Appreciate it. As we enter the afternoon on Wednesday at the Leerink Partners Conference. I'm Marc Goodman, one of the biopharma analysts, and we now have LB Pharmaceuticals, and thank you, Heather Turner, CEO, of the company. This is one of our favorite companies. The company went public not that long ago. Yeah. Are you having fun being a public entity? Oh, I mean, it's really exciting being a public entity. Yeah? Yeah. What's the good? The goal is access to capital. Uh-huh. Right? I mean. Okay. That is good. I mean, we were able to raise $300 million in the IPO, and we were able to do a PIPE last month, where we raised another $100 million, which now fully funds an opportunity to expand. Yeah into three programs. Yeah. Which we'll get into, but so, but yeah, I guess that is a positive. There's really not been any negatives yet because it's too early, right? That's right. Well, we also knew what we were getting ourselves into. 'Cause you've done this before. A lot of us have been there, done that, so we actually had a pretty good sense of what it is to be public. Yeah. Yeah. Let's talk about LB-102. Let's talk about where it came from. Maybe just give us a little bit of a history. Yeah. LB- 102 was founded in the late 2000s. It was really founded to see if there was an opportunity to improve upon amisulpride. Amisulpride is a generic antipsychotic that's approved around the world, widely used even to this day. It was originally approved in the late 1980s and continues to be used. It's considered one of the most efficacious and one of the more safe and tolerable antipsychotics. It does have a challenge though. It has very poor blood-brain barrier permeability, and this results in the need for high doses as well as twice daily dosing, which in the populations that we're talking about can be challenging. The founders of LB thought that if there was an opportunity to improve upon this permeability, that they could create a new chemical entity that could then result in issued composition of matter IP and have an opportunity to bring it to the United States. They did this through methylating the molecule. This methylation improved the lipophilicity, which enabled more efficient transport into the CNS. We also then observed a longer residence time in the CNS, and this then led to an opportunity for lower doses and once daily dosing. What we were able to determine is that 50 milligrams of LB-102 is about the same as 70% or 400 milligrams of amisulpride. Both of those have about 70% dopamine receptor occupancy. We did in fact achieve a molecule that is a new chemical entity, does have issued composition of matter intellectual property that takes us out to 2041, 2042, depending on the patent term extension, and is much more potent. Yeah. What work was done early with the molecule? Early on, we did all of the work that you would need to do to get it into the clinic and. Yeah be treated for patients. One of the most important things that we did though was look at dopamine receptor occupancy in humans through PET receptor occupancy data, and that's really where you can start to see if you have a molecule that'll be therapeutic in schizophrenia. We know from prior studies that there is a biomarker of efficacy in schizophrenia, which is if you have dopamine receptor occupancy in the range of 60%-80%, then you would be efficacious in schizophrenia. That's why we did that work. That's how we got comfortable with the fact that we have a molecule that we think will work in schizophrenia. Those metrics hold true for your molecule too? That's right. Okay. What we determined in our Phase one trial was that we have about 70% dopamine receptor occupancy at the 50-milligram dose and about 80% at the 100-milligram dose. That's how you determined 50 was gonna be your dose basically. For the Phase three trial, we're bringing two doses. We're bringing both 50 and 100. In the Phase two schizophrenia trial, we had highly statistically significant results at each of the doses studied. We studied 50, 75, and 100. Mm-hmm. We didn't see a whole lot of difference between 50 and 75, so we decided for Phase three we would take 50 and 100 into the Phase three trial. Talk about the Phase two study a little bit. We're about a year and a few months from data, great data. Talk about, you know, what- Yeah. Like I said, we evaluated three doses. Each of those doses were highly statistically significant. Importantly, we saw a clinically meaningful reduction in the PANSS total. Mm-hmm. The improvement that we saw took these patients out of an acute schizophrenia state and into a more stabilized state, which for these patients means they can leave the hospital, which is quite meaningful. We also had a nice placebo rate. This was something that we were focused on. We appreciate the risks of placebo, so we had implemented a number of measures to help manage that placebo rate. We had a central rater that provided QC over the local raters. We had a vendor to help us identify professional patients. We also were very judicious in the scales that we chose to use in the Phase two trial. We know that using too many scales or scales that take too long to complete can really contribute to patient and/or rater fatigue. Mm-hmm. We knew that that's a risk, the placebo rate, so we were very careful. All of these measures are measures we are implementing in the Phase three trial. Yeah as well. The other thing that we measured in the Phase two trial, which we think will be very interesting, is cognition. We measured cognition utilizing Cogstate, which is a battery of tests that is used to assess an impact on cognition. We assessed it at baseline and day 28, and what we found was a very robust dose-dependent response, one that at each dose was statistically significantly better than placebo. Importantly, we didn't have to enrich the patient population for those with severe impairment at baseline. We were able to see this kind of effect in a broader patient population. At the 100 mg dose, we saw a treatment effect of 0.66, which is quite high for cognition. Cognition is an interesting domain. It's a domain that runs across many different CNS disorders. In schizophrenia, 80% of patients have some form of cognitive impairment. When you look at bipolar depression and MDD, 40%-60% of patients have some form of cognitive impairment. Demonstrating a benefit in cognition is something that we think can really differentiate LB-102 in a number of different indications that we're pursuing. Let's go back and just talk about what is the mechanism of action of amisulpride, how does it work, and then what made you think that it would work in cognition? Like, what's the- Yeah, the scientific belief? Amisulpride and LB- 102 are two highly selective molecules, so we were able to retain the binding profile of Amisulpride. LB- 102 is a very selective inhibitor of D2, D3, and 5-HT7. Mm-hmm. D2 is obviously important. That's really where you get the antipsychotic effect. That's really how you can, you know, block dopamine. D3 and 5-HT7 have both been implicated in antidepressant as well as being pro-cognitive. The other interesting attribute of Amisulpride, which also applies to LB- 102, is that it preferentially can select for the presynaptic Autoreceptors that are implicated in mood, cognition, and anhedonia, which is an inability to feel joy. This then means that for Amisulpride at high doses, it blocks dopamine. At low doses, though, it actually triggers the signaling and release of dopamine. This means that through dose, you can treat a wide range of indications, and this is an attribute that LB- 102 also has. Right. It's those combination of things that give us hope with cognition. In the Phase two on the PANSS, what was baseline PANSS, and where did patients move to on average? Baseline PANSS in our study was 94, and what we saw was a range of a total PANSS reduction of 14-16, so it took those patients out of acute schizophrenia, which is defined as a PANSS score of 80 and above. Right. Okay. They're all 80-ish or whatever. The placebo, how did the placebo do? The placebo was 9.3, which is on the lower side, but not as low as we've seen when it comes to, schizophrenia trials. Right. The delta was. Somewhere on the order of five-seven. five-seven. Yeah, exactly. That's pretty good. I mean, that's a very strong outcome. Yeah. Schizophrenia is similar to other CNS related disorders where efficacy is really the entry ticket. You need to have competitive efficacy. Patients or physicians need to know if a patient is suffering from acute symptoms of schizophrenia, that they can stabilize that patient. Once they know that, it then becomes, "Can I keep the patient on the drug? What's the safety and tolerability profile? Does it treat unmet needs that my patient currently isn't getting?" That really then becomes the calculus as to whether or not it's the drug of choice. Perfect segue to describing safety. Start with, these are the adverse events that you would expect given the long history of amisulpride, and here's the adverse events that we're seeing with our version. Amisulpride's a D2 antagonist, so it, you would expect to see EPS. You would expect to see increases in prolactin, because of the mechanism of the drug. It also tends to have other adverse events, anxiety, insomnia, that kind of thing. What we saw with LB- 102 in our Phase two trial was a very low rate of EPS. At the 50 milligram dose, we had one case of EPS. At the 100 milligram dose, we had two cases of EPS. To put it into context, at 100 milligrams, we saw a rate of EPS of about 5.6%. When you look at Amisulpride, it tends to have a rate in the teens. It really depends on the context in which it's studied, but it tends to have a rate in the teens. When you think about Vraylar, which is a partial agonist, which current estimates have it reaching $5 billion in sales, has a rate of EPS on the order of 24%-32%. EPS is something that's present with antipsychotics, and the fact that we saw such a low rate of EPS can really be a differentiator. This will be true not just in schizophrenia, but also in bipolar depression and adjunctive MDD. With respect to prolactin increase, you do expect to see a prolactin increase because of the mechanism. What we observed, though, was very, very few adverse events associated with that increase. None of them led to discontinuation, and it was in the range of 1%-5.6%. It was also lower than amisulpride, I think particularly because we were able to have a more potent dose. We have less systemic exposure. Yeah, what about anxiety, insomnia? Did you see that? We did see anxiety, insomnia in our Phase two trial. Those were the most reported adverse events. I think it's important to note that for insomnia, that tends to be a comorbid condition to schizophrenia, so a lot of patients came into our trial with a history of insomnia. Mm-hmm. It's something to just keep into account when you're looking at the numbers. We did see that. Yeah. It was not a whole lot different than placebo in terms of the adverse events that we observed, and mild to moderate, very low rate of discontinuation. Let's come back to the Phase three, which the design is the same as the Phase two, right? Just one less arm. Just one less arm, so got two doses. Where are we? When did the study start? How many patients? The study will start. Where are we enrolled? We're on track to start that study this month. Okay. We're anticipating the data to come in the second half of 2027. Mm-hmm. Targeting 460 patients at 25 sites in the United States. Again, it'll be a three-arm study. Hopefully, that helps the placebo rate, going from four arms to three arms. Yeah. Have you hired a lot of people internally to go out and, you know, kinda check these sites and make sure that they're, you know- We've been doing- the right sites? We've been doing quite a bit of work on hiring. You know, getting ready for all of the trials. Yeah. It is critically important that you do quite a bit of work on the site feasibility and the site evaluation. This is something that we also have partnered very closely with our CRO. We're using the same CRO that we used in Phase two for Phase three We know the team very well. We've developed. Which team is that? This is worldwide. Oh, yeah. Yeah. We know them very well. We've worked very closely with them. We have a strong relationship with them. A lot of the sites that we used in Phase two will also be used in Phase three, so there's some overlap there with the sites. Of course, we have familiarity with those sites as well. You said 25? 25 sites in the U.S. 25 U.S. sites. Mm-hmm. How much of that is overlap with the? It's more than half. Oh, good. Yeah. It's a group we know. Yeah. Which is great. Good. We're kicking that off on schizophrenia. Now let's talk about bipolar depression. Why should it work in bipolar depression? Why are we kinda doing this, and then what's the plan program? Yeah. There are a number of reasons why we think LB-102 will work in bipolar depression. First is mechanistic, second is the clinical history of Amisulpride, and the third is the way we've designed our clinical trial. With respect to the mechanistic reason, we talked about before that LB-102 is a selective inhibitor of D2, D3, and 5-HT7. We know that D3 and 5-HT7 have been implicated in antidepressant properties as well as being pro-cognitive. We also know that LB-102 possesses an attribute that is specific to amisulpride, which is it engages these presynaptic Autoreceptors, which means that at lower doses, it actually triggers the release of dopamine. Mechanistically, we think there's a strong rationale for why it would work. In addition, there's a lot of clinical history of Amisulpride. Amisulpride does have a labeled indication in negative symptoms. Negative symptoms carries many of the same properties as depression, anhedonia being one of the most present. It has been shown in three randomized placebo-controlled trials to be statistically significantly better than placebo in treating patients with predominantly negative symptoms. It also has been shown in depression trials to be as good, if not better than Zoloft and Paxil, and it also has shown against placebo to have a MADRS delta of around 4.8. It's been shown clinically to be highly efficacious in treating these depressive-like symptoms. Yeah. We've also designed the Phase two trial in bipolar depression to really give us what we think is an elegant design that allows us to evaluate two doses in a two-arm trial while minimizing that placebo rate. Placebo rate is one of the largest risks for these depression trials, and so the more you can manage that, the better. Keeping it to a two-arm trial, we think, is one way to really manage that placebo rate. What's the dose? For bipolar depression, we're targeting 25 and 50. Mm-hmm. All patients will start at 25 milligrams. If they haven't seen an improvement based on the CGI scale, they will escalate in a blinded protocol guided fashion. It's a six-week trial, they'll have three weeks on that first dose before it gets assessed at the end of week three. Primary endpoint is change from MADRS 10, which is the regulatory accepted endpoint for depression. Mm-hmm. In that trial, we'll also be prospectively studying anhedonia and cognition. As I mentioned, we think these are two areas where LB-102 might really differentiate. Prospectively studying that rather than looking at it in an ad hoc basis based on the MADRS subfactors, we think is an important thing for us to do. What's the anhedonia scale? I think it's gonna be SHAPS. Yeah. That's what's usually used. Yeah. Okay. That's the standard. For cognition, it's. It's DSST. DSST. Yep. It's all pretty standard. Yep. What's the plan? When does that kick in? That trial started, so that trial was initiated earlier this quarter. The plan for that is data in the first quarter of 2028, and that's all U.S. Right. Are you thinking that this is gonna take a little longer? Yeah. Generally with bipolar depression, you assume a bit higher of a screen failure rate because you really need to make sure you're getting the right patients in this trial. You wanna make sure that these patients have experienced at least one manic event. Right diagnosis of bipolar. You're working with Worldwide on this as well? Mm-hmm. Are you also working with anybody else, like other vendors or- We have a number of other vendors that we're engaged with on. Like, to double check and triple check all the Yeah. We've got the central raters and we've got vendors to help us identify professional patients and- Yeah. Are you using the group out of MGH? We're using SAFER. Yeah, you're using SAFER. Does SAFER work with the schizophrenia studies also? It's not a part of schizophrenia. It's only depression, right? That's right. Yeah. That's what they do. That's right. They'll help you with this study and then the one we're about to talk about. That's exactly right. Yeah. I always find that, I mean, it's helpful. Why not pay them? If it helps manage that placebo rate, it's well worth it. I know. I kinda feel the same way. It's definitely. Yeah. It does lead to a higher screen failure rate, so you do have to account for a little bit longer of a study. That's okay. As long... That's okay. Exactly. Yeah. That's like, yeah, exactly. Okay. Let's talk about the powering of that study before we move to the next study. What's kind of the expectation here? The expectation for that trial is we've powered it at 80% to a MADRS change of four. Okay. Again, that's MADRS 10. Yeah. Yeah. Yeah. Okay. Now the next study. What's the plan there and why? Yeah. We just completed a PIPE last month, which has enabled us to raise the capital to now pursue an adjunctive MDD trial. This development path where you start in schizophrenia, move into bipolar depression, and then move into adjunctive MDD is actually a very well-trodden development path. You get the benefit of the safety population from schizophrenia, which is at the highest dose. Yeah. You can then leverage that and use that for these other indications. You also can get the antipsychotic pricing from schizophrenia that you can then pull through these other indications. There's a method to starting in schizophrenia and moving into. Yeah bipolar depression and then adjunctive MDD. With the capital that we raised in the PIPE, we're able to do a Phase two trial that's going to be designed to be registrational, similar to what we did in our Phase two schizophrenia and also what we did with the bipolar depression trial. This will be a trial that will be in both U.S. and Europe, so it'll be a global trial. It'll also be a fixed flexible dose design. Here, we'll start at 15. At the end of week three, if you haven't seen an improvement, there will be a protocol guided blinded escalation to 25, and then that's where they stay for the rest of that trial. As you think about dose, I mentioned this idea that at higher doses you're blocking dopamine, but because of our mechanism at lower doses, you're actually triggering the release of dopamine. In bipolar depression, you need a little bit more dopamine blockade because you wanna make sure these patients don't suffer from a manic event. In depression you don't have that same risk, so you can go lower in dose. In fact, you don't want too much dopamine blockade because that can actually create symptoms akin to depression, like apathy. Yeah. You're trying to thread this needle where you can have that depression efficacy without going too high on the dopamine receptor occupancy. Okay. How big is the study gonna be? The MDD trial is gonna be about 380 patients, and again, that'll be global. Mm-hmm. The plan is to get that trial started in early 2027 with a data readout in first half of 2029. Okay. MADRS, what's the- MADRS 10 Right, MADRS 10. is the primary endpoint. Same endpoint. Same, yep. Yeah, yeah. Again, six-week trial, same exact design as the bipolar depression. Right, right, exactly. I guess while we're doing all this, we're thinking about the commercial opportunities and stuff. How do you think about, you know, the three buckets here commercially? For schizophrenia, I want us to be in a position to have all the capability and the wherewithal to launch. With one successful Phase three trial, we think we can seek approval in schizophrenia, so we're doing all that we need to do to put ourselves in a position to seek approval. That's also because you already have one positive study. It's 'cause we have one. We also think that New England Journal article helps. Yeah you know, support the strategy. We hope. We hope. Yes, that's right. We, you know, think that Phase two trial is an adequate and well-controlled trial. Right. We did bring on a chief commercial officer. She joined us towards the end of last year. She's highly experienced and has launched schizophrenia drugs as well as depression drugs. Even though we have a lot of time to data, we plan to use that time really well and really start to develop the positioning, making sure we've got the evidence that we need for the value dossiers. We're actually doing quite a bit of planning work on the commercial side to put us in a position to launch. My plan with respect to schizophrenia is launch. Right. Um- Right. We'll have data and talk about after we have the efficacy data, how many patients, how many safety data. Yeah patients, you know, like the gating issue. Yeah. I wanna get to manufacturing. Don't let me forget about it. At the same time that we're doing this Phase three schizophrenia trial, we're also initiating an open-label safety trial. That will allow us to accrue the safety population that we need. FDA's been pretty clear you need 1,500 patient exposures. Mm-hmm. 100 of those need to be at a year, 300 of those need to be at six months. Yep. The plan is to use that open label trial. Patients from the Phase three will roll into that open label trial. We'll also enroll de novo patients. Oh, overall as well. Mm-hmm. Okay. This is gonna be an outpatient trial by definition, so these will be stabilized patients. It'll be 52 weeks in duration. We also are gonna be looking at both cognition and negative symptoms in this open label trial. We think it's a nice opportunity to learn more about the effect on those two domains. It'll be over a longer period of time and in a stabilized patient population. Will you be looking at all three of them in the schizophrenia, the regular part of the? We'll be looking at all three in schizophrenia too. Yeah. In the Phase three. Yeah. There's reason to believe that you can have some cognitive benefit. We- We know that there should be some negative symptoms benefit, right? Yep. Amisulpride has demonstrated kind of both. Exactly. I mean, I'm just trying to think about the three domains of schizophrenia and can we hit all three? Yeah, I think there's an opportunity here for LB-102. Yeah. You know, of course, we have to study it in the appropriate population in order to get the labeled claim for cognition. Yep. FDA's been pretty clear that you need to study it in stabilized patients. Yeah. I think that, you know, learning more about the effect will be helpful, will be publishable at the time that we launch. It should give us some nice information on not just dose, but effect as well. Right. Amisulpride actually helped all, so. Yeah, there's actually some data on amisulpride at being pro-cognitive as well. I'm curious. This is kind of a strategy question, which is, instead of doing, for instance, two schizophrenia studies, you're running one. Mm-hmm. If it were to fail, you know. You'd have to run another one to get schizophrenia and you went right into bipolar depression. I think you know where the question's going, right? One study. Mm-hmm. We’re right at MDD adjunctive one study. Rather than doing, for instance, two bipolar depressions. You know, I’m just- Yeah If you understand what I'm saying. What was the strategy behind that and how you're thinking? In terms of the decision as to whether you do one more Phase three schizophrenia or two bipolar depression. Yeah One of the things that we thought was really important with respect to bipolar depression was to really get information on dose. Remember that trial is designed to evaluate two doses. Mm-hmm. It's designed to evaluate 25 and 50 milligrams in that patient population. I would like to have that information before I did another bipolar depression trial. Yeah. Ideally, it would be a Phase three trial that we do next. Right. Coming out of this, we'll have a lot more information on those doses. With respect to schizophrenia, based on everything that we've looked at in our Phase two trial, we think that is a very robust trial. It's got sensitivity analyses that you would expect. It's got the conservative imputation for missing data, and all of that is supportive of the primary endpoint. Yeah. Statistically, we think that Phase two trial is really robust and should and would meet the standards of an adequate and well-controlled trial, which gives us quite a bit of confidence heading into the Phase three. Talk about manufacturing CMC. Just, you know, just give us a little information on that, where we are. It's really important. That much I know. That's why I asked. You need to have clinical supply. You know, that's a small molecule, so we've been working hard to scale that and have it ready for commercial launch. The dose that we're intending to use in the Phase three trial is the one that we would intend to launch with in schizophrenia. There are opportunities, I think, to continue to improve upon the formulation. For MDD, we'll likely use a formulation that has a little bit more improvement on the cost of goods, for example. Nothing that we think would be sort of out of the ordinary in that regard. From a CMC perspective, we're highly confident in the formulation and in the clinical supply. Well, you've obviously already scaled up to a certain extent 'cause you're using the batches for Phase three. That's right. right? That's right. We're there. That's right. It's really a question of whether you can optimize- Yeah on the COGS. How are you thinking about an LAI? Is that possible? It is. With the 50-milligram success, we do believe that an LAI is feasible. This is something that we're exploring and are optimistic over the course of the next year, we'll be able to come through with the development candidate. We do think there's a lot of opportunity for LAI. It's a $6 billion market. Right now, it tends to be more popular in Europe. The thing that's interesting about it is it would open up a global opportunity in schizophrenia. Amisulpride is not amenable to a long-acting injectable. The dose is just too high. Right. This would provide an opportunity to go into jurisdictions where amisulpride has been approved. Yeah. It would, of course, create a whole new IP portfolio. Right. Right. So. Right. Where is that process now, let's say? We're in the- We're working with a company outside. We're looking at a number of different formulations. Yeah to see how feasible it is. Different companies who- Trying to figure out what the right TPP is. Yeah. Making sure that we've got a competitive, long-acting injectable. We know, for example, subcutaneous is important versus intramuscular. Yeah. We know needle gauge is important, right? Yeah. We're looking at a lot of different things. Yeah, that would be really interesting because not only for the U.S., but, like, to go back to Europe with that, I mean. Yeah, it's even, you know, being contemplated for use in bipolar depression. Yeah. Right? It's another patient population where adherence has been a bit of a challenge. Right You know, having an opportunity to provide that, I think, could be really helpful to those patients. Yeah. Anything that we didn't hit on? I mean, anything you wanna say? Anything like that that you- You know, I think just I'll reiterate that I think LB-102 is a very interesting molecule. It has an opportunity to go into a number of indications beyond just the mood disorders and the schizophrenia that we talked about today. There's this opportunity to really address a lot of unmet need that persists across all of these indications. Cognition, anhedonia are all unmet need that continue to persist in all of these indications. Seeing a benefit in that could really be differentiating. Thank you. Thanks for joining us. Yeah, thank you so much. Yeah. Appreciate it. Really appreciate it.