Research team. Really happy to be here with, Longboard Pharmaceuticals CEO, Kevin Lind. Kevin, thanks for joining us. Thank you for having us. Absolutely. All right, so maybe, yeah, I think many people are familiar with Longboard, but at this point, maybe for everyone who's not, you can give an introduction of the company and where things stand today, especially heading into an important data readout early next year. Yeah, thanks. So Longboard has a 20-year history, even though only being a public company for a couple years. So, we spun the company out of Arena Pharmaceuticals, and Arena had this tremendous medicinal chemistry group that, for whatever reason, was able to, on multiple occasions, go after well-understood targets and provide differentiated PK/PD target engagement that has now, on three occasions, translated into a commercially differentiated product. And those are going after targets that the biggest pharma companies in the world went after as well. And so, I started at Arena in 2016 to do the turnaround. Just as a reminder, while we were doing the turnaround, we were having great success, and we realized that in 2019, these neurological molecules had to move forward. But Arena was already in GI, derm, and cardiovascular, and we thought the right thing to do was to pull it out and put it into a different company, where we could actually get the right team members to focus on it, people with the neurological background to really develop these molecules, because we thought, "Look, GI folks dabbling in neuro is usually not a recipe for success." So, we went public in March of 2021, and this is what we've been focused on. The data readouts we have in the first half of next year, so we'll have phase II data, phase Ib /IIa data on 352 in January. We just recently this week announced that LP659, our S1P receptor modulator, moved into the clinic, and we'll have Phase I SAD data on LP659 in the first half of next year. So for our shareholders who were with us from the Series A and from the IPO, I think everybody was really focused on these two big events, and we'll have a significant amount of valuation inflection points over the next first half of next year. Yeah, definitely. Good intro. All right, so maybe we can just level set expectations going into the 352 PACIFIC data. Yeah. Yeah. Gonna run through a few questions. I mean, first- Yeah, do you mind if we take a step back on 352? Yeah, yeah, let's do that. Just a reminder, 352 was designed to be the most selective, most specific 5-HT2C receptor agonist out there. It's actually a super agonist, which means it has greater receptor output than the native ligand. The mechanism of action, we believe, is very well understood. Lorcaserin and fenfluramine have both demonstrated efficacy in these developmental and epileptic encephalopathies across multiple of the developmental and epileptic encephalopathies, so not just Dravet and Lennox-Gastaut, but indications like CDKL5. And so we believe that 5-HT2C is the right mechanism of action for a broad set of DEEs. We have no activity on 5-HT2B. 5-HT2B is well understood to be the bad actor for pulmonary arterial hypertension and valvulopathy, which caused fenfluramine to originally be pulled from the market and almost bankrupt one of the biggest pharma companies in the world. And so we think that our differentiated profile should create a situation where we are safe and easy add-on to current standard of care, and that's really the name of the game in these DEEs, a safe, easy to add on to current standard of care, because unfortunately these patients are not going seizure-free for the most part. And so we believe that there's a tremendous opportunity in this space. Polytherapy is going to be the norm. We're gonna be used in combination with other molecules. Most of these patients are gonna be on three or four concomitant meds, but they're still gonna be having hundreds, if not thousands, of seizures a year, which is incredibly challenging for everyone involved. So we're running a 52-patient study. It's 4-to-1 randomization. Patients start on 6 mg. If they can tolerate 6 mg they move to 9. If they can tolerate 9, they move to 12 mg. And there's a two-week titration period, followed by two months of maintenance, and then patients can move into the open-label extension. To date, we've had 100% of our patients move into the open-label extension, which is a nice thing to have. It gives us that long-term safety data that we're looking for, as we move the molecule forward. What we've said is we have 40 adults, 12 adolescents. When we started the study, we hadn't completed juvenile tox. When we spun out of Arena, we were moving as quickly as possible to advance this molecule along. So we started in adults, and then we moved down to 12-year-olds. We expect to be in two and older for phase III. We think that'll help enrollment along the way, but there's a tremendous unmet need in adults today. As I said, 40 adults, 12 peds. We'll have four patients in Dravet, we'll have 29 patients in Lennox-Gastaut, and 19 patients with other DEEs. And we'll be looking at seizure reduction versus the baseline, which is the lead-in period, which is a five-week period. Based on that data set, we'll think about how we move forward. Yeah, that makes sense. Maybe you could also quickly recap the healthy volunteer data. Oh, yeah. Yeah. Yeah, well, let me just take a quick step back. So again, mechanism of action, we think is very well understood across lorcaserin, fenfluramine, and 352. We have no detectable activity at 5-HT2B and no detectable activity at 5-HT2A. 5-HT2B, I already talked about, bad actor, pulmonary arterial hypertension, and valvulopathy. 5-HT2A is really psilocybin, and you really don't want to push that. If you give patient, or not patients, but you give people too much psilocybin, they can actually have seizures. That's not a good thing. It also is associated with insomnia. So the fact that we don't hit 2B or 2A gives us great comfort that we're going in the right direction, and that is the common denominator across lorcaserin, fenfluramine, and 352. In preclinical studies, we demonstrated efficacy where fenfluramine and lorcaserin did. And we then actually, in the preclinical models, where they didn't, which is a good thing. Again, it supports that we are working with the right mechanism of action. In our phase I study, we found no food effects. We found dose-dependent increases, time-dependent increases in exposure. We had side effects that were considered on target, so serotonergic side effects, headache, nausea, those types of things, which we were expecting to see. If you don't see those, you probably don't have a drug. We saw transient increases in prolactin. Fenfluramine, lorcaserin also showed transient increases in prolactin. You don't want sustained in this patient population, but the transient increase in prolactin is a surrogate for serotonergic engagement. And so we ran the SAD and the MAD. We have four-page posters on each in our, on our website, if anyone is interested in looking at them. And then we ran a CSF study, where we looked at translation from plasma to the CSF, and we saw great translation there. Beautiful R squared. So the drug really gets into the brain really well, and our 6 mg dose and our and our 12 mg dose really ring-fenced the Ki. So we think we've got the right dose, and it's consistent with what we saw on the MAD, where we were able to push patients up to 24 mg. But we started to see some side effects that made us think that we should back away from that dose at that level. Got it. All right, go ahead. No, does that - did that help? Yep. No, that's perfect. All right. All right, so turning over and framing expectations. Yeah. ... for the PACIFIC readout, I think maybe the first place to start is, what is a clinically meaningful% reduction in seizure frequency, and is that placebo, absolute? Yeah. What do you think about that? Well, great question. So first of all, most of the phase IIIs in this space have been about 100-150 patients. It's not powered for stat sig, right? At 52 patients, it's gonna be small. What's meaningful? Let's start with originally, seizures are not normally distributed. So we're gonna look at both mean and median. Phase III, you'll have more ends, so you'll actually look at mean. That's traditionally the regulatory endpoint. But imagine a world where we just had three patients on drug, and two patients went completely seizure-free, and one patient got sick from COVID over the summer, got a fever. Fever causes increases in seizures. Imagine that patient had a 300% increase in seizures. From a mean perspective, you would have no drug, right? You actually caused worsening. From a median perspective, you would say, "Oh, my gosh, I caused seizure freedom," which... And really, in actuality, it's somewhere in between. So we're gonna look at both mean and median in our data set. We've run significant qual and quant surveys with physicians who treat the space, and consistently, what comes back is, safe and easy to add on to current standard of care is considered preferable to increased seizure reduction. Efficacy is not the end-all, be-all here. It really isn't. These kids are not going seizure-free. Safety, caregiver burden, that echocardiogram requirement for fenfluramine every six months is a massive issue. And then the last piece is drug-drug interaction is a significant issue because these patients are on polytherapy. So if you think about adding in a new medication, taking one away, you don't want to have to think about taking two medications off. And we work through the UGT pathway, so not the S1P pathway, so we don't think we'll have some of those same drug-drug interactions that some of the other, molecules in the space, have that are problematic. So long way of getting back to what's meaningful. We know that 26% absolute seizure reduction was an approved drug for fenfluramine in Lennox-Gastaut. We know that 31% absolute seizure reduction was approved drug for zonisamide, ganaxolone. Cannabidiol had about 40% absolute seizure reduction. That's a great thing to talk to physicians about. Everybody loves talking about 40%. So if you talk to our marketing, head of marketing, and our head of med affairs, both of whom came from GW, they love talking about 40% because it sounds great to physicians. The clin ops, clin dev folks want to see placebo-adjusted because it allows them to power the phase III study. And if you look at it, cannabidiol's placebo-adjusted seizure reduction in Lennox-Gastaut is 22%, which is actually not that different from fenfluramine's placebo-adjusted effect in Lennox-Gastaut as well. So we're looking for somewhere in that range of, you know, 20% delta from placebo, but it doesn't have to be, because again, placebos bounced between 7% and 27% in these patients. So we're going to look at both absolute and placebo-adjusted. What we're really looking for is not precision on placebo counting, what you want is consistency. Because these parents need to be consistent. You're not trying to capture every single seizure that occurs, but you want consistency along the way. As we think about it, all those factors are blending together to think about how would we move forward and how would we think about it. But you know, again, generally, those are the four things. Oh, the last thing is, based on the ends, we might not see a dose response. I could imagine a world, right? So all these other medications are done with mg per kg per day. When we initiated the study, we were only in adults. We then completed juvenile tox, as I said. This study is only in mg per day. So I could imagine a world where we get equal numbers of patients on 6 mg, 9 mg, 12 mg. I could also imagine a world where we have a handful of patients on 6, and the rest are all on 12. We think that the way the molecule will be used is closer to cannabidiol. So cannabidiol is really about finding that top dose, and then physicians play in that safety and efficacy land underneath that top dose. Versus, we believe Fintepla, if you're really going to go through all the hassles of the echocardiograms every six months, if you're going to go through the REMS, if you're going to take that safety liability on, you're probably pushing for that incremental efficacy, and you're really trying to push for that top dose. We don't think that that's probably how 352 is going to be used. We want patients to get on the drug in a safe, easy-to-add-on manner and then go from there. Very well said. That's clear. Maybe also kind of lay out how much granularity we should expect with this redux. I mean, there are a lot of other DEEs. Will we see those broken out in a lot of detail, or what are your current thoughts there? You know, I think what we'll do, and we're working our way through all that right now, because the data is coming in January. We'll probably break out Dravet, Lennox-Gastaut, other DEE. Small ends, 19 other DEEs. I'm not sure it really makes sense to pull out each incremental DEE along the way. I think it'll be interesting, but it probably isn't going to be there for top-line data, and frankly, we want to learn some more along the way. We're going to try and be as disclosive as possible, but again, there's only so much you can do in looking at the top-line data versus then waiting and getting data for additional things. So we're trying to find that balance. But my sense is we'll give seizure reduction across the various DEEs, and that should help us articulate to investors where we're going to go with this molecule. Right now, we feel really confident that the four patients in Dravet should give us enough of a signal because we know fenfluramine and lorcaserin work in Dravet. The right study to do is the phase III in Dravet, not a small one to 20 patient study. You just have to run the big study. But we know that fenfluramine and lorcaserin work. We feel incredibly confident that 5-HT2C makes sense. Lennox-Gastaut, having 29 patients is really beneficial to us because that was the indication where fenfluramine had the lowest effect, so we think the bar is low, so we can generate interest. And then the other thing is, we want to be able to power that phase III, and that's where they had the least delta versus of effect. So we want to make sure we can power that phase III the right way. And then those last 19 patients give us the opportunity to have the conversation with the regulatory agencies on changing the regulatory pathway forward. Now, we're telling investors to not plan on a DEE basket approach for the phase III. We think that that is the right thing for patients, we think that's the right thing for science, and we think that that's the right thing for this mechanism of action. But we don't want to create a situation where investors are sitting there waiting for the end of phase II meeting. What we're telling investors is, assume we're going to do a phase III in Dravet, a phase III in Lennox-Gastaut, and a phase III in a third indication. It might be TSC, it might be something else. We'll see. The costs of those are well understood. They are generally about 100-150 patients. They're around $30 million-$40 million each, and we can do those in a timely fashion. Interestingly, if we can change the regulatory pathway to the other DEE, we have... It's not just the PACIFIC Study supersized. We have some interesting creative thoughts around how we would do that with multiple shots on goal. The cost is about the same. The timeline is about the same. The only thing we're waiting on is that PTRS, which includes technical and regulatory success. So we need to see the PACIFIC data to get to that technical success, and then we need to have the conversation with the agency on the regulatory success. Unless it is really compelling to go after the other DEE, we'll just follow what everybody else does, because we think we can have a multi-billion dollar drug just doing what Epidiolex or fenfluramine have done. Great. Maybe quick question on the commercial side, then. Yeah. Do we have a sense today for Fintepla, how concentrated the prescribing is, and in which types of providers? Like, I know, AES is coming up. You probably have a lot of HCP meetings there. So maybe you could give us a sense, kind of the inbound interest. Yeah, I think there's a tremendous amount of inbound interest in this molecule. We ran across that 100-physician quant survey. We said, "Look, take LGS data for Epidiolex," which was their least efficacious indication. And we said, "All right, would you use 352 or Fintepla?" And 74% of physicians would prefer 352 over Fintepla. I think that speaks to some of the question you asked, right? Some of these physicians are very comfortable with Fintepla, and they're comfortable because they have really great access to a cardiologist, and they have really good access to payer reimbursement. But we think there's a significant number of physicians who just aren't even using it. Really interesting to me is even amongst the physicians who feel comfortable with the drug, who bring it up to the parents, 25% of the time, the parents reject the drug. That's a pretty high number for somebody- for a physician to say, "Your kid has this devastating disease. I think you should be on this drug," for the parent to say, "I am not comfortable with the cardiovascular liability of that drug. I'm not comfortable with that burden. Yeah. And do you have a sense for, you know, how many of these, maybe more community-focused providers and those who are less familiar with Fintepla, do you have any early sense how much LP352 could open up those providers? I think it's... So I'll go at it a slightly different way. UCB has said they think peak sales are going to be EUR 800 million. That's fantastic. I mean, that would be a great outcome for a company our size. But if you think about it, today, they're $150,000 a year, assume peak sales are $200,000 a year, somewhere in that range. That's 4,000-6,500 patients. The U.S. Dravet market is 21,000 patients. Lennox-Gastaut is 48,000 patients. They're going to capture maybe a quarter of U.S. Dravet with no LGS, nothing in Europe. I think it speaks to how niche that product is going to be. Now, EUR 800 million niche product, but still not capturing the vast majority of these patients that are available, because we know these patients are still having hundreds to thousands of seizures a year. Got it. Maybe just to squeeze a quick one in on 659. Yeah, obviously, 352 is kind of the near-term focus, but for 659, maybe you could help us frame the initial healthy volunteer data. I mean- Yeah. So look, there are four other, five other approved S1P receptor modulators. Etrasimod, which was created at the same time as 659, is the most recent. Super exciting. The etrasimod designed to be peripherally restrictive, our molecule designed to cross the blood-brain barrier, be centrally acting. The vast majority of sales for S1Ps have been in the CNS, predominantly in MS. We don't expect to go after MS. We don't think the world needs a fifth S1P, but we do think there are significant orphan indications in the CNS where lymphocyte reduction will matter. So we'll look at T cells, B cells. We'll look at recovery to baseline. That's been a problem for fingolimod and some of these others with very long half-lives. And then, obviously, we'll look at some of the side effect profiles, bradycardia, which are probably not as meaningful in an orphan indication that we're going to go after, but it might be in a couple of them. So it's going to really depend on which indication we go after as to which ones are the most meaningful factors along the way, but we're going to be looking at all those things, and we'll be able to compare us to fingolimod, siponimod, and ponesimod, and ozanimod. Yeah, sounds great. I think that just about does it for today. Really appreciate you joining, Kevin, and look forward to hearing more soon. Hey, thanks for accommodating us so close to AES, so I can just bounce up to Orlando. Take care.