Great. It's my pleasure to be moderating this panel with Heather Turner, CEO of LB Pharmaceuticals. LB is a company that recently went public this fall, and they're developing a novel antipsychotic for schizophrenia and mood disorders. Maybe with that, Heather, I'll let you just give a brief overview on the company, and then we'll do Q&A. Sound good?
Yeah, sounds great.
Awesome.
LB Pharmaceuticals' vision is to create a fully integrated CNS company that is intent on meaningfully improving the lives of patients. The company was founded in 2015 with the goal of creating a derivative of amisulpride that could improve upon the blood-brain barrier penetration and the potency of the molecule. Based on the phase I data and the phase II data, we think that our asset, LB-102, has achieved those objectives. We announced phase II clinical trial data this year, and in that trial, we observed a highly statistically significant efficacy at each of the doses studied. Also, the potential for a class-leading safety profile among the D2 antagonists and the partial agonists, and a surprisingly compelling effect on cognition, something that we'd like to continue to pursue. We also had a really nice engagement with FDA.
In that engagement with FDA, we have an opportunity now to pursue approval in schizophrenia with just one successful phase III trial, which we think is a really great opportunity. We also are pursuing the development of LB-102 in bipolar depression, and we plan to initiate a registrational quality phase II trial in bipolar depression as well. As Paul mentioned, we completed an IPO. That IPO provided the capital that we need to complete the phase II clinical trial in bipolar depression, the phase III clinical trial in schizophrenia, as well as all of the NDA enabling studies that we'll need to do to put us in a position to seek approval in the event that we have a successful phase III trial. We also have composition of matter IP that takes us out to 2041.
This does include a patent term extension, and all of this translates into an opportunity to really generate billions of revenue for LB-102. Very excited about the prospects ahead.
Awesome. Okay. Maybe just to start, can you just review your phase II schizophrenia data? In the context of that, we all know that good drugs can fail in some of these psych trials. What gives you the confidence from both a data perspective and a trial execution perspective that you can get it right with just one study?
Yeah. In our phase II schizophrenia trial, we enrolled 359 patients. This trial was designed to be registrational, as I mentioned. All of the statistical analyses and sensitivity analyses, as well as the conservative imputation of missing data, were a part of this trial, which is what we think makes it registrational quality. We think that this trial demonstrated highly statistically significant efficacy. This is demonstrated by a clinically meaningful reduction in the PANSS total score, as well as a very strong and robust treatment effect. We also saw a safety profile that we think has the potential to be class-leading. This is based on a very low rate of EPS, as well as negligible sedation. For phase III, we're targeting bringing two doses into the trial, 50 mg -1 00 mg. This trial is going to be of similar scale and scope to the phase II trial.
In this trial, we plan to enroll about 460 patients at 25 sites. I mentioned the phase II trial was 359 patients at 25 sites, so very similar scale. We also plan to implement a number of the same measures that we did in the phase II trial to manage the placebo rate. There will be some differences between the phase II and the phase III trial. The phase II trial was four weeks in duration. We planned the phase III trial to be six weeks in duration. The phase II trial had four arms, and the phase III trial is only going to have three arms. When we think about placebo rate, we know that this is a challenge in this space. In phase II, we implemented a number of measures to manage that placebo rate.
We utilized a third-party vendor to help identify and exclude professional patients. We plan to utilize that same vendor, as well as an additional vendor, to help identify those professional patients. We used a central rater. This provides quality control over the local raters. It also provides an opportunity and facilitates communication and conversation with the sites. We were very judicious in the scales that we chose for the phase II trial. We think this is really important. If you have too many scales or if the scales take too long to complete, it really can contribute to both patient and physician fatigue, which we know can impact that placebo rate. Ultimately, and most importantly, it's critical that you have frequent, consistent engagement with the sites. This is not a space where you can just hand it off to the CRO and let the CRO manage it.
We really need to stay engaged and have that frequent contact with the sites. All of these measures that we implemented in phase II will, again, implement in phase III. We have a really significant amount of confidence in our ability to execute the phase III trial.
I think you just recently decided to increase the n a bit for your phase III. What was the thought behind that?
Yeah. The goal by increasing the n was really to increase the statistical powering of the trial. So that increase from 400 to 460 patients took the trial to 85% powering.
Okay. Is that powered for what effect size versus the phase II?
What we looked at there was a PANSS delta of six.
Okay. Okay. So phase II was what, like nine, maybe? Something nine to ten?
The PANSS delta [crosstalk] ranged anywhere from five - seven.
Oh, okay. Okay. Got it. Okay. Great. On the safety side, can you just talk about the differentiation thesis there? I think drugs like CAPLYTA, VRAYLAR, all of them have kind of different subtleties on the differentiation on the safety side. What do you see as core to LB-102 as the biggest strength?
Where we think LB-102 will emerge in terms of differentiation is in a couple of areas. We think it actually will be a branded antipsychotic of choice. This is based on a really competitive and meaningful clinical reduction in the PANSS delta. On the safety side, we did see a very low rate of EPS. We think that this could be quite differentiating, especially among the partial agonists and the antagonists. At the 50 mg dose, we saw a rate of EPS of 0.9%, which is just one case of EPS. At the 100 mg dose, we saw a rate of 5.6%. This is also quite low in comparison. If you think about VRAYLAR, it has an EPS rate of anywhere from 24%-32%. Other D2 antagonists have EPS rates in the teens.
We think there's a real opportunity from a safety perspective to differentiate in terms of EPS.
Yeah. Yeah. Okay. Great. And then just what are the learnings from amisulpride real-world use, right? So you're essentially like a chemical analog or subtly different, however you want to describe it. How many patients do we know have been exposed to amisulpride in Europe, and what are the main sort of safety takeaways and considerations there?
Yeah. So many, many thousands of patients have utilized amisulpride. Amisulpride was approved in the 1980s, so it's been around for quite some time. That said, it continues to be widely used. In 2024, in continental Europe, there were more than 2 million prescriptions written for amisulpride. It continues to be widely used. It is actually very well perceived as one of the more safe and tolerable antipsychotics. In a Lancet publication that compared 30 different antipsychotics, amisulpride was found to have the lowest all-cause discontinuation rate among antipsychotics. We believe the safety profile of amisulpride is actually quite reassuring. We would expect to have a similar safety and tolerability profile as amisulpride. We may actually even be better than amisulpride in terms of EPS, like I just mentioned.
We think that, and the reason that we think we're going to have a very similar safety and tolerability profile is the fact that we have the same CNS receptor binding as amisulpride. We actually don't hit any of the receptors associated with many of the more troubling adverse events.
Okay. Okay. Great. Anything else to add on schizophrenia?
In schizophrenia, I would just say that we really think there's an opportunity here to differentiate in a couple of different domains. In the world of schizophrenia, there's two areas of significant unmet need. The first is in cognition. The second is in negative symptoms. These are areas where there's very little in the way of treatment options. With respect to cognition, we were very pleased to see that we had a very significant, robust, dose-dependent treatment effect on cognition. At the 100 mg dose, we saw a treatment effect of 0.66x, which is quite robust. This is an area that we plan to pursue and continue to further understand in all of our future clinical trials, including bipolar depression. The other area is negative symptoms. At our 50 mg dose, we had a statistically significant benefit to placebo on the PANSS negative subscale.
This is actually consistent with what's been observed with amisulpride. amisulpride is one of the few antipsychotics that has shown in three randomized placebo-controlled trials to be statistically significantly better than placebo in treating patients with predominantly negative symptoms. This is also an area where we think we could have a potential differentiation and one that we'll continue to pursue.
I guess, do you see yourself ever running a specific negative symptoms or a specific cognition trial to isolate those effects, or is this more like a secondary endpoint story in phase III that you'll kind of try to develop out there via marketing, I guess?
We plan to continue to generate information and data to help us better understand the opportunities for cognition and negative symptoms. In the phase III program, we will be conducting an open-label safety trial. This is going to be a large safety trial so we can accrue the safety population that we need to submit for approval. In that safety trial, there will be two subset analyses. One will be in cognition, and one will be in negative symptoms. This will be in a stabilized patient population. By definition, this safety trial will be in an outpatient setting. We think we'll generate quite a bit of information there on effect and the right dose. We'll continue to look at whether or not there's real opportunity here to pursue those indications. At the very least, though, it will absolutely be a publication strategy.
Yep. Okay. Makes sense. Do you want to switch gears and just walk through the idea behind pursuing bipolar as the second indication?
Sure. We think there are a number of different reasons which make bipolar depression a compelling first indication for expansion. LB-102 is a molecule that is uniquely situated in that it has a mechanism that supports going into both psychosis-related indications as well as depression-related indications. This is the same development pathway that VRAYLAR followed, that CAPLYTA followed. We think that this is one that is available to LB-102 as well. By pursuing bipolar depression, you actually give yourself an opportunity to take advantage of the safety population that you generated in the schizophrenia trial. You can streamline approval in bipolar depression by utilizing the data from schizophrenia. You also get the benefit of the antipsychotic pricing that you get from schizophrenia. Achieving that antipsychotic pricing with the schizophrenia approval can then be pulled through the other mood disorders.
In addition to that, there's scientific and clinical rationale for heading into bipolar depression. There's data generated in amisulpride and depression that we think is really compelling. And there's also the clinical data from our phase II clinical trial, which showed that we already have a benefit and an ability to treat psychosis, which, of course, is an important part of bipolar depression.
Yeah. So it's interesting, right? I feel like sort of like you said, pretty much every other antipsychotic story goes schizophrenia, bipolar, MDD. In this one, we've got your schizophrenia, and then we've got the amisulpride MDD data. Is it simple enough to draw a line to bipolar, or is it more complicated?
You know, it's interesting. We asked this question of our KOLs. I think that there is a compelling rationale for looking at bipolar as a clinical validation, I mean, looking at MDD as a clinical validation for bipolar. I think the most important fact is the fact that amisulpride is widely used. I mentioned that there were 2 million prescriptions in 2024 for amisulpride, and 20% of those prescriptions were in mood disorders. [crosstalk] It is widely used in mood disorders. In addition to that, there is data that was supportive of a label for dysthymia, which is a form of depression. amisulpride does have dysthymia as a labeled indication in certain jurisdictions. The regulators found this data to be compelling as well. I do think that there's clinical validation in the MDD data from amisulpride.
I do think that it does clinically validate the use of LB-102 in bipolar depression. The other thing I'll note, sorry, one more point, is that depression itself is the same, whether it's unipolar or bipolar depression. It's the same chemical imbalance of the neurotransmitters. It makes sense mechanistically that you can treat major depression and/or bipolar depression with the same antipsychotic.
Makes sense. How confident are you that you have the right dose for bipolar? I know with the pharmacology of amisulpride and even other some atypicals, right? People, they want to find a mood disorders dose that slightly dials down the dopamine receptor antagonism. There is this purported mechanism with amisulpride of 5-HT7. Also, maybe at lower doses, it actually has some agonist property. Again, I guess going into this bipolar trial, there is the question of, will this drug work in bipolar? And then the second question of, are you actually in the right dose range? How do you think about that?
Yeah. So there's basically two paradigms for dosing in bipolar depression. You've got one paradigm, which is VRAYLAR, which is an antipsychotic that essentially took its schizophrenia dose and cut it in half for bipolar depression. Now, VRAYLAR had to do this because it has a very high rate of EPS. In these bipolar depression patients, they may be more susceptible to EPS. They really had to reduce that rate of EPS. They cut their dose in half. That is what was approved for bipolar depression. The other paradigm is CAPLYTA. CAPLYTA has a very low rate of EPS. It was able to utilize the same dose in schizophrenia [crosstalk] as it did in bipolar depression [crosstalk].
Really because its dosing is such a lower D2 occupancy, right [crosstalk]?
That's exactly right. Yeah. For us, because of the safety profile that we observed in our phase II trial, we really have an opportunity to assess both of those paradigms. The 50 mg dose, as I mentioned before, had only one case of EPS. Like CAPLYTA, we really don't have a concern for EPS. We can utilize the same dose in schizophrenia as bipolar depression. Because, as you mentioned, you do still need some D2 blockade in bipolar depression.
To prevent mania? Is that [crosstalk] the thought?
Exactly. That's exactly right. You don't need so much, right? Because it's a different level of psychosis than what you experience in schizophrenia [crosstalk]. In addition to that, we also can cut the dose in half for the very reasons that you noted with respect to amisulpride and how it might be used to treat depression, right? We can cut the dose in half and start at 25 mg. Where we ended up with our phase II clinical trial design was a fixed flexible dose design. In this design, all patients start at 25 mg, which is half of the schizophrenia dose. At the end of week three, if they have not seen an improvement in the CGI bipolar scale, they escalate automatically to 50 mg, which is then the schizophrenia dose. They stay at 50 mg for the remainder of the trial if tolerated.
We get an opportunity to assess two doses of LB-102 and both of those treatment paradigms. We get to do this in a two-arm trial. We know that every single time you add an arm to a depression trial, you have a risk of increasing that placebo rate. You really want to try to have as few arms as possible. We're able to assess two doses with two arms in a registrational quality trial. We'll be enrolling 320 patients at about 30 sites in the United States.
Yeah. Okay. Makes sense. What are the read-throughs and the limitations of those read-throughs from this Sunovion bipolar program for, I guess it was like an enriched enantiomer of amisulpride that was more 5-HT7 biased? On the one hand, it looks like there's some data there that shows that the drug clearly worked. On the other hand, they cut ties with it very shortly within the phase III program. I think there's some debate in the investment community of, is this validating evidence, or is it discouraging that they build on the program? How do you make sense in that?
Yeah. We believe that the data that was generated from the SEP-4199 molecule, which was the molecule being developed by Sunovion, is clinically validating for LB-102. That one, I think, point that's important to note is that if you look at the patents for the SEP-4199 molecule, it talks about the fact that it's pretty much the same as amisulpride biologically. When it was assessed in models that look at 5-HT7 activity, it functioned in a very similar way as amisulpride. It doesn't seem that those differences in the enantiomer ratios make any sort of difference in the biologic activity. The other point to note is that in two separate trials, it saw modest reductions of 17 points, which we think is quite efficacious. In the phase II trial, if you look at all of the geographies studied, it was actually statistically significantly better than placebo.
Unfortunately, that trial was marred by a high placebo rate, and we already talked about the importance of managing that placebo rate. If you look at the phase III trial, as you noted, at the point at which it was terminated, it was actually approaching a moderate delta of 6, which is actually pretty good. The reason that it was terminated, we understand, was actually not related to the clinical data and was more related to their business strategy. They had another failure that I think pushed them to get out of the space altogether.
Okay. Okay. Makes sense. Any questions from the audience? On the bipolar side, right? Again, as you get from schizophrenia to BPD to MDD, it feels like the false negative rate for other atypical antipsychotics goes up a little bit across these indications. What are you doing in the bipolar trial to mitigate that risk of just a negative study for reasons other than the drug itself?
Yeah. I think one of the things we did was the design of the trial. We know that this fixed flexible dose design provides a better opportunity to detect a signal. There was a publication that looked at a number of different depression studies, and in this publication, it highlighted the fact that these fixed flexible dose design.
Why do you think that is?
I actually think it's because it manages the placebo rate. [crosstalk] I think that you have a two-arm trial where you're able to study doses, but it just manages that placebo rate better.
Okay. In what way? When people tinker with the dose on placebo, they don't get the feeling that they get the feeling they're on placebo and there's less expectation bias? Or how does it lower the placebo rate?
I think first and foremost, the patient understands that there's a 50% chance that they're not on drug [crosstalk]. I think that's important.
Not having four arms for example [crosstalk].
That's exactly right, where you have a 75% chance of being on drug. I think that's a very important factor. The other is that we have an opportunity to look at the two doses and that both doses are part of that primary endpoint, right? It is all LB- treated patients versus placebo that factor into that primary endpoint [crosstalk]. You are maximizing your opportunity to detect a signal.
Yep. Okay. Remind me, are you doing the SAFER?
We are. [crosstalk] That's the other thing that we're doing [crosstalk].
Can you talk about that for people who don't know what it is? Because I think that is a real asset.
It is. SAFER is, in these bipolar depression trials, just like with schizophrenia, frankly, it's incredibly important for selecting the right patient for eligibility in this trial. As part of that process, we're implementing a SAFER technology, which is, it's not a technology, it's a process, frankly, that was developed out of Mass General. What you do is anytime you've identified a patient that you believe to be eligible to participate, Mass General comes in and does an assessment to ensure that this patient is, in fact, eligible. It just pressure tests the eligibility criteria to make sure that you are, in fact, enrolling the correct patient. It's a quality control check on what you're doing for enrollment in these bipolar depression trials. It does mean that you might have a higher screen failure rate, but in the end, you're getting the right patients.
You're setting yourself up for success in the trial, [crosstalk] which also goes into the timeline that you have to account for in terms of enrolling the trial.
Yeah, right. Do you want to talk about those timelines for schizophrenia and bipolar and maybe how you arrived at those timelines?
For schizophrenia, we anticipate the top line data to be read out in the second half of 2027. For bipolar depression, we expect the data to read out in the first quarter of 2028. As we think about the timelines, we look at a number of different factors. We look at the competitive landscape, the number of clinical trials that will be operating during that time. We talk to our KOLs and get a sense for how the enrollments are going. We also talk to our CRO, who obviously does many of these clinical trials and has a really real-time understanding of how they're enrolling and how the patients are coming in. We look at our own experience and our own enrollment rates from our phase II trial. All of those factors are what really ultimately drove the timelines.
Yeah. Okay. Any questions for Heather from the audience?
It was all so straightforward.
What's the thought on potentially doing MDD at some point, either later or sooner?
Yeah. I mentioned this earlier, but LB-102 is uniquely situated in that it really does have data and a mechanism to support moving into both psychosis and mood disorder indications. Of course, MDD is one that we will be looking at very closely. We're in the process now of thinking through the study design and thinking about exactly how we want to pursue that development program. We're also looking at Alzheimer's agitation in psychosis. amisulpride has a history of use in that patient population. The safety and tolerability profile that we observed in the phase II trial, we think makes it amenable for an elderly population. That is something else that we're looking at.
If you had the money only for one, what would you pick?
We'd do MDD.
You'd do MDD [crosstalk] next. Just higher probability because of the precedent?
It's also a bigger patient population, right? I mean, you really can expand into a very large patient population [crosstalk] and I think drive the opportunity for significant revenue.
Yeah. Okay.
The other one that we're looking at, frankly, and you mentioned this already, is negative symptoms, right? [crosstalk] The more we learn about the molecule and negative symptoms, the more we think that might be something that we would like to pursue.
That would be like in a population of stable positive to try to isolate it? Yeah. I mean, those studies are always so hard, though.
They're very hard and they take a long time. [crosstalk] There, again, it's critically important that you enroll the right patient in that. The FDA has very strong opinions about what that patient is. Engaging with FDA is critically important.
I think they've made the bar very, very high there.
They have, yeah.
Yeah. Okay. All right. Maybe just comment briefly on your cash runway before we wrap up.
Yeah. We were very fortunate to complete an IPO, as you mentioned. In that IPO process, we raised around $300 million, which enables us to fund the phase III schizophrenia trial, the NDA enabling studies so that we can put ourselves in a position to seek approval with success, as well as the phase II bipolar depression trial. All of that supports very critical data readouts in both of those trials. That takes us into the second quarter of 2028.
Okay. Great. All right. Thanks very much, Heather.