Good morning, everyone. Welcome to Guggenheim Innovation Conference. My name is Yatin Suneja, one of the biotech analysts here at Guggenheim. It is my pleasure to welcome our next presenting company, Bright Minds. From the company, we have Ian McDonald, who's the Chief Executive Officer. We also have Stephen Collins, the Chief Medical Officer. Ian, why don't you make some opening comments? Tell us the story of Bright Minds. What are some of the upcoming milestones that we should be focusing on? I have prepared a Q&A for you, for you both. Ian. Yeah, so the company started off as a discovery organization. We focus on the serotonin two family of receptors. We have one clinical asset at the moment, which is in a phase II study for two types of epilepsy, first being developmental and epileptic encephalopathies, the basket there, which includes around 25 syndromes. We're also looking at it in a other form of epilepsy called Absence Epilepsy, where, if approved, the compound would be the first new branded agent in decades. We have additionally recently announced a program in Prader-Willi syndrome, as well as a new 5-HT2C molecule, which will ultimately be the home of the Prader-Willi syndrome program. In addition to that, we have a number of preclinical assets which focus on the 5-HT2A receptor. Those could potentially be used in pain disorders, but more likely neuropsychiatric indications. Got it. Very good. So let's focus on the lead asset 101. I think you make a point that it is a G protein-based, it has a G protein-based agonism at the 5-HT2C receptor. What does that mean? How is it differentiated relative to, let's say, fenfluramine or even BMB-101? Within 5-HT2C, you have a couple different signaling pathways. The one responsible for the therapeutic action is the G protein pathway. We hit that. We're a full agonist at GQ, actually slightly more than 100%. We do not hit the other signaling pathway, which is called beta-arrestin. When you activate beta-arrestin chronically, you will internalize receptors from the cell surface, leading to tachyphylaxis. That tolerance development is a feature that we hope will not, will not be a part of BMB-101. All of the other compounds, bexicaserin, lorcaserin, fenfluramine, are all active at beta-arrestin as well as GQ. We think there's potential for improved efficacy with that highly selective signaling approach. Got it. What are other differentiating features of 101 relative to bexicaserin? Sure. I'll start off and I'll hand it over to Steve. First is pharmacokinetics. Our compound is a two times a day compound in a liquid formulation. We're actually looking at a once daily solid tablet, which would be primarily for the Absence patients. It's in direct contrast to bexicaserin, which has a much shorter residency time in human, therefore needs to be given 3x a day. Bexicaserin also struggles with stability. It needs to be refrigerated all the way through dosing, both of which, the 3x a day and the need for refrigeration, are really a nightmare from a patient compliance standpoint. We do not have either of those issues. It looks like we have better tolerability based on our phase I data compared to theirs, primarily on GI as well as, sorry, as well as somnolence. I'll let Steve talk. We've already touched on the biased agonism, which is a potential benefit of our compound. I'll let Steve touch on one other point, which is the dose linearity. Yeah. So the PK between these molecules is quite different. Bexicaserin has extremely rapid uptake and rapid clearance, but making it even more difficult for clinicians and families is that it has so-called nonlinear kinetics. As you increase the dose right to about 12 mg, the dose they need for efficacy, as you have any small increase, you go nonlinear. That is, the exposures go very high. When you look at their phase I published data, for example, or the data from Pacific, what you see is a large amount of GI, somnolence, et cetera. That is most probably driven by these CMAX issues. We have a slower uptake, a longer residence time. When you look at our phase I data, we are linear all the way through the dosing range. In the SAD study and in the MAD study of about 64 subjects, what we demonstrated was that we do have some typical serotonin symptom things at about three times the dose we project we need. These were headaches, things like that. They're transient and the sort of side effects that you see oftentimes in neurologic drugs of serotonin access. There's quite a separation between what we believe the effective dose will be and the dose at which we saw side effects. You have a better PK and also a differentiation on your, or potentially a better therapeutic window as well, right? That's correct. Okay. Very good. Helpful there. What work do you need to do in order to get to QD? It is pretty simple actually. The biophysics of our molecule support a once a day formulation. It is a high potency drug. There are a range, and I am not gonna get into it, but there are a range of pretty simple formulary tricks to have this as a once a day. Because it is a high potency drug, you are not talking about some huge pill that has to be taken for extended release. Got it. Then you have generated some biomarker data on QEEG. Could you just touch on that, the relevance of that? I think you and both Longboard used to talk about prolactin, like how relevant it is and what you have shown relative to what Bexicaserin has produced. Yeah. So when you're trying to figure out how you're gonna dose any drug, you can look at your preclinical information, in our case, receptor occupancy and the dose at which it worked in various animal models of seizures. But then the next is in your phase I, you say, okay, did it actually do something? Did it get in the brain? So prolactin release occurs when you have a surge of serotonin. It's a classic marker for a serotonergic drug. It does not predict that you're gonna work in epilepsy. It's like a light switch. Did you or didn't you? And what we were able to demonstrate was we had receptor engagement and release of serotonin causing prolactin release around the 40-60, 80 mg range. So we had predicted around 60, and that's what we saw. so it's very similar to bexicaserin. What we did, which we're not aware of them doing, is so-called quantitative EEG. And doing that, we were able to demonstrate a typical QEEG profile for an anticonvulsant drug. Interestingly, we also increased frontal gamma. What is that? That's a signature of things that could be, attention improving type drugs. And so since many of the anticonvulsants actually have cognition impairing capabilities, what we'd like to see over time is whether we're actually helping people with that aspect of, unfortunately, of epilepsy and anticonvulsants. Got it. Very good. In terms of the development path, I think you're running a phase 2 study. You're going after Absence and DEEs. Maybe if you can, you know, separate these two indications and walk us through first on the Absence side, what is the rationale? What is a good result? Because I think Absence is, DEE, I think our investors sort of understand because they have seen more development there, but Absence is a little bit more unique. In DEEs, as you say, well accepted. This is a team that we got Clobazam, approved for Lennox-Gastaut, major motor seizures. They're grotesquely obvious and the family can note them down. Regulatory agencies are quite comfortable. Absence seizures are much more subtle. Doesn't mean they don't have a big impact on the patient and family, but they're more subtle and calendars are just not robust. However, EEG is 100% sensitive and specific for these three per second spike and wave discharges. The agency, the FDA, has actually in a recent research roundtable meeting asked thought leaders, what are epilepsies that we need to look at and are any of them quantifiable other than a calendar? The KOLs got up and put a chart. Number one was Absence because we don't have any really good drugs for it. Now we can quantitate them with modern techniques for recording of ambulatory GEs and computer algorithms to find the seizures. What we will use as a benchmark would be the classic that this division of the FDA has used, which is a 50% reduction of seizures in 50% of people. Now, the EEG is not subject to placebo effects. You can't fake the discharge, and so what you have to do is then back off the usual, call it 15%-20% placebo effect. That translates to roughly 30%-35% decrease in 50% of people. That's most likely the bar by which the agency would look for approval. That is a 50% reduction in seizures? 50% reduction in seizures in 50%. In 50%. Yeah. And measured, how are they measured? Backing out the placebo. Correct. Sure. Right. Yeah. Yeah, I get the delta, but how are they measured then in the seizure? How are they by EEG? By EEG. Got it. Yeah. We are doing two 24-hour ambulatory QEEGs. I see. The technical advancements in the last 10 to 15 years now allow people in every epilepsy center to come in, have the EEG electrodes put on, go home, come back. The other advancement that was not there before was before you had to print out, you know, 24 hours of paper and try to read them. Now we have algorithms which can define and find the discharges and then it is checked by an epileptologist. Got it. How many absence patients are you enrolling in this study? About, 10. About 10. Probably had a few more than that. Okay. And at what dose? This is a maximum tolerated dose range study that we're starting at 0.67, going to 2 mg per kg. Got it. For the DEE, just like you put in perspective the bar for Absence, what is the bar for DEE? What exact subtypes of patient are you enrolling in your, in the study and how many? Let's take the last one and then I'll hand it off to Ian. This is an all comer. Yeah. The majority will probably be Lennox-Gastaut because of course that's the largest single entity within DEEs, but we'll have a small number of others. And as far as. Yeah, the bar, the bar is pretty simple. We have two compounds that have already been tested in same or similar populations with the same or similar mechanism. Fenfluramine, you can look at their published data, their LGS numbers were not so great. Their Dravet a lot more promising, likely due to the weight of the patients in LGS being heavier and them not being able to get full receptor target engagement. The most apples to apples comparison would be the Pacific trial, which was done with BMB-101, which is another 5-HT2C highly selective agonist. There they had in the LGS patient population roughly 50% reduction in major motor seizures within LGS. They looked a little bit better in the DEE other category. But as Steve said, the majority of the patients will be LGS, it will be more LGS weighted than the Pacific trial. That wasn't by design. This is an all comers and those who came, those are the ones who came. Got it. Where are these studies being, or this study being conducted, and how many of these DEE patient total you're expecting? Yeah. This is a multi-center trial done in Australia. We have five centers of excellence that have been recruiting there. For the next trial, we'll be looking at a global phase 2/3, which would include sites in Australia. It would also include sites in the United States, Europe, likely the U.K. as well. Got it. Given the differentiated pharmacology both on the PK and the PD side, would you expect, let's say, differentiated efficacy, whether it comes off response or time to response or magnitude of response, at least in the DEE cohort? No. I mean, the easy answer is, is that these are all, whether it's the Bexicaserin patients or ours or fenfluramine, these are highly refractory patients. I mean, the expectation would be roughly someplace between 40-60% decrease. Yeah. time to seizure is not really a parameter that's generally used for regulatory approvals. Sure. It's exploratory, but it's, the better is, you know, how did you do over a maintenance period of X time, not did it take you one week or two weeks to get an effect? Got it. Got it. When should we expect these data? These, the data will be released in early January. We wanted to make sure that we had everyone's full attention when we were releasing this data as opposed to releasing it late in December when people had other obligations. Yeah. Okay. Could you talk about the future plan or the pivotal plan, like, maybe just differentiate between the Absence and the DEE? Like how are you thinking about it? How many studies you need? What sort of FDA feedback you already have and where you need an alignment on? Yeah. So we're already deep in planning, future studies. It'll be, our next study will be in DEE where we'll run a phase 2, 3 there. Mm-hmm. We're also going to be running a phase 2, 3 in Absence Epilepsy. Those studies will be starting, obviously after we get our data and submit that package in first half of next year. The alignment will really need to be, the DEE is pretty clear. We've had a couple of companies that have been able to get buy-in on the DEE approach, including Praxis and now, Lundbeck. Where we are really blazing new ground is on Absence. There haven't been really any modern Absence trials with EEG as an endpoint. I think there's certainly a willingness to use EEG, but we're gonna need to figure out exactly, exactly what those rules are gonna be on counting seizures. Mm-hmm. Definitions on what is, what counts as one seizure, what is, what are the specific rules there. I think that's all, you know, fairly easy to get done. It will just take a conversation. Got it. Then can you put in perspective the market opportunity in absence and DEE? Yeah, DEE is fairly clear. I mean, you have some comps that are traded. I'll quote Lundbeck. They were expecting peak sales to be $1.5 billion-$2 billion on Bexicaserin in that patient population. We feel we have a superior drug to that, obviously. In Absence, we would be the first branded agent in that, in that indication. I'll let Steve talk about, talk about the current drugs that are on market and the, and the need for new therapies. But you're looking at a patient population, which could be, around 500,000 patients per year if you include the 10% of focal patients who experience Absence epilepsy. If you exclude them, you're looking at around, call it 275,000. That includes, patients, some patients with DEE, but primarily, more pure Absence indications, indications like CAE, JME, JAE, et cetera. Got it. Yeah. So unfortunately for clinicians and patients and families, there are not a lot of good choices. Ethosuximide was approved in 1956 or 1957, works decently well in childhood, stops working as kids and adolescents develop Absence or continue with their Absence. The next is Depakote, which unfortunately, while fairly effective, also has multiple black boxes, a lot of problems. Then clinicians just start throwing drugs at people. This would be, as Ian said, the first branded drug, quite an opportunity. Sales reps would be able to go in and rep against Absence seizures in any type of epilepsy. I see. Okay. Maybe a couple more questions. In terms of the number of studies that would be required in Absence versus DEE, how many there will be? Two in each. Two in each. Okay. What will be the time to market and where is Lundbeck, like, at least on the DEE side? I understand, in absence, you guys will be first to market. Yeah. I mean, I can't comment on Lundbeck's time to market. I mean, I think it's pretty clear they'll be ahead of us. I'm not sure how much ahead of us they will be. We are obviously planning on running these two studies we just described, and there'll likely need to be another study after that. Mm-hmm. but within DEE, this is a fairly large patient population. Most of those indications within the basket have no approved therapy. I would not look at this as a Dravet trial where you have a very crowded space and a number of approved therapies and a number of other compounds in development within that indication. This should be much easier to recruit for. Although I would say Absence would be certainly the easiest out of the two, given that there are no, you know, good choices beyond Depakote and Ethosuximide, which have their own challenges. Got it. In terms of the IND, what are the timeline to bring the IND into the U.S.? Yeah. We will be doing that, early next year. Early next year. Okay. Very good. Then on the Prader-Willi syndrome, we saw the announcement you're moving in there. Could you just talk about what evidence, just the, the mechanistic rationale, for going into PWS and how does 5-HT2C agonism sort of help there? Yeah. There's a genetic link to 5-HT2C in Prader-Willi syndrome patients. On SNORD-116, you have a deletion, which results in insufficient 5-HT2C development. You have a lack, but not a complete elimination of 5-HT2C tonus. By addressing 5-HT2C and, you know, putting the remaining receptors in overdrive, we feel we can ameliorate a lot of the symptoms by agonizing that receptor. The beautiful thing, at least from what we can tell, is that this should work on the constellation of symptoms within Prader-Willi syndrome. Current therapies address hyperphagia to a certain degree, but are really lacking the holistic approach to most notably the neuropsychiatric symptoms. These patients have frequent temper outbursts, obsessive-compulsive-like behavior, aggression, all of which should be addressed through 5-HT2C. In terms of the rationale beyond the mechanistic preclinical stuff we've looked at, and by the way, we've run this in a model of aggression. We've run this in an obsessive-compulsive-like behavior model. We've run this in a binge eating model, all of which show a dose-dependent improvement on those domains. There was also a clinical study done with fenfluramine. This is a small proof of concept study done in the late 1980s, before the compound was initially removed from the market due to off-target receptor liability. That compound showed improvement on weight. It showed improvement on hyperphagia, and it also showed improvement on the neuropsychiatric symptoms. We think there's strong clinical and preclinical rationale for 5-HT2C to work well with this patient population. Got it. So you have two assets, right? This is a 101 and 105. What are the differences? Are you gonna advance both of them? Just how are you thinking? Yeah. I'll walk you through the rationale here. We're doing the phase 2 study right now with BMB-101. The thought there was it's gonna take, call it, a year or so to get BMB-105 all the way through phase I studies. Instead of waiting a year for development, we thought, why not use BMB-101 to do a small proof of concept study, at which point that completes, we'll have 105 ready to go and we can switch the program into 105, thereby, you know, saving a year in terms of development time. The differences in the compound, we'll see, they're fairly similar compounds. I think from a commercial standpoint, we certainly wanted to have a differentiation of assets there. It will likely have different pharmacokinetic properties, but that'll be borne out in the phase I studies. We also have fresh IP on this. Mm-hmm. We're looking at some, you know, hopefully composition of matter with a fresh shot clock on that. Got it. Got it. Very helpful. The NOVA study, the two-way NOVA study that you just started, how would you define successful outcome? What exactly are you looking there? Basically, similar to what you see with Vykat in terms of hyperphagia, if not better. Then as opposed to Vykat or some of the other drugs that are currently being looked at solely for hyperphagia, we would look for improvements using the so-called PWS profile, which looks at agitation, aggression, OCD, et cetera. What we'd like to see would be a trend towards improvement there. This is a small study. Yeah. I don't wanna say it's gonna be X or Y%, but we look for trends in that. Got it. Got it. Very good. I think that's all I have on the asset. Maybe just one question on the financials. Like how is the balance sheet? How's the burn rate and how you are capitalized? We try to run the company as capitally efficiently as possible. So everything that I've described today is currently funded. The two phase IIs, the two phase II threes after this, the PWS study and the phase one study for BMB-105. Got it. Very good. Thank you so much, gentlemen. Very helpful. Thank you. Thank you. Thank you.