Everyone, thank you for joining us in the room and online for day three of TD Cowen's 46th Annual Healthcare Conference. I'm Joe Thome, one of the senior biotech analysts here on the team at TD Cowen. It is my pleasure to have with us today the team from Bright Minds. We have CMO Steve Collins doing the initial presentation here, and then we also have CEO Ian McDonald for some Q&A at the end. Thank you very much.
Thanks so much. Thank you guys for coming in today. I'm gonna go through this presentation fairly quickly, so we have adequate time for questions. Usual disclaimer. Just so you know that Bright Minds is a company that is been set up for now a number of years looking for novel targets around a range of serotonin potential indications, not only around 5-HT2A but also 5-HT2C. What we're gonna talk about today is our lead program, BMB-101 for the treatment of a range of seizures and Prader-Willi syndrome. Here's the executive team. We all know this, but just to formally state it, when we do this development, it's a team. There's the patients, the families, the investigators, and the company. We wanna thank all of those people.
The breakthrough study was done in two separate cohorts, in those people with refractory absence seizures and those subjects with refractory DEE. What I'm gonna talk to you now is some top-line data that was first presented in January. Study performed in Australia at five centers of epilepsy excellence. First, let's just talk a bit about BMB-101. Over the years from the 1950s on, there have been progressive elements of improvements in serotonin axis drugs. What we see in our program is what I call second or third generation, where we now specifically target 5-HT2C without activity at 5-HT2A or 5-HT2B. The molecule has superb pharmacology. It has relatively slow uptake, relatively slow clearance, allowing for twice-a-day delivery.
It has linear kinetics, that is, as you deliver the drug, it's uniformly related to exposure. If you have a dose X, you get X in the blood. If you have 1.5, you get 1.5. That compares with, say, lorcaserin, which has nonlinear kinetics right at the point it needs to be given, therefore getting to very high levels and a number of side effects. We are working on a once-a-day oral tablet that would be quite important and helpful for the absence population who have normal cognition, normal ability to take tablets. In the DEE population, a liquid formulation is quite preferred. Many of the people with significant cognition problems and difficulty swallowing. We did both a phase I study, SAD, MAD, and food effect. I should emphasize in the phase I, there were no serious adverse events.
Tolerability was quite good. We saw some transient usual issues, lethargy things at very high doses, two to three times the doses we predicted necessary for efficacy in the clinical study. In the food effect, we had exactly what you'd want. Food effect decreased the Cmax, the peak, by about 24%, but did not affect the AUC, so it didn't affect the actual exposure of the drug. Pardon me. Let's go right to it. This was a study in which we had a one-month baseline during which we had two 24-hour ambulatory EEGs to capture absence seizures and a seizure calendar.
Weekly titration from 0.67 mg per kg to 2 mg per kg, which is actually fairly quick titration in the world of epilepsy, then a maintenance phase of two weeks for absence, repeating the two 24-hour ambulatory EEGs, then at four weeks with the seizure calendar for the DEEs. What you can see here is really quite robust effects. Full disclosure, small trial. Again, we were doing something we knew the pharmacology of, and prior drugs like fenfluramine had adequately explored that are you gonna have an effect? Yes. Can you have a better effect, and can you have a safe and well-tolerated effect?
What you can see in the absence seizures is there was a 73% reduction, and in the DEEs, all comers, we'll break this down in a second, a 63%. I have to emphasize, and we'll talk about in a second more, this was an extremely refractory population, more refractory, for example, than the PACIFIC study. The average age was about 30, and the number of drugs concomitant and prior was higher than the PACIFIC study. We believe this could be a best in class. This is a drug that can work for focal as well as generalized seizures. Call it a safe Depakote, if you will. W e met obviously the endpoints here, you can see from those results.
What we would hope would be that this would be really a breakthrough for patients with refractory absence and DEE seizures. What you can see here is the design of the study that I talked to you about already. They had to have a minimum of four seizures per 24 hours in the absence group, and they had to have four seizures during the four-week for DEE. The majority of DEE subjects could not tolerate 24-hour ambulatory EEGs. One subject could, and since we're able to look at that data. We incorporated that in our evaluation of absence seizures. Absence seizures are absence seizures are absence seizures, whether they're in people who start off as childhood absence CAE, or whether they have as a part of juvenile absence or juvenile myoclonic epilepsy, it's the same seizure.
Just let's talk about how we did for enrollment, et c. Overall, we had 24 subjects. There were 15 in absence, nine in DEE, mostly Lennox-Gastaut, and that represents the population of DEEs out there. The great majority are Lennox-Gastaut. We had two other types, and I'll talk about those in a second. One Dravet, one REP. As I said before, these people had failed multiple medications. In the absence, it was a average of 3.7. The highest was somebody had failed 16 drugs. And then in the DEEs, these were quite refractory, having failed almost 10 anti-seizure medications, including one case of failure of fenfluramine. This represents exactly what happens in the real world. In an epilepsy clinic, a neurology clinic, people are on these multiple medications. Clearly, the clinical trials are add-on always for anti-seizure medications.
Going a further bit into it, as I said, the mean age is about 30. Interestingly, by accident or by happenstance, the number of median seizures on baseline were 22 for absence, and similarly for countable motor seizures. We did not count minor seizures. We did not count small head drops as atonics. These were unfortunately grotesquely obvious seizures. How did they dispose? Well, we had in the absence group, 17 who were assessed for eligibility, 15 enrolled, we discontinued three. One was a little odd. It was for taste. The patient just couldn't tolerate the taste. I will tell you that the formulation is or was extremely sweet, since then, we now have a commercial formulation, stabilizers, preservatives, and a fraction of the sucralose that was put in this.
Frankly, none of the other subjects complained about it, but this patient just couldn't tolerate it. The second had flu and said, "I'm out of here." Of course, the investigators are the people who score the relationship. The investigator said, "Well, it's possibly related." The third was a case of dizziness. Now, it turns out that this subject actually didn't qualify upon later review of records. They had too few seizures, but nonetheless, we reported on that patient on safety. We had 12, so those from the absence and one from the DEE, who we had completing maintenance. One of the patients, as I say, when we looked at these EEGs later, one of them didn't qualify because they had too few absence seizures.
Then one, unfortunately, the EEG was too poor to be able to analyze. We had 11 for the evaluable population. In DEEs, we had 10 who came in, we enrolled nine, and we had three discontinuations. The first was a person who'd had baseline behavioral problems, so on levetiracetam and had outbursts, and they kept on fluctuating. The family said, "Sorry, we just can't do this." The investigator said, "This might be possibly related." The second was a patient with atonic seizures who fell on her porch and broke her shoulder, was admitted to hospital, and was administered fentanyl and other strong opiates. Unfortunately, due to complicated hospital course from that, couldn't stay in the study. The third a patient who had lethargy, which could have been related to the drug.
We had six who completed the maintenance phase in DEE and formed that evaluable population. I'm just gonna briefly state here or show what an absence seizure is. These seizures were first identified in 1937. We're not talking about something that's, you know, a greenfield and no one's seen before. It's pathognomonic. As I've joked, if a first-year medical student can't figure out that's a three-per-second spike in wave, might wanna go to law school. They're extremely easily seen. This laser doesn't work, but I'll try. They sit on a normal background and obviously have this grotesquely obvious pattern, and it's in all electrodes across the head. It's a generalized seizure disorder.
There's well-understood pathophysiology of the circuit here and that activation of 5-HT2C receptors in subsets of interneurons in the thalamocortical circuit affect T calcium channels. This is not a T-calciumopathy. It's that T-calcium channels are part of the pathophysiology, and it's well known that we decrease those bursts. What's the treatment paradigm for absence? Well, ethosuximide was first delivered in 1957. Works pretty well for childhood absence. It does not work for any other seizure type. Unfortunately, as children progress, become adolescents, they go into two buckets. There are half of the patients don't have seizures anymore. We don't know why. They don't need to be treated. The other half, unfortunately, they get worse, and ethosuximide doesn't work. The second-line drug is Depakote. It's quite effective in many patients.
Unfortunately, it has four black boxes, teratogenicity, hepatic and bone marrow toxicity, as well as weight loss, hair loss, et c. Not a drug that clinicians like to go to, but they're forced to. After that, literally clinicians just throw drugs at people that don't work very well. As I said before, the top line was we had a median reduction of 73% in counting seizures, and these are three-second longer episodes. I can tell you that clinically that's a standard by which many clinicians say, "I can observe this as a observable effect." We also looked at all seizures, and also those of greater than three seconds. We looked at one second, two seconds, three seconds, etc .
We had not just this considerable reduction in count of seizures, but also in the AUC, the total amount of seizures over the day. They correlated, as you can see, spectacularly well. You could ask, "Well, did we do better on some duration of seizures than other?" The answer is no. As you can see here, whether you're three seconds, five seconds, or greater than 15 seconds, we worked as well for individual count as well as the AUC. Because we had 24 ambulatory EEG, we could do some aspects of sleep. We could look at sleep architecture, basically counting REM and non-REM and sleep stages. What we saw here was a considerable increase in REM. Why is that important? REM is the phase of sleep in which you consolidate memory, consolidate behavior, a bunch of other neurobehavioral aspects.
In people with epilepsy, it's well known that they have abnormally decreased REM. Just to give you an example, a average adult healthy person having seven to eight hours of sleep will have between 90 and 120 minutes of REM. What we see here is basically almost a doubling, a 90% increase up to that typical amount of REM. You could do that by cheating. If you put a person to sleep all day, yeah, you're gonna increase your REM. As you see on the right here, the overall sleep duration was spot on the same at baseline and on drug. We have hoped that this would help people not just with absence, but people with other epilepsies.
If you ask me, "Steve, is it that you're making sleep better and the seizures are better, or you're making seizures better and sleep better?" I don't know. We will certainly look at this in upcoming studies where we'll correlate not just sleep, but also measures, quantitative measures of cognition. Let's switch over to DEE here. People have said, "Well, can you break out by patient?" Absolutely we can. In Lennox-Gastaut, as I said before, these were quite refractory patients, we had a 60% decrease on average, and in the others it was greater at 76%. Let's take each patient subject one- by- one. One subject had a slight worsening of their seizures. This is a person who had six seizures at baseline and had seveb in maintenance. Yes, slightly worse. I should point out that there was no worsening of seizures.
There were no new bad seizure types in either absence or DEE that emerged. In the Dravet subject, you see there's a 52% reduction. I have to tell you that this patient came in and started having that reduction at the very first dose level. The family was highly reticent to try to push to higher doses. They had been through multiple drug trials before, they were very happy that this patient was doing as well as they did. The two Lennox-Gastauts above that, 73% and 95%. The Rett patient was obviously a spectacular result with a 100% decrease. This young lady had 15.7 motor seizures a day in baseline, I'm not talking about subtle seizures here.
Now she's been over 90 days seizure-free, including a period of time where she had pneumonia and was hospitalized, which is spectacular for that group. One of the things that I've spoken to is the fact that we had such a refractory group of patients. If you look here, what you'll see is the majority of the patients had on board really multiple drugs and had failed multiple drugs. Why is that important? Well, if you look at the left side of this graph, what you'll see is data from the PACIFIC trial from Lundbeck, in which they noted in their trial when you had patients with two or less anti-seizure medicines, you had a 75% reduction. If you had three anti-seizure medicines, you had less at 61%.
If you had greater than or equal to three, you had a -5 0.8%. You look at the right. Eight of our nine patients were at four or more, and so we had four, five, six, seven concurrent drugs, meaning at 60%, and it's a very small data set, we're at the very least as good as the effects seen in the more refractory patients at PACIFIC, and I would argue some are better. What about safety? We're getting close in time here. We had no drug-related SAEs. As I said before, there was a fracture and et cetera, et cetera. We had one severe adverse event, which was a little odd.
It was a patient who complained of dry mouth, and the investigator said, "Look, just keep on your drug." They kept on the drug at that dose, and it went away. We had no other signs of anticholinergic effect, dry eyes, urinary problems. Quite frankly, I don't know what that's all about. As I said before, obviously the patient with the fractured shoulder and fentanyl, etc , use. The majority of the AEs, if you look to the left of here, respiratory infections, no relationship. When we talk about ascribing relationship, we do not talk about company assignment. These are investigator assignments, and what you see is that, it was possibly related to fatigue, constipation, headache, drowsiness. I think we had almost as many diarrhea as constipation in this group.
Unfortunately, many wheelchair-bound, etc., GI complaints are usual. We didn't have overwhelming sedation or overwhelming GI complaints. Where are we going with this? Obviously, we feel these are quite robust effects. We are starting global regulatory phase III studies in DEE and in absence. We're in discussions with regulatory groups, the United States and Europe and Australia. Ian, did you want to talk some about market size?
I think we can skip that study.
All right. As I said, we're starting those studies. We did start a study in Prader-Willi. We don't really have time to go into it, but Prader-Willi, a deletion of chromosome 15 with a mutation of 5-HT2 receptors by a NORD 116 has problems with hyperphagia and neurobehavior, our animal models predict we work. Fenfluramine in the 1980s actually did a study which they demonstrated benefit hyperphagia behavior. Of course, you wouldn't use fenfluramine now, A, because of the safety, and B, because of the weight dose gap. With that, I'll stop. Thank you.
Great. Thank you very much. Maybe just a few questions for the remaining time, but can you go into a little bit more detail at sort of the status of your regulatory interactions to start the pivotal programs, maybe what remains to be aligned on? Is the absence endpoint in particular, I guess, clear between the company and the regulatory agencies? How do you see that?
Yeah. We've had a pre-IND for DEE. We still need to have a pre-IND for absence. Our plan there is to move ahead with EEG as the endpoint for the various reasons that Steve has mentioned. It's, it's in our minds, clearly the appropriate endpoint. We'll still need to meet with the agency and figure out exactly how that's going to be done. There are a number of different ways you can count seizures through EEG, various cutoffs, approaches. We'll need to get alignment on that.
Great. One of the main focus areas for investors in the seizure disorder space broadly is just time of enrollment for some of these studies. In absence, it seems like there's not as much kinda going on, so maybe that's a little bit more of an open area for you, especially given the compelling data. In DEEs, we have a few other companies kinda running studies at the same time. I guess, how are you gonna manage that and kinda what's your confidence that you can enroll these studies in a reasonable fashion while also still making sure you're getting the right patient in the trial?
Well, absolutely. Absence, we'll do the study United States and Australia, and we've had tremendous interest from investigators, so I don't see a problem there. For DEE, we'll use both the United States, Europe, and Australia. What we're doing is going to centers that we've worked with literally for decades, and, obviously, we prefer centers where they're not doing those sorts of studies concurrently or they finished them, and we have quite strong interest. You're right. There's some challenges there, but there's quite a bit of demand. Unfortunately for patients, they just don't have a lot of good drugs, and I'm biased obviously. You know, with our biased agonism, thank you for that, as well as the advantages of twice a day dosing, linear, and what we believe is really good safety and tolerability, I think those are all attractive elements for recruitment.
Maybe in the DEE subset, how should we think about the pivotal plan? I think various companies are taking different approaches. Either they're doing, you know, sort of a basket approach. Some are running Rett specific studies. Some are running, you know, sort of LGS specific studies. How are you gonna kind of group these patients together? Obviously, you're seeing a pretty robust response across different seizure types, so how would that best come out in the program?
Look, just the reality is the majority of the patients are Lennox-Gastaut. We're not gonna eliminate patients, nor are we going to do a just Dravet. Good luck on that study. It'll be all comers, Dup15q, etc., etc. Again, what we do is work on the final common pathway of seizures. We don't really care how you got there because we increase the interneuron GABA drive in a weight which doesn't lead to somnolence cognition, etc. It doesn't matter how you got there, we can fix it, we believe.
I know you kinda skipped over the slide here, but I think that would be helpful, to just talk about the overall, market potential for the therapy, particular maybe in absence, because we have a few drugs out there, but as you mentioned, they don't really work that well. Kinda what do you see as sort of the target peak opportunity for the therapy across both indications?
I think we see both indications being potentially multi-billion dollar. In the case of DEE, that's fairly well characterized, again, with there's already a on mechanism drug. Obviously, it has a number of liabilities, including the dose cap, and some of the REM liabilities associated with the program. With absence, you're looking at a patient population that's in the order of DEE. However, in that area, we are not competing with anybody in terms of recruitment. There are a couple of approved compounds, but a highly treatment refractory landscape, with no real options beyond ethosuximide and valproate. Valproate, again, has been used for all types of seizures, including DEE. It's something that physicians are really trying to get away from.
The issue with ethosuximide is, 1, it doesn't work for a lot of patients, and for the ones it does work for, it only works to treat absence seizures. If you have a generalized tonic-clonic seizure burden, tonic, focal, it's not going to reduce those seizures. It is purely for absence. The beauty of our drug is that it has a broad therapeutic potential for seizures. It's not limited to absence, it's not limited to focal, it's not limited to generalized tonic-clonic. It should work for all of those.
Maybe jumping over for the last few minutes to the Prader-Willi opportunity, maybe what got you excited about this mechanism in PWS, both, I guess, from the mechanistic standpoint, what we know is out there, and then I think you had a couple patients in the seizure disorder studies that saw some interesting responses, if you wanna touch on those.
Yeah. I think our compound is the first approach that really has potential to address disease modification. If you look at the biology of Prader-Willi syndrome, there is a haploinsufficiency of 5-HT2C. They have not zero 5-HT2C active tonus, but much less than a normal, healthy individual. We are, in effect, putting the remaining 5-HT2C receptors on overdrive, similar to L-DOPA, if you will. If you look at the animal knockouts of 5-HT2C, they express the symptomatology of a Prader-Willi syndrome patient.
We believe we can correct that. It's not only hyperphagia that we're going after. Perhaps more interestingly, it is the neuropsychiatric symptoms, the temper tantrums, agitation, other neurobehavioral aspects. From a caregiver perspective, you have hyperphagia, which is obviously a big deal. As patients get older, many caregivers have stated that the biggest burden is on this abhorrent neuropsych behavior.
In the current study, we had a patient at 137 kg and about 5 ft nothing. He's lost 10% of the body weight, not through nausea, but by decreasing that drive to eat. We had another subject who had not just epilepsy, but binge eating disorder. She's lost 8%, almost 9%, and the note from the family is, it's because she's not eating snacks anymore. She doesn't have this huge drive. I would expect the same thing in the Prader study.
Yeah. That's great. You're, you're looking at both, sort of an initial study in BMB-101, but then BMB-105 seems to be the candidate that you're taking forward. I guess just quickly, what's the rationale between kinda taking those two forward in these sort of individual studies, and when do you think we could see some data from either of those?
It saves us a year. We're working on the backup, you know, BMB-105, we can use BMB-101 now as a proof of pharmacology. That differentiates. BMB-105, obviously, would have, you know, longer shot clock IP-wise, et c. There was another question there. We've just initiated this study a couple weeks ago, and we expect that we'd be enrolled by about this time next year. This is a double-blind, placebo-controlled trial in between 16 and 20 some odd subjects. The same size as the first FICA study, the same size, a little bigger than the fenfluramine study, expect in 2027. Ian asked if I could get results in 2025, I said no, but, you know.
Maybe last question, obviously, you did the recent financing. I think one of the most capital-efficient companies that I've seen in sort of getting these data. What does that recent raise get you to in terms of milestones and timelines?
Yeah. That recent raise is really gonna be driving our 5-HT2C program in epilepsy. We'll have multiple readouts for that. It will also get us to the next readout of Prader-Willi syndrome, as well as development for 105 through phase I.
Great. Awesome. Well, thank you very much for the time, and, best of luck.
Thank you.