non-placebo adjusted seizure reductions for that compound. Stiripentol gets a little bit better when you start looking at EPIDIOLEX. EPIDIOLEX, I think, you're looking at placebo adjusted, call it 20% reduction, 20-odd% reduction in seizure activity. On an absolute basis with the 5-HT2C compounds, including ours, you're seeing that into 60s and 70, 50s, 60s, 70s. A material improvement over the other classes of medication. The studies that have been run with fenfluramine showed a, call it 75% reduction in Dravet patients. In Lennox-Gastaut patients, it didn't do so well. It was closer to 20%. I would note that our study was primarily Lennox-Gastaut patients, so using fenfluramine as a reference, a more challenging patient population. It was more LGS weighted than the bexicaserin study, which showed a roughly 60% reduction in seizure activity, counting major motor seizures for the DEE group. Yep. Makes sense. Bexicaserin comparison, because that's also going after broad DEEs. They're a little bit ahead of you for now. Maybe talk about your differentiation to that compound. Sure. I think you could take a look at the convenience of dosing. That compound is a 3 x a day dosing in its current formulation. It's also a compound that necessitates refrigeration in the current formulation. Our compound, in contrast, has a, let's say, smoother PK profile, where we can dose that compound twice daily. It also is rock solid from a stability standpoint, and we do not require refrigeration. That's the first aspect. Steve? The other aspect is, bexicaserin has a very rapid uptake leading to these high Cmax, these peak effects. You can look at their phase I and phase II data, and what you see is a fair degree of somnolence in GI, which is probably related to that. It's also cleared rapidly, that speaks to the need to dose this 3 x a day. It's a liquid formulation like ours is. In the DEE population, that's the preferred route because of cognitive difficulties with the tablet. I would say we are working on a once-a-day formulation, the biophysics of the molecule argue it should be doable. That would be the preferred presentation for the majority, almost all absence subjects who are normal cognition. The other differentiation with bexic, a couple others, is that they have so-called nonlinear kinetics. That is, as you increase the dose, it's predictable what the serum level is. Around 12 mg, the dose that they predict to be necessary, you go nonlinear, meaning the exposures go very high. We have linear dosing throughout our dosing range that makes it much more clinician and patient-friendly to be able to know if you change a dose, what's going to happen. Last but not least is we are a so-called biased agonist. The older drugs like fenfluramine and bexicaserin hit the serotonin receptor, which induces both the GPCR cascade. That's good. That helps stop seizures. It also induces beta-arrestin. Beta-arrestin is the intracellular system that pulls receptors off the surface when a lot of transmitter is being seen. What does that translate to? Well, it translates to tolerance or tachyphylaxis. The classic is patient comes to see the neurologist, started on a dose, get up to a decent dose, start seeing benefit of seizures, and then the phone call comes a month or several weeks later, "Seizures came back." neurologist bumps the dose. Do well for a little while. Seizures come back. Bump the dose. The patient's having more and more side effects. For a drug with nonlinear kinetics, that means you've gotten now into the place where you're going to very high exposures compared to our drug, which does not induce beta-arrestin. This is a hypothesis we'll see over time, but potentially we don't induce that mechanism by which there's less receptivity in the cell. What are congeners to that? Certainly in the GLP-1 space, they've gone to biased agonists. We're not aware of other CNS drugs that have, but clearly this could be a considerable benefit to have decreased or less tachyphylaxis. Thanks. When I think about your phase II program so far, it enrolled LGS, like you said, Dravet, Rett. When we think about broad DEEs, I believe there's hundreds, maybe, of DEEs technically out there. As you expand to phase III, you're going to be enrolling many more different kinds of DEE. To you have plenty of confidence, I'd assume. It works in broad DEEs, but like you said, Ian, earlier, the LGS is a more severe population. Is that kind of the case? Yeah. Well, they're all severe. The majority of DEEs are LGS, okay? I don't care what population-based study or what clinical study, those patients will form the majority of your patients. There are others, and we'll certainly expect to see them in a study. We're not going to exclude Dravet, but we're not going to specifically go after that. Understood. Yeah, any other disorder. There's 1,000-plus genetic mutations that result in these developmental epileptic encephalopathy patients. What we're really doing is going after the final common pathway and addressing the seizures irrespective of the origin. Yeah. the genetic reason for those seizures. Any guess about how many kinds of DEEs you could enroll ultimately in the phase III? Well, they're sort of a score or so fairly common, and then they're reportable where there's three people in the world, et cetera. To reinforce the final common pathway here, you can certainly go after a variant of a single sodium channel, and that will help those people potentially who have that. That doesn't necessarily mean you've worked on it. The analogy I've given, for better or worse, is everybody who came to this meeting today came from different places. Maybe you came from Jersey, maybe you came from Boston, maybe you came from Paris. You all got through that door to get in this room, and what we're doing is working on that door. What we're doing is not beating up the GABA receptor, which certainly leads to efficacy, but also leads to a lot of cognitive problems, somnolence, et cetera. We're increasing the tone of the GABA through action of the serotonin, and that's probably why we have what we consider to be a clearly differentiated adverse event profile from older drugs, as well as some of the newer ones. Yep. Starting phase III, again, is the base case two phase IIIs per program? Yeah. The agency, the FDA, doesn't really differentiate that much. It's a regulatory study. It's not a regulatory study, okay? We would start with a first regulatory study in absence and a first in DEE. Now, if we're supremely lucky, those will hit, and we can go to the agency and say, "Yes, we would file." Quite frankly, that's a fairly rare occurrence. We did it with clobazam. This is the team that developed clobazam for Lennox-Gastaut. It's better to say, "Yeah, more likely we would need two studies." We would have two studies to garner adequate safety and efficacy for filing. Yeah. Ultimately, what kind of placebo-adjusted efficacy delta is successful for a broad DEE study? Yeah. You've seen compounds get approved on Yeah placebo-adjusted efficacy in the teens. We would certainly hope to markedly beat that. I think you could look at some of the studies with FINTEPLA and their multiples of that in terms of placebo-adjusted response. That's certainly what we'd be gunning for. In order to have a compound that would be extremely beneficial to patients and sell well, you really need something that works better than the other drugs or at least as good with a better efficacy profile. If you can get that, it'll be successful for everyone, and I think that's what we've demonstrated so far and hope would hold up in future studies. Yeah. Earlier you said it sounds like the FDA was okay with the titration schedule, the dosing, and stuff. In terms of the patient inclusion criteria, again, the phase II was 15 prior lines. Will the phase III be as refractory? Yes. Yeah. These patients are all quite refractory. We'll probably make some adjustments in terms of trial design, yeah, stay tuned on that. The headline is it's going to be a very similar study, the one we ran in phase II, obviously upsized in terms of patients, placebo controlled, roughly the same titration schedule with a longer maintenance period. Great. Shifting to absence, where you saw a 73% seizure reduction. Very impressive. It sounds like you had the FDA meeting. Is EEG based an approvable endpoint, to be clear? Or is this kind of a subject of discussion still with the FDA? Are there precedents, basically? What we proposed was a video EEG to measure the seizures, and the agency came back and said that they agreed that that was a reasonable approach. This is a pre-IND, so these are not binding comments, but if they had had a substantial issue, we believe they would've said, "Have you thought about X, Y, or Z?" That has to do with a desire from the FDA in any division to have quantifiable endpoints. The difficulty in many of the neuropsych indications is they're patient-reported measures. If you have a really well-validated patient-reported measure, like major motor seizures, then the agency says, "Yeah, we have strong belief in that." We already know, and there's been literature for 40 years, that absence seizures, unfortunately, are not well captured by patients. They miss a ton of them. Why? Their cortex wasn't working for five seconds or whatever. They also say, "Oh, that was a seizure," when it wasn't. From our perspective, this allows the FDA, EMEA, PMDA, et cetera, to say, "Aha, now we have quantifiable, clear evidence," because the three-per-second discharge is not a biomarker, it's the event. We can make sure that that's real. Yeah. What was I going to say? You'll start the phase III also. As I think about the placebo response, when I think EEG, video EEG, it seems pretty objective, so what kind of placebo can we expect? Yeah. Yeah, you're right. You can't fake the seizure on an EEG. As I've joked, legions of epilepsy fellows have tried. It doesn't work. There will be a placebo effect around adverse events. Right? If you posit that to be 15, 20-ish%, which is sort of the average for most epilepsy seizure trials, we've certainly powered to ensure that we can show a difference between placebo and active. Right. Back in the phase II, 73%, the placebo's 0%. Near 0%. Well, we had no placebo in that study, to be clear. Right. There were no evidences when the blinded EEG readers said, "Oh, I don't know what's going on here." It probably should demonstrate what a three-per-second looks like on an EEG, but it's extremely clear. It's very easily identifiable and nothing else looks like it. Yeah. You have a lot of room to work with in heading into the phase III. It was my point. Okay, so there's that, then there's something else I wanted to ask. Oh, you're starting these two phase IIIs, when could data be? We haven't publicly guided to that, but these studies generally take, call it, a year to enroll. Okay. Ian is thinking data in 2024 is what he's going for. Okay. One year to enroll for both. All right. The QD dosing, you're working on that in the meantime. When do you have an answer whether you have a QD dose? It's a moving target. I think we're getting relatively close. I don't want to overpromise on that, but I think we're encouraged by what we're seeing. Ideally, though, should this be approved for both indications, what kind of formulations dosing will you offer patients? QD plus BID, is that correct? What kind of formulation as well? Generally, the DEE patients will struggle to swallow a pill, and there are obviously a lot of pediatrics, and these are people, unfortunately, with high cognitive burden. The ideal dosing formulation would be an oral liquid solution. You could look at sachet as well. The absence patients, in contrast, are cognitively intact. They are able to swallow a pill, an extended solid dosage tablet for absence would make sense. For the DEE, the preferred presentation would be either an oral liquid or potentially a sachet. Both of those have been approved for patients in this group of indications. Last question, a teaser on how big these studies are, and is it one-on-one randomization? These are double-blind, placebo-controlled trials with a goal of 100 completers, which should give us plenty of ability to have a separation. Thank you. Shifting gears then to another program for the same asset, although you have a second version that you'll pivot to eventually, is for PWS. You have data coming up in first half of 2027. It's a placebo-controlled phase II. Can you walk us through why you're confident this could succeed? Yes. What is success too? Yeah. There's mechanistic precedent with fenfluramine, which is a first-generation 5-HT2C agonist, that showed effect for Prader-Willi syndrome patients across the broad symptomatology, which largely consists of weight loss, hyperphagia, as well as abnormal neurobehavioral aspects, which would be things like temper tantrums when denied food, rigid, repetitive thinking, anxiety, things of that nature. We believe that 5-HT2C makes sense from a biological rationale perspective. When you look at 5-HT2C, there's a haploinsufficiency in these patients. They have less 5-HT2C tonus than a healthy individual. Basically what we're doing is taking the remaining 5-HT2C receptors and putting them on overdrive with our 5-HT2C agonist, similar to what you see with L-DOPA. Got it. What is the efficacy bar exactly? The efficacy bar, we know from a hyperphagia standpoint, our drug is one that we would expect to work in, again, that broad symptomatology that was shown with fenfluramine in Prader-Willi syndrome. If we can at least meet the hyperphagia response and/or have a strong, or really any response in the neuropsychiatric behaviors, that would be a huge win when you pair that with the strong safety profile that BMB-101 has shown so far. Yeah. The scoring system is HQ-CT. There's two scoring systems. One is HQ-CT, that's for hyperphagia, and the second is the so-called PWS profile. They were designed and validated by the same team at Vanderbilt, so Elisabeth Dykens, Elizabeth Roof, who work with us quite closely. Just fundamentally for either or both endpoints, what's clinically meaningful in terms of the point change? Well, as Ian said, the bar is fairly low for VYKAT. If you had a change of approximately four to six on a scale of moderate to severe hyperphagia, that would certainly be clinically significant. There is no drug approved on the PWS Profile, we really can't tell you X and Y. In any of the domains, whether it's obsessive-compulsive, whether it's the temper issues or agitation, if we were to have substantive changes, and again, I can't give you a count here, but meaningful changes to the patients. The study as it currently is a double-blind, placebo-controlled trial in baseline titration and two months maintenance. We'll also have instruments, we do have instruments for caregivers as well as the clinicians to report, as well as I've said, this validated PWS Profile instrument. Okay. I think that's all the time we have today. Thank you for walking us through your three programs. I appreciate it. Thanks, everyone, for listening.