All right, good afternoon. Let's get started. This is David Amsellem from the Piper Sandler Pharma team, and welcome again to the 35th Annual Piper Sandler Healthcare Conference. Our next company discussion is Longboard, and we have Brandi Roberts, CFO, and Dr. Randall Kaye, Chief Medical Officer, with us. Thanks so much for joining us. So I'll kick things off with a high-level question, maybe for you, Brandi, is just give us a quick overview of the company. I'm particularly interested in where the pipeline assets originated from. I think that would be helpful background. Sure. Happy to start, and thanks for having us today. Mm-hmm. So Longboard is a spin-out from Arena Pharmaceuticals. We spun out in 2020, and Arena had molecules that were in three different areas of indication, but also had these neuro assets that they were really excited about, but just didn't have the expertise in-house to work with. Mm-hmm. And so the idea was spin it out as a separate company and build a neuro-focused team, and that's what we've been working on for the last couple of years. We went public in March of 2021, and we're really excited because these candidates have 20 years of GPCR research behind them. Both of our programs have potential billion-dollar commercial opportunities, as well as really differentiated PK, PD, and target engagement and well-understood mechanisms of action. We're going to talk about two programs today, mostly 352- Mm-hmm ... which is a 5-HT2C super agonist that's currently in a phase Ib/IIa study called PACIFIC, and we're looking for the reduction of seizures in developmental and epileptic encephalopathies. Then LP659 is an S1P receptor modulator that we're considering for a number of rare neuroinflammatory conditions. Great. I appreciate the intro, and that's helpful background. So let's start with 352. I guess, this is for those who are less familiar with the story. You talked about the product being a super agonist. So I guess the question is: How do you define that, and more specifically, how would you think about its 5-HT2C selectivity relative to Fintepla, which is on the market? Sure. Happy to start with that. And super agonist is something that you don't hear about all the time. No, we don't hear, yeah. So definitely understand the question. Yeah. It really just means that it produces a higher receptor response than the endogenous agonist serotonin in preclinical models. Mm-hmm. It was really designed to be highly selective to 5-HT2C and have no impact on 2A or 2B, which are both known to have some undesirable side effects. And Fintepla hits 2C, 2B, and 2A. Okay. That's helpful. So, taking a step back, in terms of the development program, you've looked at 352 development more broadly, in DEEs, as opposed to taking a more specific approach to development, such as in Lennox-Gastaut or Dravet, for instance. So, I guess, talk through your development approach here and why the broader developmental and epileptic encephalopathies umbrella, as opposed to a more indication-specific approach. So the traditional approach, base case approach is- Mm-hmm ... start treating patients and assessing your compound with Dravet, then maybe go on to Lennox-Gastaut. Mm-hmm ... and maybe TSC. It's a good approach. It's a very standard approach. We think there might be a better way- Mm-hmm ... a more efficient way of gaining more data and more information a little bit more broadly. We'll talk about this in a moment, but when we think about our planned, clinical ongoing study, we're approaching it more broadly. It's an all-comer study- Right ... to allow patients that have a variety of these different developmental and epileptic encephalopathies. We think this is a discussion that we can have with regulatory authorities- Mm-hmm ... about an approach where you study safety and efficacy more broadly. It would allow for a more efficient process. Mm-hmm. But at the end of the day, that's going to require some discussions with the agency and to get alignment on that approach. Okay. Wanted to switch gears just a little bit. As you talk about, you know, this idea of being a super selective, super agonist here, one of the things that we know about Fintepla is it has a restrictive REMS. I mean, we know that that's a molecule that has a checkered history, but it certainly works as an antiepileptic. So I guess the question here is: What's your level of confidence that 352 potentially could avoid that kind of restrictive REMS, to the extent that it reaches commercialization? Sure. So LP352 does not interact with the 5-HT2B receptor at all. Yep. so we really think that the cardiovascular issues associated with Fintepla are highly unlikely- Mm-hmm ... and that's why echoes are not required in our ongoing PACIFIC study. Okay. We see this as a really important differentiator for our product. Okay. So now as you look at the development program, one thing that would be helpful is to talk through the broader DEE population. I know there's a lot of different specific DEEs. How many patients do you think this encompasses per your market research? In the overall, the four most common developmental epileptic encephalopathies, and probably why they're studied first- Mm-hmm ... is Dravet, Lennox-Gastaut, TSC- Mm-hmm ... and maybe to some degree, CDKL5. Mm-hmm. But if you look more broadly, maybe they represent perhaps half of the DEE population, at least if you're looking at U.S. numbers. Sure. The other half are other developmental and epileptic encephalopathies... some of which are syndromal, some of which have a very, very specific genetic mutation. And there's probably at least 25 of those, and I think as we get smarter and we do more genetic testing, the numbers will probably even increase. Okay. So looking at the PACIFIC study, and I know this is maybe a tough question to answer, but I'll ask it anyway. It's just a hypothetical. What do we have to see in order for you guys to move forward broadly in DEE? And I realize there's some discussion that has to happen with the FDA, but moving forward broadly in DEE as opposed to moving forward in a specific indication like Dravet or like LG, like LGS. So help us frame, you know, there's the regulatory component and what the FDA will, you know, let you do or agree to, but then there's also what you see in specific. So help us understand, you know, what you need to see in specific to continue to move forward in this broader DEE umbrella. Well, it is a tough question, but it's also- Hmm ... a very fair one because- Yeah It's the question everyone wants to- Sure ... wants to hear. So the PACIFIC study, phase Ib/IIa study, 52-patient study, 4:1 ratio of drug to placebo. So it's a relatively small study. It's framed as a safety, tolerability, and efficacy study. Mm-hmm. What's the first thing we want to look at? Can we get patients on a dose that they can tolerate? Mm-hmm. Can we get them to the maintenance phase? Mm-hmm. Can they stay in those, in that maintenance phase for the two months, and remain on therapy? What's the adverse event profile? How does it compare to other typical, ASMs that are utilized? Is it similar? Sure. Can patients stay on that medication without discontinuing due to adverse events? And then we start to look at efficacy. There's a number of ways of looking at efficacy, but there's one standard way. Mm-hmm. The standard way is you look at the efficacy on the top line, all those who were treated with LP352. Mm-hmm. You look at seizure frequency, and you look at the change in seizure frequency relative to their baseline. We count the countable motor seizures, and then you compare that directly to the placebo numbers. So what you'd want to picture is overall that we're seeing a higher degree of improvement in LP352 in terms of seizure reduction. Mm-hmm. What we've seen out there, if you kind of look broadly, is in that sort of 20%-30% range of full, absolute total reductions. Mm-hmm. And then in the placebo group, seeing reductions of 10, 12, 15%. Mm-hmm. So we're looking for that delta, that mean difference or median difference and that 20% range. Okay. That would be a sort of an overall what one would be looking for. Are we seeing similar results of what's been seen for, say, Epidiolex in the three of the core diseases and- Mm-hmm ... and ganaxolone in its treatment of CDKL5. Right. Okay. So I know this is an all-comers study, but do you have a read on the mix of patients in this study in terms of underlying seizure disorders? Can you talk to that? Sure. We went in assuming we would have ten patients with Dravet- Mm-hmm ... 10 with Lennox-Gastaut, 30 with the other, just a mixture. Where we landed was four with Dravet. Mm-hmm. A little lower than we expected, but probably not surprising, given that the age population in our study only went down to 12. Mm-hmm. and that started a little bit later, and I think most want to intervene in patients with Dravet as early as possible. So in our future studies, when we go down to probably age of two, we think Dravet will be a much more readily accessible population to study. Mm-hmm. LGS, really pleased to see 29 subjects enrolled. Okay. So, that'll be a good database to look at. Mm-hmm. LGS is a fairly heterogeneous disease. So it'll be a good to look at the kind of variability that we see overall. And then in other DEE, no clustering, we just saw a lot of different DEE types. We'll talk about potentially those DEE types in January when we go through this data. Mm-hmm. It will give us that ability of comparing those two large groups- Mm-hmm ... LGS population and DEE other, to see are there similarities, as we talked before, in tolerability, in the adverse event profile- Mm-hmm What do we see qualitatively in terms of seizure reduction? Right. And ultimately, the goal is to take that to the FDA and come to a meeting of the minds, essentially. and not just the FDA. Yeah. We intend to be doing a global program. Mm-hmm. So we'd be taking it to the European regulatory- Okay ... authorities, and we've already been interacting with the Australian regulatory authorities for this and to seek alignment. But yeah, that would be the general approach, is use the data to figure out how to power the study appropriately- Mm-hmm ... to modify inclusion, exclusion criteria, and to set up, you know, one of the pivotal discussions would be in the phase II meeting with FDA next year. Got it. Okay. Can you talk to daily dosing frequency in the PACIFIC study? Sure. Well, daily dosing, there aren't a lot of good examples. Yeah. In fact, I hear... I'm a pediatrician. My colleagues and I, we don't love that- Yeah approach because sometimes a parent spills something or the kid spills it, and you really don't know, did they get all of it? BID, twice-daily dosing is ideal. Mm-hmm. Our current formulation, liquid formulation- Mm-hmm ... administered three times daily, is good. It's acceptable. Mm-hmm. 80% of these patients are fed through a G-tube, so it can be readily administered, but BID is preferable. Okay. Doing one in the morning and one at the end of the day, it's preferable than having to remember to do another one in the middle. Yeah. But these patients are on 9, 10, 11 different medicines. They are dosing these kids in the middle of the day. Sure. It's just BID would be preferable. Yeah. So I guess that leads me to my next question is, do you have a BID? Are you going to move forward with a BID formulation? And to the extent you do so, what kind of bridging work would you have to do? Our intention is to move into a BID formulation for our phase III. Mm-hmm. The studies that we're doing are ongoing, but we anticipate we'll be able to move into a twice-daily formulation. Just going back to something you said, you would argue that even a three times a day formulation would be commercially viable, just given that most of these patients are on a feeding tube, and they're on so many different background medications, that it. It's not ideal, but it wouldn't be a non-starter in your view? Hard to ask the medical guy a commercial question. But, but as a clinician, TID is fine. Yeah. It's just BID is a lot more preferable, but clinicians would not decide to... "I'm not going to prescribe it because it's just too frequent." If it was four times a day, that would be really inconvenient. Yeah for patients, but 3 and 2, it's just 2 is a little bit... It's just a little bit easier. Yeah, understood. Yeah. We don't have a food effect either, so that's helpful when you're thinking- Yeah about the TID formulation. Okay. Can we talk about inclusion/exclusion criteria in PACIFIC regarding background antiepileptic medication and also inclusion/exclusion regarding baseline seizure frequency? Sure. Our study, the PACIFIC study, very similar to all the other studies that are out there, that are being conducted in precedent ones. Typically, these patients are on 3-4 ASMs. Mm-hmm. And we allow for up to four. That doesn't include rescue medication. Most of these patients also have a backup rescue medication- Mm-hmm -for status epilepticus, to interfere with a high frequency of seizures. We do include many of the newer medications. Epidiolex, for example- Yeah would be an allowed medication. Fenfluramine would be, we would not allow. Not allow, okay. Same exact mechanism of action. Mm-hmm. So if someone failed it, or if there was a situation where maybe it just wasn't effective via same mechanism of action, this just wouldn't be a good reason to- Sure ... to include that. But by and large, the inclusion/exclusion criteria that we use is pretty similar. Mm. The minimum criteria for seizures that are required is they need to have four countable motor seizures per month by history in the previous three months. Mm-hmm. And then we have them fill out a daily diary card during the screening period, and we look for that same thing, that minimum of four. Okay. I can tell you, in this, in this population, they- They're having much more. They have much more- Yeah ... than four. Yeah. It's not unusual for, these patients to have a seizure a day- Mm-hmm ... but the biggest challenge for these families is that you can't predict when it's gonna happen. Sure. Okay, that, no, that makes sense. Can you talk to statistical powering, in the trial? I wish I could, but in a 52 patient study- It's not- It's not a 4-to-1 ratio. Yeah. The study was not powered for efficacy. Remember, the major- Yeah ... focus was on safety and tolerability. Okay. So, you know, will we apply statistics? Yes. Will we do comparisons between groups? But I wouldn't anticipate a study that has about 40 patients on drug and about 10 on placebo- Yeah -to demonstrate statistical significance. This is to look at the data and use that data to power the subsequent studies, to be able to ascertain what kind of treatment effect size are we seeing and what kind of variability do we see in the 52 patients that we're assessing. And to be clear, though, you feel like you'd get enough information from this study to then move into a pivotal phase III program? Or do you think that, you know, a phase II, another phase II, you know, could be an intermediate step? I think it's unlikely that there would be an intermediate step. You know, whereas maybe I downplay when I say it's only 52 patients- Mm ... there is an absolute wealth of data that we have. Yeah. I mentioned, well, we have countable motor seizures, but we also measure in daily diary all of the seizures. Sure that these patients have. It's a pretty rich database. Yep. Plus, the safety and tolerability supplements it quite well. And today, we're only talking about top-line data- Mm-hmm ... but in a period of time after that, we'll be releasing, looking at additional data and other ways of looking at treatment response. Mm-hmm. So I think at some point earlier this year, you had guided to data being available the end of this year. Now it's pushed out into early 2024. Anything to read into there as far as that, like, I don't want to even call it delay? I appreciate that. Okay. Yeah. We were actually just narrowing our guidance. So we had said we expected data around year-end. Mm. We just had a bunch of people who kept asking us, "Does that mean December or January? Yeah. We just clarified and said January. Okay. Yeah. So there's really nothing there? No, nothing there. Okay. Yeah. That's helpful. So let's go back to the path forward, which I know that you get these questions asked in maybe 20 different ways. But let's... Another hypothetical here is, let's suppose that the FDA says, "Now, you know, kind of run it the old-fashioned way. Do an LGS program or a Dravet's program."... Does that take a good bit longer to do to get to an NDA, as opposed to doing a DEE kind of umbrella program, if you will? Yeah, and maybe I'll take a step back and kind of just talk about how we're thinking about it in terms of kind of base case- Yeah. Upside case. Yeah, that'd be helpful. So, you know, we've now met lots of advocacy groups, lots of caregivers, and we really feel like the broad DEE approach is really the best thing for patients. Mm-hmm. But we're considering the indication-specific approach as our base case. You know, we think that doing that, where we do three indications simultaneously, think that that's easy for investors to understand in terms of kind of timing, cost- Mm-hmm. number of patients. That's kind of what everybody's done. It's been the kind of the tried-and-the-true method. But when we continue to see this unmet medical need across all those other DEEs, and understanding kind of how our molecule is working, we think it's really suited to treat a broader group of patients, more than just LG, Dravet, and one other indication. Sure. We would really like to look at that, and we really don't think it would be, you know, too different in terms of number of patients and cost and timelines. Mm-hmm. We might actually be able to get some efficiencies out of that type of approach. But again, as Randall mentioned, we'll get our data, we'll go have a conversation with the agency. Yep. But in terms of kind of overall, they're very similar. Got it. Okay. So one more question on the clinical program. What non-clinical work on 352 remains outstanding in order to get you to an NDA? The non-clinical work is pretty routine- Yeah ... It's... It's all kind of in place. Mm-hmm. In this study and in most programs, it's not, none of which is gaining. Some of the studies that you do in non-clinical look over a longer period—longer periods of time, like a year or so- Mm-hmm ... of exposure, often even more. They're all in place, but I wouldn't look at the non-clinical program to find anything interesting from a gating standpoint. We're satisfied with where we are- Mm-hmm ... and don't anticipate much for bumps. Okay. So, I'll ask you this question, Brandi. Is this on the commercial landscape? I know it's early, but I think it's an appropriate question, is on pricing for 352. What's a good comparator here? You know, I look at Epidiolex as one where it's approved in three different seizure types, but it is used pretty broadly. Is that a good way to think about it, or are there other comparators? How do you think about it? Yeah, I mean, I think our pricing really depends on the label that we get. Sure. You know, if we're approved in a few indications, then I could see us using a higher price. And if we have a broader label, then maybe we could consider something that's lower. We usually look at Fintepla as the comparator. You do? Especially considering that our base case is kind of going that indication-specific route. I think when you look at Epidiolex, you have to consider the fact that they had unbranded cannabidiol at people's disposal as well, so they had to take that into consideration when they were pricing Epi as well. Okay. Well, let's switch gears. We have about three minutes left. I want to make sure we talk about LP659. So, S1P receptor modulator, a little bit different, well, more selective. So wanted to... Dr. Kaye, maybe you can go through what about LP659 is differentiated, at least from a receptor biology perspective. Sure. So, when people typically think of S1P receptor modulators, you think, MS- Yep ... multiple sclerosis- Mm-hmm ... neurodegenerative disease. What our approach has been is to create a selective S1P receptor modulator that focuses on S1P1 and S1P5 to some degree, so- Mm-hmm ... not interacting with two and three, which are often sort of the, relatively speaking, bad players that contribute negatively to, from an adverse event profile standpoint. We are excited that we're getting into the clinic- Mm-hmm ... activating our clinical trial site- Mm-hmm ... and are moving into the initial component, which is a single ascending dose study- Mm-hmm ... where we get our first, initial, look at this, novel agent in, Mm-hmm ... first in human. These are healthy volunteers, and then at some point, presumably, you'll do multiple ascending dose work as well. Yeah, always- Yeah ... start with healthy, healthy volunteers. Yeah. Single ascending dose first. But we should start to get some interesting data. Obviously, safety and tolerability- Yeah ... help you figure out what dose we're going to be looking at, but it's your first chance of starting to look at a little bit of the profile, because what's- Mm-hmm ... typical with these agents is you get white blood cell count and lymphocyte reductions- Sure ... and you want to get some specificity there and see what kind of changes we're seeing as we're honing in on the right potential indication that would be most amenable to our compound. Yeah, and speaking of indication, I mean, there's a lot in the class in MS, so presumably, that's not something you'd be willing to pursue. Well, I don't want to put words in your mouth, but what other indications or maybe types of, you know, therapeutic settings might be interesting for a compound like this? Yeah, the inflammatory neurologic conditions are, are definitely a viable option. Sure. There are a number of them that have a high unmet medical need, are treatable from a pharmacologic standpoint- Yep ... but just aren't, don't happen to be, but they are good, very interesting targets. You didn't put words in my mouth, but MS is probably well fulfilled at this point- Yeah ... at least by S1P receptor, agents. Okay, well, we have just about half a minute left, so let's just talk through upcoming milestones and 352 and 659. Yeah, appreciate it. So you know, obviously, we're looking forward to having our data from the PACIFIC study in January. Mm-hmm. We really think there are multiple ways to win with 352, not only in the approved 4 DEEs, but also in broadening the market and looking at other DEEs. And we're really excited to get going and move forward into a phase III program next year. And then also really excited about 659. We've just briefly talked about it this morning- Mm-hmm ... but announced that we've initiated our first study in humans- Mm-hmm ... and so excited about that, and more to come next year on that, too. When you say more to come on that, multiple ascending dose work at some point next year, is that fair? Well, I think we'll have the data from the SAD in the first half, and then- Okay ... we'll get going on the MAD as soon as we can. Got it. Okay, great. Well, we're out of time. Thanks, thanks, Brandi. Thanks, Dr. Kaye, and- Yep, thank you. ... thanks everyone in the audience. Thanks for having us. All right, thank you.